Toxicological and epidemiological studies on effects of airborne fibers: Coherence and public health...

Abstract

Airborne fi bers, when suffi ciently biopersistent, can cause chronic pleural diseases, as well as excess pulmonary fi brosis and lung cancers. Mesothelioma and pleural plaques are caused by biopersistent fi bers thinner than ∼ 0.1 μ m and longer than ∼ 5 μ m. Excess lung cancer and pulmo-nary fi brosis are caused by biopersistent fi bers that are longer than ∼ 20 μ m. While biopersistence varies with fi ber type, all amphibole and erionite fi bers are suffi ciently biopersistent to cause pathogenic eff ects, while the greater in vivo solubility of chrysotile fi bers makes them somewhat less causal for the lung diseases, and much less causal for the pleural diseases. Most synthetic vitreous fi bers are more soluble in vivo than chrysotile, and pose little, if any, health pulmonary or pleural health risk, but some specialty SVFs were suffi ciently biopersistent to cause patho-genic eff ects in animal studies. My conclusions are based on the following: 1) epidemiologic studies that specifi ed the origin of the fi bers by type, and especially those that identifi ed their fi ber length and diameter distributions; 2) laboratory-based toxicologic studies involving fi ber size characterization and/or dissolution rates and long-term observation of biological responses; and 3) the largely coherent fi ndings of the epidemiology and the toxicology. The strong depen-dence of eff ects on fi ber diameter, length, and biopersistence makes reliable routine quantita-tive exposure and risk assessment impractical in some cases, since it would require transmission electronic microscopic examination, of representative membrane fi lter samples, for determining statistically suffi cient numbers of fi bers longer than 5 and 20 μ m, and those thinner than 0.1 μ m, based on the fi ber types.

Abbreviations: ACGIH American Conference of Governmental Industrial Hygienists, AM Alveolar macrophage, BAL bronchoalveolar lavage, BMRC British Medical Research Council, CNT carbon nanotube, FEV 1 forced expiratory volume in 1 s, FVC forced vital capacity, HEI-AR Health Eff ects Institute-Asbestos Research, IARC International Agency for Cancer Research, IL-1 β Interleukin 1 β IL-6 Interleukin 6, IL-8 Interleukin 8, IP intra-peritoneal, an in vivo dose delivery technique for fi bers, IRIS EPA ’ s Integrated Risk Information System IRIS, ISO International Standards Organization, IT intra-tracheal, an in vivo dose delivery technique for fi bers, LA , Libby (MT) amphibole fi ber, MMMF Man-made mineral fi ber, an alternate name for SVF, MMVF Man-made vitreous fi ber, an alternate name for SVF, MPPCF Millions of particles per cubic foot, MTD Maximum tolerated dose, NRC National Research Council, NIOSH National Institute for Occupa-tional Safety and Health, OSHA Occupational Safety and Health Administration, PAH polynuclear aromatic hydrocarbon, PCOM Phase-contrast optical method (determining fi ber count concentration), PEL Permissible exposure limit, PMN Polymorphonuclear leukocytes, RCF Refractory ceramic fi ber, RNS Reactive nitrogen species, ROS Reactive oxygen species, SEM Scanning Electron Microscopy, SH Spontaneously hypertensive rat, SHHF Spontaneously hypertensive heart failure rat, SIC silicon carbide, SIR Stan-dardized incidence ratio, SMR Standardized mortality ratio, SVF Synthetic vitreous fi ber, TEM Transmission electron microscopy, TLV Threshold limit value, UICC International Union Against Cancer (English translation of name of organization in French), UK Unit-ed Kingdom, US United States, WHO World Health Organization, WKY Wistar Kyoto rat.

Address for correspondence: Morton Lippmann, PhD, Department of

Environmental Medicine, New York University School of Medicine, 57

Old Forge Road, Tuxedo, NY 10987, USA. Tel: – 845-731-3558. Fax:

– 845-351-5472. E-mail: [email protected]

Keywords

airborne fi bers, amphibole, asbestos, asbestosis, biopersistence, chrysotile, erionite, fi ber size, glass and rockwool fi bers, lung cancer, mesothelioma, pleural plaques, refractory ceramic fi bers, size-dependent fi ber toxicity, synthetic vitreous fi bers

History

Received 21 January 2014 Revised 19 May 2014 Accepted 22 May 2014 Published online 21 August 2014

http://informahealthcare.com/txcISSN: 1040-8444 (print), 1547-6898 (electronic)

REVIEW ARTICLE

Toxicological and epidemiological studies on eff ects of airborne fi bers: Coherence and public health implications

Morton Lippmann

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, USA

Crit Rev Toxicol, 2014; 44(8): 643–695© 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10408444.2014.928266

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Crit Rev Toxicol, 2014; 44(8): 643–695644 M. Lippmann

Table of Contents

Abstract .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 643 Introduction and background ... ... ... ... ... ... ... ... ... ... ... ... ... ... 644

Inhaled inorganic fi bers can cause l esions that d iff er from those c aused by t oxic c hemicals ... ... ... ... ... ... ... ... ... 644

Nature, c haracteristics, and s ources of i norganic a irborne fi bers ... ... 645 Major c ommercial u ses of i norganic fi bers . ... ... ... ... ... ... ... ... 645 Defi nitions of a sbestos, a sbestos fi bers, a sbestos b odies,

and a sbestosis ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ..645 Asbestos and asbestos fi bers ... ... ... ... ... ... ... ... ... ... ... ... ... 645 Asbestos bodies .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 645 Asbestosis ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 646 Other airborne inorganic fi bers ... ... ... ... ... ... ... ... ... ... ... ... 646

Association of a irborne m ineral fi bers with h uman d iseases in the t wentieth c entury . ... ... ... ... ... ... ... ... ... ... ... ... ... ... 646

Objectives of this critical review . ... ... ... ... ... ... ... ... ... ... ... ... ... 646 Extent of the literature reviewed ... ... ... ... ... ... ... ... ... ... ... ... ... 647 Physicochemical properties of fi bers .. ... ... ... ... ... ... ... ... ... ... ... 647

Asbestos . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 647 SVFs ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 647 Other airborne mineral fi bers . ... ... ... ... ... ... ... ... ... ... ... ... ... 648

Erionite ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 648 Wollastonite ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 648

Non-mineral inorganic fi bers .. ... ... ... ... ... ... ... ... ... ... ... ... ... 648 Early evidence that diseases are caused by the inhalation of

airborne asbestos fi bers .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 648 Asbestosis ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 648 Lung cancer ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 649 Mesothelioma ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 649 Pleural plaques and pleural thickening ... ... ... ... ... ... ... ... ... ... 650

More recent biological responses to specifi c types and sizes of inhaled mineral fi bers ... ... ... ... ... ... ... ... ... ... ... ... ... 650 Occupational mineral fi ber exposures ... ... ... ... ... ... ... ... ... ... 650 Environmental mineral fi ber exposures .. ... ... ... ... ... ... ... ... ... 652 Human responses to specifi c types and sizes of

inhaled SVF . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 654 SVF exposure and mesothelioma ... ... ... ... ... ... ... ... ... ... ... 655 SVF exposure and respiratory morbidity . ... ... ... ... ... ... ... ... 656

Summary of human responses to long-term fi ber inhalation exposures ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 656

Responses to asbestos in animal exposure studies ... ... ... ... ... ... 656 Fibrogenesis responses ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 656 Carcinogenesis responses ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 657 Animal inhalation studies with both asbestos and SVF ... ... ... ... 657 Intratracheal and intraperitoneal in vivo exposures

in animals ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 658 Summary of pulmonary and pleural responses in animals . ... ... 659

Exposures to airborne inorganic fi bers ... ... ... ... ... ... ... ... ... ... ... 660 Exposure indices . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 660 Exposure levels ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 661

Fiber deposition mechanisms in the respiratory tract ... ... ... ... ... 662 Impaction and sedimentation ... ... ... ... ... ... ... ... ... ... ... ... ... 662 Electrostatic precipitation ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 662 Interception ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 662 Diff usional displacement ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 662 Deposition sites and patterns . ... ... ... ... ... ... ... ... ... ... ... ... ... 662

Fiber retention, translocation, disintegration, and dissolution ... ... 663 Retention ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 663 Translocation .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 664 Disintegration . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 664 Clearance ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 664 Overload associated with high lung burden ... ... ... ... ... ... ... ... 665

Fiber dissolution . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 666 Comparisons of d issolution r ates of SVF and a sbestos fi bers ... 668

Fiber retention in the lungs ... ... ... ... ... ... ... ... ... ... ... ... ... ... 669 Exposed humans ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 669 Exposed laboratory animals ... ... ... ... ... ... ... ... ... ... ... ... ... 669

Exposure – response relationships for fi ber-related cancer .. ... ... ... 670 Dosage applied and resulting biological responses ... ... ... ... ... ... 671

Fiber translocation and retention within the thorax ... ... ... ... ... 672 Biological mechanisms accounting for fi ber toxicity ... ... ... ... ... 672

Toxicity of inhaled durable fi bers ... ... ... ... ... ... ... ... ... ... ... ... ... 673 Infl uence of fi ber type ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 674 Infl uence of fi ber diameter . ... ... ... ... ... ... ... ... ... ... ... ... ... ... 675 Infl uence of fi ber length . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 675 Risk assessment for inorganic fi bers ... ... ... ... ... ... ... ... ... ... ... 675

Critical fi ber dimensions aff ecting disease pathogenesis ... ... ... ... 676 Asbestosis ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 676 Mesothelioma ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 678 Lung cancer ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 679 Summary of critical fi ber dimensions . ... ... ... ... ... ... ... ... ... ... 680 Implications of critical fi ber dimensions to health relevant

indices of exposure . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 681 Risk assessment issues ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 681

Use of appropriate measures of fi ber exposure .. ... ... ... ... ... ... 681 Asbestos-related mesothelioma . ... ... ... ... ... ... ... ... ... ... ... ... 681

Pleural versus peritoneal mesotheliomas ... ... ... ... ... ... ... ... 681 Asbestos-related lung cancer . ... ... ... ... ... ... ... ... ... ... ... ... ... 682 Asbestos risks versus those of synthetic vitreous and

other inorganic fi bers .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 683 Discussion .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 683

A diff erent risk paradigm is needed for fi ber toxicity .. ... ... ... ... 683 Diff erences in critical fi ber characteristics for the diff erent

asbestos-related diseases ... ... ... ... ... ... ... ... ... ... ... ... ... ... 684 Summary of human responses to long-term mineral

fi ber inhalation exposures ... ... ... ... ... ... ... ... ... ... ... ... ... ... 684 Summary of animal responses to long-term mineral

fi ber inhalation exposures ... ... ... ... ... ... ... ... ... ... ... ... ... ... 684 Infl uence of lung retention on pulmonary responses . ... ... ... ... 685 Pleural responses ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 685 Coherence of the biological responses in humans and

animals ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 685 Coherence of the human and animal response data with

known characteristics of fi ber type and dimensional distributions ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 685

Overall summary of in vivo biological responses to various durable fi bers .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 686

My current perspectives on the role of airborne inorganic fi bers in causing health eff ects . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 686 Refl ection on the contributions of the pioneers in the fi eld ... ... 686 What I now know with reasonable certainty ... ... ... ... ... ... ... ... 687 What I consider to be uncertain are the following .. ... ... ... ... ... 687 What I consider to be the key research needs to refi ne the

remaining uncertainties associated with exposures to durable airborne fi bers ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 687

Implications of our enhanced understanding on factors aff ecting fi ber toxicity . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 687 Risk assessment .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 687 Possible ambient air exposure standards for airborne

inorganic fi bers ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 688 Strategies to control exposures to ambient air fi bers . ... ... ... ... 688

Conclusions ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 688 Acknowledgments . ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 688 Declaration of interest ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 688 References.. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 688

Introduction and background

Inhaled inorganic fi bers can cause lesions that diff er from those caused by toxic chemicals

Fibers, by defi nition, are elongated particles that can have

diff erent interactions with phagocytic and epithelial cells

than more compact particles of the same chemical composi-

tion, especially when the fi ber length approaches or exceeds

the sizes of the cells that they encounter. This is especially

so when the airborne fi bers that are inhaled and retained in

the thorax are insoluble in vivo . Such fi bers are retained for

periods longer than the life of the cells. Their interactions with

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Airborne fi ber eff ects-Coherence and Public Health Implications 645DOI 10.3109/10408444.2014.928266

Table 1. Asbestos fi ber types.

Commercial

fi ber name Mineral name

Mineral

group

Major cations

within the silicates

Chrysotile Chrysotile Serpentine Mg, FeCrocidolite Riebeckite Amphibole Na, Mg, FeAnthophyllite Anthophyllite Amphibole Mg, FeAmosite Grunerite Amphibole Fe, Mg, MnActinolite Actinolite Amphibole Ca, Fe, MgTremolite Tremolite Amphibole Ca, Mg, Fe

Winchite Amphibole Ca, Mg, FeRichterite Amphibole Ca, Mg, Fe

Chrysotile, Actinolite, Anthophyllite, and Tremolite are generally

encountered as asbestiform minerals, and are grayish white in color.

Actinolite asbestos is found as a contaminant of Amosite from South

Africa.

Amosite is the asbestiform version of Grunerite, and is brown in color.

Anthophyllite asbestos was commercially worked in Finland.

Crocidolite is the asbestiform version of Riebeckite, and is blue in color.

Tremolite asbestos is exploited commercially in Korea, and is a

contaminant in some Chrysotile ores and of Vermiculite ore mined in

Libby, Montana.

Winchite and Richterite are the major asbestiform contaminants of

Vermiculite ore mined in Libby, Montana.

successive generations of cells can initiate localized biological

processes leading to cell death and the release of endogenous

mediators and enzymes that contribute to fi brosis and carcino-

genesis.

Nature, characteristics, and sources of inorganic airborne fi bers

Inorganic fi bers in ambient and occupational environments

originate from mechanical processes in mining and processing

ores that contain major fractions of naturally occurring fi brous

minerals, such as asbestos and zeolite fi bers. As hazards from

these naturaly occurring mineral fi bers became evident, they

have been replaced in commerce by synthetic vitreous fi bers

(SVFs), such as continuous glass fi laments, glass-, slag-, and

mineral wools, as well as refractory ceramic fi bers (RCFs).

In recent years, new high technology synthetic fi bers, such as

carbon nanotube (CNTs) and nanowires, have also found their

way into commercial products. Organic fi bers of cotton and

wool are not covered in this review.

Major commercial uses of inorganic fi bers

There are many commercial products containing inorganic

fi bers that are commonly found in buildings, including ther-

mal system insulation; structural fi reproofi ng; acoustical

and decorative fi nishes; fl oor and ceiling tiles; and asbestos-

containing felts. (Sawyer 1989). Asbestos has also been used

in motor vehicles for brake and clutch linings. A number of

construction products have, in the past, contained asbestos

fi bers as well, for example, spackling, patching, and plastering

compounds used in dry-wall construction and interior repair.

In recent years, the largest usage has in high-density cement

products. In addition to natural mineral fi ber, many of these

formulations contained SVF in combination with asbestos,

and over recent decades, SVFs have replaced asbestos in many

applications. The major asbestos-containing items to be found

in buildings were outlined by Spengler et al. (1989).

Defi nitions of asbestos, asbestos fi bers, asbestos bodies, and asbestosis

Asbestos and asbestos fi bers

Case et al. (2011) discussed defi nitions of “ asbestos ” provided

by various research scientists, technical advisory groups, and

regulators in considerable detail. They noted that the defi ni-

tions advocated by mineralogists diff ered from those preferred

by health scientists, and both types have evolved over time.

For the purpose of this part of the review focused on the pub-

lic health implications of the inhalation of asbestos fi bers, I

will use asbestos as a term that covers a family of crystalline

SiO 3 minerals varying in crystal structure and metals content

as described by Langer et al. (1990) and Meeker et al. (2003).

The mineralogy and cation composition of asbestos fi bers vary

within and between the members of the family, and are sum-

marized in Table 1. They can occur as “ asbestiform ” fi bers,

that is, fi bers with relatively large ratios of length to width

(i.e., aspect ratio), separating them from other SiO 3 minerals

and giving them commercial importance during the twentieth

century. Asbestos fi bers are good thermal and acoustic insu-

lators; those low in iron (Fe) are good electrical insulators.

In particular, their high tensile strength and fl exibility made

them useful as reinforcing agents in building products. These

products can vary in asbestos content from major to minor

fractions. For asbestiform fi ber content of a product exceeding

1%, the US Environmental Protection Agency (EPA) has des-

ignated it as an asbestos-containing material. Consideration

has been given to lowering this threshold in recent years, and

regulations with lower limits have been adopted in Ontario

and California.

The fi brous nature of some asbestos minerals is due to

their crystallographic properties. The sheet SiO 3 structure of

the serpentine mineral known as chrysotile asbestos results

in a deformation that causes the sheets to form cylindrical or

“ tubular ” fi brils (Whittaker and Zussman 1956). Weak inter-

atomic bonds bind many hundreds of individual fi brils, form-

ing a “ curly ” fi ber (Yada 1967). The other asbestos minerals

discussed herein are known as amphiboles. They have double-

chain SiO 3 structures, and they form straighter, “ rodlike ”

fi bers. Mechanical manipulations of the crystal structures, and

their defects, facilitate the release of the ultimate amphibole

asbestos fi bers (Chisholm 1983, Veblen 1980). Specifi c types

of asbestos fi bers in air are often encountered as part of a

mixture that includes other fi bers and/or other more compact

particles. As examples, some chrysotile ore bodies contain a

small percentage of tremolite, and some amosite ores contain

a small percentage of actinolite. In Libby MT, the vermiculite

ore contains as much as 20% by weight of amphibole fi ber (a

mixture of winchite, richterite, and tremolite). Furthermore, in

the past, asbestos fi bers had often been added to products such

as cement, fl oor and ceiling tiles, and textiles, and fi bers can be

released into the air when such products that remain in place

are mechanically degraded, removed, or discarded.

Asbestos bodies

Asbestos bodies found in the thorax include long asbestos

fi bers that are encapsulated within cellular products. However,

in some cases, their concentration within bronchoalveolar

lung lavage fl uid (BALF), or in tissues within the lung has not

been shown to be a good index of disease risk. For example,

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Sebastien et al. (1988) showed that simple collection and

quantifi cation of asbestos bodies from sputum samples of WR

Grace workers at Libby Montana, detected in samples, were a

better indicator of radiographic abnormality than was cumu-

lative exposure based on air measurements and categorized

as fi bres/cc-years. However, attempts to extend this to other

exposed groups failed McDonald et al. (1992).

Asbestosis

Asbestosis is a diff use pulmonary fi brosis caused specifi cally

by cumulative inhalation exposure to asbestos fi bers. It diff ers

histologically from silicosis, a more focal form of pulmonary

fi brosis that is caused by cumulative inhalation exposure to

crystalline silica (SiO 2 ). Both of these pneumonconioses are

progressive over time and can lead to respiratory insuffi ciency

and premature mortality. Medical diagnosis of asbestosis is

generally made using radiography, but lesser levels of intersti-

tial fi brosis can be found by histology.

Other airborne inorganic fi bers

A conservative hypothesis is that the biological eff ects of

zeolite mineral fi bers and of some biopersistent SVFs are

essentially the same as those produced by asbestos fi bers,

varying only in potency rather than in nature. This hypothesis

is based on the morphological and toxicological similari-

ties between these fi bers. The concern arises from the well-

documented evidence that asbestos and zeolite fi bers can cause

lung fi brosis, bronchial cancer, and mesothelioma in humans

and that, in laboratory studies, some biopersistent SVFs and

CNTs may also cause these diseases in animals, as discussed

in the section on biological eff ects of size-classifi ed fi bers in

toxicology studies that follows later in this critical review. We

need to know the extent to which the structural similarities of

the fi bers, that is, their fi brous forms and durability, makes them

hazardous, or whether the diff erent chemical compositions of

the various fi bers can make them safer. Epidemiological stud-

ies of occupational cohorts indicate that SVFs are generally

much less hazardous than asbestos fi bers for pneumoconiosis

and lung cancer, and are of little risk in terms of mesothelioma

(Hesterberg et al. 2012, Boff etta et al. 2014).

Association of airborne mineral fi bers with human diseases in the twentieth century

Occupational exposures to airborne asbestos fi bers have

been causally associated with asbestosis since the early

decades of the twentieth century (Hoff man 1918, Ellman

1933, Merewether and Price 1930, Lanza et al. 1935). In the

second half of the twentieth century, such exposures have

been shown to also cause signifi cant numbers of excess lung

cancers (Gloyne 1951, Doll 1955), and of mesothelioma, a

cancer of the lung pleura and peritoneum that has few, if any

other known causes (Wagner et al. 1960, Selikoff et al. 1964).

Furthermore, mesotheliomas have occurred in populations,

other than workers, having lower levels of asbestos fi ber expo-

sures (Wagner et al. 1960, McCaughey et al. 1962), as well

as in populations exposed to erionite, a naturally occurring

fi brous zeolite mineral (Wagner et al. 1985). In the latter part

of the twentieth century, studies on workers and residents of

Libby Montana who were exposed to dust originating from the

processing of vermiculite ore had much greater background

rates of lung fi brosis, lung cancer, and mesothelioma that could

be accounted for by the 5 – 20% of amphibole asbestos fi bers in

the vermiculite ore. The amphibole fi bers in Libby included

tremolite fi bers (6%), but larger percentages of winchite (84%)

and richterite (11%) (Meeker et al. 2003), varieties previously

associated with excess disease and mortality (McDonald et al.

1986, 2004, Larson et al. 2012, Sanchez et al. 2008, Webber

et al. 2008). Since the biological mechanisms that underlie

the known fi brogenic and carcinogenic actions of asbestos

and erionite fi bers remain somewhat speculative, the safety

of asbestos substitutes, primarily the relatively biopersistent

SVFs, for products used for fi re protection; thermal and acous-

tic barriers; and fl oor tiles and wall panels to provide structural

strength and stability, has remained an issue of some concern.

Objectives of this critical review

The fi rst objective is to provide brief background summary

discussions of the most informative literature on fi ber expo-

sures and their health eff ects, with respect to:

physical and chemical properties of the various airborne •inorganic fi bers found in occupational and ambient air set-

tings, especially crystalline form, fi ber diameter and length

distributions, and solubility in vivo ;

exposure assessment methods, and their various limitations •in providing useful indices of health risks;

epidemiological evidence linking exposure to inorganic •fi bers with disease;

toxicological evidence concerning physical, chemical, and •host factors aff ecting disease processes, providing a broad

perspective on the critical insights gained from such stud-

ies;

extent of the coherence of the epidemiological and toxico- •logical evidence;

critical dosimetric factors infl uencing biological responses, •that is,

fi ber dimensions,

fi ber durability in vivo , and

deposition, retention and translocation of fi bers in vivo.

The second objective is to outline the public health implica-

tions of the risk assessment process for airborne fi bers imposed,

until recently, by limitations of knowledge, with respect to the

following:

exposure assessment methods; • hazard assessments of the diff erent inorganic fi ber types; • biological mechanisms accounting for inorganic fi ber – • induced fi brosis and cancer.

Then, the third objective is to provide the conclusions that

I have drawn concerning the hazards associated with the inha-

lation of airborne fi bers including the following:

the validity of the “ amphibole hypothesis ” regarding asbestos •toxicity;

the role of mineralogic classifi cations of crystalline silicates •in defi ning toxicity;

the relative risks of fi brous amphiboles; chrysotile; mineral and •glass wools; refractory ceramics; and other inorganic fi bers;

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how to defi ne optimal indices of risk-related airborne inor- •ganic fi ber exposure concentration;

minimization of risks associated with airborne inorganic •fi bers by:

manufacturers of commercial fi brous products;

vendors and users of commercial fi brous products;

regulators of occupational and environmental exposures.

Finally, the fourth objective is to outline the key knowledge

gaps limiting our ability to adequately assess risks associated

with the inhalation of inorganic fi bers, and opportunities to

reduce the risks with targeted controls of exposures.

Extent of the literature reviewed

A comprehensive literature review covering all aspects of

airborne inorganic fi bers and their health eff ects is considered

beyond the scope of this paper, which is focused on addressing

the objectives listed above. In selecting the relevant papers, I

took advantage of the screening performed in recent years by

others. In particular, I took advantage of the Bibliography of the

∼ 1,500 asbestos references up through the year 2,000 that was

compiled by Wayne Berman, as well as those in more recent

review papers by Hodgson and Darnton (2000); Hesterberg and

Hart (2001); Pierce et al. (2008); Yarborough (2006); Berman

and Crump (2008a, b); Price (2010); Mossman et al. (2011);

Case et al. (2011); EPA-SAB (2013); Bernstein et al. (2013);

and Boff etta et al. (2014).

Physicochemical properties of fi bers

Asbestos

Chrysotile, a serpentine mineral, is a rolled sheet SiO 3 with

sheet thickness of 7.3 Å . It is a sandwich of magnesium

SiO 3 with the magnesium on the outside of the sheet. By

contrast, the amphibole forms are solid cylindrical fi bers that

are completely encased in SiO 3 . In terms of chemical prop-

erties, chrysotile fi bers are soluble in acid while amphibole

fi bers are not. This can be important in terms of the fi bers

phagocytosed by macrophages, where they encounter an

acidic environment. Each of the asbestos fi ber types has a

unique size range in terms of both airborne and tissue evalu-

ations (Pooley and Clark 1980, Burdett 1985). Transmission

electron microscopy (TEM)-based size distributions and

fi ber-type identifi cation of airborne asbestos were reviewed

by Berman and Chatfi eld (1989). They concluded that about

9% (range: 1 – 50%) of chrysotile, 4% (range: 1 – 18%) of

crocidolite, and 25% (range: 8 – 43%) of amosite meet the

industrial hygiene defi nitions of asbestos (i.e., fi bers � 5

μ m long, � 0.25 μ m wide, and aspect (length/width)

ratio � 3:1 or 5:1; American Conference of Governmental

Industrial Hygienists [ACGIH]; World Health Organization

[WHO]). Fibers of � 0.25 μ m wide are not seen through

phase-contrast optical microscopy (PCOM), which cannot

distinguish between fi ber types. The count concentrations

of fi bers in the air and their dimensions will often diff er

from those encountered in vivo , especially for chrysotile,

whose fi bers subdivide into fi brils once they are deposited

within the lungs. Evaluations made using TEM reveal that

1) crocidolite forms very fi ne fi bers (0.04 – 0.15 μ m in

diameter); 2) amosite fi bers are thicker (0.06 – 0.35 μ m); 3)

anthophyllitefi bers are the thickest among the amphiboles;

and 4) chrysotile ’ s fi brils are the smallest (0.02 – 0.05 μ m)

among the commonly encountered asbestos types. The spe-

cifi c properties aff ecting the biological activity of asbestos

fi bers include fi ber type, length, diameter, and their durabil-

ity within the lungs and at other sites in the body.

Characterizing the health risks of asbestos fi bers is even

more complicated when the concentrations of the more

hazardous forms of the fi bers are present as a small fraction

of the concentration of other, less hazardous fi bers, or of

more compact dust particles. X-ray analyses can provide for

separate analyses and enumerations of multiple fi ber types,

but the presence of large amounts of non-fi brous mineral

particles can make it quite diffi cult to visualize and measure

the numerical concentrations of individual fi bers.

The length of asbestos fi bers retained in vivo does not

change substantially for the amphibole fi bers, while chryso-

tile fi bers gradually dissolve in the lung. In contrast, SVFs

in vivo may break up into shorter pieces, as well as become

thinner due to dissolution. Both non-asbestiform asbes-

tos minerals and SVFs can break up during mechanical

processing into cleavage fragments that include particles

that are relatively long and thin, and meet the criteria for

fi ber counting protocols. Positive carcinogenic responses

have also been reported for SiC fi ber whiskers and cleavage

fragments that met the size limits recommended by WHO.

SVFs

SVF, man-made mineral fi bers (MMMF), and man-made

vitreous fi bers (MMVF) are generic names for fi bers that are

generally made by spraying or extruding molten glass, rock, or

furnace slag. The production technologies, and their historical

development, were summarized by Konzen (1984). Both fi ber

lengths and diameters are polydisperse, especially for fi bers

produced by spraying of molten glass, and subsequent fabrica-

tion of fi ber mats for commercial products such as insulation,

fi lters, and fi ber-reinforced composites results in the breakage of

fi bers into shorter length segments. For SVFs, the manufacturing

process can be manipulated to produce diff erent compositional

and dimensional distributions for product performance, and

Konzen (1984) reported that the average fi ber diameters decreased

from 10 to 12 μ m in the 1940s to ∼ 7.5 μ m in later products,

and that the percentage with diameters � 1 μ m decreased from

2.8 to 1.7% over the same period. Specialty products, such as

glass microfi bers, require much more energy to produce and are

much more expensive. The superior properties of microfi bers for

insulation and tensile strength lead to their use in applications

where the greater costs can be justifi ed, such as space shuttle

cabins and earplugs. The chemical compositions of SVF vary

with the source materials, and their mechanical properties and

durability, both in the products and in the body after inhala-

tion and deposition, can vary greatly with their composition. In

recent years, product formulations that have shorter half-times

in the lungs, that is, lesser durability, have been introduced as a

means of reducing their toxicity. Both the concept and applica-

tion of such product stewardship by the glass fi ber industry were

described in detail by Hesterberg et al. (2012).

Rock and slag wools are terms used for vitreous products

made from the precursor materials that are melted, drawn,

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centrifugally spun, and steam- or air-jet blown. These pro-

cesses produce discontinuous fi bers that are relatively short

in length. Feldspar and kaolinite are used in ceramic fi ber

manufacture. Limestone is been used for the production of

rock wool. Slags are byproducts from many sources including

iron and steel making; and base-metal and copper smelting,

and are used in slag wool production. The bulk and trace metal

chemistry of these products vary greatly. The principal RCF in

commerce is of alumina – SiO 2 composition. These fi bers have

greater stability at high temperatures than glass or slag wools

and are better asbestos substitutes for thermal insulation.

The principal focus of SVFs in this section is on human

exposures to widely used commercial fi brous glass, and the

health risks associated with them. The principal basis for the

assessment is 1) the epidemiological data on occupational

exposures and their eff ects; 2) the biological responses to fi ber

suspensions inhaled by laboratory animals, or injected into

their lungs or pleural or peritoneal spaces; and 3) the aerody-

namics, deposition, and clearance of airborne fi bers within the

respiratory tract.

Diff erent cationic metals in SiO 2 melts may coordinate

oxygen diff erently, due to their cation charge (Z) and ionic

radius (R). Z/r 2 is the determining factor in infl uencing cation

fi eld strength. The aluminum – silicon ceramic fi bers are stable

(similar Z/r 2 values), and are therefore durable in vivo . Slag

wools, rich in trace metals, are usually neither stable nor dura-

ble in biological hosts, and high-soda glasses are even more

unstable. The issue of fi ber durability is of extreme biologi-

cal importance. Because SVFs are generally less stable than

asbestos in vivo , they appear to carry less risk of producing

disease (Lippmann 1990).

Most commercially available vitreous fi bers that are used in

insulation, fi re retardant, and acoustical applications have diam-

eters that range from about 4 to 6 μ m. These values are consistent

with aerodynamic diameters in the range of 12 – 18 μ m (Timbrell

1972). Thus, most commercial SVF fi bers are too large for air-

borne penetration into the thorax, providing one important basis

for the conclusion that commercial SVFs are less biologically

hazardous than asbestos fi bers (Lippmann 1990).

Insulating glasses may be coated with binders, for example,

phenol-formaldehyde resins, or with mineral oil lubricants in

a range of concentrations. The biological signifi cance of these

coating materials for long-term, chronic diseases is unknown.

Lockey et al. (2012) has demonstrated that RCF longer than

5 μ m is biopersistent in human lungs for at least 20 years.

Other airborne mineral fi bers

Erionite

A naturally occurring zeolite mineral also exists in a fi brous

form. It has been implicated as a potent cause of mesothelioma

in humans and animals (Wagner et al. 1985, Baris et al. 1981,

1987, Baris and Grandjean 2006, Carbone et al. 2007, Ryan

et al. 2011).

Wollastonite

A naturally occurring calcium silicate (CaSiO 3 ) is available

in a fi brous form. However, it is not biopersistent and is not

considered to be hazardous (Maxim and McConnell 2005).

Non-mineral inorganic fi bers

The rapid development of nanotechnology has made it possible

to fabricate carbon lattices forming mutiwalled tubes, metal-

lic nanowires, and silicon carbide and alumina whiskers with

extremely high aspect ratios and lengths greatly exceeding

5 m m. Products incorporating CNTs, nanowires, and whiskers

combine high tensile strength with durability while being light

in weight. For CNTs, some commercial formulations were

less durable than others in Gambles solution in vitro (Osmond-

McLeod et al. 2011), who measured the durability and infl am-

mogenic impact of CNTs after incubation for up to 24 weeks

in Gambles solution. Three single-walled and multi-walled

CNT types showed no or minimal losses of mass, change in

fi ber length, or morphology, while a fourth type of long CNT

lost 30% of its mass within 3 weeks and lost pathogenicity

when injected into the peritoneal cavities of mice. Schinwald

et al. (2012a) indicated that silver nanowires injected into mice

IP retained in vivo structural integrity for 1 day, but not for

one week.

Durable man-made fi bers can also be produced from pure

chemicals. For example, DuPont developed Fybex (potas-

sium octatitinate) and Kevlar, an aramid (poly paraphenylene

terephthalamide), as fi brous asbestos substitutes. Fybex

produced mesotheliomas in hamsters (Lee et al. 1981), and

DuPont did not pursue commercial application. By contrast,

Kevlar fi brils, while long and thin, were not biopersistent

(Donaldson 2009), and had biological eff ects similar to those

associated with nuisance dusts (Lee et al. 1983, Donaldson

2009). These “ chemical ” fi bers will therefore not be discussed

in any detail here.

Early evidence that diseases are caused by the inhalation of airborne asbestos fi bers

Asbestosis

The fi rst disease to be associated with the inhalation of air-

borne inorganic fi bers was asbestosis. In an introduction to a

paper on asbestosis, Sayers and Dreessen (1939) noted that

the fi rst record of a case of asbestosis in the United Kingdom

(UK) was described by Montague Murray in 1900. They also

noted that Hoff man (1918) was the fi rst American to 1) call

attention to the magnitude of the asbestosis problem, reporting

13 deaths from asbestosis among asbestos textile workers and

2) provide the fi rst complete description of the disease and

of the “ curious bodies ” , subsequently named asbestos bodies.

Asbestos bodies contain asbestos fi bers, and were seen in lung

tissue and sputum in two cases in the UK by Cooke (1927).

Ellman (1933) provided a more complete overall descrip-

tion of the disease and its progression. He noted that the slow

development of a characteristic type of fi brosis distinguishes

pulmonary asbestosis; it produces insidious lung changes;

but the patient may be comparatively free from symptoms for

years, usually from 5 to 15 years; in some cases, symptoms

may not arise until years after the worker has left the industry

and his exposure to asbestos dust. Ellman also noted the length

of time that may elapse between exposure to the dust and a

fatal termination, and the fact that this period is only one-half

of that in silicosis. Asbestos fi bers in the lungs produce pulmo-

nary fi brosis as the result either of actual mechanical trauma,

or of a toxic eff ect comparable with that exerted by SiO 2 in

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cases of silicosis. The asbestos fi bers continue to injure the

lungs, and the disease is a progressive one, which, if suffi cient

fi bers are retained, causes chronic pulmonary disease and

premature mortality. The timing is dependent largely upon the

nature and concentration of the dust.

In a larger study of asbestosis in the UK, Merewether and

Price (1930) estimated that there were about 2,200 persons in

the UK exposed in their daily work to the inhalation of asbes-

tos dust, either pure or admixed with a small proportion of

cotton. This fi gure did not include the considerable number

of workers exposed to the infl uence of mixed dusts of which

asbestos is but one, and commonly not more than 20% of the

mixture. They selected 363 workers exposed to chrysotile,

crocidolite, or amosite, with a preference for those longest

employed, with 75.5% being employed more than 8 years,

and 36.7% employed for more than 10 years. Of the workers

examined, 95 were found to have a diff use fi brosis of the lungs

attributable to the inhalation of the dust, and that the risk fell

most heavily on those longest employed and on those engaged

in the more dusty processes.

Studies of occupational exposures to asbestos in the 1930s

in the United States (US) included exposure measurements

based on total dust counts in terms of millions of particles per

cubic foot (MPPCF).

The study of Lanza et al. (1935) involved exposure to

serpentine (presumably chrysotile) asbestos fi bers in 5 US

plants. Maximum dust counts, based on impinger samples,

at Plants B and D were below 10 MPPCF, as were counts

in most departments in Plants A, C, and E. Maximum dust

counts reached 44.5 in the Felt Department of Plant A; 43 in

the Preparation Department at Plant C; and 82 at the Prepara-

tion Department at Plant E. They concluded that:

Prolonged exposure to asbestos dust caused a pulmonary 1)

fi brosis of a type diff erent from silicosis and demonstrable

on X-ray fi lms.

Cases of defi nite cardiac enlargement were frequently found 2)

to be associated with asbestosis.

A predisposition to tuberculosis due to asbestos dust was 3)

not indicated.

It is not known how much asbestosis may add to the mor-4)

tality of pneumonia and acute non-tuberculosis pulmonary

infections.

It is not practicable as yet to establish standards for the 5)

asbestos content of air.

The amount of dust in the air in asbestos plants studied can 6)

be substantially reduced.

In the study, by Sayers and Dreessen (1939), of 541 textile

mill employees in N. Carolina exposed to Canadian chrysotile

asbestos, which may have included some tremolite, pulmonary

asbestosis was the principal eff ect found, with the most seri-

ous form of the disease in carders, spinners, weavers, twisters,

willowers, and pickers. The exposures, reported in terms of

dust counts, ranged from 0.1 to 76 MPPCF. Defi nite clinical

and roentgenographic evidence of pulmonary asbestosis was

seen in persons after 5 – 10 years of work to exposures exceed-

ing 5 MPPCF, but there was no mention about lung cancer or

mesothelioma.

Much of the epidemiological evidence cited in the

section on “ early evidence ” had methodological limitations by

modern standards. It consisted of case reports, case series, and

other descriptive studies. However, not only are the cited stud-

ies are of historical interest, but they contribute meaningfully

toward establishing associations between asbestos exposures

and human health eff ects even when they lack fully adequate

comparison groups.

Lung cancer

It is now well known that: 1) workers exposed to asbestos

fi bers have an increased risk of developing bronchogenic

carcinoma; 2) workers who also smoke cigarettes have a lung

cancer risk greater than those of nonsmokers with equiva-

lent asbestos fi ber exposures; and 3) exposed workers also

exposed to cigarette smoke have a lung cancer risk greater

than additive (Markowitz et al. (2013). Cancers can arise from

the epithelial lining of the large airways or terminal bronchi-

oles. Bronchogenic carcinomas have a variety of histologic

appearances: adenocarcinoma; squamous cell carcinoma

(presumably arising in areas of squamous metaplasia of the

respiratory epithelium); large cell carcinoma; and small cell

(oat cell) carcinoma. These are the same histologic types of

cancer associated with cigarette smoking in the absence of

asbestos exposure (Mossman and Craighead 1987).

In the UK, where most of the asbestos was imported from

Quebec, Lynch and Smith (1935) made the fi rst report of lung

cancer in persons with asbestosis. However, it only involved

two cancer cases. Also, in the UK, Gloyne (1951) reported

lung cancer in 17 out of 21 necropsies of persons with asbesto-

sis, but only in 55 of 796 (6.9%) of necropsies of persons with

silicosis. Doll (1955) reported on all of the 105 necropsies per-

formed on persons employed in a large asbestos works. There

were 18 lung cancers, with 15 of them having asbestosis.

Of the 113 men employed for at least 20 years, there were 11

lung cancer cases versus 0.8 expected. Doll did not indicate

the type of asbestos being processed in the mill.

Mesothelioma

In a South African crocidolite mining area of the North

Western Cape Province, Wagner et al. (1960) reported that

inhaled asbestos was signifi cantly associated with diff use pleu-

ral mesothelioma in 33 histologically proven cases, while there

were no cases in other parts of South Africa. Some of these

cases were heavily exposed workers, and asbestosis was seen

in most of them, while other cases were in residents who had

lesser exposures, and who did not have evidence of asbestosis.

In the United States, Selikoff et al. (1964) studied 632 build-

ing trade insulation workers exposed intermittently to amosite

asbestos in New York and New Jersey, of whom 45 died from

lung (42) or pleural cancers (3). There was also one peritoneal

mesothelioma. Of the 255 deaths in this cohort, 12 died from

asbestosis, and 29 died from of cancer of the stomach, colon,

or rectum.

Lung cancer and mesothelioma can also occur in people

without radiographic evidence of lung fi brosis. deKlerk et al.

(1997) demonstrated that the level of radiographic fi brosis

conferred additional risk of lung cancer beyond that associ-

ated with level of exposure, but that asbestosis was not a pre-

requisite for the diagnosis of asbestos-associated cancer. On

the other hand, a number of pulmonologists have argued that

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lung cancer is not observed without the histologic presence of

fi brosis. In the series of animal inhalation studies conducted in

the 1990s, neither lung cancer nor mesothelioma was observed

in rats or hamsters without the presence of fi brosis, which

usually occurred as early as 3 months after the exposure was

initiated (Hesterberg and Hart 2001, Bernstein et al. 2005a, b).

Pleural plaques and pleural thickening

Pleural plaques in UK asbestos workers were fi rst described

by Gloyne (1930). Such pleural plaques were observed

by Wagner et al. (1960) in South African asbestos workers

exposed to crocidolite and amosite asbestos. Further evidence

has accumulated that inhalation exposure to airborne asbestos

fi bers is associated with pleural plaques that are detectable by

examination of X-ray images.

More recent biological responses to specifi c types and sizes of inhaled mineral fi bers

There is now an enormous literature on airborne fi bers and the

relationships between inhalation exposures and the diseases

that are associated with such exposures. Unfortunately, in most

cases, the measurements made to characterize the exposures

have neither specifi ed the fi ber types nor characterized the

distributions of their fi ber lengths and diameters, all of which

are major determinants of the health eff ects that may result

from the exposures.

Occupational mineral fi ber exposures

There were marked diff erences among occupational cohorts

exposed to asbestos in the ratio of excess lung cancer to meso-

thelioma. Peritoneal mesotheliomas have usually been attrib-

uted most often to amosite fi ber exposure, but even when only

pleural tumors are considered, the cancer ratios vary remark-

ably. English shipyard workers with exposure to mixed fi ber

types, including a substantial amount of crocidolite fi bers, suf-

fered a high mesothelioma risk but no excess of lung cancer

(Rossiter and Coles 1980), whereas among workers exposed

to fi bers at a South Carolina chrysotile textile plant, there was

a marked excess of lung cancer and a very low incidence of

pleural mesothelioma (McDonald et al. 1984, Dement et al.

1982, 1994). These relatively early data indicated that fi brous

amphiboles, particularly crocidolite, may have been more of

a mesothelioma risk than a lung cancer risk, while chrysotile,

the most heavily used form of asbestos, appears to have caused

much more lung cancer than crocidolite.

A National Research Council study (NRC 1984) summarized

mortality data for mesothelioma and lung cancer in asbestos-

exposed occupational cohorts. In 20 studies with an excess in

respiratory cancer and/or mesothelioma, the percentage of the

excess of mesothelioma varied from 0 to 100, with a mean

( � S.D.) of 38 � 29%. Meurman et al. (1974, 1979) reported

44 lung cancers (vs. 22 expected), but no mesotheliomas, in

1,045 anthophyllite workers in Finland, probably related to

anthophyllite fi bers, which have larger fi ber diameters than

other forms of asbestos. By contrast, in several occupational

cohorts the mesotheliomas accounted for more than 70% of

the asbestos-related cancers, including 1) Newhouse et al.

(1982), with 7,474 British workers exposed to chrysotile, and

some of them were also exposed to crocidolite fi bers, with

9 mesotheliomas occurring in those exposed to both to croci-

dolite and only 1 in those exposed only to chrysotile. For the

whole population, there were only 3 more than the 140 expected

lung cancers; 2) Rossiter and Coles (1980) with 6,076 British

shipyard workers exposed to mixed asbestos fi bers, with 31

mesotheliomas and 13 fewer lung cancers than the expected

number of 101; 3) Jones et al. (1980) with 578 British female

workers exposed to crocidolite fi bers, with 17 mesotheliomas

and 6 lung cancers more than the 6 expected; and 4) New-

house, et al. (1982) with 3,708 British female workers exposed

to mixed asbestos fi bers, with 2 mesotheliomas and 5 fewer

lung cancers than the 11 expected.

Based on a pooling of the results from various cohorts

with mixed exposures by fi ber type, Doll and Peto (1985) and

Nicholson (1986) concluded that, among working men, the

ratio of excess lung cancer to pleural mesothelioma is about

thrice greater for chrysotile than for crocidolite fi bers, with

substantially lower ratios for working women. However, their

pooling concealed the most extreme inconsistencies, most

notably the marked excess of mesothelioma in the absence

of any detectable excess of lung cancer observed among

UK shipyard workers by Rossiter and Coles (1980), and in

the subgroup of UK friction product workers with crocidol-

ite fi ber exposures studied by Berry and Newhouse (1983).

The literature with regard to ratios was brought up-to-date by

McCormack et al. (2012), who assembled data from 55 asbes-

tos cohorts. They estimated ratios of 1) absolute number of

asbestos-related lung cancers to mesothelioma deaths; and 2)

excess lung cancer relative risk (%) to mesothelioma mortal-

ity per 1000 non-asbestos-related deaths. The ratios varied

by asbestos type; there were means of 0.7 (95% confi dence

interval (CI) of 0.5, 1.0) asbestos-related lung cancers per

mesothelioma death in crocidolite cohorts (n � 6); 6.1 (3.6,

10.5) in chrysotile (n � 16); 4.0 (2.8, 5.9) in amosite (n � 4);

and 1.9 (1.4, 2.6) in mixed asbestos fi ber cohorts (n � 31). In

a population with 2 mesothelioma deaths per 1000 deaths at

ages 40 – 84 years (e.g., US men), the estimated lung cancer

population-attributable fraction due to mixed asbestos was

estimated to be 4.0%. Thus, all types of asbestos fi bres other

than crocidolite kill at least twice as many people through lung

cancer than through mesothelioma. For chrysotile, still widely

used today, primarily in high-density cement products, asbes-

tos-related lung cancers cannot be robustly estimated from few

mesothelioma deaths and the latter cannot be used to infer no

excess risk of lung or other cancers.

Markowitz et al. (2013) examined lung cancer mortality

from the National Death Index for 1981 to 2008 for 2,377

male North American insulators with chest X-ray, spiromet-

ric, occupational, and smoking data (collected in 1981 – 1983)

and 54,243 non – asbestos- exposed blue-collar male workers

from Cancer Prevention Study II (for whom occupational and

smoking data were collected in 1982). For workers with 30 – 39

years of work as insulators, 61.4% had parenchymal asbestosis

on chest X-ray (65.0% for ever-smokers and 45.9% for never-

smokers). There were pleural abnormalities in 62.1% of work-

ers without asbestosis and in 81.3% of workers with asbesto-

sis. Lung cancer caused 339 (19%) insulator deaths and was

increased by asbestos exposure alone among nonsmokers (rate

ratio � 3.6; 95% CI � 1.7 – 7.6) for asbestosis among nonsmok-

ers (7.40, CI � 4.0 – 13.7), and for smoking without asbestos

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exposure (10.3, CI � 8.8 – 12.2). The joint eff ect of smoking

and asbestos alone was additive (14.4, CI � 10.7 – 19.4), and

with asbestosis, supra-additive (36.8, CI � 30.1 – 45.0). Insula-

tor lung cancer mortality halved within 10 years of smoking

cessation and converged with that of never-smokers 30 years

after smoking cessation.

The only strong evidence against the inference that mesothe-

lioma is seldom, if ever, caused by chrysotile fi bers alone is in

the signifi cant number of mesothelioma cases among Quebec

chrysotile miners and millers. However, these mesotheliomas

may have been due to a small percentage of fi brous tremolite

in the chrysotile ore (Mossman et al. 1990). Tremolite consti-

tuted less than 1% of the fi ber but more than half of the long

( � 5 μ m) fi bers found in the lung tissue of deceased workers.

High levels of crocidolite fi bers were also found in lung tissue

from British textile workers who suff ered a high incidence of

mesothelioma, but were exposed mainly to chrysotile fi bers

(Wagner et al. 1982).

Based on his extensive personal experience and professional

judgment as a lung pathologist, Churg (1988) reviewed the

only 53 cases of chrysotile exposure-related cases of mesothe-

liomas that he considered acceptable. He reported that 41 of

them occurred in mine dust exposures involving co-exposure

to tremolite fi bers and that there were far fewer cases of meso-

thelioma in these miners than in cases of pulmonary fi brosis

and of lung cancer.

On a further examination of the Quebec asbestos cohort

of ∼ 11,000 chrysotile workers by McDonald and McDonald

(1997), of whom 80% had already died, they addressed the

amphibole hypothesis by analyzing the deaths among the ∼

4,000 miners employed by the largest company in the Thet-

ford region. The numbers of cancer deaths, by type, were as

follows: mesothelioma (21), lung (262), larynx (15), stomach

(99), and colon and rectum (76). Risks, in relation to case

referents, were analyzed by logistic regression separately

for those working in the fi ve chrysotile mines located cen-

trally (Town of Thetford) and for the ten mines located more

peripherally (Town of Asbestos), on the basis that tremolite

concentrations were four times higher in the central region.

Odds ratios were elevated for workers at the centrally located

chrysotile mines for mesothelioma and lung cancer, but not for

gastric, intestinal, or laryngeal cancers; while for the workers

at the more peripherally located chrysotile mines, there was

little or no elevation in odds ratio for any of the cancer groups.

Dust exposures of the two groups were similar, and lung tissue

analyses showed that the concentration of tremolite fi bers was

much higher in the lungs from the central area in comparison

with those from workers at the peripheral mines (McDonald

et al. 1997). The Quebec chrysotile miners and millers suf-

fered 230 lung cancers compared with 184.0 expected and 10

mesotheliomas. Begin et al. (1992), based on experience in

Quebec up to 1990 had concluded that the incidence of pleural

mesothelioma in chrysotile miners and millers, while less than

that for crocidolite workers, was well above the North Ameri-

can male rate.

In an earlier study of Thetford chrysotile mine workers

by Gibbs (1979), pleural calcifi cations were also more com-

mon among miners who had worked in the centrally located

mines than those who worked in the peripherally located

mines. While this early paper did not report the fi ber types

being handled in these two diff erent regions, it subsequently

was determined that there were more tremolite fi bers in the

exposure atmospheres in the central region, which I suggest

could account for much of both pleural calcifi cation and

cancers of the lung and pleura. This is consistent with the

results of the studies by Dodson et al. (1990) and Boutin

et al. (1996) that suggested that some of the diff erence in

potency in the dusts of the central region may have been due

to the greater long-term retention of longer amphibole fi bers

in the lung and pleural lymph nodes than is the case for the

two regions common exposure to chrysotile fi bers. How-

ever, the fi ndings of studies that examined that characterized

fi bers in lung and pleural tissues, long after fi ber exposures,

need to be interpreted cautiously. The simple fi nding of

“ more of X ” in “ location Y ” is not proof of causation, or

even mechanism; it is simply proof of presence under static

circumstances. Also, any study of fi bers in human tissues

may show diff erent degrees of fi ber breakage over time, and

there will be a greater tendency, via diff erential fi ber type

breakdown, to “ shorter chrysotile ” which could contribute

to lower potency.

The summary and discussion of the results of the experi-

mental animal inhalation studies, which follows this section,

supports the critical role of amphibole fi bers in the causation

of mesothelioma.

Dufresne et al. (1996) found that distributions of fi bers in

lungs of Quebec miners and millers with and without asbes-

tosis supported the critical infl uence of long fi bers on fi brosis

and cancer incidence. Mean concentrations were higher in

cases, than in controls: for chrysotile fi bers, 5 – 10 μ m long in

patients with asbestosis with or without lung cancer; for trem-

olite fi bers, 5 – 10 μ m long in all patients; for crocidolite, talc,

or anthophyllite fi bers, 5 – 10 μ m long in patients with meso-

thelioma; for chrysotile and tremolite fi bers � 10 μ m long in

patients with asbestosis; and crocidolite, talc, or anthophyllite

fi bers � 10 μ m long in patients with mesothelioma. Cumula-

tive smoking index (pack-years) was higher in the group with

asbestosis and lung cancer, but was not statistically diff erent

from the two other disease groups.

Another cohort of heavily exposed asbestos workers who

worked only with chrysotile from Quebec was a South Carolina

asbestos textile plant. There was an initial absence of pleural

mesothelioma in spite of the substantial risk of lung cancer

(59 observed, 29.6 expected; Dement et al. 1982, McDonald

et al. 1984). In follow-up study of the South Carolina cohort

by Dement et al. (1994) based on 15 years of additional expe-

rience, there were two deaths attributable to mesothelioma,

and the number of lung cancers had risen to 126, and was

expressed as an increase in relative risk of 2.3% for each year

of cumulative chrysotile fi ber exposure. The high lung can-

cer incidence in the South Carolina cohort was attributed, by

Loomis (2010), to fi bers longer than 20 μ m, based on regres-

sions using TEM-based bivariate fi ber length and diameter

distributions measured on archived membrane fi lter samples.

In a further analysis of these data, Hamra et al. (2014), using

a hierarchical Bayesian model, found that this approach could

make the trend of increased cancer with fi ber length vanish.

However, I am not convinced that this “ fi nding ” is warranted,

but rather an exercise that shows that the choice of a model can

be highly infl uential in the outcome.

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Direct comparison of workers employed for similar dura-

tion to diff erent forms of asbestos in the UK (e.g., in mining or

gas mask manufacture) indicated a much higher mesothelioma

risk of amphibole fi bers than for chrysotile fi bers. Chrysotile

friction products workers in the UK suff ered no detectable

increase in lung cancer, and 11 of the 13 mesotheliomas in

this cohort occurred in the subgroup of workers with known

exposure to crocidolite fi bers (Berry and Newhouse 1983,

Newhouse and Sullivan 1989). Chrysotile textile workers in

Britain suff ered a high risk of mesothelioma in contrast to

those in South Carolina. The only marked diff erence between

these two textile plants was the use of some crocidolite (less

than 5% of the fi ber processed) in the UK plant.

The form of the mesothelioma dose response for asbestos

was explored by Hodgson and Darnton (2000), in a review of

occupational experience. They concluded that for comparable

high-level occupational fi ber exposures to chrysotile, amosite,

and crocidolite, the mesothelioma risks were 1:100:500,

respectively.

Rodelsperger and Bruckel (2006), in a mesothelioma case-

control study, examined fi ber burdens in the lungs of 66 cases

and controls. They did not fi nd a signifi cant odds ratio for

chrysotile, but reported a signifi cant exposure – response rela-

tionship for amphibole fi bers longer than 5 μ m.

From diff erences in retention of fi bers of diff erent sizes,

based on lung fi brosis at the same lung tissue sites of a heavily

exposed anthophyllite worker, Timbrell developed a model for

the lung retention of fi bers as a function of length and diam-

eter. Fiber retention rose rapidly with fi ber lengths between

2 and 5 μ m, and peaked at ∼ 10 μ m. Fiber retention also rose

rapidly with fi ber diameters between 0.15 and 0.3 μ m, peaked

at ∼ 0.5 μ m, and dropped rapidly between 0.8 and 2 μ m. The

utility of the model was demonstrated by applying it to the

prediction of the lung retention of Cape crocidolite and Trans-

vaal amosite workers on the basis of the measured length and

diameter distributions of airborne fi bers. The predicted lung

distributions did, in fact, closely match those measured in

lung samples from a Cape worker (Timbrell 1984) and from

a Transvaal worker (Timbrell 1983). Timbrell concluded that

fi brosis is most closely related to the surface area of fi bers with

diameters between 0.15 and 2 μ m and lengths greater than

∼ 2 μ m.

In a study by Dodson et al. (1990) comparing the fi ber

content of tissues from chronically exposed shipyard work-

ers, they reported that while 10% of amphibole fi bers in

pleural plaque samples were longer than 5 μ m and 8% were

longer than 10 μ m, the corresponding fi gures for chrysotile

fi bers were 3.1 and 0%. In lymph nodes, the corresponding

Figures for � 10 μ m and � 5 μ m lengths were 6.0 and 2.5%

for amphiboles and 0 and 0% for chrysotile. In lung tissue,

they were 41.0 and 20.0% for amphiboles and 14.0 and 4.0%

for chrysotile.

A study of vermiculite miners exposed to amphibole fi bers

(tremolite, richterite, and winchite) in Libby, Montana, but

not to chrysotile, or to other forms of amphibole asbestos,

provided an opportunity to examine the role of amphibole

contamination of commercially important asbestos-containing

products (McDonald et al. 2004). The miners had signifi cantly

elevated risks of lung cancer, non-malignant respiratory

disease, and mesothelioma. They concluded that amphibole

fi bers, and Libby amphiboles in particular, are likely to be

disproportionately responsible for cancer mortality in persons

exposed to commercial products containing asbestos. Weill

et al. (2011) examined lung function, radiological changes

in workers, and residents in Libby MT. The prevalence of

pleural plaques increased with age and was higher in work-

ers (20 – 46%) than in residents (0.4 – 13%). Alexander et al.

(2012) examined radiographs of 461 Libby residents and dem-

onstrated that a history of direct contact with waste from the

vermiculite operations, and of ever playing in the waste piles,

was associated with pleural abnormalities.

Substantial quantities of vermiculite from Libby, MT, were

shipped to a manufacturing facility in Ohio for expansion and

processing of the vermiculite between 1921 and 1990. Rohs

et al. (2008) described low-level fi ber-induced radiographic

changes in a cohort of 431 plant workers who were available

for participation in their study, and 280 of them completed

both chest radiographs and interviews. Of them, 80 had pleu-

ral changes, and 8 had interstitial changes. The pleural changes

were dose related, with 54% in the highest exposure quartile,

and 7% in the lowest quartile. Dunning et al. (2012) reported

that 2 workers from this plant died of mesothelioma, while 1

more, diagnosed with mesothelioma, survived at the time the

paper was prepared.

Thus, Libby amphibole fi ber exposures are clearly associ-

ated with excess interstitial pleural disease as well as excess

with pulmonary disease. It is unfortunate that relatively little is

known about the fi ber dimensional distributions of the Libby

fi bers, severely limiting our ability to sort out the contributions

of fi ber length, diameter, and mineral structure variations to

disease causation.

Evidence that interstitial and pleural changes are associ-

ated with occupational exposures to erionite, a fi brous mineral

other than asbestos, was provided by Ryan et al. (2011), for

residents of North Dakota who worked with road gravel con-

taining erionite.

In summary, the above literature is consistent with my

hypothesis that mesothelioma is largely, if not exclusively,

caused by amphibole fi bers. This published evidence in

humans is consistent, as I will discuss subsequently, with

evidence in animals. However, it should be noted that others,

in the past, have disagreed with my conclusion that mesothe-

lioma is largely, if not exclusively caused by amphibole fi bers.

(Frank et al. 1997, Smith and Wright 1996, Stayner et al. 1996,

Dodson et al. 2003).

Environmental mineral fi ber exposures

Most of the literature dealing with the eff ects of low-level

environmental exposure to mineral fi bers has been focused on

mesothelioma, but some case reports (Casey et al. 1985, Baris

et al. 1987) have described diff use lung fi brosis attributable to

erionite fi bers.

Mesothelioma among people not occupationally exposed

to asbestos has been reported among people living near

asbestos mining and processing areas, including members of

households with asbestos workers as well as those without.

Presumably, exposures to fi bers were higher in homes with

workers bringing home dust on their work clothing and shoes,

but quantitative exposure data are lacking: for such sources;

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for windborne dust from naturally-occurring soils containing

mineral fi bers; and for upwind industrial point sources. As

discussed by Case and Abraham (2009), one notable example

of the latter category was a plant that processed scrap material

containing 30% crocidolite for use in paving driveways.

Wagner et al. (1960) reported that one-third of the meso-

thelioma cases reported in his South African population were

not occupationally exposed to amphibole asbestos. Also, three

studies from Europe and one from the United States reported

excess neighborhood cases around factories processing South

African amphiboles (Newhouse and Thompson 1965, Hain

et al. 1974, Magnani et al. 1995, Hammond et al. 1979).

In the United Sates, there was very heavy and visible com-

munity exposure to chrysotile asbestos in Manville, NJ (Borow

et al. 1973). Berry (1997) reported on the environmental, non-

occupational component of mesothelioma incidence among

persons living in Manville. Prior to removal of occupational

cases, residents of Manville had an average annual (1979 – 1990)

mesothelioma rate of 636 male cases and 96 female cases per

million, about 25 times higher than average state rates. Cases

were removed from the analysis when their “ usual employ-

ment ” was reported as being at the asbestos plant, as evidenced

through union lists or occupational information from either the

Cancer Registry or mortality records. While reports of “ usual

employment ” are often associated with signifi cant exposure

misclassifi cation, they can be useful in preliminary screen-

ing. Standardized incidence ratios (SIRs) were computed for

residents of Manville and Somerset County (less the Manville

population) by sex. Mesothelioma rates of New Jersey, less

than that of Somerset County 1979 – 1990, were used to gener-

ate the expected number of cases. The SIRs for Manville males

and females were, respectively, 10.1 [95% CI: 5.8 – 16.4] and

22.4 (95% CI: 9.7 – 44.2). Male and female Somerset County

mesothelioma SIRs were 1.9 (95% CI: 1.4 – 2.5) and 2.0 (95%

CI: 1.0 – 3.6), respectively. Some of these excesses were due

to household exposures, but clearly the generally community

exposures caused some of the excess.

Pan et al. (2005) studied the association between residential

proximity to naturally occurring asbestos (chrysotile and trem-

olite) and mesothelioma risk in northern California. Logistic

regression analysis from a subset of 1,133 mesothelioma cases

and 890 control subjects with pancreatic cancer showed odds

of mesothelioma decreased ∼ 6.3% per 10 km distance from

the nearest asbestos source, adjusted for age, sex, and occupa-

tional exposure to asbestos. There were no data on chrysotile

versus tremolite exposure. Cox et al. (2013) and Berman et al.

(2013) used the results of the Pan et al. (2005) as a case study

of causal versus spurious exposure-response associations in

risk analysis, and concluded that the association was likely to

refl ect bias and cofounding rather than purely causal eff ects.

Mesotheliomas among non-occupationally exposed people

living near crocidolite-mining and -milling regions in South

Africa and Western Australia have been known to occur for

some time (Wagner and Pooley 1986, Reid et al. 1990). For

a population living near the Wittenoom crocidolite mine in

Western Australia, Hansen et al. (1997) were able to show a

signifi cant exposure – response relationship based on proximity

and duration of exposure.

In a case – control study, Case et al. (2002) studied female

residents of Quebec without occupational exposures to asbes-

tos living in the Town of Thetford (where the chrysotile ore was

contaminated with tremolite) and the Town of Asbestos (where

there was no tremolite). There were lung-retained tremolite

fi bers in non-occupationally exposed women in Thetford, but

not in the Town of Asbestos. There were 6 defi nite or probable

cases and the 4 possible cases of pleural mesothelioma in the

Town of Thetford, but none in the Town of Asbestos.

Populations without occupational exposures to mineral

fi ber may also have high incidences of mesothelioma. These

include populations living in regions where the soil, contain-

ing erionite, crocidolite, or tremolite fi bers, is used to coat the

walls of their residences.

One extreme case is the study of Baris et al. (1987) of

people living in four villages in Central Cappadocia in Turkey.

Three villages (Karain, Sarihidir, and Tuzkoy) were exposed

to erionite, a fi brous zeolite, and a fourth village (Karlik)

lacked this exposure and served as a control. There were 141

deaths during the study period in the four villages, including

33 mesotheliomas, 17 lung cancers, 1 cancer of the larynx, 8

cancers of other sites, and 13 cancers not specifi ed. Thus, there

were 72 cancers out of 141 deaths, with at least 33 of them due

to mesothelioma. The age- and sex-specifi c mortality rates per

1000 person-years from mesothelioma and respiratory cancer

for the four villages were 20.2, 13.5, 5.2, and 0 for males from

Karain, Sarihidir, Tuzkoy, and Karlik, respectively. The corre-

sponding rates for females were 10.9, 3.9, 4.9, and 0. Sebastien

et al. (1984) examined ferruginous bodies in the sputum of

residents of Karain, Tuzkoy, and Karlik. They found that the

content of ferruginous bodies increased with age in Karain and

Tuzkoy, but only one of 19 specimens from Karlik had any.

Mesothelioma cases among residents of Cyprus, who had

no occupational exposures to fi bers, were attributed to envi-

ronmental tremolite fi bers (McConnochie et al. 1987). In

California, the incidence of mesothelioma was associated with

distance of homes from natural outcrops containing asbestos

(Pan et al. 2005).

Metintas et al. (2002, 2012) studied mortality rates in

Eskisehir, a rural region in the center of western Turkey, where

the soil contained tremolite fi bers, or a mixture of tremolite,

actinolite, and chrysotile fi bers, and was used to whitewash

buildings. In the 2002 paper, they studied 1,886 residents in

asbestos-exposed villages. The reported mean indoor fi ber

concentration was 0.089 f/mL, and the outdoor mean was 0.012

f/mL. The average annual average mesothelioma incidence

rates were 11.5 � 10 � 6 for men and 16.0 � 10 � 6 for women.

In the 2012 paper, they studied 3,143 residents in 15 asbestos-

exposed villages, and 2,175 residents in nearby villages without

asbestos exposure. The cumulative fi ber counts ranged from

0.2 to 4.6 fi ber-years/mL (2.7 for men and 4.0 for women).

The annual average incidence for lung cancer was 13.5 � 10 � 6

in men and 4.7 � 10 � 6 in women in the asbestos-exposed vil-

lages, and 6.0 � 10 � 6 in men and 1.5 � 10 � 6 in women in the

control villages. In addition, there was excess chronic obstruc-

tive pulmonary disease in both men and women. The standard-

ized mortality ratio (SMR) was 1.59.

Kurumatani and Kumagai (2008) studied 73 mesothelioma

deaths in nonoccupationally exposed residents of Amagasaki

City in Japan. There was an asbestos cement pipe plant within

the city that used an annual average of 4,600 tons of crocidol-

ite and 4,600 tons of chrysotile fi bers between 1957 and 1975.

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Dispersion modeling was used to classify fi ve city areas by esti-

mates of fi ber concentration. They reported that mesothelioma

SMR declined linearly with relative fi ber concentration for both

men and women, with signifi cantly elevated SMRs out to 2,200

meters. There was no mention of excess lung cancer deaths.

Maule et al. (2007) studied mesothelioma deaths in non-

occupationally exposed residents of Casale Monferrto, Italy.

There was an asbestos cement pipe plant within the city

between 1907 and 1986 that used an asbestos mixture of 10%

crocidolite, small amounts of amosite, and the balance being

chrysotile fi bers. Concentrations of fi bers longer than 5 μ m

measured using scanning electron microscopy (SEM) in 1984

varied inversely with distance from the plant with the highest

concentration being 11 f/L. In 1990 – 1991, the highest mea-

sured concentration by TEM was 7.4 f/L.

Musti et al. (2009) did a case – control study of 48 mesothe-

lioma deaths and 273 controls in non-occupationally exposed

residents of Bari, Italy. There was an asbestos cement pipe

plant within the city between 1934 and 1989 that used an

asbestos mixture of 15% crocidolite, 5% amosite, and 80%

chrysotile fi bers in 1974. They reported a mesothelioma odds

ratio of 5.3 (95% CI: 1.2 – 23.7) for people living within 500

meters of the plant.

Barbieri et al. (2012) studied the asbestos fi ber burdens in

the lungs of 8 residents living near the asbestos-cement plant

in Casale Monferrato or in Bari, Italy, using SEM and X-ray

microanalysis. The measured amphibole fi ber burdens (with

lengths greater than 1 μ m and diameters between 0.13 and

3 μ m) ranged from 110,000 to 4,300,000 f/gram of dry lung

tissue, and there were no chrysotile fi bers. They reported that

there was a linear relationship between lung fi ber burden and

estimated cumulative environmental exposure.

Luo et al. (2010) described asbestos-related diseases from

environmental exposure to crocidolite fi bers from blue clay

surface soil in Da-yao, China. In addition to the widespread

exposure to crocidolite fi bers in windblown soil, there are also

much heavier fi ber exposures to workers making or refurbish-

ing blue clay stoves. They reported that, in 1985, the aver-

age fi ber count in the crusher room was 6.6 f/mL with a peak

of 25.4 f/mL, far exceeding the threshold limit value of 0.1 or

0.2 f/mL, and more than 80% of the airborne asbestos fi bers

were 5 – 20 μ m in length. The prevalence of pleural plaque

was 20% among peasants in Da-yao over 40 years of age in

their cross sectional survey. The average number of mesothe-

lioma cases was 6.6 per year in the 1984 – 95 period and 22 per

year in the 1996 – 99 period, in a population of 68,000. For

those mesothelioma cases that were histologically confi rmed,

there were 3.8 cases/year in the fi rst period and 9 cases/year

in the second. Of the 2,175 peasants in this survey, 16 had

asbestosis. Lung cancer deaths were signifi cantly increased in

three cohort studies. The annual mortality rate for mesothe-

lioma was 85, 178, and 365 per million for the three cohorts,

respectively. The higher exposed peasants had a fi vefold

increased mesothelioma mortality compared to their lower

exposed counterparts. There were no cases of mesothelioma

in comparison groups where no crocidolite was known to exist

in the environment. In the third cohort study, almost one of

fi ve cancer deaths (22%) was from mesothelioma. The ratios

of lung cancer to mesothelioma deaths in the 3 cohorts that

they studied were 1.3, 3.0, and 1.2, respectively).

The methodological limitations of many of the older epi-

demiological studies described above should be recognized.

Depending on the study, these limitations include ecological

design, absence of an appropriate comparison group, crude

proximity-based exposure assessment, small numbers, and

poor information on potential occupational and household

exposure (although some relative risks are so large as to be

unlikely to be attributable entirely to error or bias).

Human responses to specifi c types and sizes of inhaled SVF

SVF Exposure and Lung Cancer: Many of the earliest studies

of SVF production workers have reported excess lung cancer

among some cohorts, primarily those heavily exposed to slag

wool and rock wool in earlier years, when exposure levels were

largely uncontrolled (Enterline et al. 1983, 1987, Shannon

et al. 1984, 1987, Saracci et al. 1984, Simonato et al. 1986).

In the large multinational study in Europe involving approx-

imately 22,000 SVF production workers at 13 plants in seven

countries, the overall lung cancer SMR was 125, and the SMR

for the subcohort with more than 30 years was 170. Adjust-

ment for regional variations in mortality substantially reduced

the excess lung cancer incidence for those workers exposed

only to glass wool but not for those exposed to rock wool/slag

wool. Within this group, most of the excess occurred in the

group with 20 – 29 years since fi rst exposure (SMR of 270). The

SMR was 244 for those with 30 or more years, who worked

before dust controls were installed. In a follow-up study of the

sub-cohort of rock and slag wool workers in Scandanavia and

Germany, for whom smoking and other occupational exposure

data were available, Kj æ rheim et al. (2002) reported that, for

a smoking-adjusted model with a 15 year lag, the lung cancer

odds ratio for the second, third, and fourth cumulative expo-

sure quartiles were 1.3, 1.0, and 0.7, suggesting that the fi ber

exposures were not causal.

Berrigan (2002) performed a meta-analysis for 10 SVF

occupational cohorts and reported that the aggregate respira-

tory cancer SMRs were signifi cantly elevated for glass wool

(123) and rock wool (132). Similar results were obtained in the

meta-analysis of Lipworth et al. (2009), who reported an SMR

of 122 for glass wool, and 132 for rockwool.

Enterline et al. (1987) reported the 1946 – 1982 mortality

experience of 16,661 SVF workers employed 6 months or

more during 1940 – 1963 at one or more of 17 US manufac-

turing plants. Using local death rates to estimate expected

deaths, there was a statistically signifi cant excess in all

malignant neoplasms and in lung cancer 20 or more years

after fi rst employment. For respiratory cancer the excess

was greatest for mineral wool workers and workers ever

exposed in the production of small diameter fi bers. These

two groups of workers are believed to have had mean expo-

sures to respirable fi bers of around 0.3 fi bers/mL. For glass

wool workers and glass fi lament workers, SMRs for respira-

tory cancer were much lower. For these workers, exposures

were estimated to be about 1/10 the level for mineral wool

and small diameter fi ber workers. There were few positive

relationships between respiratory cancer SMRs and duration

of exposure, time since fi rst exposure, or measures of fi ber

exposure. A smoking survey showed SVF workers to have

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cigarette-smoking habits similar to all US white males. In a

case-referent study, which controlled for smoking, there was

a statistically signifi cant relationship between fi ber exposure

and respiratory cancer for mineral wool workers but not for

fi brous glass workers.

Marsh et al. (2001a) introduced and summarized the results

of the 1986 – 1992 update on this large US cohort. It involved

a new historical exposure reconstruction for glass fi bers,

arsenic, asbestos, asphalt, epoxy, formaldehyde, polynuclear

aromatic hydrocarbons (PAHs), phenolics, SiO 2 , styrene,

and urea (Smith and Wright 1996), and a nested case – control

study of the 631 respiratory cancer cases, including their

smoking histories (Stone et al. 2001, Marsh et al. 2001b). The

only outcome with a statistically signifi cant 6% (p � 0.05)

excess risk was respiratory cancer. However, the duration

of fi ber and other exposures, the cumulative exposures, and

the time since fi rst exposure were not associated with the

cancer risk. The smoking habit data (Buchanich et al. 2001)

indicated more smoking in the exposure cohort than in the

referent population, suggesting that at least some of the can-

cer excess was due to smoking. For female workers, there

was no respiratory cancer excess for the period 1946 – 1992

(Stone et al. 2004).

Shannon et al. (1987) conducted a historical prospective

mortality study at an insulating wool plant in Ontario, Can-

ada. It covered 2557 men who had worked for at least 90 days

and were employed between 1955 and 1977, with follow-up

to the end of 1984. There were 157 deaths in the 97% of

men traced. Mortality was compared by the person-years

method with that of the Ontario population. Overall, mortal-

ity was below that expected (SMR � 84). Cancer deaths were

slightly raised, owing entirely to an excess in lung cancer.

The 21 deaths from this cause give a signifi cantly high SMR

of 176. All but two of these cases occurred among “ plant-

only ” employees. However, the interpretation of these data

remains diffi cult because the SMRs by length of exposure

and time since fi rst worked were not consistent with a causal

relationship.

Engholm et al. (1987) conducted a large population study

of the incidence of respiratory cancer in male Swedish con-

struction workers in relation to exposure to SVFs. There were

examinations at regular health check-ups in 1971 – 1974, and

they were followed for mortality through 1983 and for can-

cer incidence through 1982. There was a case – control study

within the cohort on 518 cases diagnosed as having respira-

tory cancer. The subjects were classifi ed into categories based

on self-reported exposure and on estimates of average inten-

sity of exposure. Smoking habits and density of population

were included as potential confounders. Overall, there was an

excess of mortality from industrial accidents and an excess

incidence of mesothelioma, but in other respects the mortality

and the cancer incidence in this population compared favor-

ably with those of the general Swedish population. For lung

cancer the overall incidence was below that expected, but

there was a risk related to high asbestos exposure. The risk

fell close to unity for SVFs when both exposures were fi tted

simultaneously.

The human experience, based on long-term follow-up on

SVF workers in the USA, Canada, and Europe, is encour-

aging. Many of these workers were exposed to very high

concentrations of fi bers in the 1940s and 1050s. As summa-

rized by Doll (1987), the evidence of excess lung cancer among

these workers appears confi ned to those subcohorts exposed

to slag or rock wool, or to those exposed to small diameter

biopersistent glass fi bers as well as to conventional fi brous

glass. When Doll excluded short-term and offi ce workers, and

compared the numbers of deaths with those that would have

been expected had the workers experienced national mortal-

ity rates (or provincial rates in the Canadian series), he found

that the mortality from lung cancer (SMR � 121) was raised

but that the mortality from other cancers (SMR � 101), other

respiratory disease (SMR � 103), and all other causes of death

(SMR � 100) was close to that expected. Division of the work-

ers by type of product and time since fi rst exposure showed

that the mortality from lung cancer was highest in the rock

or slag wool sector of the industry (SMR � 128), intermedi-

ate in the glass wool sector (SMR � 110), and lowest in the

continuous-fi lament glass sector (SMR � 93) and that within

the fi rst two groups mortality rose with time since fi rst expo-

sure to a maximum after 30 or more years (rock or slag wool,

SMR � 141; glass wool, SMR � 119). Within the US glass

wool industry, the mortality from lung cancer was higher in

those men who had ever been exposed to small diameter fi bers

(SMR � 124) than in others (SMR � 108). No relationship

was observed with duration of employment or with cumulative

fi ber dose. In a case – control study, however, a weak relation-

ship with cumulative fi ber dose was observed in the rock and

slag wool sectors of the industry after diff erences in smoking

habits had been taken into account. No evidence was obtained

of a risk of mesothelioma or any other type of cancer. Doll

concluded that an occupational hazard of lung cancer has been

demonstrated in the rock and slag wool section of the industry

and possibly in the glass wool section. Uncertainty about fi ber

counts in the early years of the industry and about the extent

to which other carcinogens were present in the atmosphere of

the plants precludes an estimate of the quantitative eff ects of

exposure to current fi ber levels, except that it is unlikely to be

measurable.

Wong and Musselman (1994) described results from an

epidemiologic study of SVF workers in the United States for

workers at nine plants that made or used slag wool. These

included four plants previously studied and fi ve additional

plants. This was a nested case – control study based on 55 lung

cancers. They analyzed lung cancer risk in relation to cumula-

tive fi ber exposure (concentration and duration) and smoking

history, and controlled for other co-exposures such as asbestos

contamination. No increased lung cancer risk with exposure

to slag wool fi bers was found. This paper provided guidelines

to estimate the magnitude of potential confounding eff ects of

co-exposures such as smoking.

In an analysis of the mortality experience of a cohort of

RCF workers through 2000, LeMasters et al. (2003) reported

no excess for all deaths or respiratory cancers, but there was an

excess for urinary system cancer.

SVF exposure and mesothelioma

On their examination of mesothelioma risk, Marsh et al.

(2001c) reported one case in the exposed cohort, while the

expected SMR for the referent group was 2.19 (SMR � 46).

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Lacourt et al. (2013) performed a case – control study of

1,199 male French workers and 2,379 controls. The workers

were exposed to asbestos, rockwool, SiO 2 , or combinations

of asbestos and either rockwool fi bers or SiO 2 particles. For

pleural mesothelioma, there was a signifi cant dose-related

association with rockwool fi bers, but not for SiO 2 particle

exposure after adjustment for occupational exposure to asbes-

tos. Co-exposure to asbestos with either rockwool fi bers or

SiO 2 particles potentiated the mesothelioma rates.

SVF exposure and respiratory morbidity

For symptoms, lung function changes related to exposures to

SVFs, the epidemiologic evidence had been largely negative

(Utidjian and deTreville 1970, Hook et al. 1970, Hughes et al.

1993, Malmberg et al. 1984). In terms of X-ray abnormalities,

the only positive fi ndings reported by Hughes et al. (1993)

were for a population cohort exposed to very thin glass fi bers.

The best-documented respiratory morbidity eff ects are

for SVF workers exposed to RCFs. LeMasters et al. (1998)

reported on an industry-wide RCF cohort that was charac-

terized as either production or non-production activities and

duration of production employment. Both male and female

production workers had signifi cantly more respiratory symp-

toms. For male production workers, there was a signifi cant

decline, over 10 years, in forced vital capacity (FVC) for both

smokers and non-smokers, while only the male smokers had

a signifi cantly greater decline in forced expiratory volume in

1 second (FEV 1 ). Female nonsmokers had a greater decline

in FVC than their male counterparts. In a follow-up study by

McKay et al. (2011) that extended the observations for up to

17 years, there was no consistent decline in lung function asso-

ciated with RCF exposure.

In an early report on RCF workers, LeMasters and Lockey

(1994) reported a correlation between pleural changes and

RCF exposures. In a recent report, Lockey et al. (2012)

reported on lung tissue fi ber burden on 10 RCF workers with

no asbestos exposure, and a 20-year longitudinal radiographic

study on 1,323 RCF workers. They concluded that RCF was

biopersistent for up to 20 years and that they may contribute

to a signifi cant association between cumulative fi ber exposure

and radiographic pleural changes.

Studies of an industry-wide cohort in Europe by Trethowan

et al. (1995) found no excess in illness or chest X-ray abnor-

malities related to fi ber exposures (For further information,

consult the IARC Monograph on Man-Made Vitreous Fibres

(IARC 2002) and Boff etta (2014)).

Summary of human responses to long-term fi ber inhalation exposures

One common theme in the epidemiologic literature on both

workers and community residents is that amphibole (especially

crocidolite and tremolite) and erionite fi bers are most often more

commonly associated with mesothelioma and pleural plaques

than are chrysotile fi bers, while chrysotile fi bers are more often

more commonly associated with lung cancer and asbestosis than

are amphibole fi bers. Furthermore, in those studies of workers

exposed to chrysotile who developed mesothelioma, there was

tremolite in the chrysotile source. The greater association of

chrysotile fi ber exposure with lung cancer than with mesothe-

lioma is likely related to the large historical usage of chryso-

tile, and to the longer length of chrysotile fi bers in most cases.

Hodgson and Darnton (2000) concluded that the risk of lung

cancer is 10 times higher for amosite and 50 times higher for

crocidolite in comparison with chrysotile, which is likely due to

the greater biopersistence of the amphiboles.

A second theme comes from the few studies that addressed

the issue of critical fi ber lengths. Loomis (2010) demonstrated

that the high lung cancer incidence in the South Carolina textile

workers cohort was most closely associated with chrysotile fi ber

longer than 20 μ m, while the Rodelsperger and Bruckel (2006)

mesothelioma case – control study did not fi nd a signifi cant

odds ratio for chrysotile, but reported a signifi cant exposure –

response relationship for mesothelioma for amphibole fi bers

longer than 5 μ m. The studies of fi bers retained in human

lung tissues of Timbrell for crocidolite, amosite, anthophyl-

lite, and chrysotile miners (described in Lippmann 1988),

by Dufresne et al. (1996) for Quebec chrysotile miners, and

by Dodson et al. (1990) for shipyard workers are consistent

with these diff erent critical lengths for lung and pleural

diseases.

For SVF, there is little evidence for any health hazard asso-

ciated with conventional fi brous glasses, but there are greater

risk potentials for the more biopersistent SVFs among spe-

cialty glasses, glass- and slag wools and RCFs. However, the

risks for the more biopersistent SVFs are clearly much lower

than those for chrysotile asbestos fi bers, which, in turn, are

lower than those for amphibole fi bers and erionite fi bers.

Responses to asbestos in animal exposure studies

One reason that the relative potencies of the various mineral

forms of asbestos after long-term inhalation exposure are still

not fi rmly established is the unfortunate reliance, in many of

the studies, on a common source of a standardized supply of

asbestos dusts prepared by the International Union Against

Cancer (UICC) and utilized, in most studies, at uniform mass

concentrations. In mechanically mixing and homogenizing the

dust supplies, most of the longer fi bers were broken down into

lengths too short to elicit much lung fi brosis or cancer. This

was subsequently demonstrated in the studies of Davis et al.

(1986a, b, 1988) using amosite and chrysotile with fi bers lon-

ger than the UICC dusts.

Toxicological studies are most useful for comparing the

toxicity of the various fi ber types (chrysotile, amphiboles,

SVFs, etc.) when the fi ber size distributions are similar. The

comparisons are more easily interpretable in results from

laboratory exposures studies, where the fi ber size distribu-

tions and dosages can be manipulated and well characterized.

Studies involving human experience seldom involve detailed

knowledge of the fi ber types in the breathing zone, or of their

distributions of lengths and widths. The following summary

is focused on the papers that provided quantitative informa-

tion on the infl uences of fi ber type and/or fi ber dimensions on

the health-related responses that could be interpreted in either

qualitative or when possible, in quantitative terms.

Fibrogenesis responses

In studies involving inhalation exposures of rats to UICC

asbestos for 1 day to 2 years, Wagner et al. (1974) found that

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amosite and crocidolite were the least fi brogenic of the fi ve

types of UICC asbestos, the others being Canadian chrysotile,

Rhodesian (Zimbabwe) chrysotile, and anthophyllite.

Davis et al. (1978) used UICC chrysotile A, amosite, and

crocidolite in 12-month rat exposures at respirable mass

concentrations comparable with those used by Wagner et al.

(1974), and found a similar pattern; that is, chrysotile was

the most fi brogenic, and amosite and crocidolite the least.

Hiett (1978) exposed guinea pigs by inhalation for 9 and 18

days, and also found that chrysotile was more fi brogenic than

amosite. Davis et al. (1986b) subsequently repeated the proto-

col with amosite for fi ber lengths both shorter and longer than

that of UICC amosite. The short amosite produced virtually no

fi brosis, whereas the long amosite was more fi brogenic than

chrysotile. The most fi brogenic asbestos was tremolite.

Carcinogenesis responses

Some of the studies that reported carcinogenic responses also

noted histological evidence of fi brogenic responses as well.

Davis et al. (1991) studied the carcinogenicity of six diff erent

tremolite asbestos minerals. Three of them were considered

to be asbestiform, while the three others were considered to

be cleavage fragments. The carcinogenicity was high for all

three asbestiform materials, and was very low for two of the

cleavage fragment dusts. Carcinogenicity was at an intermedi-

ate level for the third cleavage fragment material in rats, which

contained more fragments in the size range that that met the

WHO counting criteria and would be counted as fi bers.

The series of rat inhalation studies performed by Davis

and colleagues, at the Institute of Environmental Medicine in

Edinburgh that have also produced numerous lung cancers,

have provided the most relevant evidence on the importance

of fi ber length on carcinogenicity in the lung. Davis et al.

(1978), in attempting to examine the infl uence of fi ber num-

ber concentration in their inhalation studies, had 5 exposure

groups that included 3 at respirable mass concentrations of

10 mg/m 3 , 1 each with chrysotile, crocidolite, and amosite.

Of these, the amosite produced the lowest number concentration

of fi bers � 5 μ m in length. This fi ber count was then matched

with crocidolite (5 mg/m 3 respirable mass) and chrysotile (2

mg/m 3 respirable mass). In explaining the greater fi brogenic

and carcinogenic responses in the chrysotile-exposed ani-

mals than the crocidolite- or amosite-exposed groups, they

emphasized the greater number of � 20- μ m-long fi bers in the

chrysotile aerosol. The ratio of � 20- to � 5- μ m-long fi bers in

the chrysotile was 0.185 compared to 0.040 for crocidolite and

0.011 for amosite. The diameter distributions of all three types

of asbestos were similar, with a median diameter of ∼ 0.4 μ m.

The importance of fi ber length to lung cancer was further

investigated by Davis et al. (1986b) in inhalation studies with

amosite aerosols that were both shorter and longer than the

UICC amosite studied earlier with the same protocols. Both

aerosols had median diameters between 0.3 and 0.4 μ m. The

short-fi ber amosite (1.7% � 5 μ m in length) produced no

malignant cancers in 42 rats, whereas the long-fi ber amosite

(30% � 5 μ m, 10% � 10 μ m) produced 3 adenocarcinomas,

4 squamous carcinomas, and 1 undiff erentiated carcinoma in

40 rats. In terms of adenomas, the frequencies were 3/40, 2/43,

0/42, and 1/81 for the long, UICC, short, and control groups,

respectively. Davis et al. (1985) also studied tremolite asbestos

using the same protocols. Its length distribution was similar

to those of the chrysotile in the 1978 study and of the long

amosite in the 1986 study (i.e., 28% � 5 μ m, 7% � 10 μ m), but

its median diameter was lower, that is, 0.25 μ m. It produced

2 adenomas, 8 adenocarcinomas, and 8 squamous carcinomas

in 39 rats. Davis (1988) compared the carcinogenic eff ects of

“ long ” and “ short ” chrysotile at 10 mg/m 3 . Unfortunately, the

discrimination between “ long ” and “ short ” fi bers was less suc-

cessful than that achieved for amosite. PCOM fi ber counts for

the fi bers � 10 μ m in length for the “ long ” and “ short ” chryso-

tile were 1,930 and 330 f/mL, whereas for the amosite they

were 1,110 and 12 f/mL, respectively. Despite the much more

rapid clearance of the chrysotile from the lungs, the tumor

yields were higher. For the “ long ” fi ber, there were 22 tumors

for the chrysotile vs. 13 for the amosite. For the “ short ” fi ber,

there were 7 vs. 0. Davis (1987) concluded that fi bers � 5 μ m

in length may be innocuous, since the tumors produced by the

“ short ” chrysotile are explicable by the presence of 330 f/mL

longer than 10 μ m.

The comparisons in tumor yields for the “ long ” and the

“ short ” amosite and chrysotile are complicated by the dif-

ferences in biopersistence between the two fi ber types, and

the unknown number counts of fi bers in length categories

other than � 5 and � 10 μ m. Furthermore, even for the � 5-

and � 10- μ m categories, there were diff erences in the fi ber

counts by factors of 2 – 3, and the ratios would likely be higher

for longer length categories. Thus, while the precise character-

ization of the eff ects of long fi bers on tumor yields in rats can-

not be made on the basis of Davis et al. (1986b) and Davis and

Jones (1988), it is clear, at least to me, that the implications

of Davis (1987) conclusions are clear, that is, that asbestos

fi bers � 5 μ m in length are likely innocuous, and that the sig-

nifi cant yields of lung tumors in rats and human populations

exposed to chrysotile are almost certainly attributable to its

relatively high content of long fi bers.

Animal inhalation studies with both asbestos and SVF

Miller et al. (1999b) reviewed the collective outcomes of 18

rat inhalation studies involving fi bers of amosite, silicon car-

bide whiskers, 4 vitreous products (glass fi ber 100/475, and

3 Man-Made Vitreous Fibers (MMMFs, aka SVFs), that is,

MMVF10, MMVF21, and MMVF22), and 3 RCFs, that is,

RCF1, RCF2, and RCF4. The primary infl uences on biologi-

cal responses was the number of fi bers � 1.0 μ m in diameter

and � 20 μ m in length, and the dissolution rate of the fi bers.

Another important observation was that in vivo and in vitro

cell responses did not signifi cantly predict the risk of cancer

following inhalation.

McConnell et al. (1999) exposed hamsters for 78 weeks

to amosite and two diff erent fi brous glasses (MMVF10a and

MMVF33) at 250 – 300 f/ml for fi bers � 5 μ m in length, and

to amosite at 125 and 25 f/ml. MMVF10a produced only

mild infl ammation, while MMVF33 produced more severe

infl ammation and mild interstitial and pleural fi brosis, as well

as one mesothelioma. It should be noted that a relatively bio-

durable fi ber glass (MMVR 33 � 475 fi ber glass), at a much

lower exposure level than chrysotile, produced signifi cant

pleural hyperplasia and a single mesothelioma in the hamster

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(McConnell et al. 1995; and McConnell et al. 1999), while

amosite produced severe pulmonary fi brosis and many meso-

theliomas (3.6%, 25.9% and 19.5% at the low, medium, and

high doses). The eff ects were most closely related to the

retained fi bers � 20 μ m in length and were consistent with the

in vitro dissolution rates.

Cullen et al. (2000) compared the pathogenicity of amosite

with that of two special purpose glass microfi bers having

low dissolution rates (104E and 100/475) in a study in which

rats were exposed for 7 h/days, 5 days/week for 12 months to

1,000 f/mL longer than 5 μ m. In terms of mesothelioma and

lung cancers produced (after the exposures and twelve months

without further exposure), 104E and amosite fi bers were con-

siderably more potent than 100/475 fi bers. They attributed the

lower pathogenicity of 100/475 to the greater leaching of its

component elements while in the lungs.

Berman et al. (1995) analyzed the lung tumor and mesothe-

lioma responses from 13 of the chronic inhalation studies in

rats performed by Davis and colleagues in Edinburgh in rela-

tion to new TEM measurements of the fi ber distributions on

archived chamber atmosphere sampling fi lters. The measure

highly correlated with tumor incidence was the concentration

of fi bers � 20 μ m in length.

In the long-term rat inhalation studies, 10 mg/m 3 of

short amosite ( ∼ 0.1% � 10 μ m), UICC amosite ( ∼ 2.5% � 10

μ m), UICC crocidolite ( ∼ 3% � 10 μ m), and Oregon erionite

(7.4% � 10 μ m) failed to produce malignant lung cancers,

whereas 10 mg/m 3 of UICC chrysotile, long amosite and

tremolite (all with � 10% � 10 μ m) all produced malignant

lung tumors. Although there was no clear-cut infl uence of fi ber

diameter on tumor yield, the results suggest that carcinogenesis

incidence increases with both fi ber length and diameter. Since

Timbrell (1983) had shown that asbestos fi ber retention in the

lungs peaks between 0.3 and 0.8 μ m diameter, it is likely that

the thinner fi bers, which are more readily translocated to the

pleura and peritoneum, play relatively little role in lung car-

cinogenesis. Therefore, it appears that the risk of lung cancer

is associated with long fi bers, especially those with diameters

between ∼ 0.3 and 0.8 μ m, and that fi bers � 10 μ m in length

are needed.

In my own review of the literature on the long-term rat inha-

lation studies with amosite, brucite, chrysotile, crocidolite,

erionite, and tremolite (Lippmann 1994), I found that, for lung

cancer, the percentage of lung tumors (y) could be described

by a relation of the form

y � a bf cf 2,

where f is the number concentration of fi bers, and a , b , and c

are fi tted constants. The correlation coeffi cients for the fi tted

curves were 0.76 for � 5 μ m f/mL, 0.84 for � 10 μ m f/mL,

and 0.85 for � 20 μ m f/mL, and seemed to be independent

of fi ber type. This supports the hypothesis that the critical

length for lung cancer induction is in the 10- to 20- μ m range.

In terms of the critical sites within the lungs for lung cancer

induction, it has been shown that brief inhalation exposures to

chrysotile fi ber produce highly concentrated fi ber deposits on

bifurcations of alveolar ducts, and that many of these fi bers are

phagocytosed by the underlying type II epithelial cells within

a few hours. Churg (1994) has shown that both chrysotile and

amphibole fi bers retained in the lungs of former miners and

millers do not clear much with the years since last exposure.

Thus, lung fi brosis and tumors may be caused by that small

fraction of the inhaled long fi bers that are retained in the

interstitium below small airway bifurcations, where clearance

processes are ineff ective.

Intratracheal and intraperitoneal in vivo exposures in animals

Various intracavity injection studies have been conducted in

attempts to understand the potential health risk from exposure

to diff erent fi ber types and the mechanisms by which fi bers

cause toxic eff ects in the lung or mesothelium. However,

it is important to note that these non-physiological exposure

methods diff er markedly from the manner in which humans

are exposed by inhalation. The numerous problems associ-

ated with the intracavity injection methods have been dis-

cussed by Eastes and Hadley (1996); Collier et al. (1995);

McClellan et al. (1992); McClellan and Hesterberg (1994);

McConnell et al. (1995), as refl ected in reviews conducted by

various national and international government agencies,

including the US Offi ce of Science and Technology Policy

(OSTP) 1985, International Program on Chemical Safety

(WHO 1988): National Institute for Occupational Safety and

Health (NIOSH 1977, 1986): the World Health Organization

(WHO 1992): the National Research Council (NRC 2000) of

the National Academy of Science: and, the Agency for Toxic

Substance and Disease Registry (ATSDR 2004). Their major

concerns are as follows: a) implantation/injection of fi bers

bypasses the natural defense mechanisms that are operative in

the lung when fi bers are inhaled, and b) very large fi bers, not

normally inhaled into the lung, can be implanted or injected.

Fibers with a large aerodynamic diameter are non-respirable,

which means they have limited potential for becoming air-

borne, remaining suspended in the air and traveling with the

inhaled air into the lower lung; c) intra-cavity injection studies

typically use very large quantities with high concentrations

resulting at the injection site. With these large quantities,

“ Normal physiology, homeostasis and detoxifi cation or repair

mechanisms may be overwhelmed and cancer, which other-

wise might not have occurred, is induced or promoted ” (OSTP

1985); and d) Target cells for the fi bers that are injected or

implanted into the abdominal cavity are not the same as for

respiratory tissues that are exposed via inhalation of fi bers.

The IP route of administration produced false-positive

results in a series of chronic inhalation studies of SVFs con-

ducted in the 1990s (Hesterberg and Hart 2001). These fi nd-

ings led IARC to downgrade most SVFs to “ not classifi able ”

as human carcinogens (IARC 2002). When these SVFs were

tested IP, they produced a signifi cant increase in mesothe-

liomas (Roller et al. 1996, Miller et al. 1999a). IARC (2002),

and NTP (2011), and California ’ s Offi ce of Environmental

Health Hazard Assessment (OEHHA 2011) classifi ed these

same SVFs as non-carcinogenic, based on the results of well-

conducted inhalation studies.

Wright and Kuschner (1977) used short and long asbestos

and SVF fi bers in IT instillation studies in guinea pigs. For

suspensions containing fi bers longer than ∼ 10 μ m, all of the

materials produced lung fi brosis, although the yields varied

with the materials used. However, with equal masses of short

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fi bers of equivalent fi ber diameters, none produced any fi bro-

sis. The yields were lower for the long glass fi bers than for

the long asbestos; this was attributed to their lesser durability

within the lungs.

Miller et al. (1999a) reviewed the collective outcomes of

9 rat intraperitoneal (IP) injection studies involving fi bers

of amosite, silicon carbide whiskers, four SVFs (100/475,

MMVF10, MMVF21, MMVF22), and three refractory

ceramic fi brous products (RCF1, RCF2, RCF4) on mesothe-

lioma. They reported a link between the numbers of injected

fi bers � 20 m m in length, and the biopersistence in the rat lung

of fi bers � 5 μ m in length.

Shannahan et al. (2012) instilled rat-respirable sized Libby,

MT, amphibole (LA) asbestos in saline into Wistar-Kyoto

(WKY), spontaneously hypertensive (SH), and SH heart fail-

ure (SHHF) rats at 0, 0.25 or 1.0 mg LA doses. All of the rats

developed concentration- and time-dependent interstitial fi bro-

sis. The SHHS rats developed atypical hyperplastic lesions of

bronchiolar epithelial cell origin at 3 and 6 months.

Schinwald et al. (2012a) injected mice IP with 120-nm-

thick silver nanowires with mean lengths of 3, 5, 10, 14, and

28 μ m, along with short and long nickel nanowires (4 and 20

μ m long), CNTs (13 and 36 μ m long), and two amosite asbestos

dusts (long fi bers with 100% longer than 5 μ m, 50% � 15 μ m,

and 35% � 20 μ m, and short with 3% � 5 μ m). They reported

an acute pleural response with a threshold fi ber length of

4 μ m. They suggested that fi bers that are 5 μ m or longer that are

translocated to the pleural space, both free and in macrophages,

are retained because they cannot negotiate the stomata in the

parietal pleura, where they can elicit infl ammation.

Schinwald et al. (2012b) also injected mice IT with 120-

nm-thick silver nanowires with mean lengths of 3, 5, 10, 14,

and 28 μ m to investigate the threshold fi ber length for the

onset of pulmonary infl ammation after aspiration exposure,

and to examine fi ber length in relation to macrophage loco-

motion in an in vitro wound healing assay. They reported a

length-dependent response in the lung, with a threshold length

of 14 μ m. For impaired motility, there was a length threshold

at 5 μ m.

Murphy et al. (2013) exposed mice by IT by pharyngeal

aspiration of CNTs in 3 length ranges, 1 – 2, 1 – 5, and 84% lon-

ger than 15 μ m. They reported that the long nanotubes, but not

the two shorter samples, produced an infl ammatory response

at 1 week post-exposure in the bronchoalveolar lavage (BAL)

fl uid, as well as a progressive thickening of the alveolar septa.

They also reported only the long nanotubes also produced an

infl ammatory response and pulmonary lesions along the chest

wall and diaphragm at 6 weeks post-exposure, but not 1 week.

Summary of pulmonary and pleural responses in animals

The most common theme from the epidemiologic literature,

that is, that amphibole (especially crocidolite and tremolite)

and erionite fi bers are most often more closely associated

with mesothelioma and pleural plaques than are chrysotile

fi bers, could not be tested adequately in rat inhalation studies

because rats developed very few mesotheliomas over their ∼ 2

years lifespans. However, it is possible that the mesothelioma

yield may have been infl uenced by the high mass concentra-

tions used in most of the chronic inhalation studies in rats,

which may have introduced lung overload. In any case, when

rats were exposed to crocidolite or erionite, the crocidolite

produced 1 lung cancer in 28 rats (but no mesotheliomas),

whereas the erionite produced no lung cancers in 28 rats but

did produce 27 mesotheliomas.

In terms of the second theme, that chrysotile fi bers are more

often more closely associated with lung cancer and asbestosis

than are amphibole fi bers, the best evidence comes from the

long series of studies by Davis and colleagues who exposed

rats to equal number concentrations of fi bers � 5 μ m in length

of chrysotile, crocidilite, and amosite, all with median diam-

eters of ∼ 0.4 μ m. The concentration ratios of � 20 to � 5 μ m

were 0.185, 0.040, and 0.011, respectively. There were greater

fi brogenic and carcinogenic responses in the chrysotile expo-

sures than in the crocidolite or amosite exposures. When they

subsequently used amosite with fi ber lengths both shorter and

longer than UICC amosite, the short amosite produced virtu-

ally no fi brosis, whereas the long amosite was more fi brogenic

than chrysotile. For a comparable study with short, UICC, and

long chrysotile, the highest lung tumor yield was for the long-

fi ber chrysotile (Davis and Jones 1988). When Berman et al.

(1995) analyzed the lung tumor and mesothelioma responses

from 13 of the studies by Davis and colleagues in relation to

new TEM measurements of the fi ber distributions on archived

chamber fi lters, the measure most highly correlated with tumor

incidence was the concentration of fi bers � 20 μ m in length.

In my own review of the chronic rat inhalation studies with

amosite, brucite, chrysotile, crocidolite, erionite, and tremolite

(Lippmann 1994), I found that, for lung cancer, the percentage

of lung tumors correlated best with fi bers � 20 μ m in length

and seemed to be independent of fi ber type.

Similar conclusions, concerning the infl uence of fi ber

length, were drawn by Miller et al. (1999b) for 18 rat inhala-

tion studies involving fi bers of amosite, silicon carbide (SiC)

whiskers, various SVFs, and various RCFs. In their analysis,

the primary infl uence on biological responses was the number

of fi bers � 1.0 μ m in diameter and � 20 μ m in length, along

with the dissolution rate of the fi bers. Another important

observation was that in vivo and in vitro cell responses did not

signifi cantly predict the risk of cancer following inhalation.

Likewise, when McConnell et al. (1999) exposed hamsters for

78 weeks to amosite and two diff erent fi brous glasses. One of

the glasses produced only mild infl ammation, while the other

one produced more severe infl ammation and mild interstitial

and pleural fi brosis, as well as one mesothelioma. Amosite

produced severe pulmonary fi brosis and many mesotheliomas.

The eff ects were most closely related to the retained fi bers � 20

μ m in length, and were consistent with the in vitro dissolution

rates. Cullen et al. (2000) also compared the pathogenicity of

amosite with that of glass microfi bers having low dissolution

rates (104E and 100/475) in a study in rats. In terms of meso-

thelioma and lung cancers produced, a biopersistent glass and

amosite fi bers were considerably more potent than the more

soluble glass fi bers.

For asbestos fi bers and SVFs instilled IT in guinea pigs,

Wright and Kuschner (1977) found that fi bers longer than

∼ 10 μ m were needed to produce lung fi brosis. Variation in

yields was attributed to their varying in vivo durability. For

Libby amphibole (LA), asbestos instilled into WKY, SH, and

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SHHF rats, Shannahan et al. (2012) reported that all of the rats

developed concentration- and time-dependent interstitial fi bro-

sis. For mice, injected IT with 120-nm-thick silver nanowires

with mean lengths of 3, 5, 10, 14, and 28 μ m, Schinwald et al.

(2012b) reported a length-dependent response in the lung,

with a threshold length of 14 μ m. For impaired motility, there

was a length threshold at 5 μ m. For mice exposed IT to CNTs

in 3 length ranges, 1 – 2, 1 – 5, and 84% longer than 15 μ m, Mur-

phy et al. (2013) reported that the long nanotubes, but not the

two shorter samples, produced an infl ammatory response at

1 week post-exposure in the BALF, as well as a progressive

thickening of the alveolar septa. They also reported that only

the long nanotubes also produced an infl ammatory response

and pulmonary lesions along the chest wall and diaphragm at

6 weeks post-exposure, but not at 1 week.

Miller et al. (1999a) reviewed the collective outcomes of 9

rat IP injection studies involving fi bers of amosite, SiC, four

SVFs, and three RCFs on mesothelioma, and reported links

between the numbers of injected fi bers � 20 m m in length, and

the biopersistence in the rat lung of fi bers � 5 μ m in length.

Schinwald et al. (2012a) injected mice IP with 120-nm-thick

silver nanowires with mean lengths of 3, 5, 10, 14, and 28

μ m, along with short and long nickel nanowires (4 and 20 μ m

long), CNTs (13 and 36 μ m long), and two amosite asbestos

dusts (long fi bers with 100% longer than 5 μ m, 50% � 15 μ m,

and 35% � 20 μ m, and short with 3% � 5 μ m). They reported

an acute pleural response with a threshold fi ber length of 4

μ m. They suggested that fi bers that are 5 μ m or longer that are

translocated to the pleural space, both free and in macrophages,

are retained because they cannot negotiate the stomata in the

parietal stomata, where they can elicit infl ammation.

Exposures to airborne inorganic fi bers

Exposure indices

There has never been a fully satisfactory method for measur-

ing airborne fi ber exposures relevant to health eff ects, and

much confusion has arisen because the various methods used

do not produce indices that can readily be inter-converted.

Three diff erent types of concentration indices have been used.

Initially, the most widely used index in the United States was

the number of particles per unit volume of air, expressed in

MPPCF and determined from dust samples collected in liq-

uid impinger fl asks that were analyzed by the (now obsolete)

US Public Health Service standard optical microscopic dust-

counting technique. It used a 10X objective lens and counted

the number of particles that settled to the bottom of a dust-

counting cell that was initially fi lled with a liquid suspension

of particles from the impinger fl ask. Since measurements

of total particle counts provided no discrimination between

fi brous and non-fi brous particles, and for the fi bers in the mix-

ture that were counted, no information on the type of fi ber or

their dimensional distributions, the relationships between dust

counts and the health risks were tenuous at best. Dust counts

were useful primarily for evaluating changes in exposure at a

given facility.

Since fi bers were known to be a very variable fraction of the

total dust in most cases, and it was already clear that long fi bers

were of most concern, dust counting for occupational asbestos

exposure evaluations was replaced, beginning in the 1960s in

the UK, by a technique that collected both the fi bers and the

other dusts on membrane fi lters, and counted only those fi bers

that were longer than 5 μ m (Walton 1982, Ogden 2003). In

any case, fi bers shorter than ∼ 5 μ m could not be reliably iden-

tifi ed by light microscopy, and the best resolution of the fi bers

could be obtained, using phase-contrast optics. These consid-

erations led to the adoption of a counting procedure that uses

a 45X phase-contrast objective lens for counting of the fi bers

that could be seen (i.e., those � 0.25 μ m in diameter) collected

on a membrane fi lter, provided that they have a length � 5

μ m and an aspect ratio � 3 (ACGIH-AIHA Aerosol Hazards

Evaluation Committee 1975). While the fi bers � 0.25 μ m in

diameter cannot be resolved, this PCOM is still specifi ed in the

US Occupational Safety and Health Administration (OSHA)

occupational health standard for asbestos. Table 2 summarizes

recommended occupational exposure limits and standards used

in the US. Detailed guidance on the use of the PCOM method

has been provided by the National Institute for Occupational

Safety and Health (NIOSH 1979), the International Standards

Organization (ISO 1993), and the World Health Organization

(WHO 1997). While the PCOM method permitted a distinction

between long fi bers � 0.25 μ m in diameter and more compact

particles, it did not permit discrimination between asbestos

fi bers and SVFs, or between chrysotile and amphibole fi bers.

Where such discrimination is needed, samples of the dust col-

lected on the membrane fi lter are transferred to electron micro-

scope grids, where the fi bers with diameters of all sizes can

be reliably identifi ed as individual fi bers by fi ber type, length,

and diameter using analytical TEM. Walton (1982), Chisholm

(1983), and Langer et al. (1990) have reviewed the chemistry,

structure, and properties of asbestos.

The third type of concentration index is based on the mass

concentration of asbestos or on the mass concentration pass-

ing a pre-collector meeting the British Medical Research

Council (BMRC) or ACGIH sampler acceptance criteria for

“ respirable ” dust. Some of the recent animal inhalation studies

report the chamber concentrations in terms of the “ respirable ”

mass based on samples collected using samplers that meet the

BMRC criteria (Vincent 1999).

Environmental exposures have been measured in terms of

either fi ber count or fi ber mass. Fiber counts have been made

using both PCOM and TEM. The reported concentrations

have diff ered according to the size distributions of the fi bers,

Table 2. Recommended air concentration limits and standards for

asbestos.

Group Year Limit

ACGIH 1946 5 � 10 6 particles/ft 3 ACGIH 1968 a 12 fi bers/mL or 2 � 10 6 particles/ft 3 ACGIH 1970 a , 1974 b 5 fi bers/mLOSHA 1972 c 5 fi bers/mLNIOSH 1976 0.1 fi ber/mLACGIH 1978 a , 1980 b 0.2 fi ber/mL for crocidolite

0.5 fi ber/mL for amosite2.0 fi ber/mL for chrysotile and other forms

ACGIH

OSHA

1997 a

1976 c

0.1 fi ber/mL for all forms

2.0 fi ber/mLOSHA 1986 c 0.2 fi ber/mLOSHA 1992 c 0.1 fi ber/mL

a Notice of intent.

b Adopted as threshold limit value (TLV).

c Adopted as a permissible exposure limit (PEL).

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the resolving power of the microscope, and whether there was

any discrimination in the analyses according to fi ber type.

A fi ber-mass index was developed by Selikoff et al. (1972)

in a method in which the fi bers and fi ber bundles in the sample

are fi rst mechanically reduced to individual fi bers and fi brils,

which are then identifi ed and measured by TEM. Mass con-

centrations of all fi bers and fi brils, irrespective of their sizes,

in terms of ng/m 3 , are calculated from the numbers of fi bers

and fi brils and their dimensions. This index bears little relation

to health risks since it includes the mass from fi bers below 5

μ m in length that pose little, if any, risk and usually dominate

the mass concentration, and it provides no information on the

lengths of the airborne fi bers.

The use of these various exposure indices has sometimes

led to the development of site- or industry-specifi c exposure –

response relationships for one or more of the asbestos-related

diseases, but there are no generic relationships to demonstrate

their adequacy as indices of exposure or health risk. A report of

the Health Eff ects Institute-Asbestos Research (HEI-AR 1991)

established that: 1) short asbestos fi bers (i.e., those shorter than

5 m m in length) pose little, if any, health risk; and 2) that the

standard analyses, that count all asbestos fi bers, or the mass

they represent, are inadequate to defi ne the concentrations of

the longer fi bers that do pose cancer risks. Support for the need,

for such a fi ber-length cut-off , was provided by an Expert Panel

assembled by the Agency for Toxic Substances and Disease

Registry (ATSDR; ERG 2003a). The Report on the Expert

Panel on Health Eff ects of Asbestos and SVFs: The Infl uence

of Fiber Length ” stated that: “ Many of the short fi bers that

reach the gas exchange region of the lung are cleared by alveo-

lar macrophages (AMs), and the rate of clearance by phago-

cytosis has been found to vary with fi ber length........there is a

strong weight of evidence that asbestos and SVFs shorter than

5 μ m are unlikely to cause cancer in humans. ” Similarly, in

a Peer Consultation report prepared for the US EPA, it was

stated that there was agreement among the panelists convened

that the available data suggest that the risk of fi bers less than 5

μ m in length is very low (ERG 2003b). Independent analyses

of published data from chronic rat inhalation studies having

fi ber length, diameter, and compositional data and biological

outcomes have provided key evidence that the health risks are

due to long fi bers, especially those longer than 10 μ m (Lipp-

mann 1988, Berman et al. 1995; Berman and Crump 2001).

The more recent report by the EPA ’ s Science Advisory Board

(SAB) panel on the risks of exposure to amphibole asbestos in

Libby, MT (EPA-SAB 2013), concurred in these judgments.

Exposure levels

Esmen and Erdal (1990) reviewed historical published PCOM-

based data on human occupational and non-occupational expo-

sure to fi bers. They concluded that for the traditionally defi ned

asbestos fi bers, that is, fi bers � 5 μ m long, large amounts of

the available data suff er from the diversity of sample collec-

tion and analysis methods. Simple generalizations suggest that

occupational exposures are generally several orders of mag-

nitude higher than environmental exposures; currently extant

data and the current routine measurement practices present

signifi cant diffi culties in the consistent interpretation of the

data with respect to health eff ects.

For workers exposed to SVFs in the 17 US plants pro-

ducing and using ordinary fi brous glass insulation products

that were studied for health eff ects by Enterline et al. (1983,

1987), Esmen (1984) reported that 35% of the airborne fi bers

were � 5 μ m in length and that only 3.9% were less than

1.0 μ m in diameter. The average exposure concentrations, as

determined by PCOM, were between 0.01 and 0.05 f/mL in

13 plants handling ordinary glass fi bers. For a slag wool plant,

the average was ∼ 0.07 f/mL, while for a rock wool plant and a

glass microfi ber plant, the averages were ∼ 0.25 f/mL.

On the basis of measurements of airborne fi ber concentra-

tions made in the period 1977 – 1980 in European SVF plants,

Cherrie et al. (1986) reported that the average combined

occupational group concentrations in the rock and glass wool

plants were generally low ( � 0.1 f/mL). In the glass continu-

ous-fi lament factories, the airborne fi ber concentrations were

very low ( � 0.01 f/mL). The average plant median for fi ber

length ranged from 10 to 20 μ m, and the corresponding median

diameters ranged from 0.7 to 2 μ m. In general the glass wool

fi bers were thinner than the rock wool fi bers. Higher levels

(between 0.1 and 1.0 f/mL) were found in some insulation

wool production, secondary production, and user industries.

The highest levels ( � 1.0 f/mL) occurred in very fi ne glass-

fi ber production and in other specialty insulation wool usage.

There are relatively few published data on the concentra-

tions of airborne asbestos fi bers in public buildings. The HEI-

AR-sponsored Literature Review Panel compiled the available

data, both published and such unpublished data as it could

assemble (HEI-AR 1991). In their report, the HEI-AR Panel

concluded that:

A large number of buildings in the US and other countries

had been examined for airborne asbestos fi bers within the

previous 20 years, yielding many thousands of air measure-

ments (most unpublished). However, few building environ-

ments had been characterized in suffi cient detail or sampled

with suffi cient analytical sensitivity to adequately describe the

exposures of building occupants. Specifi c details are especially

lacking for episodic and point-source releases of fi bers into

the air of buildings from maintenance and engineering activi-

ties, from repair and renovation operations, and from normal

custodial functions.

Such data as were available to the HEI-AR panel on the

airborne concentrations of asbestos fi bers of the dimensions

most relevant to human health (i.e., fi bers � 5 μ m long), as

measured by TEM, generally showed average concentrations

on the order of 0.00001 f/mL for outdoor rural air (except

near asbestos-containing rock outcroppings) and average

concentrations up to about 10-fold higher in the outdoor

air of urban environments. However, outdoor urban average

concentrations above 0.0001 f/mL had been reported in cer-

tain circumstances as a result of local sources: for example,

downwind from, or close to, frequent vehicle braking or

activities involving the demolition or spray application of

asbestos products. Data on ambient indoor levels of asbestos

from direct TEM measurements were averaged for each of

a number of individual buildings. The following data were

based on 1,377 air samples obtained in 197 diff erent build-

ings not involved in litigation. The overall means of the

studies on these buildings ranged from 0.00004 to 0.00063

f/mL, with upper 90th percentiles ranging from 0.00002

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Figure 1. Particle deposition mechanisms in human tracheobronchial airways during inspiratory fl ow.

to 0.0008 f/mL. Grouped by building category, the mean

concentrations were 0.00051, 0.00019, and 0.00021 f/mL in

schools, residences, and public and commercial buildings,

respectively, with upper 90th percentiles of 0.0016, 0.0005,

and 0.0004 f/mL, respectively.

Hesterberg et al. (2012) summarized the mean values of

comparable fi ber counts outdoors, indoors, in manufacturing,

fi ber installation, and removal.

Fiber deposition mechanisms in the respiratory tract

There are fi ve mechanisms that are important with respect to

the deposition of fi bers in respiratory tract airways. These are

impaction, sedimentation, interception, electrostatic precipita-

tion, and diff usion (See Figure 1).

Impaction and sedimentation

Deposition probabilities are governed by the aerodynamic

diameter of the fi bers, which, for long mineral fi bers, are close

to thrice their physical diameters (St ö ber et al. 1970, Timbrell

1972). Most inertial deposition (impaction) occurs downstream

of air jets in the larger airways, where the fl ow velocities are

high and the momentum of a fi ber propels it out of the bend-

ing fl ow streamlines and onto relatively small portions of the

epithelial surfaces (Balashazy et al. 2005, and Su and Cheng

2006). Sedimentation, on the other hand, is favored by low

fl ow velocity, long residence times, and small airway size.

Electrostatic precipitation

Deposition occurs primarily by image forces, in which charged

particles induce opposite changes on airway surfaces. It is

dependent on the ratio of electrical charge to aerodynamic

drag. Little is known about the charge levels on SVFs in the

workplace. Jones et al. (1983) have shown that asbestos –

fi ber processing operations do generate fi brous aerosols with

relatively high charge levels, and that these charge levels are

suffi cient to cause an enhancement of fi ber deposition in the

lungs. Such an enhancement of fi ber deposition for chryso-

tile asbestos was seen in rats that were exposed by inhalation

(Davis 1976).

Interception

Deposition increases with fi ber length becoming a signifi cant

fraction of the airway diameter. The greater the length, the

more likely it is that the position of a fi ber end will cause it

to touch a surface that the center of mass would have missed.

When an end of the fi ber contacts the airway surface, the aero-

dynamic drag brings the whole fi ber to the surface where it is

captured.

Diff usional displacement

Deposition results from collisions between air molecules and

airborne fi bers. For compact particles, diff usion becomes an

important deposition mechanism for particle diameters smaller

than about 0.5 μ m. Fibers of similar diameter would be more

massive and therefore be displaced less by a single molecular

impact. Long fi bers may have nearly simultaneous impacts

from several gas molecules, and their random trajectories may

tend to damp the net displacement. On the other hand, a single

collision near a fi ber end may rotate the fi ber suffi ciently to

alter its interception probability. The role of diff usion in fi ber

deposition is poorly understood. Gentry et al. (1983) measured

the diff usion coeffi cients of chrysotile and crocidolite asbestos

fi bers and found good agreement with theoretical predictions

for chrysotile (0.4 μ m of mean diameter) but poor agreement

with the more rod-like crocidolite (0.3 μ m of mean diameter).

Deposition sites and patterns

The conductive airway region of the human lung consists of

a series of bifurcating airways. The trachea is the only airway

segment with a length-to-diameter ratio much greater than

three. Single symmetrical fi bers suspended in a laminar fl ow

stream tend to become aligned with the fl ow axis as they move

through a lung airway. On the other hand, fi ber agglomerates

or non-fi brous particles would have more random orientations

that would depend on their distributions of masses and drag

forces. A fi ber whose fl ow orientation diff ers from axial align-

ment would have an enhanced probability of deposition by

interception.

A fi ber ’ s alignment is radically altered as it enters a daugh-

ter airway, and this loss of alignment with the fl ow at the entry

contributes to its deposition by interception at or near the

carinal edge. To the extent that a fi ber is entrained in the sec-

ondary fl ow streams that form at bifurcations, its deposition

probability by interception is further enhanced.

Sussman et al. (1991a) performed an experimental study

of fi ber deposition within the larger tracheobronchial air-

ways of the human lung using replicate hollow airway casts.

For crocidolite fi bers with diameters primarily in the 0.5- to

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0.8- μ m range, interception increased the total deposition, with

the eff ect increasing with fi ber length, especially for fi bers of

� 10 μ m in length. The eff ect was more pronounced at 60 L/

min than at 15 L/min. This is consistent with greater axial

alignment of the fi bers during laminar fl ow within the airway.

Morgan and Holmes (1984) and Morgan et al. (1980)

exposed rats for several hours by inhalation (nose only) to

glass fi bers 1.5 μ m in diameter and 5, 10, 30, or 60 μ m long.

For fi bers longer than 10 μ m, essentially all were deposited,

mostly in the head. These results, together with the results of

their earlier studies on asbestos fi bers, indicate that penetra-

bility of airborne fi bers into the rat lung drops sharply with

aerodynamic diameter above 2 μ m. The results reported by

Morgan and Holmes provided experimental verifi cation that

increasing fi ber length increases lung deposition within the

tracheobronchial airways.

Sussman et al. (1991b) found that the deposition patterns

of fi bers in the larger lung airways are similar to those for

particles of more compact shapes. In other words, the added

deposition due to interception increased the deposition

effi ciencies without changing the pattern of deposition.

Most of the studies on particle deposition patterns and

effi ciencies in hollow bronchial airway casts of the larynx

and the larger conductive airways of the human bronchial

tree have been focused on deposition during constant fl ow

inspirations. For studies of deposition during cyclic inspira-

tory fl ows, Gurman et al. (1984a, b) used a variable-orifi ce

mechanical larynx model (Gurman et al. 1980) at the inlet

in place of the fi xed-orifi ce laryngeal models used in the

prior constant-fl ow tests. In one series of tests, two repli-

cate casts were connected in tandem. The corresponding

terminal endings were connected with rubber tubing. Depo-

sition in the downstream cast was analyzed to determine the

deposition pattern and effi ciencies during expiratory fl ow

(Schlesinger et al. 1983).

Concern about sites of enhanced surface deposition

density is stimulated by the observation that the larger bron-

chial airway bifurcations, which are favored sites for deposi-

tion, are also the sites most frequently reported as primary

sites for bronchial cancer (Schlesinger and Lippmann 1978).

Deposition patterns within the non-ciliated airways distal

to the terminal bronchioles may also be quite non-uniform.

Brody et al. (1981) studied the deposition of chrysotile

asbestos in lung peripheral airways of rats exposed for 1 h to

4.3 mg/m 3 of respirable chrysotile. The animals were studied

at 0, 5, and 24 h and at 4 and 8 days after the end of the expo-

sure. The pattern of retention on the epithelial surfaces was

examined using SEM of lung sections cut to reveal terminal

bronchiolar surfaces and adjacent airspaces. The rat does not

have recognizable respiratory bronchioles, and the airways

distal to the terminal bronchioles are the alveolar ducts. In rats

studied immediately after exposure, asbestos fi bers were rarely

seen in alveolar spaces or on alveolar duct surfaces except at

alveolar duct bifurcations. There were relatively high concen-

trations on bifurcations nearest the terminal bronchioles and

lesser concentrations on more distal duct bifurcations. In rats

studied at 5 h, the patterns were similar, but the concentrations

were reduced. Subsequent studies have shown that crocidolite

asbestos (Roggli et al. 1987), Kevlar aramid synthetic fi bers

(Lee et al. 1983, Donaldson 2009), and particles of more

compact shape (Brody and Roe 1983) deposit in similar pat-

terns, and that the deposition patterns seen in the rat also occur

in mice, hamsters, and guinea pigs (Warheit and Hartsky

1990).

The sudden enlargement in air path cross-section at the

junction of the terminal bronchiole and alveolar duct may play

a role in the relatively high deposition effi ciency at the fi rst

alveolar duct bifurcation. Little has previously been known

about the fl ow profi les in this region of the lung. However,

Briant (1988) has shown that a net axial core fl ow in a distal

direction and a corresponding net annular fl ow in a proximal

direction take place during steady-state cyclic fl ow in tracheo-

bronchial airways and that this could account for such concen-

trated deposition on the bifurcations of distal lung airways.

Fiber retention, translocation, disintegration, and dissolution

The fate of fi bers deposited on surfaces within the lungs

depends on both the sites of deposition and the characteristics

of the fi bers. Within the fi rst day, most fi bers deposited on the

tracheobronchial airways are carried proximally on the sur-

face of the mucus to the larynx, to be swallowed and passed

into the gastrointestinal tract. The residence time for fi bers on

the surface of the tracheobronchial region is too short for any

signifi cant change in the size or composition of the fi bers to

take place.

Retention

In the inhalation study of Brody et al. (1981) with chryso-

tile, their examination of tissues by TEM revealed that fi bers

deposited on the bifurcations of the alveolar ducts were taken

up, at least partially, by type I epithelial cells during the 1-h

inhalation exposure. In the 5-h period after exposure, signifi -

cant amounts were cleared from the surfaces, and there was

further uptake by both type I cells and AMs. Within 24 h after

the exposure, there was an infl ux of macrophages to the alveo-

lar duct bifurcations. The observations provide a basis for fi ber

penetration of the surface epithelium that does not hypothesize

movement within macrophages.

Accumulation of fi bers in distal lung airways may, by itself,

slow the clearance of fi bers and other particles from the lung.

Ferin and Leach (1976) exposed rats by inhalation to 10, 5, or

1 mg/m 3 of UICC amosite or Canadian chrysotile for periods

ranging from 1 h to 22 days. Exposures at 10 mg/m 3 for 1 – 3 h

or for � 11 days at 1 mg/m 3 suppressed the pulmonary clearance

of TiO 2 particles. Bellmann et al. (2001) demonstrated that dur-

ing chronic exposure to a refractory ceramic aerosol containing

both fi bers and shot (more compact particles), the clearance of

the fi bers was retarded by the presence of the shot.

The most direct evidence for the eff ect of altered dust

clearance rates on the retention of inhaled fi bers in humans

comes from studies of the fi ber content of the lungs of asbes-

tos workers in various countries. Timbrell (1982) developed

a model for fi ber deposition and clearance in human lungs

based on his analysis of the bivariate diameter and length

distributions found in air and lung samples collected at an

anthophyllite mine at Paakkila in Finland. The length and

diameter distributions of the airborne dust at this particular

mine were exceptionally broad, and historic exposures were

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Figure 2. Eff ect of lung fi brosis on fi ber retention in human lungs as a

function of fi ber length. The fi brosis scores are: A: Minimal; B: Slight; C:

Moderate; D: Marked; and E: Severe. Source: Lippmann (1988).

very high. For workers with the highest exposure and most

severe lung fi brosis (Ashcroft et al. 1988), the fi ber distribu-

tions in some tissue segments approached those of the air-

borne fi bers. Adjacent tissue, analyzed for extent of fi brosis,

showed severe fi brotic lesions. He concluded that long-term

retention was essentially equal to deposition in such segments.

Figure 2 shows a series of retention curves for diff erent degrees

of lung fi brosis. These curves were determined by comparing

the anthophyllite fi ber size distributions in other tissue sam-

ples from the same lung with the distribution in the sample

for which all fi bers deposited were retained. Lung fi brosis was

associated with increased fi ber retention, and fi ber retention

was clearly associated with fi ber length and diameter. The

critical fi ber length for mechanical clearance from the lungs

with minimal fi brosis was ∼ 17 μ m.

Bernstein et al. (2005b, 2010, 2011) studied retention of

“ pure ” chrysotile, amosite and tremolite fi bers in the lungs of

rats in relation to fi ber length. While chrysotile fi bers of all

lengths cleared rapidly from the lungs, there was prolonged

retention of amosite and tremolite fi bers longer than 20 μ m at

the end of the study (365 days post-exposure).

Fibers deposited in the non-ciliated airspaces beyond

the terminal bronchioles are more slowly cleared from their

deposition sites by a variety of mechanisms and pathways.

These can be classifi ed into two broad categories, that is,

translocation and disintegration. These fi ber pathways and

their consequences are illustrated in Figure 3.

Translocation

Translocation refers to the movement of the intact fi ber: 1)

along the epithelial surface to dust aggregations at the respira-

tory bronchioles; 2) onto the ciliated epithelium at the terminal

bronchioles; or 3) into and through the epithelium, with sub-

sequent migration to interstitial storage sites within the lung,

along lymphatic drainage pathways, and for very thin short

fi bers, access via capillary blood to distant sites, as suggested

by Monchaux et al. (1981). Boutin et al. (1996) suggested that

thin fi bers longer than 5 or 10 μ m migrate toward the parietal

pleura via the lymphatic pathway, where they accumulate pref-

erentially in anthracotic “ black spots ” of the parietal pleura.

In a study by Dodson et al. (1990) comparing the fi ber

content of tissues from chronically exposed shipyard workers,

they reported that while 10% of amphibole fi bers in pleural

plaque samples were longer than 5 μ m and 8% were longer

than 10 μ m, the corresponding fi gures for chrysotile fi bers

were 3.1 and 0%. In lymph nodes, the corresponding fi gures

for � 10 μ m and � 5 μ m lengths were 6.0 and 2.5%, respec-

tively, for amphiboles and 0 and 0%, respectively, for chryso-

tile. In lung tissue, they were 41.0 and 20.0% for amphiboles

and 14.0 and 4.0% for chrysotile. Boutin et al. (1996) noted

that the black spots that concentrate longer fi bers were in close

contact with early pleural plaques. These studies indicate

that fi ber translocation is dependent on both fi ber diameter

and fi ber length, and that length is an important determinant

of biological responses. Translocation may also occur after

ingestion of the fi bers by AMs if the fi bers are short enough

to be fully ingested by the macrophages. Holt (1982) proposed

that fi bers phagocytosed by AMs are carried by them toward

the lung periphery by passing through alveolar walls and that

some of these cells aggregate in alveoli near larger bronchioles

and then penetrate the bronchiolar wall. Once in the bronchio-

lar lumen, they can be cleared by mucociliary transport.

Lentz et al. (2003) reviewed the literature on the dimen-

sions of fi bers that may translocate to the parietal pleura and

concluded that the critical dimensions were as follows: diam-

eter � 0.4 μ m and length � 10 μ m. They attributed the pleural

plaques that developed in refractory ceramic manufacturing

workers to these translocated fi bers.

Disintegration

Disintegration refers to a number of processes, including the

subdivision of the fi bers into shorter segments; partial disso-

lution of components of the matrix, creating a more porous

fi ber of relatively unchanged external size; or surface etching

of the fi bers, creating a change in the external dimensions of

the fi bers and/or complete dissolution.

For SVF, fi ber breakup is virtually all by length. The break-

down into smaller-diameter fi brils that is characteristic of

asbestos fi bers is seldom seen. For SVFs, the relative impor-

tance of breakage into length segments, partial dissolution,

and surface etching to the clearance of fi bers depends upon

the size and composition of the fi ber.

Clearance

Roggli and Brody (1984) exposed rats for 1 h to a chrysotile

aerosol, and showed that fi ber clearance was associated with

sequential dimensional changes in the retained fi bers, with a

tendency for long, thin fi bers to be retained within the intersti-

tium of the lung parenchyma. Roggli, et al. (1987) subsequently

performed essentially the same study with a crocidolite aerosol.

For the crocidolite, there was a progressive increase in mean fi ber

length with increasing time post-exposure, but the change was

less pronounced than that for chrysotile. In addition, there was no

change in fi ber diameter with time for the crocidolite. By contrast,

the longitudinal splitting of the chrysotile into fi brils had caused a

marked reduction of diameter with time.

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Figure 3. (A) Paradigm for the roles of fi ber deposition, clearance, translocation, retention, and biopersistence in pathological eff ects. Adapted, in part,

from Donaldson et al. (2006). (B) Hypothesized sequence of events leading to pleural responses as a consequence of long fi ber retention at the parietal

pleura stomatal openings. Reproduced, with permission, from Donaldson et al. (2010).

Jones et al. (1988) extended the inhalation studies to lower

concentrations; rats inhaled UICC amosite asbestos at ∼ 0.1

mg/m 3 (equivalent to 20 f/mL) for 7 h/day, 5 days/week,

for up to 18 months. The lung burdens were compared with

the previous results for concentrations of 1 and 10 mg/m 3 .

They showed lung burdens rising pro rata with exposure

concentration and exposure time, fi tting a kinetic model

that took into account sequestration of material at locations

where it cannot be cleared. Tran et al. (1997) showed that

the overloading of the lung by fi bers less than 15 μ m long,

as well as compact particles, follows the same kinetics. For

longer fi bers ( � 25 μ m), the disappearance was indepen-

dent of length and lung burden, implying that the clearance

of such fi bers occurs by dissolution and fragmentation into

shorter lengths.

Overload associated with high lung burden

Based upon 6-week inhalation studies of UICC amosite in rats,

Bolton et al. (1983) reported strong evidence for an overload

of clearance at high lung burdens of insoluble particles of low

toxicity (exceeding about 1500 μ g/rat), in which a breakdown

occurs of the intermediate-rate clearance mechanisms (time

constants of the order of 12 days). Their hypothesis is con-

sistent with the results of other inhalation studies in rats with

asbestos (Wagner and Skidmore 1965), quartz (Ferin 1972),

and diesel soot (Chan et al. 1984). Vincent et al. (1985) modi-

fi ed the above hypothesis on the basis of additional 1-year rat

inhalation studies. They found lung burden to scale to exposure

concentration in a way that seemed to contradict the overload

hypothesis stated earlier, possibly due to the toxicity elicited

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by the particles. However, the general pattern exhibited by the

results for asbestos is similar to that for rats inhaling diesel

fumes. They off ered a modifi ed hypothesis that, whereas over-

load of clearance can take place at high lung burdens after

exposure has ceased, it is cancelled by the sustained stimulus

to clearance mechanisms provided by the continuous chal-

lenge of chronic exposure. The linearity of the increase in lung

burden is explained in terms of a kinetic model involving

sequestration of some inhaled material to parts of the lung

where it is diffi cult to clear. The particular sequestration model

favored by Vincent et al. (1985) is one in which the longer a par-

ticle remains in the lung without being cleared, the more likely

it will be sequestrated (and therefore less likely be cleared).

Muhle et al. (1988) measured the in vivo clearance rates of

tracer particles during chronic exposures to biopersistent

dusts in rats and hamsters, and reported decreases in clearance

half-times for concentrations greater than 3 – 14 μ g/m 3 .

Oberd ö rster (2002) studied the slow clearance phases for both

compact and fi brous biopersistent particles. For the fi bers longer

than 20 μ m, which are associated with pulmonary fi brosis and

lung cancer, the clearance half-times ranged from 1,300 days

for amosite and crocidolite to 41 days for ceramic fi bers and 0 –

2 days for SVFs.

Fiber dissolution

A diff erential lung clearance between the curly chrysotile fi bers

and the more rod-like amphibole asbestos fi bers was shown for

rats that underwent chronic inhalation exposures (Wagner et al.

1974). The lung burdens of the amphibole fi bers rose continu-

ously throughout 2 years of exposure and declined slowly in

the rats removed from exposure after 6 months. By contrast,

the lung burdens of both Quebec and Zimbabwe chrysotile

fi bers rose much more slowly during exposure and seemed to

decline after 12 months, even with further exposure.

In a situation where the continuous exposure to asbestos

fi bers is very high, as occurred in historical human and animal

exposures, clearance of biosoluble fi bers from the lung can be

overwhelmed by the continuous high-level deposition of new

fi bers. In addition, the lung macrophages can become over-

loaded by the high deposition rate of fi bers, resulting in even

greater accumulation of fi bers in the lung. All fi bers can cause

infl ammation, which results in fi brosis and tumorigenesis if

the exposures are high enough. A high exposure level and rate

of deposition in the deep lung can overcome the impact of the

biosolubility and relatively rapid clearance of fi bers at these

high levels. Thus even relatively biosoluble mineral fi bers,

such as chrysotile, can produce lung disease if exposure levels

are high. Most of the early animal inhalation studies exposed

animals to 10 mg/m 3 of chrysotile, which results in around

10,000 WHO f/cc (Bernstein et al. 2013). If animals were

exposed to chrysotile at 100 – 200 f/cc, it is unlikely that lung

disease would have occurred in a chronic animal inhalation

study.

The biopersistence of chrysotile fi bers from other sources

was studied following inhalation exposures to aerosols with

large number concentrations of fi bers � 20 μ m in length. For

chrysotile from the Cana Brava mine in central Brazil, the

clearance half-time of the fi bers � 20, those of 5 – 20, and those

of � 5 μ m in length were 1.3, 2.4, and 23 days, respectively

(Bernstein et al. 2004). For chrysotile from the Coalinga mine

in California (Calidria RG144), the clearance half-time of the

fi bers � 20, those of 5 – 20, and those of � 5 μ m in length were

7 h, 7 d, and 64 d, respectively, while for tremolite asbestos,

there was no clearance from the rat lungs over the one-year

period of observation (Bernstein et al. 2005a). The tremolite

exposures produced lung infl ammation, granulomas, and

lung fi brosis, while the chrysotile, despite involving a much

higher long fi ber concentration, did not produce any measur-

able response. For chrysotile from the Eastern Townships of

Quebec, the clearance half-time for fi bers � 20 μ m in length

was 11.4 d, which was similar to that for glass and stone wools

previously studied (Bernstein et al. 2005b).

Diff erential retention was also found in humans. Churg

(1994) reported on analyses of lung tissue for 94 chrysotile

asbestos miners and millers from the Thetford region of

Quebec, Canada. Both the exposure atmosphere, and the

retained chrysotile, contained a very small percentage of

tremolite, yet the lungs contained more tremolite than chryso-

tile, and the tremolite content increased rapidly with the

duration of exposure increased. While most of the inhaled

chrysotile was rapidly cleared from the lungs, a small fraction

seemed to be retained indefi nitely. After exposure ended, there

was little or no clearance of either chrysotile or tremolite from

the lungs.

Albin et al. (1994) studied retention patterns in lung tissues

from 69 Swedish asbestos-cement workers and 96 controls.

Chrysotile had relatively rapid clearance, whereas amphiboles

(tremolite and crocidolite) had a slower clearance. They also

noted that 1) chrysotile retention may be dependent on dose

rate; 2) chrysotile and crocidolite retention may be increased

by smoking; and 3) that chrysotile and tremolite retention may

be increased by the presence of lung fi brosis.

In summary, the in vivo solubility of chrysotile fi bers,

both in humans and in rats, is much greater than those of the

various amphibole fi bers.

Chrysotile, the amphibole asbestos types, and erionite

fi bers are all crystalline minerals with defi ned structural ele-

ments that endow them with tensile strength, fl exibility, and

resistance to high temperatures. By contrast, vitreous fi bers

lack crystalline structures, can be broken down into shorter

segments by mechanical stresses, melt at lower temperatures

than the mineral miners, and most of them are more soluble in

cells and bodily fl uids and in simulants of such fl uids that are

used in in vitro assays. SVF exposures in the animal inhalation

studies conducted in the 1990s were in the range of 100 – 200

f/cc, which are orders of magnitude lower than chrysotile fi ber

exposure. Furthermore, the SVFs were much thicker, resulting

in lower deposition rates than those of chrysotile fi bers in the

deep lung.

Morgan et al. (1982) and Morgan and Holmes (1984) stud-

ied the retention of 1.5- μ m-diameter glass fi bers administered

IT to rat lungs. Retention at 1 year for 5- μ m-long fi bers was

10%, and 20% for 10- μ m-long fi bers, while for fi bers of 30

or 60 μ m length, there was no measurable clearance during

the fi rst 9 months. Thus, macrophage-mediated mechanical

clearance became less eff ective with increasing fi ber length.

For the glass fi bers, there was much less dissolution of the

5- and 10- μ m fi bers than of the 30- and 60- μ m fi bers. For 1.5-

μ m diameter fi bers, the dissolution of the long fi bers was very

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non-uniform. Some were little changed in dimension, whereas

others were reduced in diameter to 0.2 μ m. On the other hand,

for rockwool fi bers � 20 μ m in length, there was no observ-

able change in fi ber dimensions after 6 months. Morgan and

Holmes (1984) attributed the dependence of dissolution on

fi ber length to the diff erences in intra- and extra-cellular pH.

The shorter fi bers within macrophages were exposed to a

pH of 7.2, whereas those outside were exposed to the extra-

cellular pH of 7.4. Bernstein et al. (1984) and Hammad (1984)

also found evidence of substantial in vivo dissolution of glass

fi bers. LeBouff ant et al. (1984) used X-ray analysis on indi-

vidual fi bers recovered from lung tissue to show the exchange

of cations between the fi bers and the tissues. For example, the

fi bers can lose calcium and gain potassium.

Insight into the solubility of fi bers in vivo was also obtained

from in vitro solubility tests. Griffi s et al. (1981) found that

glass fi bers suspended either in buff ered saline or in serum

simulant at 37 ° C for 60 days exhibited some solubility and

that the sodium content of the residual fi ber was reduced. For-

ster (1984) used Gamble ’ s solution for tests on samples of 18

diff erent SVFs at temperatures of 20 ° C and 37 ° C and for

exposure times ranging from 1 h to 180 days using static tests,

tests with once-daily shaking, tests with continuous shaking,

and tests with single fi bers in an open bath. All of the fi bers

exhibited at least some solubility. Klingholz and Steinkopf

(1982, 1984) studied dissolution of mineral wool, glass wool,

rock wool, and basalt wool at 37 ° C in water and in a Gamble ’ s

solution modifi ed by omission of the organic constituents.

Most of the tests used a continuous-fl ow system in which the

pH was 7.5 – 8. There was relatively little dissolution in dis-

tilled water in comparison with that produced by the modifi ed

Gamble ’ s solution. The surfaces of the fi bers developed a gel

layer that, for the smaller diameters, extended throughout the

fi ber cross-section. Thus, the fi bers can become both smaller

in outline and more plastic to deformation.

Scholze and Conradt (1987) performed a comparative in vitro

study of the chemical durability of SVFs in a simulated extra-

cellular fl uid under fl ow conditions for 7 vitreous, 3 refractory,

and 3 natural fi bers. The leachates were analyzed, and the silicon

(Si) concentrations used to roughly classify the fi bers according

to glass network dissolution. A durability ranking of fi ber mate-

rials was expressed in terms of a characteristic time required for

the complete dissolution of single fi bers of given diameter. SVFs

exhibited relatively poor durability (with network dissolution

velocities ranging from 3.5 to 0.2 nm per day for a glass wool

and an E glass fi ber, respectively), whereas natural fi bers were

very persistent against the attack of the biological fl uid (e.g.,

� 0.01 nm per day for crocidolite).

Johnson et al. (1984) exposed rats to SVF aerosols at

10 mg/m 3 for 7 h/day, 5 days/week for 1 year (as compared to

the single exposure of several hours duration used by Morgan

and Holmes). The percentage of glass fi bers with diameters

less than 0.3 μ m that were recovered from the lungs was con-

sistently less than that in the original fi ber suspension, and the

reduction was more marked in the rats sacrifi ced following a

period of recovery than from those killed at the end of the

exposure. The degree of fi ber etching increased with residence

times in the lungs. Glass wool with and without resin was also

etched, but to a lesser extent, and the etching of the rock wool

fi bers was considerably less.

Collier et al. (1994) studied the behavior of two experi-

mental continuous fi lament glass fi bers of 2 μ m diameter and

50 μ m length following IP injections of 5 mg in rats. They had

in vitro dissolution rates of 150 and 600 ng/cm 2 /hr. In the lung,

the diameters of the long fi bers ( � 20 μ m) declined at a rate

consistent with their exposure to a neutral pH environment.

The diameters of shorter fi bers declined much more slowly,

consistent with exposure to the more acidic environment

found in the phagolysosomes of AMs. In the peritoneal cavity,

all fi bers, regardless of length, dissolved at the same rate as

short fi bers in the lung. The eff ect of dose on the distribu-

tion of fi bers in the peritoneal cavity was investigated using

experimental glass fi bers and a powder made from ground

fi bers. At doses up to 1.5 mg, both fi bers and powder were

taken up by the peritoneal organs in proportion to their surface

area, and uptake was complete 1 – 2 days after IP injection.

At higher doses, the majority of the material in excess of

1.5 mg formed clumps of fi bers (nodules) that were either

free in the peritoneal cavity or loosely bound to peritoneal

organs. These nodules displayed classic foreign body reactions,

with an associated granulomatous infl ammatory response.

Collier et al. (1997) reported on the clearance of two

stone-wool fi bers administered to rats by IT instillation:

one a conventional product (MMVF21) and the other an

experimental, more soluble fi ber (HTN). Unlike glass wool,

stone wool is more soluble at the acid pH in macrophages

than in the more neutral lung tissue. They found that

MMVF21 had relatively slow clearance, with somewhat

faster clearance for short fi bers. The clearance of HTN was

much faster.

Eastes and Hadley (1995) administered suspensions of fi bers

to rats by IT instillation, and the numbers, lengths, and diam-

eters of fi bers recovered from the lungs were measured by

PCOM at intervals up to 1 yr. Five diff erent glass fi bers had

dissolution rates ranging from 2 to 600 ng/cm 2 /h measured

in vitro in simulated lung fl uid at pH 7.4. For fi bers longer

than 20 μ m, the peak diameter decreased steadily with time

after instillation, at the same rate measured for each fi ber in vitro , until it approached zero. Measurements of the total

number of fi bers remaining in the rats ’ lungs at times up to

1 year after IT instillation suggest that few of the admin-

istered fi bers were being cleared by macrophage-mediated

transport via the conducting airways. They concluded that

glass fi bers longer than 20 μ m are removed from the lung

by dissolution at the same rate measured in vitro .

In an in vivo inhalation study using 9 fi ber types, Bernstein

et al. (1996) exposed rats to an aerosol (mean diameter of

∼ 1 μ m) at a concentration of 30 mg/m 3 , 6 h/day for 5 days,

with post-exposure sacrifi ces at 1 h, 1 day, 5 days, 4 weeks,

13 weeks, and 26 weeks. At 1 h following the last expo-

sure, the 9 types of fi bers were found to have lung burdens

ranging from 7.4 to 33 � 10 6 fi bers/lung with geometric

mean diameters of 0.40 – 0.54 μ m, refl ecting the diff erent

bivariate (both fi ber diameter and length) size distributions

in the exposure aerosols. The fi bers cleared from the lungs

following exposure, with weighted half-lives ranging from

11 to 54 days. The clearance was found to closely refl ect

the clearance of fi bers in the 5- to 20- μ m length range. An

important diff erence in removal was seen between the long

fi ber (L � 20 μ m) and shorter fi ber (L between 5 and 20

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μ m and L � 5 μ m) fractions, depending upon composition.

For all glass wools and the stone wools, the longer fi bers

were removed faster than the shorter fi bers. It was found

that the time for complete fi ber dissolution based on the

acellular in vitro dissolution rate at pH 7.4 was highly cor-

related ( r � 0.97, p � 0.01) with the clearance half-times of

fi bers � 20 μ m in length. No such correlations were found

with any of the length fractions using the acellular in vitro

dissolution rate at pH 4.5. Examination of the fi ber length

distribution and particles in the lung from 1 h through 5

days of exposure indicated that, especially for those fi bers

that form leached layers, fi ber breakage may have occurred

during this early period. These results demonstrate that, for

fi bers with high acellular solubility at pH 7.4, the clearance

of long fi bers is very rapid.

Comparisons of dissolution rates of SVF and asbestos fi bers

Bellmann et al. (1986), using IT instillation of reference sus-

pensions of UICC crocidolite and chrysotile A, as well as of

suspensions of glass fi bers in rat lungs, examined the residual

fi bers after 1 day and 1, 6, 12, and 15 months. Crocidolite

fi bers longer than 5 μ m did not decrease in number for over 1

year. The number of chrysotile fi bers � 5 μ m doubled, prob-

ably as a result of longitudinal fi ber bundle splitting, while

the number of glass fi bers � 5 μ m was reduced by dissolution,

with a half-time of 55 days. All fi bers � 5 μ m in length were

cleared with half-times of 100 – 150 days. When the crocidolite

fi bers were pretreated in acid, there was no change in reten-

tion. On the other hand, acid-treated chrysotile and glass fi bers

had much more rapid clearance, with half-times of 2 and 14

days, respectively.

In a 2-year follow-up study, Bellmann et al. (1987) reported

the persistence of some SVFs, crocidolite, and chrysotile in

the rat lung after IT instillation. Experiments were based on

the assumption that thin, long, and durable fi bers are of special

importance for the carcinogenic potency. Parameters measured

included number of fi bers; diameter and length distribution of

fi bers retained in lung ash; and leaching of various elements

from fi bers longer than 5 μ m. For a special type of glass

microfi ber and for ceramic wool, which both had low alkaline

earth content, the half-times of lung clearance were similar

to that for crocidolite. Another type of glass microfi ber, with

a very low half-time, had a high alkaline earth content and a

median diameter of about 0.1 μ m. The glass and rock wools

studied, which were thicker than the other fi bers, had interme-

diate half-times.

In a study on in vivo dissolution of inhaled fi bers by Eastes

and Hadley (1995), rats were exposed for 5 days to 4 types of

airborne, respirable-sized SVF and to crocidolite fi bers. The

SVFs included two glass wools, and one each of rock and slag

wool. After exposure, animals were killed at intervals up to 18

months, and the numbers, lengths, and diameters of a repre-

sentative sample of fi bers in their lungs were measured. Long

fi bers ( � 20 μ m) were eliminated from the rats ’ lungs at a rate

predicted from the dissolution rate measured in vitro . The long

SVFs were nearly completely eliminated in several months,

whereas the long crocidolite asbestos fi bers remained in sig-

nifi cant numbers at the end of the study. The number, length,

and diameter distributions of fi bers remaining in the rats ’ lungs

agreed well with a computer simulation of fi ber clearance that

assumed that the long fi bers dissolved at the rate measured for

each fi ber in vitro , and that the short fi bers of every type were

removed at the same rate as short crocidolite asbestos. Thus,

long SVFs were cleared by complete dissolution at the rate

measured in vitro , and short fi bers did not dissolve and were

cleared by macrophage-mediated physical removal.

Eastes and Hadley (1996) fi tted much of the data cited

above into a mathematical model of fi ber carcinogenicity and

fi brosis. Their model predicts the incidence of tumors and

fi brosis in rats exposed to various types of rapidly dissolving

fi bers in an inhalation study or in an IP injection experiment.

It took into account the fi ber diameter and the dissolution rate

of fi bers longer than 20 μ m in the lung, and predicted the mea-

sured tumor and fi brosis incidence to within approximately the

precision of the measurements. The underlying concept for

the model is that a rapidly dissolving long fi ber has the same

response in an animal bioassay as a much smaller dose of a

durable fi ber. Long, durable fi bers have special signifi cance,

since there is no eff ective mechanism by which these fi bers

may be removed. In particular, the hypothesis is that the eff ec-

tive dose of a dissolving long fi ber scales as the residence time

of that fi ber in the extracellular fl uid. The residence time of a

fi ber is estimated directly from the average fi ber diameter, its

density, and the fi ber dissolution rate as measured in simulated

lung fl uid at neutral pH. The incidence of fi brosis in chronic

inhalation tests, the observed lung tumor rates, and the inci-

dence of mesothelioma in the IP model were all well predicted

by the model. The model allows one to predict, for an inhala-

tion or IP experiment, what residence time and dissolution rate

are required for an acceptably small tumorigenic or fi brotic

response to a given fi ber dose. For an inhalation test in rats

at the maximum tolerated dose (MTD), the model suggests

that less than 10% incidence of fi brosis would be obtained at

the MTD of 1- μ m-diameter fi bers if the dissolution rate were

greater than 80 ng/cm 2 /h. The dissolution rate that would

give no detectable lung tumors in such an inhalation test in

rats is much smaller. Thus, a fi ber with a dissolution rate of

100 ng/cm 2 /h has an insignifi cant chance of producing either

fi brosis or tumors by inhalation in rats, even at the MTD. This

model provides manufacturers of SVFs with design criteria for

fi brous products that minimize, if not eliminate, their potential

for producing adverse health eff ects. Hesterberg et al. (2012)

assembled a sample tabulation of data on lung deposition,

biopersistence, in vitro dissolution, and pathogenicity for

amosite, crocidolite, and 9 diff erent SVFs. These data are pre-

sented in Table 3.

Support for the consideration of biopersistence data for the

prediction of fi brosis and tumor responses in rats from both IP

injection studies and chronic inhalation studies for fi bers � 5

and � 20 μ m in length was provided by Bernstein et al. (2001a,

b). For the inhalation studies, they used collagen deposition

at the broncho-alveolar junction as a predictor of interstitial

fi brosis on the basis that it has been shown to be associated

with tumor response in previous studies.

As noted earlier, Lockey et al. (2012) has demonstrated

that RCFs longer than 5 μ m are biopersistent in human lungs

for at least 20 years, while for CNTs, some commercial for-

mulations were less durable than others in Gambles solution

in vitro (Osmond-McLeod et al. 2011), who measured the

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Table 3. Lung deposition, biopersistence, and in vitro dissolution of SVFs correlated with lung pathogenicity. Reproduced, with permission, from

Hesterberg et al. (2012).

Lung depositionb Lung clearance In vitro dissolution Pathogenicity

F/L � 106 � st. dev. F � 20 μ m pH 7 pH 4.5 Chronic inhalation

Fiber Type F/L � 5 μ m F/L � 20 μ m WT1/2

c (days) K ddis

K eleach

Fibrosis Tumors References

Amosite Asbestos 10.9 � 1.0 1.6 � 0.3 418 � 1 nd McConnell et al. (1994)

Crocidolite Asbestos 29.8 � 7.1 1.0 � 1.0 817 � 1 nd McConnell et al. (1994)

MMVF32 Special Purpose E Glass 5.7 � 1.3 1.3 � 0.3 79 9 7 Davis et al. (1996)

RCF1a Refractory 8.3 � 2.0 1.5 � 0.2 55 3 nd Mast et al. (1995a)

MMVF33 Special Purpose 475 Glass 7.1 � 0.6 1.4 � 0.3 49 12 13 � McConnell et al. (1999)

MMVF21 Rock Wool 7.7 � 1.0 1.1 � 0.1 67 20 72 � McConnell et al. (1994)

MMVF10 Insulation Glass Wool 8.6 � 1.6 1.0 � 0.2 14.5 300 329 � � Hesterberg et al. (1998a,b)

X607e Hybrid SVF 3.6 nd 9.8 990 nd � � Hesterberg et al. (1993)

MMVF11 Insulation Glass Wool 5.6 � 1.2 1.0 � 0.2 9 100 25 � � Hesterberg et al. (1993)

MMVF22 Slag Wool 3.4 � 0.6 0.4 � 0.1 9 400 459 � � McConnell et al. (1994)

MMVF34 Stone Wool 9.1 � 1.7 1.5 � 0.4 6 59 1010 � � Kamstrup et al. (1998)

a Tables from Hesterberg and Hart (2001) and Hesterberg et al. (1998b).

b Details of fi ber classifi cation are contained in the papers referenced in footnote a.

c WT 1/2

, weighted clearance half-time in days.

d k dis

(dissolution rate, k dis

� ng/cm 2 h) values for MMVF34 from Kamstrup et al. (1998); others from Eastes and Hadley (1996). K

dis values may diff er

from those published elsewhere due to varying methodologies.

e K leach

dissolution rate constant of leaching elements represented by Ca and Mg at pH 4.5 (rounded up to whole numbers).

durability and infl ammogenic impact of CNTs after incuba-

tion for up to 24 weeks in Gambles solution. By compari-

son, chrysotile asbestos became shorter after incubation in

this in vitro dissolution system and lost its infl ammogenic

eff ects, while amosite asbestos did not. Three single-walled

and multi-walled CNT types showed no or minimal losses of

mass, change in fi ber length, or morphology, while a fourth

type of long CNT lost 30% of its mass within 3 weeks and

lost pathogenicity when they were injected into the peritoneal

cavities of mice. Schinwald et al. (2012a) indicated that silver

nanowires injected into mice IP retained in vivo structural

integrity for one day, but not for one week.

Fiber retention in the lungs

Exposed humans

Amphibole fi bers may account for much of the mesothelioma

incidence among exposed workers, even when they are pre-

dominantly exposed to chrysotile, since amphibole fi bers are

more biopersistent. Pooley (1976) examined postmortem lung

tissue from 20 workers with asbestosis in the Canadian chryso-

tile mining industry and found that amphibole fi bers were

present in 16. In 7 of the 16, they were more numerous than

chrysotile fi bers. In a later study of lung asbestos in chryso-

tile workers with mesothelioma, Churg et al. (1984) reported

that the concentration ratio between cases and controls was

9.3 for tremolite but only 2.8 for chrysotile. In a Norwegian

plant using 91.7% chrysotile, 3.1% amosite, 4.1% crocidolite

and 1.1% anthophyllite, Gylseth et al. (1983) reported that the

percentage of chrysotile in lung tissue ranged between 0 and

9, while the corresponding numbers for the amphiboles were

from 76 to 99.

Case et al. (2000) examined the relationships between

asbestos fi ber type and length in the lungs of chrysotile textile

workers, as well as of chrysotile miners and millers in Que-

bec. Despite the lower cancer risk of the Quebec workers, the

chrysotile, tremolite, total amphibole, and total count of fi bers

longer than 18 μ m were all highest in the Quebec workers.

In their review of the assessment of mineral fi bers from

human lung tissue, Davis et al. (1986a) attributed the high

amphibole/chrysotile ratios to the dissolution of chrysotile

within lung tissue, and the generally poor correlation between

dust counts and mesothelioma as likely to be due to the dif-

ferences among the various asbestos types in the fraction that

reaches the pleural surface. Amosite fi bers need to be longer to

produce pulmonary fi brosis and pulmonary tumors in experi-

mental animals than to produce mesotheliomas after injection

(Davis et al. 1986b). Davis (1987) noted that both chrysotile

and amphibole asbestos fi bers inhaled by rats are plentiful in

the most peripheral alveoli bordering on the pleura, but pen-

etration of the external elastic lamina of the lung appears to be

a rare event. On the other hand, erionite, a natural zeolite fi ber,

caused a very high incidence of mesotheliomas in humans

exposed to low environmental concentrations (Baris et al.

1987) and 100% incidence in rats exposed by inhalation (Wag-

ner et al. 1985). Davis (1987) reported that the erionite used by

Wagner et al. (1985) had a general appearance and fi ber size

distribution very close to that of UICC crocidolite, which pro-

duced a much smaller mesothelioma yield in rats exposed by

inhalation. He attributed the diff erence in the enhanced ability

of erionite to cross the pleural membrane.

Exposed laboratory animals

As noted previously, the biopersistence of chrysotile fi bers in

rats was studied following inhalation exposures to aerosols

with large number concentrations of fi bers � 20 μ m in length.

For chrysotile, the clearance half-time of the fi bers � 20, those

of 5 – 20, and those of � 5 μ m in length were 1.3, 2.4, and 23

days in one study (Bernstein et al. 2004). and 7 h, 7 days,

and 64 days, respectively, in another (Bernstein et al. 2005a),

while for tremolite asbestos, there was no clearance from the

rat lungs over the one-year period of observation (Bernstein

et al. 2005a). These results demonstrate that long-term chryso-

tile and amphibole fi ber retention in the rat model are quite

consistent with the results in humans.

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Exposure – response relationships for fi ber-related cancer

As noted by the HEI-AR Literature Review Committee

(HEI-AR 1991), the majority of published dose-specifi c esti-

mates of the cancer risk caused by asbestos exposure have been

based on models that were based on the experience gained

from studies of occupational cohorts, and assume that:

The increase in relative risk of lung cancer is proportional 1.

to cumulative asbestos exposure, and the eff ects of asbestos

and cigarette smoking multiply each other.

The increase in mesothelioma incidence caused by each 2.

brief period of exposure is proportional to the amount of

that incremental exposure (exposure level � duration) and

to a power of time since it occurred, independent of age or

smoking. The power of time is approximately 2 or 3.

Similar risk assessment models were used in various govern-

ment-sponsored reports, including those of the EPA, the NRC,

and the Consumer Product Safety Commission (CPSC) in

the US and comparable bodies in the UK and Canada. The

validity of these models has not been confi rmed.

For lung cancer, the model implies that the eff ects of ciga-

rette smoking and asbestos on lung cancer risk are multiplica-

tive. This would mean that an exposure that doubles the rate

among smokers (from a lifetime risk of about 0.1 to 0.2) would

also double the rate among nonsmokers (from about 0.005 to

0.01), but this may not be true. Lung cancer is so rare among

nonsmokers, even after quite heavy asbestos exposure, that their

risk cannot be estimated precisely. In fi tting models, a major

uncertainty is the choice of the lung cancer rate in unexposed

workers. Local or national rates will not be appropriate if the

workers ’ smoking habits are (or were, in the past) atypical.

The risk estimates ( K L ) derived from diff erent studies

varied by two orders of magnitude. This in part refl ected statis-

tical variation, but even when 95% confi dence limits were con-

sidered, there were highly signifi cant diff erences between the

diff erent estimates. Possible reasons for this extreme heteroge-

neity include faulty model, lack of accounting for diff erences

in hazard associated with diff erent fi ber types and dimensions,

inaccuracies in exposure estimates, and the use of inappropri-

ate lung cancer rates in calculating SMRs.

One unsatisfactory aspect of the published literature on

mesothelioma is the lack of adequately analyzed mortality

data. The death rate rises sharply with time since exposure,

yet only a few data sets have been analyzed by time since

fi rst exposure, and only four of these reports also provided

estimates of average exposure level. Furthermore, there are

serious weaknesses in all three studies, particularly for assess-

ing the eff ects of chrysotile. The exposure data and results

for the cement factory workers ’ study reported by Finkelstein

(1983) are of doubtful reliability for quantitative risk assess-

ment, and there are no contemporary exposure data for the

insulation workers (Selikoff et al. 1979) or the amosite textile

workers (Seidman et al. 1979). Moreover, none of these four

cohorts was exposed only to chrysotile.

In the absence of any satisfactory basis for direct estimation

of the dose-specifi c mesothelioma risk caused by any specifi c

type of asbestos, particularly chrysotile, HEI-AR (1991) eval-

uated and modifi ed previous predictions for mesothelioma by

comparing observed and predicted ratios of mesothelioma to

excess lung cancer in diff erent cohorts. The predictive model

for mesothelioma used by HEI-AR was proposed to explain

the observation that mesothelioma incidence is independent of

age and approximately proportional to the third power of time

since fi rst exposure. The model was formally fi tted in the only

cohort for whom individual exposure data were available (Peto

et al. 1985). This limited analysis, based on only ten cases,

suggested that brief exposure causes less mesothelioma risk

than that predicted.

The eventual lung cancer risk is assumed to be indepen-

dent of age at exposure, but the predicted mesothelioma risk

is much greater when exposure begins at an early age. These

models therefore predict that the mesothelioma risk exceeds

the lung cancer risk, even among smokers, for childhood expo-

sure, whereas exposure in middle age causes a relatively trivial

mesothelioma risk. Among nonsmokers, the lung cancer risk

is much less than the mesothelioma risk irrespective of age at

exposure.

The clearest diff erence between the eff ects of diff erent fi ber

types is in the proportion of mesotheliomas that are present in

the peritoneum. Almost all cases among chrysotile workers

(usually with some exposure to crocidolite and/or tremolite)

or among crocidilite miners are pleural, whereas workers with

some amosite exposure have suff ered similar and sometimes

higher risks of peritoneal than pleural mesothelioma (Levin

et al. 1998). The only exception appears to be female gas

mask workers exposed mainly to crocidolite, for whom sev-

eral mesotheliomas were peritoneal. The possibility that some

amosite exposure occurred in these workers was, however, not

discussed. The inference that most peritoneal mesotheliomas

are caused by amosite exposure is generally accepted (HEI-AR

1991).

The limitations of the prior modeling by Nicholson (1986)

of the human risk model that was used in EPA ’ s Integrated

Risk Information System (IRIS) http://www.epa.gov/iris/

subst/0371.htm led Berman and Crump (2008a) to perform a

sensitivity analysis that incorporated the eff ects of fi ber size.

On this basis, they concluded that amphibole asbestos fi bers

are at least 200 times more potent for mesothelioma than

chrysotile fi bers.

Direct comparison of workers employed for similar dura-

tion with diff erent forms of asbestos (e.g., in mining or gas

mask manufacture) indicates a much higher mesothelioma risk

of amphiboles than for chrysotile. Chrysotile friction products

workers in the UK suff ered no detectable increase in lung

cancer, and 11 of the 13 mesotheliomas in this cohort occurred

in the subgroup of workers with known exposure to crocidolite

(Berry and Newhouse 1983, Newhouse and Sullivan 1989).

Chrysotile textile workers in Britain suff ered a high risk of

mesothelioma in contrast to those in South Carolina, although

there was a substantial lung cancer risk in both cohorts. The

only marked diff erence between these two textile plants

was the use of some crocidolite (less than 5% of the fi ber

processed) in the UK plant.

For modeling purposes, risk extrapolations for community

residents have had to rely on the models based on occupa-

tional cohorts. Within the range of observation, the models

are consistent with the conservative assumption of a linear,

non-threshold response. Thus, one can, in theory, predict risks

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at the much lower exposure levels observed in downwind of

industrial plants and waste disposal sites, natural outcrops

of soils containing fi bers, and for occupants of schools and

of commercial and public buildings. Such predictions are

unlikely to underestimate the risks and are more likely to over-

estimate them.

In contrast to risk estimations based on human experience

in occupational populations and logical extrapolations to

background concentration levels, as in the model of Doll and

Peto (1985) described above, Larson (2003) applied the EPA-

Proposed Guidelines for Carcinogen Risk Assessment (EPA

1996) to a set of lung cancer mortality data to obtain a “ safe ”

fi ber concentration based on a default linear extrapolation to

one excess death per one million people, as specifi ed for car-

cinogenic hazardous air pollutants by the Clean Air Act. He

found that the “ safe ” concentration was 1/1,000 of ambient air

background concentrations of asbestos fi bers. Because the cal-

culated “ safe ” level cannot be achieved, Larson suggested that

that his risk assessment techniques be used only for airborne

carcinogens that have only anthropogenic sources. Perhaps,

because he was an EPA employee, he did not question the reli-

ability of the EPA-Proposed Guidelines, with their numerous

conservative defaults (Lippmann 2003).

Our current inability to: 1) reliably measure the concentra-

tions of health-relevant fi bers at concentrations near back-

ground levels: and 2) reliably quantitate the risks, if any, of

exposures at such levels, has often led to confusion, alarm,

and misguided acts of risk avoidance. For example, removal

of in-place asbestos insulation in schools and public buildings

has often increased rather than decreased exposures to asbes-

tos fi bers for workers doing the remediation and for building

occupants after the remediation. In the HEI-AR (1991) study

of undisturbed airborne asbestos fi bers indoors, the increase

in cancer risk associated with 20 years of exposure to daily

8-h exposures in commercial buildings, public buildings, and

schools at average concentrations of fi bers � 5 μ m in length in

such buildings of 0.0002 f/mL corresponds to a lifetime risk

of about 2 � 10 – 6 . Furthermore, it should be noted that fi ber

concentrations in buildings are seldom much higher than con-

centrations in the air outside the buildings, and therefore much

of this small risk is related to the entry of outdoor fi bers into

the building with the ventilation air. Another example was the

inappropriate focus, following the collapse of the World Trade

Center buildings, on asbestos fi bers in air and residual dust as

indices of health risk of rescue workers and volunteers, work-

ers removing debris, and neighborhood residents, offi ce work-

ers, and service workers. The measured airborne fi ber levels

neither warranted that level of concern nor could be related to

the health eff ects that were documented.

Dosage applied and resulting biological responses

Fiber dimensions, chemical composition, and surface proper-

ties are important factors in biological reactivity of mineral

and vitreous fi bers. Most of what we know about the infl uence

of these factors has come from toxicological studies where

the variables can be eff ectively controlled. The pathological

eff ects produced by fi bers depend upon both the character-

istics of the fi bers, their deposition rates and sites, and their

persistence at sensitive sites. A number of carefully designed

studies have been performed in which the size distributions of

fi ber suspensions have been well characterized as well as their

persistence and/or eff ects.

For convenience, many of these laboratory-based studies

administered the fi bers in saline suspensions via IT injection

into the lungs, by IP injection into the pleura or peritoneum,

and to cells and tissues in vitro . IP and IT delivery result in

longer and/or thicker fi bers reaching distal sites than would

have been possible if the fi bers were inhaled, and would have

much less uniform distributions than inhaled fi bers. For in vitro

exposures, there could be more uniform distributions, but the

length and diameter distributions of the fi bers might not match

those occurring during in vivo inhalation. Thus, the relevance

of the responses to those that would have occurred with more

physiologic dosing needs to be interpreted cautiously.

In order to facilitate fair comparisons of the asbestos fi ber

types, most of the controlled IT, IP, and inhalation exposure

studies in laboratory animals have used samples that were

prepared to the specifi cations established by the UICC, in

which the bulk fi bers of each type was ground up in order to

get more comparable fi ber size distributions in a substantially

large resource that could be provided to diff erent investigators.

Unfortunately, in retrospect, the UICC decision to mechani-

cally process the bulk fi bers that they had collected as a central

resource was an unfortunate one, since the processed fi bers

had relatively few fi bers long enough to be highly toxic.

Toxicological studies are most useful for comparing the

toxicity of the various fi ber types (chrysotile, amphiboles,

erionite, SVFs, etc.) when the fi ber size distributions are

similar. The comparisons are more easily interpretable in

results from laboratory exposures studies, where the fi ber size

distributions and dosages can be manipulated and well char-

acterized. Studies involving human experience seldom involve

detailed knowledge of the fi ber types in the breathing zone or

their lengths and widths.

For fi bers injected IP (Davis 1976, Pott et al. 1976, Wagner

et al. 1976), or for fi bers suspended within a pledget against

the lung pleura, a similar kind of fi ber size and composition

dependence was observed as that described in the pioneering

study of Stanton and Wrench (1972). The yield of mesothe-

liomas varied with fi ber diameter and length, and with dose,

with very little response when long, thin fi bers were not

included. Asbestos fi bers were more eff ective than glass in

these studies. At 2 mg of chrysotile, crocidolite, or glass fi ber,

Pott, et al. (1976) found only slight degrees of fi brosis, but

tumor yields from 16 to 38% in rats. When the chrysotile was

milled to the extent that 99.8% of the fi bers were shorter than

5 μ m, the dose required to produce a comparable tumor yield

(32%) was 50 times greater.

Various hypotheses have been proposed to account for the

greater pathological eff ects produced by asbestos than by SVFs.

One was the contamination of the surface by trace metal and/

or organic carcinogens. The early study of Stanton and Wrench

(1972) concluded that surface contaminants played no role in

mesothelioma yield, and that the carcinogenicity of asbestos

and fi brous glass was primarily related to the structural shape

of these fi brous materials rather than their surface properties.

However, subsequent experience with erionite fi bers suggests

that surface properties may play a role in mesothelioma yield.

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Fiber translocation and retention within the thorax

As noted earlier, fi ber translocation occurs: 1) along the epi-

thelial surface to dust foci at the respiratory bronchioles; 2)

onto the ciliated epithelium at the terminal bronchioles; or 3)

into and through the epithelium, with subsequent migration

to interstitial storage sites within the lung, along lymphatic

drainage pathways, and 4) for very thin short fi bers, via capil-

lary blood to distant sites (Monchaux et al. 1981). Fiber length

determines fi ber translocation and clearance to and from the

pleural and peritoneal spaces (Moalli et al. 1987) with fi bers

longer than 8 μ m being trapped at the mesothelial lining. The

black spots that concentrate longer fi bers are in close contact

with early pleural plaques (Boutin et al. 1996). Thus, fi ber

translocation is dependent on both fi ber diameter and fi ber

length, and that length is an important determinant of biologi-

cal responses. Translocation also occurs via AMs for fi bers

short enough to be fully ingested by the macrophages. Fibers

phagocytosed by AMs are carried by them toward the lung

periphery by passing through alveolar walls and that some of

these cells aggregate in alveoli near larger bronchioles and

then penetrate the bronchiolar wall, where they can be cleared

by mucociliary transport (Holt 1982).

Based on analyses of RCFs collected personal monitoring

fi lters of workers and a model for their deposition, Lentz et al.

(2003) concluded that the critical dimensions for transloca-

tion to the parietal pleura were as follows: diameter � 0.4 μ m

and length � 10 μ m. They attributed the pleural plaques that

developed in refractory ceramic manufacturing workers to

these translocated fi bers.

Biological mechanisms accounting for fi ber toxicity

Pulmonary epithelial cells and macrophages are the initial tar-

get cells of inhaled particles that are deposited in the terminal

airways and alveolar spaces. Phagocytosis of mineral fi bers by

macrophages leads to generation of reactive oxygen species

(ROS), and release of lysosomal enzymes, arachidonic acid

metabolites, neutral proteases, chemotactic factors, and growth

factors (Adamson 1997). The interactions between mediators

released from macrophages and other infl ammatory cells and

the target cell populations can initiate a sequence of events

culminating in: fi brosis of the lungs and pleura; bronchogenic

carcinoma; and malignant mesothelioma. However, for briefer

exposures (two-weeks) to chrysotile fi bers, the early fi brotic

lesions in rats are gradually resolved over the course of the

following year (Pinkerton et al. 1997).

Short fi bers are less damaging than long fi bers, with a major

reason being that they can be fully ingested by macrophages

(Beck et al. 1971), and can therefore be more rapidly cleared

from the lung surfaces. The fi brogenic response to long fi bers

results, at least in part, from the release of tissue-digesting

enzymes from AMs whose membranes are pierced by the fi bers

they are attempting to engulf (Allison 1977), a phenomenon

that has been called frustrated phagocytosis. The fi bers may

also cause direct physical injury to the alveolar membrane.

The induction of fi brosis impairs clearance of deposited fi bers,

increasing the persistence of fi bers in the lung.

Churg et al. (2000) reviewed the issue of what makes a fi ber

fi brogenic and concluded that fi ber length, biopersistence, and

dose play important roles in fi brogenesis since short fi bers,

readily degraded fi bers, and small numbers of fi bers are not

fi brogenic, and do not produce signifi cant quantities of the

mediators produced by biopersistent longer fi bers that do

produce fi brogenesis.

Macrophage stimulation is not confi ned to asbestos fi bers,

but also occurs with other high aspect ratio durable fi bers, such

as CNTs. Murphy et al. (2012) examined the in vitro eff ects of

a large range of CNT to stimulate the release of acute phase

cytokines (IL-1 β , TNF a , and IL-6), and the chemokine IL-8

from both Met5a mesothelial cells and THP-1 macrophages.

Exposure to CNT resulted in signifi cant cytokine release by

the macrophages, but not by the mesothelial cells. The mac-

rophage response was fi ber-length dependent and resulted

from frustrated phagocytosis. They also showed that they

could stimulate cytokine release by the mesothelioma cells

by treating them with conditioned media from CNT-treated

macrophages and that they could attenuate the response by

inhibition of phagocytosis during the initial CNT macrophage

treatments.

Cations within the crystal lattice may aff ect the toxicity

of asbestos fi bers. Mg 2 ions on the surface of chrysotile

asbestos are important in cytotoxicity and carcinogenic-

ity; acid-leached fi bers are less active than native fi bers

(Monchaux et al. 1981). The Fe 2 and Fe 3 content of

amphibole fi bers may be important because these cations can

catalyze the Fenton or Haber – Weiss reactions, generating

highly toxic and potentially mutagenic ROS (Weitzman and

Graceff a 1984, Zalma et al. 1987).

Diff use, bilateral interstitial fi brosis of the lungs charac-

terizes asbestosis, a disease that usually develops in humans

after prolonged exposure to high doses of asbestos fi bers.

Progressive scarring of the alveolar walls due to increased

proliferation of fi broblasts and deposition of collagen pro-

duces radiographic evidence of disease, and interferes with

gas exchange, leading to disability and premature death. The

sequence of events that lead to the development of asbestosis

includes the following: 1) Asbestos fi bers are phagocytized by

alveolar and/or interstitial macrophages; 2) Release of ROS

from AMs causes acute injury to the alveolar epithelial lining.

The importance of hydrogen peroxide in the pathogenesis of

asbestosis was demonstrated by the protection against asbestos-

induced pulmonary fi brosis provided by catalase conjugated to

polyethylene glycol (Mossman et al. 1990); 3) Phagocytosis

of asbestos fi bers by alveolar or interstitial macrophages also

triggers increased synthesis and release of growth factors for

fi broblasts. Growth factors are released from macrophages

exposed to asbestos fi bers in vitro or in vivo : a homologue

of platelet-derived growth factor (Bauman et al. 1990) and

transforming growth factor- β (TGF- β ) (Kane and McDonald

1993). These growth factors cause chemotaxis of infl amma-

tory cells and fi broblasts, stimulation of collagen synthesis,

and inhibition of collagen degradation.

Another reaction to asbestos exposure is the development

of acellular fi brous scars, called pleural plaques, on the pari-

etal pleural lining and diaphragm that can lead to reduced vital

capacity. Asbestos exposure may also lead to pleural eff usions

or diff use fi brosis of the visceral pleura.

The most important reaction of the pleural and peritoneal

linings to asbestos fi bers is development of diff use malignant

mesothelioma, a rare neoplasm that is closely associated with

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both occupational and environmental exposures to amphibole

forms of asbestos or erionite fi bers after a long latent period

(up to 30 – 60 years). Increased incidence in cigarette smokers

or in workers with asbestosis has not been reported. However,

in the series of animal inhalation studies of SVFs and asbestos

conducted in the 1990s, every fi ber type that caused mesothe-

liomas in rats and hamsters also caused lung fi brosis, usually as

early as 3 months after the exposure was initiated (Hesterberg and

Hart 2001). While asbestosis/fi brosis was not detected radio-

graphically in the human studies, histopathological evidence

for fi brosis may have been present. This malignant neoplasm

has a variable histology, ranging from epithelial to fi broblastic

or mixed patterns. Malignant mesothelioma has usually spread

diff usely when fi rst diagnosed and responds poorly to radiation

or chemotherapy (Craighead 1987). The following sequence

of events is hypothesized to lead to the development of diff use

malignant mesothelioma:

Penetration of fi bers with diameters 1) � 0.1 μ m through

the pulmonary epithelia that reach the pleura or peritoneal

lining via lymphatic drainage (Viallat et al. 1986).

Retention of the thin fi bers with lengths longer than 5 2) μ m

within the stomata of the parietal pleura (Donaldson et al.

2010).

Release of ROS causes acute injury to the mesothelial 3)

cell monolayer lining the pleural or peritoneal spaces.

This injury can be prevented by coating the administered

fi bers with the iron chelator, deferoxamine, with exogenous

superoxide dismutase, or with catalase (Goodglick and

Kane 1990, Kane and Macdonald 1993).

Acute injury to the mesothelial lining, which is repaired 4)

by proliferation of adjacent, uninjured mesothelial cells.

Growth factors released from macrophages, following

phagocytosis of asbestos fi bers, and factors such as TNF

alpha and HMGB1 (high mobility group B1 protein)

released from mesothelial cells (Hillegass et al. 2013) may

modulate mesothelial cell regeneration (Kane and McDon-

ald 1993).

Direct interaction of asbestos fi bers with the regenerating 5)

mesothelial cell population, which may cause chromosomal

aberrations and aneuploidy. Additional DNA damage may

be produced by reactive oxygen species, especially the

hydroxyl radical produced by the iron-catalyzed Haber –

Weiss reaction (Barrett et al. 1989, Floyd 1990).

Priming and activation of the NLRP3 infl ammasome by 6)

either crocidolite or erionite fi bers, leading to the release

of IL-1 β , IL-6, IL-8, and VEGF (Hillegass et al. 2013).

While the mass concentration of fi bers needed to elicit

the response to erionite was four times greater than that

for crocidolite, the micrographs included in Supplementary

Figure 2 of the Hillegass et al. paper show that the erionite

preparation used contained much thicker fi bers along with

some thin enough to produce the eff ect.

Repeated episodes of mesothelial cell injury and regen-7)

eration may lead to the emergence of a subpopulation of

autonomously proliferating cells.

Neoplastic mesothelial cells may produce growth factors 8)

that promote growth of an invasive tumor.

Bronchogenic carcinomas that develop in cigarette smokers

show multiple alterations in proto-oncogenes and tumor-

suppressor genes. It is unknown whether similar molecular

changes are present in those malignant tumors that result from

cigarette smoking in combination with asbestos exposure. Most

of the experimental evidence suggests that asbestos fi bers act

as a co-carcinogen or tumor promoter in the respiratory lining,

in conjunction with multiple components of cigarette smoke

that may act as initiators.

Some of these eff ects of asbestos fi bers on the lung epi-

thelia may be mediated by ROS, since they are decreased

by addition of various scavenging enzymes (e.g., superoxide

dismutase, catalase) to these in vitro model systems. Asbestos

fi bers generate reactive oxygen and nitrogen species (ROS/

RNS), causing oxidation and/or nitrosylation of proteins and

DNA. The ionic state of iron within asbestos fi bers infl uences

the oxidant-inducing potential and its infl uence on macromol-

ecules, signal conduction pathways, infl ammation and prolif-

eration (Shukla et al. 2003).

Pietruska et al. (2010) examined variations in suscepti-

bility of human epithelial cells to genotoxicity by asbestos

fi bers (crocidolite and Libby MT amphiboles) in terms of

oxidative DNA damage that is repaired by X-ray repair cross-

complementing protein 1 (XRCC1). They reported that

XRCC1 knockdown enhanced the genotoxicity of amphibole

fi bers by elevated formation of clastogenic micronuclei.

Toxicity of inhaled durable fi bers

The inhalation of durable inorganic fi bers can aff ect the lung

airways, leading to pulmonary fi brosis and lung cancer. Very

thin fi bers deposited in the lungs translocate to pleural sites

within 7 days, where, if they are durable, they can accumu-

late and induce pleural plaques, pleural eff usion, and meso-

theliomas (Nishimura and Broaddus 1998). Thus, chrysotile

and other thin biosoluble fi bers are unlikely to cause pleural

diseases. Other fi bers are cleared from the airways by muco-

ciliary transport within 1 to 2 days to the larynx and then

pass through the gastrointestinal (GI) tract and may account

for reported excesses in GI cancers in occupational cohorts.

Fibers not translocated to pleural sites or rapidly removed by

mucociliary clearance can be phagocytosed and cleared within

a few weeks. The long fi bers with long-term residence in the

lungs can cause pulmonary fi brosis and lung cancer.

There have been signifi cant advances in our knowledge

about the deposition and elimination of durable fi bers in recent

years, as well as some new knowledge about exposure-response

in controlled animal inhalation, IT, IP, and in vitro exposure

studies. There have also been increments of additional knowl-

edge of human exposure – response relationships for asbestos

fi bers, especially for workers and residents in Libby, MT,

whose exposure to amphibole asbestos fi bers not regulated

by OSHA Standards (i.e., richterite and winchite) produced

pleural abnormalities, mesothelioma, and excess lung cancer.

This new knowledge has generated some new insights into the

critical fi ber parameters aff ecting fi ber-related disease patho-

genesis. However, there are still many important questions

that remain to be addressed. In some cases, the behavior and

risks of airborne SVFs and other durable fi bers can be inferred

from those of either compact particles or asbestos fi bers. On

the other hand, the validity of such inferences depends on

some critical assumptions about the aerodynamic properties

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of the various durable fi bers and about the responses of lung

and mesothelial cells to such fi bers. The diff erences may be

critical, and more in vivo studies with mineral, synthetic vitre-

ous, and other durable fi bers should be performed in order to

further clarify these issues. In the interim, we already know a

great deal about the nature and extent of fi ber toxicity and the

factors that modify its expression. This knowledge provides an

improved basis for more defi nitive risk assessment for these

various fi bers.

Infl uence of fi ber type

SVFs diff er from both amphibole and chrysotile asbestos

fi bers in several critical ways that tend to produce less lung

deposition and more rapid elimination of SVF fi bers that do

deposit in the lungs. One diff erence is in diameter distribution.

Except for glass microfi ber, SVFs tend to have relatively small

mass fractions in diameters small enough to penetrate through

the upper respiratory tract. Furthermore, once deposited, the

asbestos fi bers, especially chrysotile fi bers, may split into a

larger number of long thin fi bers within the lungs, while both

amphiboles and SVFs rarely split longitudinally. SVFs are

more likely to break into shorter length segments than amphi-

bole fi bers, while chrysotile fi bers may break into shorter

segments after partial dissolution when inhaled at high mass

concentrations, but not when inhaled at lower concentrations

Bernstein et al. (2013).

Comparative retention and toxicity studies with various

kinds of asbestos and other fi brous minerals, SVFs, and other

durable fi bers indicate that properties other than fi ber dimen-

sions aff ect fi ber retention and toxicity. Among these are

solubility; specifi c surface area; surface electrical charges that

may contribute to redox reactions generating active oxygen

species; etc. Thus, dimensional characteristics alone, although

important, are insuffi cient indicators of fi ber toxicity.

The compositional diff erences in solubility among the

fi bers aff ect the toxic potential, among both the asbestos types

and the other durable fi bers. Conventional glass fi bers dissolve

much more rapidly than some other SVFs and than amphi-

bole asbestos fi bers. Dissolution of glass fi bers takes place

both by surface attack and by leaching within the structure.

The diameters are reduced and the structure is weakened,

favoring break-up into shorter segments that are cleared by

macrophages. Since the smallest diameter fi bers have the

greatest surface-to-volume ratio, they dissolve most rapidly.

Thus, the relatively small fraction of the airborne glass fi bers

having diameters small enough to penetrate into the lungs are

the most rapidly dissolved within the lungs.

The more durable and less soluble SVFs, that is, some of

the more biopersistent slag and rock wools, specialty glasses,

and ceramic fi bers, require a higher degree of concern because

of their longer retention within the lungs. In vitro studies and

studies of dissolution in simulated lung fl uids can be very

useful in preliminary evaluations of the toxic potential of the

various SVFs, although they may not adequately represent

solubility rates occurring at the much lower concentrations

found in in vivo studies. Thus, the dissolution of SVFs in vivo

depends on many additional factors that cannot readily be

simulated in model systems. For example, the diff erences in

solubility in vivo of long and short fi bers noted by Morgan and

Holmes (1984) were attributed to small diff erence in intrac-

ellular and extracellular pH. The mechanical stress on fi bers

in vivo may also contribute to their disintegration, and cannot

readily be simulated in model systems. Thus, hazard evalua-

tions of specialty product SVFs made for limited and specifi c

applications should include detailed in vivo studies in which

animals are exposed to appropriate sizes and concentrations of

the fi bers of interest.

In the case of conventional fi brous glasses, we have suf-

fi cient information to conclude that the occupational health

risks associated with the inhalation of fi bers dispersed during

their manufacture, installation, use, maintenance, and disposal

are not measurable (Doll 1987), and hence of an extremely

low order. The health risks from casual and infrequent indoor

air exposure of building occupants to relatively low concen-

trations of fi brous glass are therefore essentially nil. These

judgments are based on a series of interacting factors, each of

which individually leads to a far lower order of risk of conven-

tional glass fi bers than asbestos. Specifi cally:

Conventional glass fi bers are less readily aerosolized than 1)

asbestos during comparable operations, as demonstrated by

the much lower fi ber counts measured at various industrial

operations (Cherrie et al. 1986, Esmen 1984).

A much smaller fraction of conventional glass fi bers than 2)

asbestos fi bers have small enough aerodynamic diameters

to penetrate into lung airways (i.e., fi bers with diameters

below ∼ 3 μ m) (Konzen 1984).

The glass fi bers that can penetrate into the lungs are much 3)

less durable within the lung than asbestos. They tend to

break up into shorter segments, so that fewer fi bers longer

than the critical length limits are retained at critical sites.

They also tend to dissolve, further reducing their retention

(Bernstein et al. 1984).

The inherent toxicity of conventional glass fi bers is much 4)

lower than that of asbestos fi bers of similar dimension, as

shown by studies in which fi ber suspensions are applied

directly to target tissues by IT instillation (Wright and

Kuschner 1977) or the IP application of a fi ber mat to the

lung pleura (Stanton and Wrench 1972).

In consideration of these factors, the risk of lung fi brosis

is virtually nil for conventional glass fi bers unless there is

continuous exposure at concentrations high enough to main-

tain a high level of lung burden. The risk of lung cancer for

conventional glass fi bers is also virtually nil unless there is

continuous exposure to long fi bers at high concentrations

because of the relatively rapid breakup of long fi bers into short

fi ber segments within the lungs. Finally, the risk of mesothe-

lioma from inhaled conventional glass fi bers is virtually nil

under almost any circumstance. There are hardly any glass

fi bers thin enough to cause mesothelioma in the aerosols, and

the very few that may be present would dissolve rapidly within

the lungs.

For more durable SVFs, such as some slag and mineral

wools and RCFs, the evidence for an absence of risk is more

problematic. Berrigan (2002) reviewed 10 case – control and

10 cohort studies of workers exposed to SVF and reported a

small, but signifi cant risk of lung cancer for glass and a slightly

larger risk of rock wool based on meta-analyses. On the other

hand, both Lipworth et al. (2009) and Boff etta et al. (2014),

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cited, as a suffi cient basis to discount any excess risk: 1) the

absence, in these and more recent studies of dose-response;

2) the likelihood of detection bias; and 3) possible residual

bias by asbestos exposure and smoking history. For mesothe-

lioma, Lacourt et al. (2013) reported that, for a large French

case-control study, workers exposed to mineral wool had a sig-

nifi cant, dose-related excess risk and that co-exposure to either

asbestos fi bers or quartz particles had much larger mesothe-

lioma risks. For RCFs, there is no epidemiologic evidence, but

Lockey et al. (2012) provided evidence that such fi bers were

biopersistent and associated with radiographic pleural changes

in the lungs.

Review of the in vitro studies clearly indicates that fi ber

length, diameter, and composition are critical determinants

of fi ber biopersistance, cytotoxicity and cell transformation.

Review of the in vivo animal studies, both by inhalation and

by injection, shows that fi ber dimensions and composition are

important factors aff ecting pathological measures such as pleu-

ral and lung fi brosis, mesothelioma, and lung cancer. Review

of human exposure – response shows that the proportions of the

diff erent diseases caused by asbestos, that is, asbestosis, lung

cancer, and mesothelioma, vary greatly among occupational

cohorts, and that the mesothelioma/lung cancer ratio tends to

increase with decreasing fi ber diameter for the durable amphi-

bole forms of asbestos. Review of the literature on biopersis-

tance indicates that the chemical composition and fl exibility of

the fi bers accounts, at least in major part, for the lesser toxicity

of most SVFs than of asbestos fi bers, and especially of amphi-

bole fi bers.

For CNT, Donaldson et al. (2006) noted that they had a

special ability to stimulate mesenchymal cell growth and to

cause granuloma formation and fi brogenesis. Donaldson et al.

(2010) proposed a mechanism for short-fi ber clearance from

the pleura through stomata in the parietal pleura, in which

fi bers longer than 5 μ m were retained, causing infl ammation

and pleural pathology (See Figure 2).

Infl uence of fi ber diameter

Fiber diameter aff ects airborne fi ber penetration into and

along the lung airways and thereby the initial deposition pat-

terns. The aerodynamic diameters of mineral fi bers are about

thrice their physical diameters (Timbrell 1972, St ö ber et al.

1970). Thus, few fi bers with diameters larger than ∼ 3 μ m will

penetrate into the lungs (Lippmann 1990). Fibers with diam-

eters 0.1 μ m are less well retained in the lungs than fi bers

with larger diameters (Lippmann and Timbrell 1990). Fibers

with large surface-to-volume ratios are more subject to dis-

solution within the lungs (Lippmann 1990). Those suffi ciently

durable not to readily dissolve can readily penetrate the epi-

thelial surface and be translocated to the lung interstitium and

pleural surfaces, where fi bers with lengths greater than 5 μ m

are retained at the parietal to cause infl ammation and lesions.

(Murphy et al. 2013). The fi bers that remain in the lung paren-

chyma can cause fi brosis and lung cancer, and those durable

fi bers that are translocated to pleural surfaces can cause meso-

thelioma. Thus, for asbestosis and lung cancer, the upper fi ber

diameter limit is on the order of 3 μ m. For mesothelioma, the

upper fi ber diameter limit is likely to be much less for two

reasons. First, the fi bers thinner than ∼ 0.1 μ m penetrate to the

gas-exchange region to a greater extent where long, thin fi bers

are retained at the parietal pleura.

Infl uence of fi ber length

Fiber length can also aff ect fi ber penetration into and along

the airways. As the length increases beyond ∼ 10 μ m, the

interception mechanism begins to signifi cantly enhance depo-

sition (Sussman et al. 1991a, b). Thus, longer fi bers have

proportionately more airway deposition and less deposition in

the gas-exchange region. Lung retention also increases mark-

edly with increasing fi ber length above 10 μ m for biopersistent

fi bers, both on theoretical grounds (Yu et al. 1990) and on the

basis of analysis of residual lung dust in humans (Pooley and

Wagner 1988, Churg and Wiggs 1987, Timbrell et al. 1987)

and animals (Morgan 1979). Furthermore, fi bers shorter than

about 6 μ m in length can readily penetrate through tracheo-

bronchial lymph nodes and be translocated to more distant

organs (Oberd ö rster et al. 1988).

Exact specifi cation of the critical lengths for the diff erent

diseases had remained diffi cult until recently, since the earlier

experimental studies generally have had, of practical neces-

sity, to use imperfectly classifi ed fi ber suspensions. The recent

work of Poland et al. (2008), Murphy et al. (2011, 2012),

Osmond-McLeod et al. (2011), and Schinwald et al. (2012a,

b), using well-characterized CNTs and metallic microwires,

has been highly informative about the infl uence of fi ber length

on short-term biological responses.

The earlier experimental studies had the uncertainties

associated with the use of very high concentrations, and

apportioning attribution of the cytotoxicity and pathology pro-

duced to the eff ects of fi ber size vs. dust overload phenomena.

Increasing fi ber length is important to lung fi brosis insofar as

it increases the total surface area of the fi brous particles. In

terms of critical fi ber lengths, pleural fi brosis and mesothe-

lioma are caused by thin fi bers up to 5 μ m in length, while

lung cancer is caused by fi bers longer than 20 μ m in length.

Risk assessment for inorganic fi bers

For asbestos, occupational exposures to all fi brous forms

have caused asbestosis and contributed to excesses of lung

cancers. For mesothelioma, inhalation of amphibole and eri-

onite fi bers in workers and the general population has been

causal. While occupational exposure to chrysotile asbestos

has been associated with cases of mesothelioma, these cases

were more likely due to the contamination of most commercial

chrysotile with amphibole fi bers, and if chrysotile fi bers do

cause mesothelioma, they are considerably less potent in that

regard than amphibole fi bers. More defi nitive conclusions will

require studies having better descriptions of the fi ber sizes and

compositions.

For SVFs, the International Agency for Research on

Cancer (IARC 2002) has, on the basis of their own review of

the data on carcinogenic risk, concluded that: 1) for humans,

there is inadequate evidence for the carcinogenicity of glass

wool, continuous glass fi lament, rock (stone) wool/slag wool,

and RCFs; 2) for experimental animals, there is inadequate evidence for the carcinogenicity of continuous glass fi lament,

and for certain newly developed, less biopersistent fi bers

(X-607 and HT wools and A, C, F, and G), limited evidence

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for insulation glass wool, rock (stone) wool, slag wool,

and more biopersistent fi bers such as fi ber H, and suffi cient evidence for the carcinogenicity of special purpose glass fi bers,

including E-glass and “ 475 ” glass fi bers, as well as for RCFs.

For all inorganic fi bers, as for other airborne toxicants, the

dose makes the poison. However, for these fi brous toxicants,

the physical form and properties can be as important, or more

important, than the chemical form. The aerodynamic diam-

eters of the fi bers, and therefore their deposition patterns and

effi ciencies within the lung airways, are determined largely by

fi ber width. For fi bers � 10 μ m in length, interception enhances

airway deposition, but even more importantly, these longer

fi bers elicit cellular responses that shorter fi bers do not, and

they also are subject to diff erent clearance pathways and rates.

Another physical property, their solubility within lung fl uids,

then becomes a major determinant of their toxicity. While

these special determinants of risk are being increasingly rec-

ognized, they are not yet refl ected in Standards or Guidelines

for exposure assessment, an essential tool in risk assessment.

Thus, there is an urgent need for new and improved occupa-

tional and ambient air quality limits for specifi c fi ber composi-

tions that recognize fi ber length and diameter as critical risk

factors. Dissolution rate in vivo is the other main dimension in

the risk equation. Fortunately, the SVF manufacturing indus-

try in the US and the European Community has recognized

the critical importance of fi ber biopersistence to risk, and has

revised many product formulations so that they have higher

dissolution constants.

Critical fi ber dimensions aff ecting disease pathogenesis

In Table 4, from Lippmann (1988), I summarized my con-

clusions on critical fi ber diameters and lengths, based on the

frequency of pathological diagnoses and mineral fi ber dimen-

sions measured: 1) in human lung samples from asbestos-fi ber-

exposed workers, and 2) the lengths and diameters of fi bers in

membrane fi lter samples drawn from the exposure chambers of

animals undergoing long-term inhalation exposures to mineral

fi bers. I found that the critical fi ber dimensions were diff erent

for asbestosis, mesothelioma, and lung cancer. In the sections

below, for each disease associated with the inhalation of min-

eral fi bers, I fi rst summarize the key studies that supported

my 1988 conclusions, and then the more recent literature that

appears, for the most part, to be consistent with each of them.

An alternate selection of critical fi ber lengths and diameters

was made by Berman et al. (1995), which assigned empirical

weights for relative potency to fi bers with the ranges: � 0.3 μ m

in diameter and 5 – 40 μ m long; � 0.3 μ m in diameter and � 40

μ m long; and � 3 μ m in diameter and � 40 μ m long. The

Berman et al. (1995) criteria were also based on air samples

of the exposure chambers of animals undergoing long-term

inhalation exposures to mineral fi bers, with more thorough

analyses of the TEM bivariate fi ber size distributions per-

formed on archived membrane fi lters.

Loomis et al. (2010), using the bivariate fi ber size data from

the archived fi lters, concluded that the strongest association

with lung cancer mortality was for fi bers 20 – 40 μ m in length.

Case et al. (2011) compared the Lippmann (1988), the Berman

et al. (1995) and the Loomis et al. (2010) parameters with the

textile workers lung cancer mortality and found that the best fi t

was for the Lippmann et al. criterion for lung cancer.

Asbestosis

Asbestosis has been caused by exposure to high concentra-

tions of respirable fi bers of all of the commercially exploited

kinds of asbestos. Within the respirable fraction, the fi bers

often diff er in both diameter and length distributions and in

retention times.

Timbrell et al. (1987) analyzed both retained fi bers and

the extent of fi brosis in lung samples from exposed asbestos

workers. He analyzed the fi ber distributions in 0.5 g lung

samples from several hundred workers. He also measured the

degree of fi brosis in paraffi n sections prepared from adjacent

samples of the same specimens. Using adjacent tissues, he was

able to make valid comparisons accounting for the degree of

pulmonary fi brosis. There were wide intra- and inter-subject

variations in both fi ber concentrations and fi brosis scores

in mineworkers ’ post-mortem lung specimens for amosite

(Transvaal, South Africa), anthophyllite (Paakkila, Finland),

and crocidolite (NW Cape and Transvaal, South Africa and

Wittenoom, Australia). As illustrated in Figure 4, the fi brosis-

producing ability of the fi bers was independent of amphibole

type when normalized by the total surface area of long resident

fi bers per unit weight of lung tissue, presumably because the

surface area was the key factor that determined the magnitude

of the fi ber-tissue interface. When fi ber quantity is expressed

as number or total mass, there was a wide range of the con-

centrations of retained fi ber required to produce the same

degree of fi brosis. Timbrell et al. (1987) also reported results

for three Wittenoom workers whose dominant exposure was

to chrysotile asbestos. For them, chrysotile produced a simi-

lar degree of fi brosis to Wittenoom crocidolite for equal fi ber

mass concentrations in the lungs. Long tissue residence had

almost completely dispersed the chrysotile fi bers into fi brils,

giving them a surface/mass ratio resembling that of fi ne Wit-

tenoom crocidolite fi bers, indicating that the fi brogenicity of

the retained chrysotile per unit of surface area within the lungs

was similar to that of the amphiboles. Timbrell et al. (1987)

also reported that amphibole mineworkers with a given fi ber

mass concentration in their lungs showed much higher degrees

of fi brosis than gold miners with roughly the same mass con-

centration of quartz. The amphibole and quartz produced

about the same fi brogenicity per unit of surface area, but the

amphibole fi bers, with their greater surface area, had greater

fi brosis-producing capability.

Knowledge of the interrelationships between retained fi bers

and fi brosis is critical in understanding the pathogenesis of

the disease but is inadequate, by itself, in evaluating expo-

sures to airborne fi bers, so Timbrell (1983, 1984) developed

Table 4. Summary of recommendations on asbestos exposure indices.

Source: Lippmann (1988).

Disease Relevant exposure index

Asbestosis Surface area if fi bers with:Length � 2 μ m; diameter � 0.15 μ m

Mesothelioma Number of fi bers with:

Length � 5 μ m; diameter � 0.1 μ mLung cancer Number of fi bers with:

Length � 10 μ m; diameter � 0.15 μ m

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Figure 4. Relationships between lung fi brosis scale and relative concentrations of fi bers per unit weight of dry lung tissues. The lines connect data points

from the same subject. The relative fi ber surface area normalizes the data better than either the relative fi ber number concentration or the fi ber mass

concentration. Source: Lippmann (1988).

a mathematical model relating fi ber deposition and retention

to analyses of lung samples. He relied on pulmonary tissue

samples from a female worker at Paakkila who had exposure

to an amphibole (anthophyllite) at high concentrations of

fi bers having a wide range of diameters and lengths suffi cient

to encompass the size limits of respirable fi bers. Her lungs

contained 1.3 mg of fi ber per gram of dry tissue, and she

had asbestosis. One lung sample contained a fi ber distribu-

tion matching the expected deposition. Timbrell speculated

that severe fi brosis in the tissue in this sample had blocked

the macrophage-mediated clearance. Another sample from the

same lung yielded a retention pattern more closely matching

those found in other Paakkila workers, with small fi ber bur-

dens and virtually no short fi bers. He assumed that the latter

represents long-term retention in the normal lung.

From the diff erences in retention, Timbrell developed

a model for the retention of fi bers as a function of length

and diameter. Fiber retention rose rapidly with fi ber lengths

between 2 and 5 μ m and peaked at ∼ 10 μ m. Fiber reten-

tion also rose rapidly with fi ber diameters between 0.15 and

0.3 μ m, peaked at ∼ 0.5 μ m, and dropped rapidly between

0.8 and 2 μ m. The utility of the model was demonstrated by

applying it to the prediction of the lung retention of Cape

crocidolite and Transvaal amosite workers on the basis of

the measured length and diameter distributions of airborne

fi bers. The predicted lung distributions did, in fact, closely

match those measured in lung samples from a Cape worker

(Timbrell 1984) and from a Transvaal worker (Timbrell

1983). Thus, fi brosis is most closely related to the surface

area of fi bers with diameters between 0.15 and 2 μ m and

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lengths greater than ∼ 2 μ m. The work of King et al. (1946)

showing that chrysotile with length of 2.5 μ m produced

interstitial fi brosis in rabbits following multiple intratra-

cheal instillations is consistent with a critical fi ber length

of ∼ 2 μ m.

Churg et al. (2000) examined putative biological mecha-

nisms involved in fi brogenesis and concluded that 1) fi ber

length, biopersistence, and dose it remains uncertain whether

AMs are central to fi brosis or whether fi bers penetrating tissue

are the real eff ecter agents; 2) short fi bers, readily degraded

fi bers, and small numbers of any fi bers are non-fi brogenic; and

3) the ability of macrophages to clear fi bers is probably crucial

to preventing fi brosis.

Schneider et al. (2010) extended his analyses of the role

of asbestos exposure in causing diff use pulmonary interstitial

pulmonary fi brosis to patients with a history of asbestos expo-

sure, but whose biopsies did not meet established criteria for a

diagnosis of asbestosis. They found that the fi brosis scores of

those diagnosed with asbestosis correlated best with counts of

amphibole fi bers, as did most of the cases with diff use pulmo-

nary interstitial pulmonary fi brosis.

While the human studies cited above are the most informa-

tive about the infl uence of fi ber exposures that aff ect pneu-

moconiosis progression, animal and other exposure studies

have also been informative with respect to critical fi ber

dimensions for pneumoconiosis, beginning with Wright and

Kuschner (1977), who instilled short- and long-asbestos and

SVF fi bers into the lungs of guinea pigs. For suspensions

containing fi bers longer than ∼ 10 μ m, all of the materials

produced lung fi brosis, although the yields varied with the

materials used. However, with equal masses of short fi bers

of equivalent fi ber diameters, none produced any fi brosis.

The yields were lower for the long glass fi bers than for the

long asbestos, which was attributed to their lesser durability

within the lungs.

Bernstein et al. (2010, 2011) did a 6 h/day, 5-day inhalation

exposure study that examined a commercial chrysotile product

used as a joint compound along fi ne particles from joint sand-

ing, and compared the results with those for amosite fi bers, in

terms of translocation and pathological response in the pleu-

ral cavity over 1 year of follow-up. The number of fi bers was

examined using TEM and confocal microscopy. The chrysotile

fi bers longer than 20 μ m cleared with a half-time of 4.5 days

and were not observed in the pleural cavity, and there was

no pathological response to the chrysotile-particle mixture.

By contrast, long amosite fi bers with a half-time of � 1,000

days were observed in the pleural cavity within 7 days, and

interstitial fi brosis was seen within 14 days. By 90 days, the

long amosite fi bers induced an infl ammatory response in the

parietal plera.

In more recent work, Murphy et al. (2013) exposed mice by

IT by pharyngeal aspiration of CNTs in 3 length ranges: 1 –

2 μ m, 1 – 5 μ m, and 84% longer than 15 μ m. They reported

that the long nanotubes, but not the two shorter lengths, pro-

duced an infl ammatory response at 1 week post-exposure

in the BAL fl uid, as well as a progressive thickening of the

alveolar septa. They also reported only the long nanotubes

also produced an infl ammatory response and pulmonary

lesions along the chest wall and diaphragm at 6 weeks

post-exposure, but not at 1 week.

Mesothelioma

Early animal inoculation experiments had suggested a fairly

high value of diameter, for example, 1.5 μ m (Stanton et al.

1977) and 1 μ m (Pott et al. 1976), below which a fi brous

material, so long as it is durable in lung fl uids, can produce

mesothelioma. However, if fi bers with diameters � 0.5 μ m

produced mesothelioma, then occupational exposures to

anthophylite at Paakkila, where the dust clouds contained on

the order of 50 fi bers/mL (PCOM) and a high proportion of

fi bers in the 0.5- to 3- μ m-diameter range, should have pro-

duced many mesotheliomas, as well as the observed excesses

in fi brosis and lung cancer. Despite the very high exposures of

the Paakkila population, few mesotheliomas were observed.

Timbrell ’ s (1983) examination of the size distributions and

mesothelioma incidence at Paakkila and other asbestos mines

worldwide led him to conclude that a good correlation was

obtained if the threshold diameter was reduced to 0.1 μ m.

The few mesotheliomas that Paakkila fi ber had produced in

animals were, most likely, caused by the use of excessive

doses, 10,000 times that observed in man. Paakkila asbestos

contained only 1% of fi bers with diameters below 0.1 μ m, but

with such a large dose, there was an enormous absolute num-

ber of thin fi bers. Harington (1981) noted that the data for the

northwest Cape in South Africa, where numerous mesothe-

liomas have been reported, and for the northeastern Transvaal,

where mesotheliomas are rare, are consistent with a low fi ber-

diameter limit. In the northwest Cape, about 60% of the fi bers

had diameters � 0.1 μ m, whereas for the Transvaal, only about

1% had diameters � 0.1 μ m, a percentage that is comparable

with that for the Paakkila fi bers.

Timbrell (1983) also noted that the length distributions at

Paakkila and the northwest Cape point to a need to reduce

the 10- μ m length threshold for mesothelioma in Stanton ’ s

criteria. Paakkila had a high percentage of fi bers longer

than 10 μ m, whereas the northwest Cape had virtually none.

And yet, the northwest Cape has been the major source of

mesothelioma.

In the Lippmann (1988) review of the literature on mesothe-

lioma induction in rats exposed by inhalation to fi brous aero-

sols, as summarized in Table 4, I concluded that, for mesothe-

lioma, the relatively low mesothelial tumor yields was highly

dependent upon fi ber type. Combining the data from various

long-term rat inhalation studies by fi ber type, the percentage of

mesotheliomas was 0.6% for Zimbabwe (Rhodesian) chryso-

tile, 2.5% for the various amphiboles as a group, and 4.7% for

Quebec (Canadian) chrysotile. This diff erence, together with

the fact that Zimbabwe chrysotile had 2 – 3 orders of magni-

tude less tremolite than Quebec chrysotile, provides support

for the hypothesis that the mesotheliomas that have occurred

among chrysotile miners and millers could be largely due to

their incidental, lower level, exposures to tremolite fi bers. The

chrysotile fi bers appeared to have been insuffi ciently bioper-

sistent, with the more durable tremolite fi bers accounting for

the mesotheliomas.

Combining the fi ndings of Timbrell with the results of the

Davis et al. (1986b), rat inhalation experiments with length-

classifi ed fi bers lead to the conclusion that the critical fi bers

for mesothelioma induction have lengths between 5 and

10 μ m. Davis et al. reported that IP injections of short amosite

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(1.7% � 5 μ m) produced only one mesothelioma among 24

rats (after 837 days), whereas UICC amosite (11% � 5 μ m,

2.5% � 10 μ m) produced 30 mesotheliomas among 32 rats,

and long amosite (30% � 5 μ m, 10% � 10 μ m) produced 20

mesotheliomas among 21 rats. Thus, fi bers shorter than 5 μ m

were ineff ective, and an appreciable fraction longer than 10

μ m appears to be unnecessary.

While, as for pneumoconiosis, the older inhalation exposure

studies cited above are the most informative about the infl u-

ence of fi ber dimensions that aff ect mesothelioma yield, the

fi ndings from IP administration of fi ber suspensions are also

informative with respect to critical fi ber dimensions for meso-

thelioma. For fi bers injected IP (Pott et al. 1976), the yield of

mesotheliomas varied with fi ber diameter and length, and with

dose, very little response when thin fi bers were not included.

Asbestos fi bers were more eff ective than glass in these studies.

At 2 mg of chrysotile, crocidolite, or glass fi ber, tumor yields

of from 16 to 38% in rats were observed. When the chrysotile

was milled to the extent that 99.8% of the fi bers were shorter

than 5 μ m, the dose required to produce a comparable tumor

yield (32%) was 50 times greater.

In more recent work, Schinwald et al. (2012a) injected mice

IP with 120-nm-thick silver nanowires with mean lengths of 3,

5, 10, 14, and 28 μ m, along with short and long nickel nano-

wires (4 and 20 μ m long), CNTs (13 and 36 μ m long), and

two amosite asbestos dusts (long fi bers with 100% longer than

5 μ m, 50% � 15 μ m, and 35% � 20 μ m, and short fi bers with

only 3% � 5 μ m). They reported an acute pleural response with

a threshold fi ber length of 4 μ m. They suggested that fi bers

that are 5 μ m or longer and that are translocated to the pleural

space, both free and in macrophages, are retained because they

cannot negotiate the stomata in the parietal pleura, where they

can elicit infl ammation.

Lung cancer

Excess incidence of lung cancer has been reported for work-

ers exposed to amphiboles (amosite, anthophyllite and cro-

cidolite), to chrysotile, and to mixtures of these fi bers (NRC

1984), but these studies have been uninformative with respect

to the fi ber parameters aff ecting the lung cancer incidence.

The series of rat inhalation studies performed by Davis et al.

(1978), which produced lung cancers, have provided the most

relevant evidence on the importance of fi ber length on carci-

nogenicity in the lung.

Davis et al. (1978), in attempting to examine the infl uence

of fi ber number concentration in their inhalation studies, had

5 exposure groups that included 3 at respirable mass concen-

trations of 10 mg/m 3 , 1 each with chrysotile, crocidolite, and

amosite. Of these, the amosite produced the lowest number

concentration of fi bers � 5 μ m in length. This fi ber count was

then matched with crocidolite (5 mg/m 3 of respirable mass) and

chrysotile (2 mg/m 3 of respirable mass). In explaining the greater

fi brogenic and carcinogenic responses in the chrysotile-exposed

animals than the crocidolite- or amosite-exposed groups, they

emphasized the greater number of � 20- μ m-long fi bers in the

chrysotile aerosol. The ratio of � 20- to � 5- μ m long fi bers in

the chrysotile was 0.185 compared to 0.040 for crocidolite and

0.011 for amosite. The diameter distributions of all three types

of asbestos were similar, with a median diameter of ∼ 0.4 μ m.

The importance of fi ber length to lung cancer was further

investigated by Davis et al. (1986b) in inhalation studies with

amosite aerosols that were both shorter and longer than the

UICC amosite studied earlier with the same protocols. Both

the shorter and longer amosite aerosols had median fi ber

diameters between 0.3 and 0.4 μ m. The short-fi ber amosite

(1.7% � 5 μ m in length) produced no malignant cancers in

42 rats, whereas the long-fi ber amosite (30% � 5 μ m,

10% � 10 μ m) produced 3 adenocarcinomas, 4 squamous

carcinomas, and 1 undiff erentiated carcinoma in 40 rats. In

terms of adenomas, the frequencies were 3/40, 2/43, 0/42,

and 1/81 for the long, UICC, short, and control groups,

respectively. Davis et al. (1985) also studied tremolite asbes-

tos using the same protocols. Its length distribution was

similar to those of the chrysotile in the 1978 study and of the

long amosite in the 1986 study (i.e., 28% � 5 μ m, 7% � 10

μ m), but its median diameter was lower, that is, 0.25 μ m. It

produced 2 adenomas, 8 adenocarcinomas, and 8 squamous

carcinomas in 39 rats. Davis (1987) then compared the

carcinogenic eff ects of “ long ” and “ short ” chrysotile at

10 mg/m 3 . Unfortunately, the discrimination between “ long ”

and “ short ” fi bers was less successful than that achieved for

amosite. PCOM fi ber counts for the fi bers � 10 μ m in length

for the “ long ” and “ short ” chrysotile were 1,930 and 330

f/mL, whereas for the amosite they were 1,110 and 12 f/

mL, respectively. Despite the much more rapid clearance of

the chrysotile from the lungs, the tumor yields were higher.

For the “ long ” fi ber, there were 22 tumors for the chryso-

tile vs. 13 for the amosite. For the “ short ” fi ber, there were

7 vs. 0. Davis (1987) concluded that fi bers � 5 μ m in length

may be innocuous, since the tumors produced by the “ short ”

chrysotile are explicable by the presence of 330 f/mL longer

than 10 μ m.

In another study, Wagner et al. (1985) exposed rats by inha-

lation to 10 mg/m 3 of respirable dust composed of either UICC

crocidolite (52.7% � 5 μ m, 11.6% � 10 μ m, median diameter

0.30 μ m) or Oregon erionite (44% � 5 μ m, 7.4% � 10 μ m,

median diameter of 0.22 μ m). The UICC crocidolite produced

1 squamous carcinoma in 28 rats (but no mesotheliomas),

whereas the erionite produced no carcinomas in 28 rats but

did produce 27 mesotheliomas.

In his study of fi bers retained within the lungs of Quebec

chrysotile workers, Case et al. (2000) found that high con-

centrations of fi bers � 18 μ m in length, and it is reasonable

to conclude that such long-resident fi bers can account for the

high incidence of lung cancer in these workers.

In summary, 10 mg/m 3 of short amosite ( ∼ 0.1% � 10

μ m), UICC amosite ( ∼ 2.5% � 10 μ m), UICC crocidolite ( ∼

3% � 10 μ m), and Oregon erionite (7.4% � 10 μ m) failed to

produce malignant lung cancers, whereas 10 mg/m 3 of UICC

chrysotile, long amosite, and tremolite (all with � 10% � 10

μ m) all produced malignant lung tumors. Although there was

no clear-cut infl uence of fi ber diameter on tumor yield, the

results suggest that carcinogenesis incidence increases with

both fi ber length and diameter. Since Timbrell (1983) had

shown that fi ber retention in the lungs peaks between 0.3 and

0.8 μ m diameter, it is likely that the thinner fi bers, which are

more readily translocated to the pleura and peritoneum, play

relatively little role in lung carcinogenesis. Therefore, the risk

of lung cancer was most closely associated with long fi bers,

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especially those with diameters between ∼ 0.3 and 0.8 μ m,

and that substantial numbers of fi bers � 10 μ m in length are

needed.

As noted earlier in Lippmann (1994), I found that, for lung

cancer, the percentage of lung tumors (y) could be described

by a relation of the form

y � a bf cf 2 ,

where f is the number concentration of mineral fi bers, and a , b ,

and c are fi tted constants. The correlation coeffi cients for the

fi tted curves were 0.76 for � 5 μ m f/ml, 0.84 for � 10 μ m f/

ml, and 0.85 for � 20 μ m f/ml, supporting the hypothesis that

the minimum length for lung cancer induction is in the 10- to

20- μ m range.

In terms of the critical sites within the lungs for lung cancer

induction, brief inhalation exposures to chrysotile fi ber pro-

duces highly concentrated fi ber deposits on bifurcations of

alveolar ducts, and that many of these fi bers are phagocytosed

by the underlying type II epithelial cells within a few hours

(Brody et al. 1981, 1983). Churg (1994) has shown that both

chrysotile and amphibole fi bers that retained in the lungs of

former miners and millers do not clear much with the years

since last exposure. Thus, lung tumors may be caused by that

small fraction of the inhaled long fi bers that are retained in the

interstitium below small airway bifurcations, where clearance

processes are ineff ective.

Short fi bers can be fully ingested by macrophages (Beck

et al. 1971) and are more rapidly cleared from the lungs. The

fi brogenic response to long fi bers may result from the release

of tissue-digesting enzymes from AMs whose membranes are

pierced by the fi bers they are attempting to engulf (Allison

1977), a phenomenon called frustrated phagocytosis. The

induction of fi brosis impairs clearance of deposited fi bers,

increasing the persistence of fi bers in the lung.

The critical fi ber length is on the order of the diameter of an

AM, that is, about 10 – 15 μ m in rats and 15 – 20 μ m in humans.

This is consistent with the incidence of lung cancer in rats

exposed to fi brous aerosols, that is, that the hazard is related

to the number of fi bers longer than ∼ 10 μ m deposited and

retained in the lungs. The Timbrell (1983) model for humans

predicts alveolar retention of deposited fi bers approaching

100% for 10- μ m-long fi bers in the 0.3- to 0.8- μ m diameter

range. Airborne fi bers longer than ∼ 100 μ m may be much

less hazardous than those in the 10- to 100- μ m range because

they do not penetrate deeply into the airways, as interception

increases with fi ber length.

While the older inhalation exposure studies cited above are

the most informative about the infl uence of fi ber dimensions

that aff ect lung cancer, the fi ndings from IT administration of

fi ber suspensions, as summarized in the section on Biological

Mechanisms, are also informative with respect to critical fi ber

dimensions for lung cancer.

Schinwald et al. (2012b) injected mice IT with 120-nm-

thick silver nanowires with mean lengths of 3, 5, 10, 14,

and 28 μ m to investigate the threshold fi ber length for the

onset of pulmonary infl ammation after aspiration exposure,

and to examine fi ber length in relation to macrophage loco-

motion in an in vitro wound healing assay. They reported

a length-dependent response in the lung, with a threshold

length of 14 μ m. For impaired motility, which aff ects par-

ticle clearance from the lungs, there was a length threshold

at 5 μ m.

Murphy et al. (2013) exposed mice by IT by pharyngeal

aspiration of CNTs in 3 length ranges: 1 – 2, 1 – 5, and 84% lon-

ger than 15 μ m. They reported that the long nanotubes, but not

the two shorter samples, produced an infl ammatory response

at 1 week post-exposure in the BAL fl uid, as well as a progres-

sive thickening of the alveolar septa. They also reported only

the long nanotubes produced an infl ammatory response and

pulmonary lesions along the chest wall and diaphragm at 6

weeks post-exposure, but not at 1 week.

Summary of critical fi ber dimensions

The various hazards associated with the inhalation of mineral

fi bers, that is, asbestosis, mesothelioma, and lung cancer are

all associated with fi bers with lengths that exceed critical

values. However, it now appears that the critical length is

diff erent for each disease, that is, ∼ 2 μ m for asbestosis, ∼ 5

μ m for mesothelioma, and ∼ 15 μ m for lung cancer. There

are also diff erent critical values of fi ber diameter for the

diff erent diseases. For asbestosis and lung cancer, which

are most closely related to fi bers retained in the lungs, only

fi bers with diameters � 0.15 μ m appear to be critical on the

basis that thinner fi bers can be more readily cleared by pas-

sage into lymphatic drainage pathways. On the other hand,

for mesothelioma, which is initiated by fi bers that migrate

from the lungs to the pleura and peritoneum, the hazard may

be related to fi bers with smaller diameters that have access

to lymphatic pathways.

Although all durable fi bers of suffi cient length can pro-

duce fi brosis and cancer, as documented in various animal

studies, it appears that factors other than fi ber size can

infl uence the extent of the response. For example, inhaled

erionite appears to be much more potent for mesothelioma

in both humans and animals because of its greater ability to

penetrate the pleural surface. On the other hand, the animal

and human data appear to diff er on the ability of inhaled

chrysotile to induce mesothelioma. Animal data indicate

that chrysotile produces as much or more mesothelioma

than the amphiboles, whereas human data more often impli-

cate amphiboles, even when the predominant exposures are

to chrysotile.

The preceding implies that short fi bers will have a low

order of toxicity within the lung, comparable with that of

non-fi brous SiO 3 minerals. Within this concept, the critical

fi ber length would most likely be on the order of the diameter

of an AM, that is, about 10 – 15 μ m in rats and 15 – 20 μ m in

humans. This line of reasoning leads to the same conclusion

reached on the basis of the incidence of lung cancer in rats

exposed to fi brous aerosols, that is, that the hazard is related

to the number of fi bers longer than ∼ 10 μ m deposited and

retained in the lungs. The Timbrell (1983) model predicts

alveolar retention of deposited fi bers approaching 100%

for 10 μ m long fi bers in the 0.3- to 0.8- μ m diameter range.

Airborne fi bers longer than ∼ 100 μ m may be much less

hazardous than those in the 10- to 100- μ m range because

they do not penetrate deeply into the airways, as interception

increases with fi ber length.

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Implications of critical fi ber dimensions to health relevant indices of exposure

Although all durable fi bers in the right size range can cause

the asbestos-related diseases, they may have diff erent potencies

and need diff erent concentration limits. The remainder of this

discussion addresses the indices of exposure but not the con-

centration limits for the fi bers that fall within the indices. The

concentration limits warrant separate and further discussion.

The current occupational exposure index, based on PCOM

for fi bers with an aspect ratio � 3 and a length � 5 μ m, was a

reasonable choice, when it was made, for occupational expo-

sures involving specifi c known fi ber types. However, it is now

apparent that it cannot, as a single index, provide a scientifi -

cally adequate index for all of the diff ering hazards resulting

from exposures to: chrysotile; the various amphibole fi bers;

other mineral fi bers; and the various SVFs and other durable

fi bers. Its most important inadequacies for occupational expo-

sure evaluations in mining, milling, and manufacturing indus-

try include: 1) thin fi bers of health relevance, that is, those

with widths � ∼ 0.25 μ m, cannot be resolved by PCOM; and

2) the PCOM protocol identifi es the presence, but not the

fi ber composition or the distribution of lengths and widths for

the � 5 μ m long fi bers that can be visualized. It has further

limitations for occupational exposures in demolition, building

renovation, asbestos remediation projects, emergency response

to steam pipe explosions, building collapses, etc., where most

of the dust collected on the sampling fi lter is non-fi brous. The

background dust makes the counting of fi bers diffi cult, if not

impossible, and the fi bers that can be seen have a variety of

compositions and toxicities.

Some of these limitations can be overcome by using ana-

lytical TEM and X-ray diff raction analysis for fi ber counting

and analysis. These measurement methods enable visualiza-

tion of fi ber widths down to and below ∼ 0.1 μ m, and compo-

sitional analysis of each individual fi ber in the fi eld of view.

Unfortunately, such analyses are considerably more expensive

than PCOM for routine analyses, and the standard laboratory

protocols have not utilized the available capabilities to gener-

ate fi ber length and diameter distribution data.

There is an additional limitation of the EPA-endorsed TEM

methodology when it is applied to most exposure assessments

for evaluating carcinogenic risks to the general public. This

problem was discussed by HEI-AR (1991) and is summarized

in the next section. The TEM methodology has traditionally

been used in EPA-endorsed protocols to enumerate the count

of all fi bers greater than 0.5 μ m in length, which ends up with

counts dominated by fi bers much shorter than 5 μ m, and scans

of too little fi lter area to get statistically precise numbers of the

more health-relevant fi bers longer than 5, 15, or 20 μ m.

EPA has considered the adoption of new dimensional

criteria for hazardous fi bers based on a proposal by Berman

and Crump (2001), and it sponsored a Peer Consultation

Workshop (ERG 2003b) on the topic, but has yet to establish

such criteria.

It is now clear that exposure-related measurements of fi ber

number concentrations for human health risk evaluations

should be made by TEM, limited to those longer than 5 μ m,

and characterized in terms of the fi ber types and both the length

and diameter distributions. The concentration data should be

reported in terms of: 1) the number concentrations of fi bers

thinner than 0.1 μ m, which are most relevant for the risks

of pleural diseases; and 2) in terms of the fi bers longer than

∼ 15 μ m, which are most for the risks of pulmonary diseases.

Risk assessment issues

Use of appropriate measures of fi ber exposure

The calculation of exposure-specifi c risk depends as much on

having appropriate measurements of exposure as on estimation

of toxicity, yet too little attention has been paid to the qualities

of the exposure data. In the past, substantial excess risks have

only been observed for cohorts for which individual exposures

were estimated based on reasonably extensive historical dust

measurements of total particle count, or of fi ber counts made

using the PCOM method, both of which we now know were

of limited relevance to risk. Furthermore, there was little or no

measurement of exposure in some of the dustiest areas, and

the conversion of total particle counts to PCOM fi ber counts

was based on inconsistent measurements at relatively low lev-

els. Despite their reliance on such crude indices of exposure,

the historic studies of exposure – response relationships have

provided some very useful insights on key variables aff ect-

ing fi ber toxicity, especially fi ber type. These are reviewed in

the sections that follow for: 1) asbestos-related mesothelioma;

2) asbestos-related lung cancer; and 3) asbestos risks versus

those of synthetic vitreous and other inorganic fi bers.

Asbestos-related mesothelioma

As noted earlier, McCormack et al. (2012) assembled

data from 55 asbestos cohorts. They estimated ratios of: 1)

absolute number of asbestos-related lung cancers to mesothe-

lioma deaths; and 2) excess lung cancer relative risk (%) to

mesothelioma mortality per 1000 non-asbestos-related deaths.

The ratios varied with means of 0.7 asbestos-related lung cancers

per mesothelioma death in crocidolite cohorts; 6.1 in chrysotile;

4.0 in amosite; and 1.9 in mixed asbestos fi ber cohorts.

Pleural versus peritoneal mesotheliomas

As noted earlier, the clearest diff erence between the eff ects of

diff erent fi ber types is in the proportion of mesotheliomas in

the peritoneum. Almost all cases among chrysotile workers

having some exposure to crocidolite and/or tremolite, and

among crocidilite miners, are pleural, while with some amosite

workers have suff ered similar and sometimes higher risks of

peritoneal than pleural mesothelioma (Levin et al. 1998). An

exception was for female gas mask workers exposed mainly to

crocidolite, where several mesotheliomas were peritoneal. The

inference that most peritoneal mesotheliomas are caused by

exposure to amosite fi bers, which have larger fi ber diameters

than crocidolite fi bers, is generally accepted (HEI-AR 1991).

Hodgson and Darnton (2000) concluded that, for comparable

high-level occupational fi ber exposures to chrysotile, amosite,

and crocidolite, the mesothelioma risks were 1:100:500,

respectively. Rodelsperger and Bruckel (2006), in a meso-

thelioma case – control study, examined fi ber burdens in the

lungs of 66 cases and controls. They did not fi nd a signifi cant

odds ratio for chrysotile, but reported a signifi cant exposure –

response relationship for amphibole fi bers longer than 5 μ m.

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These results are consistent with chrysotile being much less

biopersistent, and with amosite fi bers being thicker and less

likely to reach the pleura.

For eight environmental exposures that involved exposures

judged to be on the high side (but without extensive exposure

measurements), Bourd è s et al. (2000) concluded that the rela-

tive mesothelioma risk, in comparison with background risk,

of household exposures was 8.1, while that for neighborhood

risk was 7.0. The prediction that risks at high levels of expo-

sure can be linearly extrapolated to very low concentrations

cannot be tested epidemiologically. Exposure levels have

never been recorded accurately, and the predicted risks at low

levels are far too low to be observable. The opposite belief

that the mesothelioma risk is anomalously high following very

low exposure is not supported by observation. In particular,

the mesothelioma risk following short exposure to chrysotile

may, if anything, be less than that predicted. Peto et al. (1985)

studied approximately 18,000 men with no previous asbestos

exposure employed in 1933 or later in a chrysotile textile plant.

The incidence of mesothelioma was high among men with 20

or more years ’ exposure, but only two cases were observed

among more than 16,000 men with under 10 years ’ exposure,

and one of these seems certain not to have been caused by his

employment, as the man was employed for only 4 months and

died 4 years later. The current model for mesothelioma may

thus overestimate the risk of brief (under 10 years) environ-

mental exposure, at least for chrysotile.

Asbestos-related lung cancer

For a population with 2 mesothelioma deaths per 1000 deaths

at ages 40 – 84 years (e.g., US men), McCormack et al. (2012)

estimated lung cancer population attributable fraction due to

mixed asbestos was 4.0%. Thus, all types of asbestos fi bres

other than crocidolite kill at least twice as many people through

lung cancer than through mesothelioma. The observation that

excess lung cancer risk is roughly proportional to cumulative

dose at high concentrations does not constitute very strong

evidence of a linear relationship with fi ber level, particularly

at very low levels. This prediction is even more diffi cult to

test directly for lung cancer than for mesothelioma, as lung

cancer is so common in the general population, aff ecting more

than one smoker in 10 and about one nonsmoker in 200, that

even quite large increases in risk are diffi cult to estimate reli-

ably. Prolonged low exposure to chrysotile in friction prod-

ucts, asbestos cement, and chrysotile mining has produced no

detectable excess of lung cancer (Paustenbach et al. (2004).

Even in chrysotile textile production, the sector in which the

highest dose-specifi c risks for chrysotile have been observed,

over 10 years ’ exposure at low average levels (about 5 f/mL)

produced little increase in risk in the UK study reported by

Peto et al. (1985). Workers employed for less than 10 years in

the South Carolina plant studied by Dement et al. (1983), who

were more heavily exposed than the UK workers, suff ered an

increased risk (SMR � 1.9). Moreover, there is evidence that

the relative risk of lung cancer in chrysotile-exposed workers

eventually falls after exposure to chrysotile has ceased (Walker

1984, Peto et al. 1985). The risk is very likely to diff er between

chrysotile and the amphiboles, with Hodgson and Darnton

(2000) putting the risk diff erential between 1:10 and 1:50. In

the absence of evidence that the model used for lung cancer

underestimates the long-term risk of brief or low exposure,

and in view of the previously cited reassuring observations,

the resulting predictions may, if anything, be too high for envi-

ronmental exposure. Camus et al. (1998) examined the risk

of developing lung cancer among non-occupationally exposed

women living in the vicinity of the Quebec chrysotile mines

and mills. While the relative risk predicted by EPA ’ s IRIS

model was 2.1, the measured risk was 1.0.

No extensive measurements of historical exposure levels

are available for the cohorts exposed predominantly to cro-

cidolite or amosite. Estimated levels have been published for

the crocidolite miners of Western Australia (Armstrong et al.

1988) and varied from 20 to 100 f/mL. Most were employed

for less than a year, however, and more than half had estimated

cumulative exposures below 10 f/mL years, although only

5% exceeded 100 f/mL years. In a subsequent publication,

deKlerk et al. (1989) reported a case – control analysis indicat-

ing a signifi cantly elevated lung cancer risk only in the minor-

ity of workers (about 3%) exposed for over 5 years, among

whom the relative risk was 2.2, based on 11 deaths. No other

study provides any useful exposure data for pure crocidolite,

however, and this study alone is inadequate as a basis for a

fi rm conclusion.

The situation for amosite is also unsatisfactory. The only

study of amosite workers for which dose estimates have

been provided (Seidman et al. 1979; see Nicholson 1986 for

updated lung cancer data) is a cohort of men manufacturing

amosite insulation in Paterson, New Jersey, at the beginning of

World War II. The dose estimates were based on very limited

measurements taken more than 25 years later in two diff erent

factories using similar materials and equipment. There was a

marked increase in lung cancer SMR, even in men employed

for less than 2 months (SMR � 264, based on 15 deaths), and

possible estimates of K L vary from 0.01 (using the lung cancer

rate in short-term workers as the baseline) to 0.04 (by regres-

sion on the SMR, based on local rates) (Nicholson 1986). The

SMR for men exposed for over 2 years was 650, and there

were 14 mesotheliomas (7 pleural, 7 peritoneal). There are

three major diffi culties in interpreting this study: the lack of

any direct exposure data, the anomalous pattern of SMR in

relation to duration of exposure, and the uncertainties related

to extrapolation from brief very high exposure to prolonged

low exposure.

Both amosite and crocidolite have caused high risks of meso-

thelioma after brief exposure, which has not been observed

for chrysotile. Brief amosite exposure can also cause a high

lung cancer rate. Moreover, there is consistent evidence that

the ratio of mesothelioma to excess lung cancer is much lower

for chrysotile than for amosite, and even lower for crocidolite.

One interesting inconsistency relates to the groups of work-

ers exposed to some crocidolite who suff ered a substantial risk

of mesothelioma but no detectable excess of lung cancer, in

contrast to the more heavily exposed crocidolite miners, who

appear to have suff ered a larger excess of lung cancer than

of mesothelioma. Perhaps, the most plausible interpretation of

these (and many other) diff erences is that diff erent fi ber sizes

have diff erent eff ects, either in their ability to reach the bron-

chus or to reach the lung and penetrate the pleura, or in their

biological activity in diff erent tissues. Unfortunately, however,

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our understanding of these processes is at present too limited

to justify more specifi c conclusions.

Asbestos risks versus those of synthetic vitreous and other inorganic fi bers

Although there has been a signifi cant advance in recent years

in: 1) our knowledge about the deposition and elimination

of SVFs and other inorganic fi bers; and 2) knowledge about

exposure-response in controlled animal inhalation studies;

3) cancer among heavily exposed workers in the vermiculite

industry and in residents with incidental exposures to amphi-

bole asbestos and erionite fi bers; and 4) some new insight into

the critical fi ber dimensions aff ecting disease pathogenesis.

There are also many important questions which remain to be

addressed. In some cases, the behavior and risks of airborne

SVFs and other durable fi bers can be inferred from those

of either compact particles or asbestos fi bers. On the other

hand, the validity of such inferences depends on some critical

assumptions about the aerodynamic properties of the various

fi bers and about the responses of lung and mesothelial cells

to such fi bers. The diff erences may be critical, and more in vivo studies with SVFs and other durable fi bers should be per-

formed in order to further clarify these issues. In the interim,

we already know a great deal about the nature and extent of

fi ber toxicity and the factors that modify its expression. This

knowledge provides a good basis for more defi nitive risk

assessments for such fi bers.

There are also diff erences in solubility among the fi bers

that aff ect the toxic potential among both the asbestos types

and the other durable fi bers. Conventional glass fi bers appear

to dissolve much more rapidly than other SVFs and asbes-

tos. Dissolution of glass fi bers takes place both by surface

attack and by leaching within the structure. The diameters are

reduced and the structure is weakened, favoring break up into

shorter segments. Since the smallest diameter fi bers have the

greatest surface-to-volume ratio, they dissolve most rapidly.

Thus, the relatively small fraction of the airborne glass fi bers

having diameters small enough to penetrate into the lungs are

the most rapidly dissolved within the lungs.

As noted earlier, the more biopersistent SVFs require a

higher degree of concern because of their longer retention

within the lungs. Morgan and Holmes (1984) attributed diff er-

ences in solubility in vivo of long and short fi bers to small dif-

ferences in intracellular and extracellular pH. The mechanical

stress on fi bers in vivo may also contribute to their disintegra-

tion and cannot readily be simulated in model systems.

In the case of conventional fi brous glasses, we have suf-

fi cient epidemiological information to conclude that the occu-

pational health risks associated with the inhalation of such

fi bers dispersed during their manufacture, installation, use,

maintenance, and disposal have not been measurable (Doll

1987), and hence are of an extremely low order. The health

risk from casual and infrequent indoor air exposure of build-

ing occupants to relatively low concentrations of fi brous glass

is therefore essentially nil. These judgments are based on the

following factors: 1) Conventional glass fi bers are less read-

ily aerosolized than asbestos during comparable operations,

as demonstrated by the much lower fi ber counts measured

at various industrial operations (Cherrie et al. 1986, Esmen

1984); 2) a much smaller fraction of conventional glass fi bers

than asbestos fi bers have small enough aerodynamic diam-

eters to penetrate into lung airways (i.e., fi bers with diameters

below ∼ 3 μ m) (Konzen 1984); 3) The glass fi bers that can

penetrate into the lungs are much less durable within the lung

than asbestos. They tend to break up into shorter segments,

so that fewer fi bers longer than the critical length limits are

retained at critical sites. They also tend to dissolve, further

reducing their retention (Bernstein et al. 1984, Eastes and

Hadley 1995,1996); 4) The inherent toxicity of conventional

glass fi bers is much lower than that of asbestos fi bers of simi-

lar dimension, as shown by studies in which fi ber suspensions

are applied directly to target tissues by IT instillation (Wright

and Kuschner 1977) or application of a fi ber mat to the lung

pleura (Stanton and Wrench 1972).

Thus, the risk of lung fi brosis is virtually nil unless there is

continuous exposure at concentrations high enough to maintain

a high level of lung burden for this relatively rapidly cleared

type of particulate. The risk of lung cancer is also virtually

nil unless there is continuous exposure to long fi bers at high

concentrations because of the relatively rapid breakup of long

fi bers into short fi ber segments within the lungs. Finally, the

risk of mesothelioma from inhaled conventional glass fi bers is

virtually nil under almost any circumstance. There are hardly

any glass fi bers thin enough to cause mesothelioma in the

aerosols, and the very few that may be present would dissolve

rapidly within the lungs.

In the latest IARC update of its carcinogenic hazard

identifi cation scheme for SVFs (IARC 2002), glass wool,

continuous glass fi laments, rock (stone) wool, and slag wool

were given ratings of 3 (not classifi able as to its carcinogenic-

ity to humans), while RFCs and special purpose SVFs given

ratings of 2B (Possibly carcinogenic to humans).

Discussion

A diff erent risk paradigm is needed for fi ber toxicity

Fibers represent a diff erent biological challenge than more

compact particles because their length can alter where they

deposit, the pathways for translocation to other sites within

and beyond the thorax, and where they may be retained

for long periods of time. Fibers longer than ∼ 10 μ m have

enhanced lung airway deposition due to interception and,

when they exceed ∼ 20 μ m in length, have enhanced retention

because they cannot be effi ciently cleared by phagocytic cells

that cannot fully ingest them. Frustrated phagocytosis leads to

cell lysis and the release of digestive enzymes, which contrib-

ute to pulmonary fi brosis and lung cancer. Fibers thinner than

∼ 0.1 μ m behave like ultrafi ne particles insofar as they can 1)

penetrate the pulmonary epithelia, which serve as barriers for

particles with larger diameters, and 2) pass through lymphatic

channels. Thin fi bers that are longer than ∼ 5 μ m cannot pass

through pleural stomata, and they accumulate in the stomata,

where they cause infl ammation that leads to pleural fi brosis

and mesothelioma.

While fi bers can represent greater toxic challenges than

more compact particles, they also share some challenges com-

mon to all particles that diff er from those of gaseous air pollut-

ants. All particles that deposit on respiratory epithelia deliver

more concentrated local doses than the individual molecules

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of gas-phase pollutants that deposit more uniformly via diff u-

sion. The greater local dosage may initiate foreign body reac-

tions from the surface cells that they encounter.

Like particles in general, the total mass concentrations of

fi bers, that we now know can cause excess mortality and mor-

bidity in the general population, are low in relation to those

of most toxic gases and vapors. As discussed in my recent

CRT paper on the toxicity of ambient air particulate mat-

ter and its chemical components (Lippmann 2014), some of

the more soluble components of ambient air fi ne particulate

matter (PM 2.5

), with concentrations in the low ng/m 3 range,

generate ROS that may account for the excesses in disease

associated with the PM 2.5

mass concentration in the ambient

air. By contrast, there is little evidence that the in vivo dis-

solution of chemical components of inhaled fi bers contributes

to the adverse eff ects associated with their inhalation. Rather,

partial dissolution of the fi bers reduces their toxicity, as for

chrysotile asbestos fi bers in comparison with the amphibole

asbestos fi bers, or eliminates their toxicity, as for conventional

glass fi bers.

Diff erences in critical fi ber characteristics for the diff erent asbestos-related diseases

As noted in this critical review paper, inhaled asbestos fi bers

cause two diseases whose only other causes are fi bers with

similar dimensional and biopersistance characteristics. These

are: 1) a diff use pulmonary fi brosis that diff ers from the more

focal pulmonary fi brosis caused by crystalline quartz par-

ticles; 2) mesothelioma, a cancer of the pleura and peritoneum

that is not known to be caused by any other air pollutants; 3)

various mineral and vitreous fi bers also increase lung cancer

mortality, a disease that is also caused by non-fi brous air pol-

lutants. It is also important to recognize that the incidences

of these three diseases that are associated with the inhalation

of biopersistent fi bers have diff erent fi ber size dependences.

Lung fi brosis is related to the surface area of fi bers longer than

∼ 2 μ m: mesothelioma is caused by fi bers thinner than ∼ 0.1 μ m

that are longer than ∼ 5 μ m, and lung cancer is caused by fi bers

with diameters up to 3 μ m that are longer than ∼ 20 μ m.

The only caveats that I have about these diff erent criti-

cal fi ber dimensions for the diff erent fi ber-related diseases,

and about critical dissolution rates for fi bers in vivo , con-

cerns interspecies extrapolation. The specifi city that I have

relied upon comes primarily from toxicological studies. The

population-based studies in humans have seldom been based

on bivariate TEM fi ber size distributions, lack fi ber size dis-

tribution data for the diff erent mineral types, and are gener-

ally limited to adults. The Loomis et al. (2010) study on the

critical fi ber lengths for chrysotile asbestos textile workers

has provided, by far, the best example for confi rming that

lung cancer in humans is most closely associated with fi bers

longer than ∼ 20 μ m. Some diff erence in critical fi ber length

may be expected considering that human macrophages are

somewhat larger than those of laboratory animals. While in vivo dissolution rates are not likely to vary much between

humans and laboratory animals, lifespans are very diff erent,

and the time between exposures to fi bers and the expres-

sion of disease is measured in months to a few years in the

laboratory animals and decades in humans. Thus, fi bers may

need to be considerably more biopersistent to cause disease

in humans than in laboratory animals.

Summary of human responses to long-term mineral fi ber inhalation exposures

As noted earlier, one common theme is that amphibole and eri-

onite fi bers are more closely associated with mesothelioma and

pleural plaques than chrysotile, while chrysotile fi bers are more


than are amphibole. Furthermore, in those limited numbers

workers exposed to chrysotile who developed mesothelioma,

there was more tremolite in their lungs than chrysotile.

A second theme comes from the few studies that addressed

the issue of critical fi ber length. Loomis (2010) demonstrated

that the high lung cancer incidence in the South Carolina tex-

tile workers cohort was most closely associated with chrysotile

fi ber longer than 20 μ m. The Rodelsperger and Bruckel (2006)

mesothelioma case – control study did not fi nd a signifi cant

odds ratio for chrysotile, but did report a signifi cant exposure –

response relationship for lung cancer for amphibole fi bers

longer than 5 μ m.

Summary of animal responses to long-term mineral fi ber inhalation exposures

The most common theme from the epidemiologic literature,

that is, that amphibole (especially crocidolite and tremolite)

and erionite fi bers are most often more closely associated with

mesothelioma and pleural plaques than are chrysotile fi bers,

could not be tested adequately in rat inhalation studies because

rats developed very few mesotheliomas over their ∼ 2 years

lifespans. However, when rats were exposed to crocidolite or

erionite, the crocidolite produced 1 lung cancer in 28 rats (but

no mesotheliomas), whereas the erionite produced no lung

cancers in 28 rats but did produce 27 mesotheliomas.

In terms of the second theme, that chrysotile fi bers are more


than are amphibole fi bers, the best evidence comes from the

long series of studies by Davis and colleagues who exposed

rats to equal number concentrations of fi bers � 5 μ m in length

of chrysotile, crocidilite, and amosite, all with median diam-

eters of ∼ 0.4 μ m. The concentration ratios of � 20 to � 5 μ m

were 0.185, 0.040, and 0.011, respectively. The fi brogenic

and carcinogenic responses were greater in the chrysotile

exposures than in the crocidolite, or amosite exposures were

probably related to the greater lengths of the chrysotile fi bers.

When they subsequently used amosite with fi ber lengths both

shorter and longer than UICC amosite, the short amosite

produced virtually no fi brosis, whereas the long amosite was

more fi brogenic than chrysotile. For a comparable study with

short, UICC, and long chrysotile, the highest lung tumor yield

was for the long-fi ber chrysotile. When Berman et al. (1995)

analyzed the lung tumor and mesothelioma responses from

13 of the studies by Davis and colleagues in relation to new

measurements of the fi ber distributions on archived chamber

fi lters, the measure most highly correlated with tumor inci-

dence was the concentration of fi bers � 20 μ m in length. In

my own review of the chronic rat inhalation studies with

amosite, brucite, chrysotile, crocidolite, erionite, and tremolite

(Lippmann 1994), I found that, for lung cancer, the percentage

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of lung tumors correlated best with fi bers � 20 μ m in length,

and seemed to be independent of fi ber type.

Similar conclusions concerning the infl uence of fi ber

length were drawn by Miller et al. (1999b) for 18 rat inhala-

tion studies involving fi bers of amosite, SiC whiskers, various

SVFs, and various RCFs. The primary infl uences on biologi-

cal responses was the number of fi bers � 1.0 μ m in diameter

and � 20 μ m in length, along with the dissolution rate of the

fi bers. Another important observation was that in vivo and

in vitro cell responses did not signifi cantly predict the risk

of cancer following inhalation. Likewise, when McConnell

et al. (1999) exposed hamsters for 78 weeks to amosite and

two diff erent fi brous glasses. One of the glasses produced

only mild infl ammation, while the other one produced more

severe infl ammation and mild interstitial and pleural fi brosis,

as well as one mesothelioma. Amosite produced severe pul-

monary fi brosis and many mesotheliomas. The eff ects were

most closely related to the retained fi bers � 20 μ m in length,

and were consistent with the in vitro dissolution rates. Cullen

et al. (2000) also compared the pathogenicity of amosite to

that of glass microfi bers having low dissolution rates (104E

and 100/475) in a study, but in rats. In terms of mesothelioma

and lung cancers produced, a biopersistent glass and amosite

fi bers were considerably more potent than the more soluble

glass fi bers.

Infl uence of lung retention on pulmonary responses

For long and short asbestos fi bers and SVF instilled IT into

guinea pigs, fi bers longer than ∼ 10 μ m of all types produced

lung fi brosis (Wright and Kuschner 1977). Libby amphibole

(LA) asbestos instilled into rats caused concentration- and

time-dependent interstitial fi brosis, with SHHS rats develop-

ing bronchiolar epithelial lesions (Shannahan et al. 2012). For

silver nanowires, injected into mice IT, there was a length-

dependent response in the lung, with a threshold length of 14

μ m. For impaired motility, there was a length threshold at 5 μ m

(Schinwald et al. (2012b). For mice exposed IT to CNTs (1 – 2,

1 – 5, and 84% longer than 15 μ m), the long nanotubes, but

not the shorter samples, produced an infl ammatory response

at 1 week in BAL fl uid, as well as a progressive thickening

of the alveolar septa. The long nanotubes also produced an

infl ammatory response and pulmonary lesions along the chest

wall and diaphragm at 6 weeks post-exposure (Murphy et al.

(2013).

Pleural responses

For 9 rat IP injection studies (amosite, SiC, 4 SVEs, and 3 RCFs),

mesothelioma was linked with number of injected fi bers � 20

u m in length, and biopersistence in rat lungs with fi bers � 5

μ m in length. For mice injected IP with silver nanowires (mean

lengths of 3, 5, 10, 14, and 28 μ m), along with nickel nano-

wires (4 and 20 μ m long), CNTs (13 and 36 μ m long), and two

amosite asbestos dusts (long fi bers with 100% longer than 5 μ m,

50% � 15 μ m, and 35% � 20 μ m, and short with 3% � 5 μ m),

there was an acute pleural response with a threshold fi ber length

of 4 μ m (Schinwald et al. 2012a), suggesting that fi bers 5 μ m

or longer that are translocated to the pleural space are retained,

where they can elicit infl ammation, because they cannot negoti-

ate the stomata in the parietal stomata.

Coherence of the biological responses in humans and animals

The McCormack et al. (2012) assembly of data from 55 asbes-

tos cohorts is informative with respect to the insights that it

provides on the issue of coherence, especially in terms of esti-

mated ratios of: 1) absolute number of asbestos-related lung

cancers to mesothelioma deaths; and 2) excess lung cancer

relative risk (%) to mesothelioma mortality per 1000 non-

asbestos-related deaths. The ratios varied by asbestos type;

there were means of 0.7 asbestos-related lung cancers per

mesothelioma death in crocidolite cohorts; 6.1 in chrysotile;

4.0 in amosite; and 1.9 in mixed asbestos fi bers. Thus, all

types of asbestos fi bres other than crocidolite kill at least twice

as many people through lung cancer than through mesothe-

lioma. For chrysotile, there were too few mesothelioma deaths

to infer no excess risk of lung or other cancers.

Thus, the epidemiologic evidence is very convincing with

respect to the greater potency of amphibole fi bers than chryso-

tile fi bers in causing mesothelioma in humans. For humans,

the few studies that were able to investigate the infl uence of

fi ber length pointed to fi bers � 20 μ m in length as the most

potent inducers of pulmonary fi brosis and lung cancer.

In contrast to the human experience, there were too few

mesotheliomas in the long-term rat inhalation exposure stud-

ies with amphiboles and chrysotile to demonstrate coherence.

However, the extremely high incidence of mesothelioma in

hamsters exposed to erionite did demonstrate that durable

mineral fi bers can be potent inducers of mesothelioma. With

respect to the infl uence of fi ber dimensions on lung cancer

incidence, there is fi rm evidence that fi bers that are longer

than ∼ 20 μ m are most highly infl uential in rats.

Neither the human nor the in animal long-term inhalation

exposure studies were able to shed light on the infl uence of

fi ber diameter on health eff ects. For that, we need to look

to the fi ndings of in vivo animal exposures using IT and IP

administration. However, examination of the fi ber content of

the lungs of asbestos workers and animals exposed by inhala-

tion shows that chrysotile is cleared much more rapidly from

the lungs than the amphiboles. Chrysotile fi bers break down

within the lungs both by disaggregation into fi brils and by dis-

solution. The diff erences between the responses to chrysotile

in animals and those in humans may be due to their diff erences

in persistence, that is, time of persistence of the long fi bers in

the lung relative to the time interval between exposure and the

expression of the disease. In other words, the long fi bers may

be retained in the lung for a longer fraction of the lifespan in

the rat.

Coherence of the human and animal response data with known characteristics of fi ber type and dimensional distributions

Knowing that both fi ber type and dimensional distributions

aff ect the type and potency of asbestos fi bers, and that dimen-

sional distributions vary with fi ber type, we should expect that

crocidolite, with the greatest proportion of thin fi bers than the

other amphiboles would be more potent in terms of causing

pleural plaques and mesothelioma in humans than the other

amphiboles. Since amosite, with thicker fi bers, is intermedi-

ate in its association with mesothelioma, and anthophyllite,

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with the thickest fi bers, is least associated with mesothelioma

in humans, the weight of the evidence supports the supposi-

tion that thin amphibole fi bers are most potent for causing the

pleural diseases. The fact that chrysotile, which has thin fi bers,

causes relatively little pleural disease in humans, and that little

may be due to the tremolite within the fi ber mix, is most likely

due to the much greater in vivo solubility of chrysotile fi bers,

especially of the thinnest fi bers, than of the amphiboles. Thin

chrysotile fi bers � 5 μ m in length may dissolve before they

can even reach the pleura, and if they do, they may dissolve

before they produce any chronic eff ect.

Pulmonary fi brosis and lung cancer have been most closely

related to asbestos fi bers � ∼ 20 μ m of all of the asbestos types,

and have been more closely associated with chrysotile fi ber

exposures than with amphibole fi ber exposures. These fac-

tors may be related to the much greater usage and exposures

to chrysotile. Also, there is evidence that at least some long

chrysotile fi bers, as well as tremolite fi bers that accompany

some chrysotiles, are retained within the lungs for long time

periods. The lengths of fi bers � 10 μ m in the exposure cham-

bers of the chronic rat inhalation studies of Davis et al. (1985,

1987) of short- and long-fi bers of amosite and chrysotile by

PCOM were 1,930 and 330 f/mL for chrysotile, whereas for the

amosite they were 1,110 and 12 f/mL. Despite the much more

rapid clearance of the chrysotile from the lungs, the tumor

yields for chrysotile were higher. For the “ long ” fi ber, there

were 22 tumors for the chrysotile vs. 13 for the amosite. For the

“ short ” fi ber, there were 7 vs. 0. Thus, there were substantial

exposures to long fi bers in the short chrysotile exposure (330

f/mL longer than 10 μ m). Since chrysotile fi bers are the thin-

nest among the asbestos types, and the PCOM counts could not

include fi bers � 0.25 μ m in width, the exposures to long, thin

chrysotile fi bers in both human and chronic animal inhalation

studies were much larger than those based on PCOM counts.

For the exposures to the less biopersistent SVFs, there has

been little evidence for either pleural or pulmonary diseases

for uncomplicated exposures. Since SVFs, with the excep-

tion of the relatively small volumes of glass microfi bers,

have very small fractions of fi bers less than even 1 μ m, we

should not have expected any pleural responses. Considering

their relatively rapid in vivo dissolution, we should not have

expected any pulmonary responses to the fi bers � ∼ 20 μ m in

length. The limited evidence of some responses for some more

biopersistent RCFs and slagwools is consistent with what we

should have expected.

In summary, when we take what we now know about the

infl uences of fi ber type, dimensional distributions, and biop-

ersistence into account, the nature and extent of pleural and

pulmonary responses to the chronic inhalation of airborne

fi bers of chrysotile, various amphiboles, and SVFs are coher-

ent, even when we have had to rely on inadequate methods of

exposure assessment.

Overall summary of in vivo biological responses to various durable fi bers

Durable fi bers thinner than 1) ∼ 0.1 μ m in diameter are trans-

located from the lung parenchyma to pleural sites where

they can initiate pleural infl ammation, plaque formation,

and mesothelioma.

Durable fi bers thicker than 2) ∼ 0.1 μ m in diameter that remain

on or in cells at or near the lung parenchyma can initiate

lung infl ammation, pulmonary fi brosis, and lung cancer.

Pleural responses require that the fi bers have lengths 3) � 5

μ m.

Pulmonary responses to fi bers require fi ber lengths 4)

greater than ∼ 20 μ m.

All varieties of amphibole asbestos and erionite 5)

fi bers are suffi ciently durable in vivo to be considered to

be highly toxic and diff erences in their abilities to produce

lung and pleural responses depend primarily on their fi ber

length and diameter distributions.

Chrysotile asbestos fi bers are less toxic than amphi-6)

bole fi bers because of their greater in vivo solubility leads

to their dissolution and breakage by length. However, air-

borne chrysotile fi bers are often present in longer lengths

than those of other asbestos fi bers, and lengths � 20 μ m are

not rapidly cleared from the lungs.

SVFs, RCFs, CNTs, and other inorganic fi bers are 7)

generally less toxic than amphibole fi bers in humans and in

the rat due to in vivo dissolution, but can have compositions

that make them biopersistent.

My current perspectives on the role of airborne inorganic fi bers in causing health eff ects

Refl ection on the contributions of the pioneers in the fi eld

My review of the extensive literature on the associations of

inhalation exposures to durable airborne fi bers, and their

health eff ects has left me with several general impressions.

These are:

Many of the pioneering investigators were remarkably 1.

astute observers of informational signals and their signifi -

cance. I call particular attention to:

Ellman (1933), who recognized very early on that inha-a.

lation exposure to asbestos dust caused a delayed lung

fi brosis that diff ered from, and progressed more rapidly,

than silicosis;

Gloyne (1930), who recognized very early on that inha-b.

lation exposure to asbestos dust caused pleural plaques;

Lanza et al. (1935), who recognized very early on that c.

the amount of dust in the air in asbestos plants studied

could and should be substantially reduced;

Gloyne (1951) and Doll (1955), who recognized rela-d.

tively early on that exposure to asbestos dust caused

excess lung cancer;

Wagner et al. (1960), who recognized relatively early on e.

that exposure to asbestos dust caused mesothelioma;

Stanton and Wrench (1972); Davis (1976); Pott et al. f.

(1976), and Wright and Kuschner and (1977), who rec-

ognized relatively early on that in vivo animal exposures

could eff ectively be used to do comparative studies on

chronic disease following IT and IP administration of

asbestos, other mineral and synthetic fi bers;

Stanton and Wrench (1972) and Wright and Kuschner g.

(1977), who recognized relatively early on that fi ber

dimensions were critical determinants of chronic eff ects;

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Wright and Kuschner (1977), who recognized relatively h.

early on that fi ber durability was a critical determinant

of biological responses.

2. There were serious technical limitations facing the some-

what later generations of investigators who sought to gain

a better understanding of risk factors accounting for the

biologic responses to fi bers. These included: A) inadequate

knowledge and tools for measuring the concentrations and

relevant physicochemical characteristics of the airborne

fi bers in occupational and laboratory environments; B)

inadequate knowledge and tools for the preparation of

well-characterized doses of fi bers for toxicological stud-

ies; C) reliance on experimental models based on chemical

toxicity rather than on models of physical factors aff ecting

biological processes; and D) reliance on fi ber concentration

measurement methods and data that did not include fi ber

concentrations by fi ber type, length, and diameter.

3. There was a failure of research sponsors to encourage sophis-

ticated research that could overcome the persistent techni-

cal problems of exposure assessment for airborne fi bers

through, for example, Requests for Research Proposals, an

exception being the industrial support of research on fi ber

durability and its management in product development.

4. Substantial recent progress on elucidating and controlling

factors aff ecting fi ber toxicity is being made at Centers

employing state-of-the-art physical and biological tech-

niques such as the MRC/University of Edinburgh Centre for

Infl ammation Research supported by the Colt Foundation,

the Owens-Corning Corp., and by Navistar Inc., which con-

tinued the research program initiated by Dr. Paul Kotin at

Johns-Manville.

What I now know with reasonable certainty

Fiber dimensions and types are critical determinants of bio-1.

logical responses, with diff erent critical fi ber lengths and

diameters for lung fi brosis, pleural plaques, mesothelioma,

and lung cancer.

Short fi bers that are eff ectively cleared from epithelial cells 2.

by phagocytic cells and mucociliary clearance can be con-

sidered to be nuisance dusts.

Fibers longer than 3. ∼ 20 μ m, which are retained in pulmonary

airways can, if they are biopersistent, cause lung cancer.

Very thin fi bers penetrate lung epithelia and translo-4.

cate via lymphatic channels to pleural surfaces where

fi bers longer than ∼ 5 μ m, if they are biopersistent, cause:

can cause pleural plaques and mesothelioma.

Fiber durability, a function of fi ber type, is an impor-5.

tant key modifying factor for the longer fi bers, aff ecting the

number of responders and/or the extent of response.

All long amphibole fi bers are suffi ciently durable 6. in vivo to be

considered to be biopersistent and, except for the substantial

infl uence of their diff ering dimensions, to be equally toxic.

Chrysotile fi bers, except for the long fi bers that remain 7.

outside of phagocytic lung cells, are less biopersistent than

amphibole fi bers.

Mesotheliomas associated with exposures to the process-8.

ing of chrysotile fi bers are most likely caused by the co-

presence of amphibole fi bers (e.g., tremolite) in some

chrysotile ore bodies.

Conventional fi brous glass, especially glass products 9.

recently reformulated for greater biosolubility, dissolves

too quickly in vivo to cause lung fi brosis or cancer.

Durable fi bers can continue to expose cells 10. in vivo for

years after they are inhaled, and chronic inhalation expo-

sure is not needed for the initiation and progression of the

chronic diseases associated with fi ber exposures.

Incidental and low-level chronic exposures to durable 11.

fi bers are unlikely to lead to disability due to lung fi brosis

because of the large reserve capacity in our lungs. How-

ever, such exposures do present signifi cant cancer risks in

the general population.

The quite diff erent responses to chronic inhalation expo-12.

sures of humans and rats among chrysotile fi bers, the

various amphibole fi bers, and SVFs, in terms of pleural

and pulmonary diseases, become coherent when current

knowledge of the infl uences of fi ber type, dimensional

distributions and biopersistence are taken into account.

What I consider to be uncertain are the following

the critical coeffi cients for 1. in vivo fi ber dissolution that

determine residual human health risks;

the roles of fi ber surface area or other surface properties on 2.

health risks; and

the extent to which the results of laboratory-based 3.

toxicology studies on CNTs and metallic nanowires can

be considered to be reliable surrogates for the prediction

of adverse eff ects associated with inhalation exposures to

mineral fi bers and SVFs.

What I consider to be the key research needs to refi ne the remaining uncertainties associated with exposures to durable airborne fi bers

Determination of the factors that make rats more sus-1.

ceptible to lung cancer and hamsters more susceptible to

mesothelioma in long-term fi ber inhalation assays.

Performance of long-term fi ber inhalation studies in rats with 2.

size-classifi ed fi bers having comparable rat-respirable diam-

eters and length distributions for: an amphibole; a pure chryso-

tile; a chrysotile with a small percentage of tremolite; SVFs of

graded dissolution coeffi cients, including conventional fi brous

glass, rockwool, and RCF; and of various kinds of CNTs.

For the fi bers that produce signifi cant biological responses, 3.

determination of the extent to which fi ber dimensions, disso-

lution rates, and surface properties account for the toxicity.

Implications of our enhanced understanding on factors aff ecting fi ber toxicity

Risk assessment

As long as exposure assessment remains a weak link in the

performance of risk assessments, our ability to perform cred-

ible quantitative risk assessments will remain severely limited.

To be able to perform credible exposure assessments, we will

fi rst need to reach an expert consensus on: 1) the fi ber param-

eters that should be measured; 2) on appropriate methodolo-

gies for air sampling, laboratory analyses; and 3) procedures

and repositories for data management, retention, and access.

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Possible ambient air exposure standards for airborne inorganic fi bers

In the absence of credible exposure assessment methods, it

would be prudent, at this time, to focus our eff orts in protect-

ing general populations from exposures, and on further eff orts

to specify the usage of fi bers that are not biopersistent in new

applications. The strong dependence of eff ects on fi ber type,

diameter, length, and biopersistence makes reliable quantitative

exposure and risk assessment impractical in some cases, since it

would require TEM examination of representative fi lter samples

for statistically signifi cant numbers of fi bers longer than both 5

and 20 μ m, and thinner than 0.1 μ m, by fi ber types using x-ray

analysis of the individual fi bers. If such data cannot be gener-

ated, an alternative approach, used in the US for hazardous air

pollutants, is to designate National Emissions Standards that can

be applied to industrial operations involving the handling and/or

processing of materials containing durable inorganic fi bers.

Strategies to control exposures to ambient air fi bers

Prevention of excessive exposures will need to be based on

proven means of emission control strategies for hazardous

fi bers that can be dispersed during industrial operations involv-

ing the handling and/or processing of materials containing

durable inorganic fi bers, and during facility renovations and

demolitions. There will also be a need for continuing monitor-

ing of the eff ectiveness of the designated source controls.

Conclusions

Airborne Fibers, if they are suffi ciently biopersistent, can 1)

cause chronic pleural diseases not caused primarily by their

chemical components, as well as pulmonary fi brosis and

excess lung cancers.

Mesothelioma and pleural plaques are caused by biopersis-2)

tent fi bers thinner than ∼ 0.1 μ m and longer than ∼ 5 μ m.

Excess lung cancer and pulmonary fi brosis are caused 3)

by biopersistent fi bers that are longer than ∼ 20 μ m.

While biopersistence varies with fi ber type, all amphibole and 4)

erionite fi bers are suffi ciently biopersistent to be highly toxic.

The greater 5) in vivo solubility of chrysotile fi bers makes

them less toxic for the lungs, and much less toxic for the

pleural diseases.

The greater of lengths of airborne chrysotile fi bers 6)

∼ 20 μ m in length in human exposures and in the chronic

animal inhalation studies made them potent agents for pul-

monary fi brosis and lung cancer.

Most SVFs are more soluble 7) in vivo than chrysotile, and

pose little, if any, health pulmonary or pleural health risk.

Some specialty glass, mineral wool, and RCFs are 8)

suffi ciently biopersistent to be toxic.

Extrapolations of exposure – response relationships from the 9)

results of some early epidemiological and chronic animal

inhalation studies need to be interpreted cautiously, since

the eff ects observed may have been infl uenced by overload-

ing of clearance capacity.

These conclusions are based on: 1) epidemiologic studies that

specifi ed the origin of the fi bers by type, and especially those

that identifi ed their fi ber length and diameter distributions; 2)

laboratory-based toxicologic studies involving fi ber size char-

acterization and dissolution rates and long-term observation

of biological responses; and 3) the largely coherent fi ndings of

the epidemiology and the toxicology studies.

The strong dependence of eff ects on fi ber diameter, length,

and biopersistence makes reliable quantitative exposure and

risk assessment impractical in some cases, since it would

require TEM examination of representative membrane fi lter

samples for suffi cient numbers of fi bers longer than 5 and 20

μ m, and thinner than 0.1 μ m, by fi ber types. Prevention of exces-

sive exposures will need to be based on proven means of source

control, and continuing monitoring of their eff ectiveness.

Acknowledgments

This research was performed as part of a Center Program

supported by NIEHS (Grant ES 00260). It includes extensive

review material from my earlier review papers, specifi cally:

Lippmann (1988, 1990, 1994, 2009) and from my contri-

butions to the Final Report of the Health Eff ects Institute-

Asbestos Research (1991).

I also wish to acknowledge the seminal work on fi bers

by professional colleagues. I give special thanks to Marvin

Kuschner, who was the fi rst to introduce me to the critical

importance of fi ber dimensions and biopersistence, and to

Christopher Wagner, John Davis, Vernon Timbrell, Julian

Peto, Bruce Case, David Bernstein, Brooke Mossman, Gene

McConnell, Ken Donaldson, Tom Hesterberg, John Hadley,

and Wayne Berman for their especially insightful research

reports and comments in panel discussions at workshops on

fi bers that were sponsored by EPA, ATSDR, NIOSH, and

NIEHS. I also acknowledge the nine peer reviewers of the fi rst

submission of this CRT for their many constructive comments

and suggestions for additional citations and clarifi cations.

Declaration of interest

The affi liation of the author is as shown on the cover page.

The research that is the cornerstone of this paper was sup-

ported, in part, by the National Institute of Environmental

Health Sciences (NIEHS – Grant ES 00260), which has pro-

vided Center Program support for the author ’ s research at New

York University (NYU) since 1964. The author received no

external funding for the preparation of this paper. The author

has frequently off ered advice to government agencies on the

addressing the hazards of airborne fi bers. Prior to the submis-

sion of this manuscript for publication in CRT, the author had

not ever off ered expert testimony on behalf of individuals,

public interest groups, or corporations in legal proceedings on

scientifi c matters that are the subject of this paper. The data

summaries, other than those cited in Table and Figure cap-

tions, my syntheses, and my interpretations of the data in this

critical review are exclusively those of the author, and do not

necessarily represent those of NYU or NIEHS.

References ACGIH-AIHA Aerosol Hazards Evaluation Committee . (1975) .

Recommended procedures for sampling and counting asbestos fi bers .

Am Ind Hyg Assoc J , 36 , 83 – 90 .

Adamson IYR . (1997) . Early mesothelial cell proliferation after asbestos

exposure: In vivo and in vitro studies . Environ Health Perspect , 105 ,

1205 – 8 .

Cri

tical

Rev

iew

s in

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f M

aryl

and

on 1

0/14

/14

For

pers

onal

use

onl

y.


Albin M , Pooley FD , Str ö mberg U , Atteweil U , Mitha R , Johansson L ,

Welinder H . (1994) . Retention patterns of asbestos fi bers in lung tissue

among asbestos cement workers . Occup Environ Med , 51 , 205 – 11 .

Alexander BH , Raleigh KK , Johnson J , Mandel JH , Adgate JL ,

Ramachandran G , et al . (2012) . Radiographic evidence of

nonoccupational asbestos exposure from processing Libby vermiculite

in Minneapolis, MN . Environ Health Perspect , 120 , 44 – 9 .

Allison AC . (1977) . Mechanisms of macrophage damage in relation to

the pathogenesis of some lung diseases . In: Brain JD , Proctor DF , Reid

LM , Eds. Respiratory Defense Mechanisms Part II New York: Marcel

Dekker , pp. 1075 – 102 .

Armstrong BK , de Klerk NH , Musk AW , Hobbs MST . (1988) . Mortality

in miners and millers of crocidolite in Western Australia . Br J Ind Med ,

45 , 5 – 13 .

Ashcroft T , Simpson JM , Timbrell V . (1988) . Simple method of estimating

severity of pulmonary fi brosis on a numerical scale . J Clin Pathol , 41 ,

467 – 70 .

ATSDR . (2004) . Toxicological Profi le for Synthetic Vitreous Fibers .

Atlanta, Georgia: Agency for Toxic Substances and Disease Registry

Balashazy I , Moustafa M , Hofmann W , Szoke R , El-Hussein A , Ahmed

A-R . (2005) . Simulation of fi ber deposition in bronchial airways . Inhal

Toxicol , 17 , 717 – 27 .

Barbieri PG , Mirabelli D , Somigliana A , Cavone D , Merler E . (2012) .

Asbestos fi bre burden in the lungs of patients with mesothelioma who

lived near asbestos-cement factories . Ann Occup Hyg , 56 , 660 – 70 .

Baris YI , Artvinli M , Sahin AA , Sebastien P , Gaudichet A . (1987) .

Diff use lung fi brosis due to fi brous zeolite (erionite) . Eur J Respir Dis ,

70 , 122 – 5 .

Baris YI , Saracci R , Simonato L , Skidmore JW , Artvinli M . (1981) .

Malignant melanoma and radiological chest abnormalities in two

villages in Central Turkey: an epidemiological and environmental

investigation . Lancet , 1 , 984 – 7 .

Baris YI , Simonato L , Artvinli M , Pooley F , Saracci S , Skidmore J ,

Wagner C . (1987) . Epidemiological and environmental evidence of the

health eff ects of exposure to erionite fi bers: A four-year study in the

Cappadocian region of Turkey . Int J Cancer , 39 , 10 – 17 .

Baris YI , Grandjean P . (2006) . Prospective study of mesothelioma

mortality in Turkish villages with exposure to fi brous zeolite . J Natl

Cancer Inst , 98 , 414 – 7 .

Barrett JC , Lamb PW , Wisemen RW . (1989) . Multiple mechanisms for

the carcinogenic eff ects of asbestos and other mineral fi bers . Environ

Health Perspect , 81 , 81 – 9 .

Bauman MD , Jetten AM , Bonner JC , Kumar RK , Bennett RA , Brody

AR . (1990) . Secretion of a platelet-derived growth factor homologue

but rat alveolar macrophages exposed to particulates in vitro . Eur J

Cell Biol , 51 , 327 – 34 .

Beck EG , Bruch J , Friedricks KH , Hilscher W , Pott F . (1971) . Fibrous

silicates in animal experiments and cell-culture in morphological cell

and tissue reactions according to diff erent physical chemical infl uences .

In: Walton WH , Ed. Inhaled Particles III, Old Woking, UK: Unwin

Bros , pp. 477 – 86 .

Begin R , Gauthier JJ , Desmeules M , Ostiguy G . (1992) . Work-related

mesothelioma in Quebec, 1967 – 1990 . Am J Ind Med , 22 , 531 – 42 .

Bellmann B , Konig H , Muhle H , Pott H . (1986) . Chemical durability of

asbestos and of man-made mineral fi bres in vivo . J Aerosol Sci , 17 ,

341 – 5 .

Bellmann B , Muhle H , Pott H , Konig H , Kloppel H , Spurny K . (1987) .

Persistence of man-made mineral fi bers (MMMF) and asbestos in rat

lungs . Ann Occup Hyg , 31 , 693 – 709 .

Bellmann B , Muhle H , Creutzenberg O , Ernst H , Brown RC , S é bastien

P . (2001) . Eff ects of nonfi brous particles on ceramic fi ber (RCF1)

toxicity in rats . Inhal Toxicol , 13 , 877 – 901 .

Berman W , Chatfi eld EJ . (1989) . Interim Superfund Method for the

Determination of Asbestos in Ambient Air . Part II: Technical

Background Document. Draft Report EPA Contract No. 68-61-7290,

Task 117, USEPA, Region 9, San Francisco, CA 94105 .

Berman DW , Crump KS , Chatfi eld EJ , Davis JMG , Jones AD . (1995) .

The sizes, shapes, and mineralogy of asbestos structures that induce

lung tumors or mesothelioma in AF-HAN rats following inhalation .

Risk Anal , 15 , 181 – 95 .

Berman DW , Crump KS . (2008a) . A meta-analysis of airborne asbestos-

related risk that addresses fi er size and mineral type . Crit Rev Toxicol ,

38 , 49 – 73 .

Berman DW , Crump KS . (2008b) . Update on potency factors for asbestos-

related lung cancer and mesothelioma . Crit Rev Toxicol , 38 , 1 – 47 .

Berman DW , Crump KS . (2001) . Technical Support Document for a

Proposal to Assess Asbestos-Related Risk . Final Draft. Prepared for

the U.S. Environmental Protection Agency and the U.S. Department of

Transportation. Sept. 4 , 2001 .

Berman DW , Cox LA Jr , Popken DA . (2013) . A cautionary tale: The

characteristics of two-dimensional distributions and their eff ects on

epidemiological studies employing an ecological design . Crit Rev

Toxicol , 43 , 1 – 25 .

Bernstein DM , Drew RT , Schidlovsky G , Kuschner H . (1984) .

Pathogenicity of MMMF and the contrasts to natural fi bers. In:

Biological Eff ects of Man-Made Mineral Fibers, Vol. 2 Copenhagen:

World Health Organization, pp. 169 – 95.

Bernstein DM , Morscheidt C , Grimm H-G , Thevenaz P , Teichert U .

(1996) . Evaluation of soluble fi bers using the inhalation biopersistence,

a nine- fi ber comparison . Inhal Toxicol , 8 , 345 – 85 .

Bernstein DM , Riego Sintes JM , Ersboell BK , Kunert J . (2001a) .

Biopersistence of synthetic mineral fi bers as a predictor of chronic

inhalation toxicity in rats . Inhal Toxicol , 13 , 823 – 49 .

Bernstein DM , Riego Sintes JM , Ersboell BK , Kunert J . (2001b) .

Biopersistence of synthetic mineral fi bers as a predictor of chronic

intraperitoneal injection tumor response in rats . Inhal Toxicol , 13 ,

851 – 75 .

Bernstein DM , Rogers R , Smith P . (2004) . The biopersistence of Brazilian

chrysotile asbestos following inhalation . Inhal Toxicol , 16 , 745 – 61 .

Bernstein DM , Chevalier J , Smith P . (2005a) . Comparison of calidria

chrysotile asbestos to pure tremolite: fi nal results of the inhalation

biopersistence and histopathology examination following short-term

exposure . Inhal Toxicol , 17 , 427 – 49 .

Bernstein DM , Rogers R , Smith P . (2005b) . The biopersistence of

Canadian chrysotile asbestos following inhalation: fi nal results through

1 year after cessation of exposure . Inhal Toxicol , 17 , 1 – 14 .

Bernstein DM , Rogers R , Sepulveda R , Donaldson K , Schuler D , Gaering

S , et al . (2010) . The pathological response and fate in the lung and

pleura of chrysotile in combination with fi ne particles compared to

amosite-asbestos following short-term inhalation exposure: interim

results . Inhal Toxicol , 22 , 937 – 62 .

Bernstein DM , Rogers R , Sepulveda R , Donaldson K , Schuler D , Gaering

S , et al . (2011) . Quantitation of the pathological response and fate in

the lung and pleura in combination with fi ne particles compared to

amosite-asbestos following short-term inhalation exposure . Inhal

Toxicol , 23 , 371 – 91 .

Bernstein DM , Dunnigan J , Hesterberg T , Brown R , Velasco JAL , Barrera

R , et al . (2013) . Health risk of chrysotile revisited . Crit Rev Toxicol ,

43 , 154 – 83 .

Berrigan D . (2002) . Respiratory cancer and exposure to man-made

vitreous fi bers: a systematic review . Am J Indust Med , 42 , 362 .

Berry J , Newhouse M . (1983) . Mortality of workers manufacturing

friction materials using asbestos . Br J Ind Med , 40 , 1 – 7 .

Berry M . (1997) . Mesothelioma incidence and community asbestos

exposure . Environ Res , 75 , 34 – 40 .

Boff etta P , Donaldson K , Moolgavkar S , Mandel J . (2014) . A systematic

review of occupational exposure to synthetic vitreous fi bers and risk of

mesothekioma . Crit Rev Toxicol , 44 , 436 – 49 .

Bolton RE , Vincent JH , Jones AD , Addison J , Beckett ST . (1983) . An

overload hypothesis for pulmonary clearance of UICC amosite fi bers

inhaled by rats . Br J Ind Med , 40 , 264 – 72 .

Borow M , Conston A , Livornese L , Schalet N . (1973) . Mesothelioma

following exposure to asbestos: a review of 72 cases . Chest , 64 , 641 – 7 .

Bourd è s V , Boff etta P , Pisani P . (2000) . Environmental exposure to

asbestos and risk of pleural mesothelioma: review and meta-analysis .

Eur J Epidemiol , 16 , 411 – 7 .

Boutin C , Dumortier P , Rey F , Viallat JR , DeVuyst P . (1996) . Black

spots concentrate oncogenic asbestos fi bers in the parietal pleura:

thorascopic and mineralogic study . Am J Respir Crit Care Med , 153 ,

444 – 9 .

Briant JK . (1988) . Distinction of Reversible and Irreversible Convection

by High-frequency Ventilation of a Respiratory Airway Cast. Ph.D.

Thesis, New York University.

Brody AR , Roe MW . (1983) . Deposition pattern of inorganic particles at

the alveolar level in the lungs of rats and mice . Am Rev Respir Dis ,

128 , 724 – 9 .

Brody AR , Hill LH , Adkins B Jr , O ’ Connor RW . (1981) . Chrysotile

asbestos inhalation in rats: deposition pattern and reaction of alveolar

epithelium and pulmonary macrophages . Am Rev Respir Dis , 123 ,

670 – 9 .

Cri

tical

Rev

iew

s in

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f M

aryl

and

on 1

0/14

/14

For

pers

onal

use

onl

y.


Buchanich JM , Marsh GM , Youk AO . (2001) . Historical cohort study of

US man-made vitreous fi ber production workers: V . Tobacco smoking

habits. J Occup Environ Med , 43 , 793 – 802 .

Burdett G . (1985) . Use of a membrane fi lter, direct-transfer technique

for monitoring environmental asbestos releases. In: A Workshop on

Asbestos Fiber Measurements in Building Atmospheres. Mississauga,

Ontario: Ontario Research Foundation.

Camus M , Siemiatycki J , Meek B . (1998) . Nonoccupational exposure to

chrysotile asbestos and the risk of lung cancer . N Engl J Med , 338 ,

1565 – 71 .

Carbone M , Emri S , Dogan AU , Steele I , Tuncer M , Pass HI , Baris

YI . (2007) . A mesothelioma epidemic in Cappadocia: scientifi c

developments and unexpected social outcomes . Natl Rev Cancer , 7 ,

147 – 54 .

Case BW , Dufresne A , McDonald AD , McDonald JC , S é bastien P .

(2000) . Asbestos fi ber type and length in lungs of chrysotile textile

and production workers: fi bers longer than 18 μ m . Inhal Toxicol , 12 ,

411 – 8 .

Case BW , Camus M , Richardson L , Parent ME , Desy M , Siemiatycki J .

(2002) . Preliminary fi ndings for pleural mesothelioma among women

in the Quebec chrysotile mining regions . Ann Occup Hyg , 46 , 128 – 31 .

Case BW , Abraham JL . (2009) . Heterogeneity of exposure and attribution

of mesothelioma: trends and strategies in two American counties .

J Phys Conf Ser , 151 : 012008 .

Case BW , Abraham JL , Meeker G , Pooley FD , Pinkerton KE . (2011) .

Applying defi nitions of “ Asbestos ” to environmental and “ Low-

Dose ” exposure levels and health eff ects, particularly malignant

mesothelioma . J Toxicol Environ Health Part B , 14 , 3 – 39 .

Casey KR , Shigeoka JW , Rom WN , Moatamed F . (1985) . Zeolite

exposure and associated pneumoconiosis . Chest , 87 , 837 – 40 .

Chan TL , Lee PS , Hering WE . (1984) . Pulmonary retention of inhaled

diesel particles after prolonged exposures to diesel exhaust . Fundam

Appl Toxicol , 4 , 624 – 31 .

Cherrie J , Dodgson J , Groat S , MacLaren W . (1986) . Environmental

surveys in the European man-made mineral fi ber production industry .

Scand. J Work Environ Health , 12 , 18 – 25 .

Chisholm JE . (1983) . Transmission electron microscopy of asbestos . In:

Chissick SS , Derricott R , Eds. Asbestos . Chichester: John Wiley &

Sons , pp. 86 – 167 .

Churg A . (1988) . Chrysotile, tremolite, and malignant mesothelioma in

man . Chest , 93 , 621 – 8 .

Churg A . (1994) . Deposition and clearance of chrysotile asbestos . Ann

Occup Hyg , 38 , 625 – 33 .

Churg A , Wiggs B . (1987) . Accumulation of long asbestos fi bers in the

peripheral upper lobe in cases of malignant mesothelioma . Am J Ind

Med , 11 , 563 – 9 .

Churg A , Wiggs B , Depaoli L , Kampe B , Stevens B . (1984) . Lung

asbestos content in chrysotile workers with mesothelioma . Am Rev

Respir Dis , 130 , 1042 – 5 .

Churg A , Wright J , Gilks B , Dai J . (2000) . Pathogenesis of fi brosis

produced by asbestos and man-made mineral fi bers: what makes a fi ber

fi brogenic? Inhal Toxicol , 12 , 15 – 26 .

Collier CG , Morris KJ , Launder KA , Humphreys JA , Morgan A , Eastes

W , Townsend S . (1994) . The behavior of glass fi bers in the rat following

intraperitoneal injection . Regul Toxicol Pharmacol , 20 , S89 – 103 .

Collier CG , Morris KJ , Launder KA , Humphreys JA , Morgan A , Eastes

W , Townsend S . (1995) . The durability and distribution of glass fi bres

in the rat following intra-peritoneal injection . Ann Occup Hyg , 39 ,

699 – 704 .

Collier CG , Kamstrup O , Morris KJ , Applin RA , Vatter IA . (1997) . Lung

clearance of experimental man-made mineral fi bres, preliminary data

on the eff ect of fi ber length . Ann Occup Hyg , 41 , 320 – 6 .

Cooke WE. (1927) . Pulmonary asbestosis . Brit Med J , 2 , 1024 .

Cox LA , Popken DA , Berman DW . (2013) . Causal versus spurious

spatial exposure-response associations in health risk analysis . Crit Rev

Toxicol , 43 , 26 – 38 .

Craighead JE . (1987) . Current pathogenetic concepts of diff use malignant

mesothelioma . Human Pathol , 18 , 544 – 57 .

Cullen RT , Searl A , Buchanan D , Davis JMG , Miller BG , Jones AD .

(2000) . Pathogenicity of a special-purpose glass microfi ber (E glass)

relative to another glass microfi ber and amosite asbestos . Inhal Toxicol ,

12 , 959 – 77 .

Davis JMG . (1976) . Pathological aspects of the injection of fi ber into

the pleural and peritoneal cavities of rats and mice. In: Occupational

Exposure to Fibrous Glass, HEW Publ. No. (NIOSH) 76 – 151,

Washington, DC: DHEW, pp. 141 – 99.

Davis JMG , Beckett ST , Bolton RE , Collings P , Middleton AP . (1978) .

Mass and number of fi bers in the pathogenesis of asbestos-related lung

disease in rats . Br J Cancer , 37 , 673 – 88 .

Davis JMG , Addison J , Bolton RE , Donaldson K , Jones AD , Miller BG .

(1985) . Inhalation studies on the eff ects of tremolite and brucite dust

in rats . Carcinogenesis , 6 , 667 – 74 .

Davis JMG , Addison J , Bolton RE , Donaldson K , Jones AD , Smith

T . (1986a) . The pathogenicity of long versus short fi ber samples of

amosite asbestos administered to rats by inhalation and intraperitoneal

injection . Br J Exp Pathol , 67 , 415 – 30 .

Davis JMG , Addison J , Bolton R , Donaldson K , Jones AD . (1986b) .

Inhalation and injection studies in rats using dust samples from

chrysotile asbestos prepared by a wet dispersion process . Brit J Pathol ,

67 , 113 – 29 .

Davis JMG . (1987) . Experimental data relating to the importance of fi bre

type, size, deposition, dissolution and migration . In: Proceedings of

1987 Mineral Fiber Symposium, Lyons, IARC .

Davis JMG , Jones AD . (1988) . Comparisons of the pathogenicity of long

and short fi bres of chrysotile asbestos in rats . Br J Exp Pathol , 69 , 717 – 37 .

Davis JMG , Addison J , McIntosh C , Miller BG , Niven K . (1991) .

Variations in the carcinogenicity of tremolite dust samples of diff ering

morphology . Ann NY Acad Sci , 643 , 473 – 90 .

Davis JMG , Brown DM , Cullen RT , Donaldson K , Jones AD , Miller BG ,

et al . (1996) . A comparison of methods of determining and predicting

the pathogenicity of mineral fi bers . Inhal Toxicol , 8 , 747 – 70 .

De Klerk NH , Armstrong BK , Musk AW , Hobbs MST . (1989) . Cancer

mortality in relation to measures of occupational exposure to

crocidolite at Wittenoom Gorge in Western Australia . Br J Ind Med ,

46 , 529 – 36 .

deKlerk NH , Musk AW , Glancy JJ , Pang PS , Lund HG , Olsen N , Hobbs

MST . (1997) . Crocidolite, radiographic asbestosis and subsequent lung

cancer . Ann Occup Hyg , 41 , 134 – 6 .

Dement JM , Harris RL , Symans MJ , Shy C . (1982) . Estimates of dose-

response for respiratory cancer among chrysotile asbestosis workers .

Ann Occup Hyg , 28 , 869 – 87 .

Dement JM , Harris RL Jr , Symans MR , Shy CM . (1983) . Exposures and

mortality among chrysotile asbestos workers . Part II: Mortality. Am

JInd Med , 4 , 421 – 33 .

Dement JM , Brown DP , Okun A . (1994) . Follow-up study of chrysotile

asbestos textile workers: Cohort mortality and case-control analyses .

Am J Ind Med , 26 , 431 – 47 .

Dodson RF , Williams MG Jr , Corn CJ , Brollo A , Bianchi A . (1990) .

Asbestos content of lung tissue, lymph nodes, and pleural plaques from

former shipyard workers . Am Rev Respir Dis , 142 , 843 – 7 .

Dodson RF , Atkinson MAL , Levin JL . (2003) . Asbestos fi ber length as

related to potential pathogenicity: a critical review . Am J Indust Med ,

44 , 291 – 7 .

Doll R . (1955) . Mortality from lung cancer in asbestos workers . Br J

Industr Med , 12 , 81 – 6 .

Doll R, Peto J . (1985) . Eff ects on Health of Exposure to Asbestos. A

Report of the Health and Safety Commission. London: Her Majesty ’ s

Stationery Offi ce.

Doll R . (1987) . Symposium on MMMF, Copenhagen, October 1986:

overview and conclusions . Ann Occup Hyg , 31 , 805 – 19 .

Donaldson K , Aitken R , Tran L , Stone V , Duffi n R , Forrest G , Alexander

A . (2006) . Carbon nanotubes: a review of their properties in relation to

pulmonary toxicology and workplace safety . Toxicol Sci , 92 , 5 – 22 .

Donaldson K . (2009) . The inhalation toxicology of p -aramid fi brils . Crit

Rev Toxicol , 39 , 487 – 500 .

Donaldson K , Murphy FA , Duffi n R , Poland CA . (2010) . Asbestos, carbon

nanotubes and the pleural mesothelium: a review of the hypothesis

regarding the role of long fi bre retention in the parietal pleura,

infl ammation and mesothelioma . Partic Fibre Toxicol , 7 , 5 – 22 .

Dufresne A , B é gin R , Masse S , Dufresne CM , Loosereewanich P , Perrault

G . (1996) . Retention of asbestos fi bres in lungs of workers with

asbestosis, asbestosis and lung cancer, and mesothelioma in Asbestos

township . Occup Environ Med , 53 , 801 – 7 .

Dunning KK , Adjei S , Levin L , Hilbert T , Borton E , Kapil V , et al .

(2012) . Mesothelioma associated with commercial use of vermiculite

containing Libby amphibole . J Occup Environ Med , 54 , 1359 – 63 .

Eastes W , Hadley JG . (1995) . Dissolution of fi bers inhaled by rats . Inhal

Toxicol , 7 , 179 – 96 .

Cri

tical

Rev

iew

s in

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f M

aryl

and

on 1

0/14

/14

For

pers

onal

use

onl

y.


Ellman P . (1933) . Pulmonary asbestosis: its clinical, radiological, and

pathological features, and associated risk of tuberculosis infection .

J Industr Hyg , 25 , 165 – 83 .

Engholm G , Englund A , Fletcher CC , Hallin N . (1987) . Respiratory

cancer incidence in Swedish construction workers exposed to man-

made mineral fi bers and asbestos . Ann Occup Hyg , 31 , 663 – 75 .

Enterline PE , Marsh GM , Esmen NA . (1983) . Respiratory disease among

workers exposed to man-made mineral fi bers . Am Rev Respir Dis ,

128 , 1 – 7 .

Enterline PE , Marsh GM , Henderson V , Callahan C . (1987) . Mortality

update of a cohort of U.S. man-made mineral fi ber workers . Ann

Occup Hyg , 31 , 625 – 56 .

EPA . (1996) . Proposed Guidelines for Carcinogen Risk Assessment.

EPA/600/P-92/003C. U.S. Government Printing Offi ce, Washington,

DC. April 1996 .

EPA-SAB . (2013) . Review of EPA ’ s draft assessment entitled:

Toxicological Review of Libby Amphibole Asbestos. EPA-SAB-13-001 .

ERG . (2003a) . Report on the Peer Consultation Workshop to Discuss a

Proposed Protocol to Assess Asbestos Related Risk. Eastern Research

Group, Inc., Lexington MA. May 30, 2003 .

ERG . (2003b) . Report on the Expert Panel on Health Eff ects of Asbestos

and Synthetic Vitreous Fibers in the Infl uence of Fiber Length . Eastern

Research Group, Inc., Lexington MA. March 17, 2003.

Esmen NA . (1984) . Short-term survey of airborne fi bres in U.S.

manufacturing plants. In: Biological Eff ects of Man-Made Mineral

Fibers, Vol. 1. Copenhagen: WHO-EURO , pp. 65 – 82 .

Esmen NA , Erdal S . (1990) . Human occupational and nonoccupational

exposure to fi bers . Environ Health Perspect , 88 , 277 – 86 .

Ferin J . (1972) . Observations concerning alveolar dust clearance . Ann

NY Acad Sci , 200 , 66 – 72 .

Ferin J , Leach LJ . (1976) . The eff ect of amosite and chrysotile asbestos on

the clearance of TiO 2 particles from the lung . Environ Res , 12 , 250 – 4 .

Finkelstein MM . (1983) . Mortality among long-term employees of an

Ontario asbestos-cement factory . Br J Ind Med , 40 , 138 – 44 .

Floyd RA . (1990) . Role of oxygen free radicals in carcinogenesis and

brain ischemia . FASEB J , 4 , 2587 – 97 .

Forster H . (1984) . The behavior of mineral fi bers in physiological

solutions. In: Biological Eff ects of Man-Made Mineral Fibers, Vol. 2

Copenhagen: World Health Organization , pp. 27 – 59 .

Frank AL , Dodson RF , Williams MG . (1997) . Lack of tremolite in UICC

reference chrysotile and the implications for carcinogenicity . Ann

Occup Hyg , 41 , 287 – 92 .

Gentry JW , Spurny KR , Schormann J , Opiela H . (1983) . Measurement of

the diff usion coeffi cient of asbestos fi bers . In: Marple VA , Liu BYH ,

Eds. Aerosols in the Mining and Industrial Work Environments , Vol. 2

Ann Arbor: Ann Arbor Science Publishers , pp. 593 – 612 .

Gibbs GW . (1979) . Etiology of pleural calcifi cation: a study of Quebec

asbestos miners and millers . Arch Environ Health , 34 , 76 – 82 .

Gloyne SR . (1930) . The reaction of tissues to the asbestos fi bre with

reference to pulmonary asbestosis . Tubercle , 11 , 151 .

Gloyne SR . (1951) . A historical survey of necroscopy material in 1205

cases . Lancet , April 14, 1951 , 810 – 4 .

Goodglick LA , Kane AB . (1990) . Cytotoxicity of long and short crocidolite

asbestos fi bers in vitro and in vivo . Cancer Res , 50 , 5153 – 63 .

Griffi s LC , Henderson TR , Pickrell JA . (1981) . A method for determining

glass in rat lung after exposure to a glass fi ber aerosol . Am Ind Hyg

Assoc J , 42 , 566 – 9 .

Gurman JL , Lippmann M , Schlesinger RB . (1984a) . Particle deposition

in replicate casts of the human upper tracheobronchial tree under

constant and cyclic inspiratory fl ow . I. Experimental. Aerosol Sic

Technol , 3 , 245 – 52 .

Gurman JL , Lioy PJ , Lippmann M , Schlesinger RB . (1984b) . Particle

deposition in replicate casts of the human upper tracheobronchial

tree under constant and cyclic inspiratory fl ow . II. Empirical model.

Aerosol Sci Technol , 3 , 253 – 7 .

Gurman JL , Schlesinger RB , Lippmann M . (1980) . A variable-opening

mechanical larynx for use in aerosol deposition studies . Am Ind Hyg

Assoc J , 41 , 678 – 80 .

Gylseth B , Mowe B , Wannag A . (1983) . Fiber type and concentration in

the lungs of workers in an asbestos cement factory . Br J Ind Med , 40 ,

375 – 9 .

Hain E , Dalquen P , Bohlig H , Dabbert A , Hinz I . (1974) . Retrospective

study of 150 cases of mesothelioma in Hamburg area . Int Arch

Argeitsmed , 33 , 15 – 37 .

Hammad YY . (1984) . Deposition and elimination of MMMF. In:

Biological Eff ects of Man-Made Mineral Fibers, Vol. 2. Copenhagen:

World Health Organization , pp. 126 – 42 .

Hammond EC , Garfi nkle L , Selikoff IT , Nicholson WJ . (1979) . Mortality

experience of residents in the neighborhood of an asbestos factory .

Ann NY Acad Sci , 330 , 417 – 22 .

Hamra GB , Loomis D , Dement J . (2014) . Examining the association of

lung cancer and highly correlated fi bre size-specifi c asbestos exposures

with a hierarchical model . Occup Environ Med. (online Feb. 24, 2014) .

doi:10.1136/oemed-2013 – 101965 .

Hansen J , deKlerk NH , Musk AW , Eccles JL , Hobbs MST . (1997) .

Mesothelioma after environmental crocidolite exposure . Ann Occup

Hyg , 41 , 189 – 193 .

Harington JS . (1981) . Fiber carcinogenesis: epidemiologic observations

and the Stanton hypothesis . J Natl Cancer Inst , 67 , 977 – 89 .

HEI-AR . (1991) . Health Eff ects Institute-Asbestos Research. Report of

Literature Review Panel, Cambridge, MA .

Hesterberg TW , Miller WC , McConnell EE , Chevalier J , Hadley J ,

Bernstein D , et al . (1993) . Chronic inhalation toxicity of size-

separated glass fi bers in Fisher 344 rats . Fundam Appl Toxicol , 20 ,

464 – 76 .

Hesterberg TW , Chase G , Axten C , Miller WC , Musselman RP ,

Kamstrup O , et al . (1998a) . Biopersistence of synthetic vitreous fi bers

and amosite asbestos in the rat lung following inhalation . Toxicol Appl

Pharmacol , 151 , 262 – 75 .

Hesterberg TW , Hart GA , Chevalier J , Miller WC , Bauer J , Thevenaz

P . (1998b) . The importance of fi ber biopersistence and lung dose

in determining the chronic inhalation eff ects of X607, RCF1, and

chrysotile asbestos in rats . Toxicol Appl Pharmacol , 153 , 68 – 82 .

Hesterberg TW , Hart GA . (2001) . Synthetic vitreous fi bers: a review of

toxicology research and its impact on hazard classifi cation . Crit Rev

Toxicol , 31 , 1 – 53 .

Hesterberg TW , Anderson R , Bernstein DM , Bunn WB , Chase GA ,

Janukouski AL , et al . (2012) . Product stewardship and science:

safe manufacture and use of fi ber glass . Reg Toxicol Pharmacol , 62 ,

257 – 77 .

Hiett DM . (1978) . Experimentak asbestosis: An investigation of functional

and pathological disturbances . Br J Ind Med , 35 , 129 – 145 .

Hillegass JM , Miller JM , MacPherson MB , Westbom CM , Sayan

M , Thompson JK , et al . (2013) . Asbestos and erionite prime

and activate the NLRP3 inflammasome that stimulates autocrine

cytokine release in human mesothelial cells . Particle Fibre Toxicol ,

10 , 3948 .

Hodgson JT , Darnton A . (2000) . The quantitative risks of mesothelioma

and lung cancer in relation to asbestos exposure . Ann Occup Hyg , 44 ,

565 – 601 .

Hoff man FI . (1918) . Mortality and respiratory diseases in dusty trades

(Inorganic dusts) . U.S. Bur. Lab. Stat. No. Bulletin , 231 , 176 – 80 .

Holt PR . (1982) . Translocation of asbestos dust through the bronchiolar

wall . Environ Res , 27 , 255 – 60 .

Hook HL , Morrice G Jr , deTreville RT . (1970) . Fiberglass manufacturing

and health: results of a comprehensive physiological study. Proceedings

of the 35th Annual Meeting of the Industrial Health Foundation.

October 13 – 14, 1970. Pittsburgh, PA. IHF Bulletin No. 44 . 103 – 111 .

Hughes JM , Jones RN , Glindmeyer HW , Hammad YY , Weill H . (1993) .

Follow up study of workers exposed to man made mineral fi bres . Br J

Ind Med , 50 , 658 – 67 .

IARC . (2002) . IARC Monographs on the Evaluation of Carcinogenic

Risks to Human: Volume 81:1 – 381. – Man-Made Vitreous Fibres .

World Health Organization. International Agency for Research on

Cancer. Geneva: IARC Press .

ISO . (1993) . International Standard (ISO 8762): Air Quality –

Determination of the number concentration of airborne inorganic

fi bres by phase contrast optical microscopy – membrane fi lter method .

International Organization for Standardization CH-1211, Geneve 20,

Switzerland, 25pp .

Johnson NF , Griffi ths DM , Hill RJ . (1984) . Size distributions following

long-term inhalation of MMMF. In: Biological Eff ects of Man-Made

Mineral Fibers, Vol. 2 Copenhagen: World Health Organization, pp.

102 – 25.

Jones AD , Johnston AM , Vincent JH . (1983) . Static electrifi cation of

airborne asbestos dust . In: Marple VA , Liu BYH , Eds. Aerosols in the

Mining and Industrial Work Environments , Vol. 2 Ann Arbor: Ann

Arbor Science Publishers , pp. 613 – 22 .

Cri

tical

Rev

iew

s in

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f M

aryl

and

on 1

0/14

/14

For

pers

onal

use

onl

y.


Jones AD , McMillan CH , Johnston AM , McIntosh C , Cowie H , Bolton

RE , et al . (1988) . Pulmonary clearance of UICC amosite fi bers inhaled

by rats during chronic exposure at low concentration . Br J Ind Med ,

45 , 300 – 4 .

Jones JSP , Pooley FD , Sawle GW , Madeley RJ , Smith PG , Berry G , et al .

(1980) . The consequences of exposure to asbestos dust in a wartime

gas-mask factory . In: Wagner JC , Ed. Biological Eff ects of Mineral

Fibres, IARC Scientifi c Pub. No. 30, Vol. 2 Lyons: International

Agency for Research on Cancer , pp. 637 – 53 .

Kamstrup O , Davis JMG , Ellehauge A , Goldberg M . (1998) . The

biopersistence and pathogenicity of man-made vitreous fi bers after

short- and long-term inhalation . Ann Occup Hyg , 42 , 191 – 9 .

Kane AB , McDonald JL . (1993) . Mechanisms of mesothelial cell injury,

proliferation and neoplasia induced by asbestos fi bers . In: Warheit

DB , Ed. Fiber Toxicology: Contemporary Issues . Academic Press , pp.

323 – 47 .

King EJ , Clegg JW , Rae VM . (1946) . The eff ect of asbestos, and of

asbestos and aluminum, on the lung of rabbits . Thorax , 1 , 188 – 97 .

Kj æ rheim K , Boff etta P , Hansen J , Cherrie J , Chang-Claude

J , Eilber U , et al . (2002) . Lung cancer among rock and

lag wool production workers . Epidemiology , 13 , 445 – 53 .

Klingholz R , Steinkopf B . (1982) . Das Verhalten von Kunstlichen

Mineralfasern in einer physiologischen Modellfl assigkeit und in

Wasser . StaubReinhalt Luft , 42 , 69 – 76 .

Klingholz R , Steinkopf B . (1984) . The reactions of MMMF in a

physiological model fl uid and in water. In: Biological Eff ects of

Man-Made Mineral Fibers, Vol. 1 Copenhagen: WHO-EURO, pp.

60 – 86.

Konzen JL . (1984) . Production trends in fi bre sizes of MMMF

insulation. In: Biological Eff ects of Man-Made Mineral Fibers, Vol. 1,

Copenhagen: World Health Organization, pp. 44 – 63.

Kurumatani N , Kumagai S . (2008) . Mapping the risk of mesothelioma

due to neighborhood asbestos exposure . Am J Resp Crit Care Med ,

178 , 624 – 9 .

Lacourt A , Gramond C , Audignon S , Ducamp S , Fevotte J , Ilg AGS ,

et al . (2013) . Pleural mesothelioma and occupational coexposure

to asbestos, mineral wool, and silica . Am J Crit Care Med , 187 ,

977 – 82 .

Langer AM , Nolan RP , Addison J . (1990) . Physico-chemical properties

of asbestos as determinants of biological potential . In: Miller K , Liddle

D , Eds. CRC Monograph Asbestos and Disease Boca Raton, FL: CRC

Press .

Lanza AJ , McConnell WJ , Fehnel W . (1935) . Eff ects of the inhalation

of asbestos dust on the lungs of asbestos workers . Publ Health Rep ,

50 , 1 – 13 .

Larson RI . (2003) . An air quality data analysis system for interrelating

eff ects, standards, and needed source reductions: Part 13- Applying

the EPA Proposed Guidelines for Carcinogen Risk Assessment to a

set of asbestos lung cancer mortality data . J Air Waste Manag Assoc ,

53 , 1226 – 339 .

Larson TC , Antao VC , Bove FJ , Cusack C . (2012) . Association between

cumulative fi ber exposure and respiratory outcomes among Libby

vermiculite workers . J Occup Environ Med , 54 , 56 – 63 .

LeBouff ant L , Henin JP , Martin JC , Normand C , Tichoux G , Trolard

F . (1984) . Distribution of inhaled MMMF in the rat lung - long term

eff ects. In: Biological Eff ects of Man-Made Mineral Fibers, Vol. 2.

Copenhagen: World Health Organization, pp. 143 – 68.

Lee KP , Barras CE , Griffi th FD , Waritz RS , Lapin CA . (1981) .

Comparative pulmonary responses to inhaled inorganic fi bers with

asbestos and fi berglass . Environ Res , 24 , 167 – 91 .

Lee KP , Kelly DP , Kennedy GL Jr . (1983) . Pulmonary response to inhaled

Kevlar aramid synthetic fi bers in rats . Toxicol Appl Pharmacol , 71 ,

242 – 53 .

LeMasters G , Lockey J . (1994) . Radiographic changes among workers

manufacturing refractory ceramic fi bre and products . Ann Occup Hyg ,

38 , 745 – 51 .

LeMasters GK , Lockey JE , Levin LS , Mckay RT , Rice CH , Horvath

EP , et al . (1998) . An industry-wide pulmonary study of men and

women manufacturing refractory ceramic fi bers . Am J Epidemiol , 148 ,

910 – 9 .

LeMasters GK , Lockey JE , Yin JH , Levin LS , Rice CH . (2003) . Mortality

of workers occupationally exposed to refractory ceramic fi bers .

J Occup Environ Med , 45 , 440 – 50 .

Lentz TJ , Rice CH , Succop PA , Lockey JE , Dement JM , LeMasters GK .

(2003) . Pulmonary deposition modeling with airborne fi ber exposure

data: a study of workers manufacturing refractory ceramic fi bers . App

Occup Environ Hyg , 18 , 278 – 88 .

Levin JL , McLarty JW , Hurst GA , Smith AN , Frank AL . (1998) . Tyler

asbestos workers: mortality experience in a cohort exposed to amosite .

Occup Environ Med , 55 , 155 – 60 .

Lippmann M . (1988) . Asbestos exposure indices . Environ Res , 46 , 86 – 106 .

Lippmann M . (1990) . Man-made mineral fi bers (MMMF): Human

exposures and health risk assessment . Toxicol Ind Health , 6 , 225 – 46 .

Lippmann M . (1994) . Deposition and retention of fi bres: Eff ects on

incidence of lung cancer and mesothelioma . Occup Environ Med , 51 ,

793 – 8 .

Lippmann M . (2003) . Letter to the Editor . J Air Waste Manage Assoc ,

53 , 1298 – 300 .

Lippmann M . (2009) . Asbestos and other mineral fi bers . In: Environmental

T oxicants III: Human E xposures and Their H ealth Eff ects, 3rd Ed.

New York, NY: John Wiley , pp. 395 – 458 .

Lippmann M , Timbrell V . (1990) . Particle loading in the human lung

– Human experience and implications for exposure limits . J Aerosol

Med , 3 , S155 – 68 .

Lippmann M . (2014) . Toxicological and epidemiological studies of

cardiovascular eff ects of ambient air fi ne particulate matter (PM 2.5

) and

its chemical components: Coherence and public health implications .

Crit Rev in Toxicol , (http://infomahealthcare.com/txc. ISSN: 1547-

6898, electronic).

Lipworth L , La Vecchia C , Bosetti C , McLaughlin JK . (2009) .

Occupational exposure to rock wool and glass wool and risk of cancers

of the lung and the head and neck: a systematic review and meta-

analysis . J Occup Environ Med , 51 , 1075 – 87 .

Lockey JE , Roggli VL , Hilbert TJ , Rice CH , Levin L , Borton EK , et al .

(2012) . Biopersistence of refractory ceramic fi ber in human lung tissue

and a 20-year follow-up of radiographic pleural changes in workers .

J Occup Environ Med , 54 , 781 – 8 .

Loomis D , Dement J , Richardson D , Wolf S . (2010) . Asbestos fi ber

dimensions and lung cancer mortality among workers exposed to

chrysotile . Occup Environ Med , 67 , 580 – 4 .

Luo S , Liu X , Mu S , Tsai SP , Wen CP . (2003) . Asbestos related diseases

from environmental exposure to crocidolite in Da-yao, China . Occup

Environ Med , 60 , 35 – 42 .

Lynch KM , Smith WA . (1935) . Pulmonary asbestosis: Carcinoma of lung

in asbestosis-silicosis . Am J Cancer , 24 , 56 – 64 .

Magnani C , Terracini B , Ivaldi C , Botta M , Mancini A , Andrion

A . (1995) . Pleural malignant mesothelioma and nonoccupational

exposure to asbestos in Castale Monferrato, Italy . Occup Environ

Med , 52 , 362 – 7 .

Malmberg P , Hedenstein HJ , Kolmodin-Hedran B , Krantz S . (1984) .

Pulmonary function in workers of a mineral rock fi bre plant. Biological

eff ects of man-made mineral fi bres. Proceedings of a WHO/IARC

Conference, Vol. 1, April 20 – 22, 1982. Copenhagen, Denmark ,

pp. 427 – 35 .

Markowitz SB , Levin SM , Miller A , Morabia A . (2013) . Asbestos,

asbestosis, smoking, and lung cancer . Am J Resp Crit Care Med , 188 ,

90 – 6 .

Marsh GM , Youk AO , Stone RA , Buchanich JM , Gula MJ , Smith TJ ,

Quinn MM . (2001a) . Historical cohort study of US man-made vitreous

fi ber production workers: I. 1992 Fiberglass cohort follow-up: Initial

Findings . J Occp Environ Med , 43 , 741 – 56 .

Marsh GM , Buchanich JM , Youk AO . (2001b) . Historical cohort study

of US man-made vitreous fi ber production workers: VI. Respiratory

system cancer standardized mortality ratios adjusted for the confounding

eff ect of cigarette smoking . J Occup Environ Med , 43 , 803 – 8 .

Marsh GM , Gula MJ , Youk AO , Buchanich JM , Churg A , Colby TV .

(2001c) . Historical cohort study of US man-made vitreous fi ber

production workers: II. Mortality from mesothelioma . J Occup Environ

Med , 43 , 757 – 66 .

Mast RW , McConnell EE , Anderson R , Chevalier JC , Kotin P , Bernstein

DM , et al . (1995) . Studies on the chronic toxicity of (inhalation) of

four types of refractory ceramic fi ber in male Fisher 344 rats . Inhal

Toxicol , 7 , 425 – 67 .

Maule MM , Magnani C , Dalmasso P , Mirabelli D , Merletti F , Biggeri

A . (2007) . Modeling mesothelioma risk associated with environmental

asbestos exposure . Environ Health Perspect , 115 , 1066 – 71 .

Maxim LD , McConnell EE . (2005) . A review of the toxicology and

epidemiology of wollastonite . Inhal Toxicol , 17 , 451 – 66 .

McCaughey WTE , Wade OL , Elmes PC . (1962) . Exposure to asbestos

dust and diff use pleural mesothelioma . Brit Med J , 2 , 1397 .

Cri

tical

Rev

iew

s in

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f M

aryl

and

on 1

0/14

/14

For

pers

onal

use

onl

y.


McClellan RO , Hesterberg TW . (1994) . Role of biopersistence in

the pathogenicity of man-made fi bers and methods for evaluating

biopersistence: a summary of two round-table discussions . Environ

Health Perspect , 102 , 277 – 83 .

McClellan RO , Miller FJ , Hesterberg TW , Warheit DB , Bunn WB ,

Kane AB , et al . (1992) . Approaches to evaluating the toxicity and

carcinogenicity of man-made fi bers: summary of a workshop held

November 11 – 13, 1991, Durham, North Carolina . Regul Toxicol

Pharmacol , 16 , 321 – 64 .

McConnochie K , Simonato L , Mavrides P , Christofi des P , Pooley FD ,

Wagner JC . (1987) . Mesothelioma in Cyprus: the role of tremolite .

Thorax , 42 , 342 – 7 .

McConnell EE , Kamstrup O , Musselman RP , Hesterberg TW , Chevalier

JC , Miller WC , Thevenaz P . (1994) . Chronic inhalation study of size-

separated rock and slag wool insulation fi bers in fi sher 344/N rats .

Inhal Toxicol , 6 , 571 – 614 .

McConnell EE , Mast RW , Hesterberg TW , Chevalier J , Kotin P , Bernstein

DM , et al . (1995) . Chronic inhalation toxicity of a kaolin-based refractory

ceramic fi ber in Syrian golden hamsters . Inhal Toxicol , 7 , 503 – 32 .

McConnell EE , Axten C , Hesterberg TW , Chevalier J , Miller WC , Everitt

J , et al . (1999) . Studies of the inhalation toxicology of two fi berglasses

and amosite asbestos in the Syrian golden hamster . Part II. Results of

chronic exposure. Inhal Toxicol , 11 , 785 – 835 .

McCormack V , Peto J , Byrnes G , Stralf K , Boff etta P . (2012) . Estimating

the asbestos-related lung cancer burden from mesothelioma mortality .

Brit J Cancer , 106 , 575 – 84 .

McDonald AD , Case BW , Churg A , Dufresne A , Gibbs GW , Sebastien P ,

McDonald JC . (1997) . Mesothelioma in Quebec chrysotile miners and

millers: epidemiology and aetiology . Ann Occup Hyg , 41 , 707 – 19 .

McDonald AD , Fry JS , Woolley GJ , McDonald JC . (1984) . Dust exposure

and mortality in an American chrysotile asbestos friction products

plant . Br J Ind Med , 41 , 151 – 7 .

McDonald JC , McDonald AD , Armstrong B , Sebastien P . (1986) . Cohort

study of mortality of vermiculite miners exposed to tremolite . Occup

Envion Med , 43 , 436 – 44 .

McDonald JC , McDonald AD . (1997) . Chrysotile, tremolite and

carcinogenicity . Ann Occup Hyg , 41 , 699 – 705 .

McDonald JC , Harris J , Armstrong B . (2004) . Mortality in a cohort of

vermiculite miners exposed to fi brous amphibole in Libby MT . Occup

Environ Med , 61 , 363 – 6 .

McDonald JC , S é bastien P , Case B , McDonald AD , Dufresne A . (1992) .

Ferruginous body counts in sputum as an index of past exposure to

mineral fi bres . Ann Occup Hyg , 36 , 271 – 82 .

McKay RT , LeMasters GK , Hilbert TJ , Levin LS , Rice CH , Lockey JE .

(2011) . A long-term study of pulmonary function among US refractory

ceramic workers . J Occup Environ Med , 68 , 89 – 95 .

Meeker GP , Bern AM , Brownfi eld IK , Lowers HA , Sutley SJ , Hoefen TM ,

Vance JS . (2003) . The composition and morphology of amphiboles

from the Rainy Creek Complex, near Libby, Montana . Am Mineral ,

88 , 1955 – 69 .

Merewether ERA , Price CW . (1930) . Report on eff ects of asbestos dust on

the lungs and dust suppression in the asbestos industry . His Majesty ’ s

Stationery Offi ce .

Metintas S , Metintas M , Ucgun I , Oner U . (2002) . Malignant melanoma

due to exposure to asbestos: follow-up of a Turkish cohort living in a

rural area . Chest , 122 , 2224 – 9 .

Metintas S , Metintas M , Ak G , Kalyoncu C . (2012) . Environmental

asbestos exposure in rural Turkey and risk of lung cancer . Intl J Environ

Health Res , 22 , 468 – 79 .

Meurman LO , Kiviluoto R , Hakama M . (1974) . Mortality and morbidity

among the working population of anthophyllite asbestos miners in

Finland . Br J Ind Med , 31 , 105 – 12 .

Meurman LO , Kiviluoto R , Hakama M . (1979) . Combined eff ects of

asbestos exposure and tobacco smoking on Finnish anthophyllite

miners and millers . Ann NY Acad Sci , 330 , 491 – 5 .

Miller BG , Searl A , Davis JMG , Donaldson K , Cullen RT , Bolton RE ,

et al . (1999a) . Infl uence of fi bre length, dissolution and biopersistence

on the production of mesothelioma in the rat peritoneal cavity . Ann

Occu. Hyg , 43 , 155 – 66 .

Miller BG , Jones AD , Searl A , Buchanan D , Cullen RT , Soutar CA , et al .

(1999b) . Infl uence of characteristics of inhaled fi bres on development

of tumours in the rat lung . Ann Occup Hyg , 43 , 167 – 79 .

Moalli PA , Macdonald J , Goodglick LA , Kane AB . (1987) . Acute injury

and regeneration of the mesothelium in response to asbestos fi bers . Am

J Pathol , 128 , 425 – 45 .

Monchaux G , Bignon J , Jaurand MC , Lafuma JC , Sebastien P , Masse R ,

et al . (1981) . Mesotheliomas in rats following inoculation with acid-

leached chrysotile asbestos and other mineral fi bers . Carcinogenesis ,

2 , 229 – 36 .

Morgan A . (1979) . Fiber dimensions: their signifi cance in the deposition

and clearance of inhaled fi brous dusts . In: Lemen R , Dement LM , Eds.

Dusts and Disease Park Forest South, IL: Pathotox Publishers , pp.

87 – 96 .

Morgan A , Black A , Evans N , Holme A , Pritchard JN . (1980) . Deposition

of sized glass fi bers in the respiratory tract of the rat . Ann Occup Hyg ,

23 , 353 – 66 .

Morgan A , Holmes A . (1984) . The deposition of MMMF in the respiratory

tract of the rat, their subsequent clearance, solubility in vivo and

protein coating. In: Biological Eff ects of Man-Made Mineral Fibers,

Vol. 2 Copenhagen: World Health Organization , pp. 1 – 17 .

Morgan A , Holmes A , Davison W . (1982) . Clearance of sized glass fi bers

from the rat lung and their solubility in vivo . Ann Occup Hyg , 25 , 317 – 31 .

Mossman BT , Craighead JE . (1987) . Mechanisms of asbestos associated

bronchogenic carcinoma . In: Antman K , Aisner J , Eds. Asbestos-

Related Malignancy Orlando: Grune & Stratton , pp. 137 – 50 .

Mossman BT , Marsh JP , Sesko A , Hill S , Shatos MA , Doherty J ,

et al . (1990) . Inhibition of lung injury, infl ammation, and interstitial

pulmonary fi brosis by polyethylene glycol-conjugated catalase in a rapid

inhalation model of asbestosis . Am Rev Respir Dis , 41 , 1266 – 71 .

Mossman GT , Bignon J , Corn M , Seaton A , Gee JBL . (1990) . Asbestos:

scientifi c developments and implications for public policy . Science ,

247 , 294 – 301 .

Mossman BT , Lippmann M , Hesterberg TW , Kelsey KT , Barchowsky

A , Bonner JC . (2011) . Pulmonary endpoints (lung carcinomas and

asbestosis) following inhalation exposure to asbestos . J Toxicol

Environ Health B Crit Rev , 14 , 76 – 121 .

Muhle H , Bellmann B , Heinrich U . (1988) . Overloading of lung clearance

during chronic exposure of experimental animals to particles . Ann

Occup Hyg , 32 , 141 – 7 .

Murphy FA , Schinwald A , Poland CA , Donaldson K . (2012) . The

mechanism of pleural infl ammation by long carbon nanotubes:

interaction of long fi bres with macrophages stimulates them to amplify

proinfl ammatory response in mesothelioma cells . Part Fibre Toxicol ,

9 , 8 – 23 .

Murphy FA , Poland CA , Duffi n R , Donaldson K . (2013) . Length-

dependent pleural infl ammation and parietal pleura responses after

deposition of carbon nanotubes in the pulmonary airspaces of mice .

Nanotoxicology , 6 , 1152 – 67 .

Musti M , Pollice A , Cavone D , Dragonieri S , Bilancia M . (2009) . The

relationship between malignant mesothelioma and an asbestos cement

environmental risk: a spatial case-control in the city of Bari (Italy) . Int

Arch Occup Environ Health , 82 , 489 – 97 .

Newhouse ML , Thompson H . (1965) . Epidemiology of mesothelial

tumors in the London area . Ann NY Acad Sci , 132 , 579 – 88 .

Newhouse ML , Sullivan KR . (1989) . A mortality study of workers

manufacturing friction materials: 1941 – 86 . Br J Ind Med , 46 , 176 – 9 .

Newhouse ML , Berry G , Skidmore JW . (1982) . A mortality study of

workers manufacturing friction materials with chrysotile asbestos .

Ann Occup Hyg , 26 , 899 – 909 .

Nicholson WJ . (1986) . Airborne Asbestos Health Assessment Update,

United States Environmental Protection Agency, Offi ce of Health and

Environmental Assessment, Washington, DC, EPA/600/8 – 84/003F .

Washington, DC: EPA .

NIOSH . (1977) . Criteria for a Recommended Standard: Occupational

Exposure to Fibrous Glass . Cincinnati, OH: National Institute for

Occupational Safety and Health; Apr; DHHS (NIOSH) Publication

Number 77 – 152.

NIOSH . (1979) . USPHS/NIOSH Membrane Filter Method for Evaluating

Airborne Asbestos Fibers. DHEW (NIOSH) Publication No. 79 – 127,

89pp.

NIOSH . (1986) . Occupational Respiratory Diseases. Cincinnati, OH:

National Institute for Occupational Safety and Health, Division of

Respiratory Disease Studies; DHHS (NIOSH) Publication No. 86 – 102.

Nishimura SL , Broaddus VC . (1998) . Asbestos-induced pleural disease .

Clin Chest Med , 19 , 311 – 29 .

NRC . (1984) . Asbestiform Fibers – Nonoccupational Health Risks .

Washington, DC: National Academy Press .

NRC . (2000) . Review of the U.S . Navy ’ s Exposure Standard for

Manufactured Vitreous Fibers. Washington, DC: National Academies

Press

Cri

tical

Rev

iew

s in

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f M

aryl

and

on 1

0/14

/14

For

pers

onal

use

onl

y.


NTP . (2011) . Certain glass wool fi bers (inhalable). In: NTP. Report

on Carcinogens. 12th ed. Research Triangle Park, NC: National

Toxicology Program; http://www.ntp.niehs.nih.gov/ntp/roc/twelfth/

profi les/GlassWoolFibers.pdf.

Oberd ö rster G , Morrow PE , Spurny K . (1988) . Size dependent lymphatic

short term clearance of amosite fi bers in the lung . Ann Occup Hyg ,

32 , 149 – 56 .

Oberd ö rster G . (2002) . Toxicokinetics and eff ects of fi brous and

nonfi brous particles . Inhal Toxicol , 14 , 29 – 56 .

Ogden TL . (2003) . The 1968 BOHS chrysotile asbestos standard . Ann

Occup Hyg , 47 , 3 – 6 .

OSTP . (1985) . Offi ce of Science and Technology Policy). Chemical

carcinogens: a review of the science and its associated principles. Fed.

Regist. II, 10371 – 10442. Fed Regist, 50:10371 – 442 .

Osmond-McLeod MJ , Poland CA , Murphy F , Waddington L , Morris H ,

Hawkins SC , et al . (2011) . Durability and infl ammogenic impact of

carbon nanotubes compared to asbestos fi bers . Partic Fiber Toxicol ,

8 , 15 – 33 .

Pan XL , Day HW , Wang W , Beckett LA , Schenker MB . (2005) . Residential

Proximity to naturally occurring asbestos and mesothelioma risk in

California . Am J Resp Crit Care Med , 172 , 1019 – 25 .

Paustenbach DJ , Finley BI , Lu EI . (2004) . Environmental and occupational

health hazards associated with the presence of asbestos in brake linings

and pads . J Toxicol Environ Health B Crit Rev , 7 , 28 – 80 .

Peto J , Doll R , Hermon C , Binns W , Clayton R , Goff e T . (1985) .

Relationship of mortality to measures of environmental asbestos

pollution in an asbestos textile factory . Ann Occup Hyg , 29 , 305 – 55 .

Pierce JS , McKinley MA , Paustenbach DJ , Finley BL . (2008) . An

evaluation of reported no-eff ect chrysotile asbestos exposures for lung

cancer and mesothelioma . Crit Rev Toxicol , 38 , 191 – 214 .

Pietruska JR , Johnston T , Zhitkovich A , Kane AB . (2010) . XRCC1

defi ciency sensitizes human lung epithelial cells to genotoxicity by

crocidolite and Libby amphibole . Environ. Health Perspect , 118 ,

1707 – 13 .

Pinkerton KE , Elliot AA , Frame SR , Warheit DB . (1997) . Reversibility

of fi brotic lesions in rats inhaling size-separated chrysotile asbestos

fi bres for 2 weeks . Ann Occup Hyg , 41 , 178 – 83 .

Poland A , Duffi n R , Kinloch I , Maynard A , Wallace WAH , Seaton

A , et al . (2008) . Carbon nanotubes introduced into the abdominal

cavity of mice show asbestos-like pathogenicity in a pilot study . Nat

Nanotechnol , 3 , 111 – 4 .

Pooley FD . (1976) . An examination of the fi brous mineral content of

asbestos lung tissue from the Canadian chrysotile mining industry .

Environ Res , 12 , 281 – 98 .

Pooley FD , Wagner JC . (1988) . The signifi cance of the selective retention

of mineral dusts . Ann Occup Hyg , 32 , 187 – 94 .

Pooley FD , Clark NJ . (1980) . A comparison of fi bre dimension in

chrysotile, crocidolite, and amosite particles from samples of airborne

dust and from post-mortem lung tissue specimens . In: Wagner JC ,

Ed. Biological Eff ects of Mineral Fibres , Vol. 1 Lyons: International

Agency for Research on Cancer , pp. 79 – 86 .

Pott F , Friedrichs KH , Huth F . (1976) . Results of animal experiments

concerning the carcinogenic eff ect of fi brous dusts and their penetration

with regard to the carcinogenesis in humans . Zentralbl Bakteriol Hyg ,

162 , 467 – 505 .

Price B . (2010) . Industrial grade talc exposure and the risk of

mesothelioma . Crit Rev Toxicol , 40 , 513 – 30 .

Reid G , Keilkowski D , Steyn SD , Botha K . (1990) . Mortality of an

asbestos-exposed birth cohort: a pilot study . S Afr Med J , 78 , 584 – 6 .

Rodelsperger K , Bruckel B . (2006) . The carcinogenicity of WHO fi bers

of silicon carbide: SiC whiskers compared to cleavage fragments of

granular SiC . Inhal Toxicol , 18 , 623 – 31 .

Roggli VL , Brody AR . (1984) . Changes in numbers and dimensions

of chrysotile asbestos fi bers in lungs of rats following short-term

exposure . Exp Lung Res , 7 , 133 – 47 .

Roggli VL , George MH , Brody AR . (1987) . Clearance and dimensional

changes of crocidolite asbestos fi bers isolated from lungs of rats

following short-term exposure . Environ Res , 42 , 94 – 105 .

Rohs AM , Lockey JE , Dunning KK , Shukla R , Fan H , Hilbert T , et al .

(2008) . Low-level fi ber-induced radiographic changes caused by Libby

vermiculite: a 25-year follow-up study . Am J Respir Crit Care Med ,

177 , 630 – 7 .

Roller M , Pott F , Kamino K , Althoff GH , Bellmann B . (1996) . Results

of current intraperitoneal carcinogenicity studies with mineral and

vitreous fi bres . Exp Toxicol Pathol , 48 , 3 – 12 .

Rossiter CF , Coles RM . (1980) . H.M. Dockyard, Devonport: 1947

mortality study . In: Wagner JC , Ed. Biological Eff ects of Mineral

Fibres, IARC Scientifi c Pub. No. 30, Lyons: International Agency for

Research on Cancer , pp. 713 – 21 .

Ryan PH , Dihle M , Griffi n S , Partridge C , Hilbert TJ , Taylor R , et al .

(2011) . Erionite in road gravel associated with interstitial and pleural

changes – an occupational hazard in western United States . J Occup

Environ Med , 53 , 892 – 8 .

Sanchez MS , Gunter ME , Dyar MD . (2008) . Characterization of historical

amphibole samples from the former vermiculite mine near Libby,

Montana., U.S.A . Eur J Mineral , 20 , 1043 – 53 .

Saracci R , Simonato L , Acheson ED , Anderson A , Bertazzi PA , Claude J ,

et al . (1984) . Mortality and incidence of cancer of workers in the man-

made vitreous fi bres producing industry: An international investigation

in 13 European plants . Br J Ind Med , 41 , 425 – 36 .

Sawyer RN . (1989) . Asbestos material inventory, control concepts and

risk communications . In : Symposium on Health Aspects of Exposure

to Asbestos in Buildings Cambridge, MA: Harvard University Kennedy

School of Government , pp. 155 – 69 .

Sayers RR , Dreessen WC . (1939) . Asbestosis . Am J Public Health , 29 ,

205 – 14 .

Schinwald A , Murphy FA , Prina-Mello A , Poland CA , Byrne F , Movia

D , et al . (2012a) . The threshold length for fi ber-induced acute pleural

infl ammation: shedding light on the early events in asbestos-induced

mesothelioma . Toxicol Sci , 128 , 461 – 70 .

Schinwald A , Chernova T , Donaldson K . (2012b) . Use of silver nanowires

to determine threshold for fi bre length-dependent pulmonary

infl ammation and inhibition of macrophage migration in vitro . Part

Fibre Toxicol , 9 , 47 – 51 .

Schlesinger RB , Lippmann M . (1978) . Selective particle deposition and

bronchogenic carcinoma . Environ Res , 15 , 424 – 31 .

Schlesinger RB , Concato J , Lippmann M . (1983) . Particle deposition

during exhalation: A study in replicate casts of the human upper

tracheobronchial tree . In: Marple VA , and Liu BYH , Eds. Aerosols in

the Mining and Industrial Work Environments , Vol. 1 Ann Arbor: Ann

Arbor Science Publishers , pp. 165 – 76 .

Schneider F , Sporn TA , Roggli VL . (2010) . Asbestos fi ber content of lungs

with diff use interstitial fi brosis . Arch Pathol Lab Med , 134 , 457 – 61 .

Scholze H , Conradt R . (1987) . An in vitro study of the chemical durability

of siliceous fi bers . Ann Occup Hyg , 31 , 683 – 92 .

Sebastien P , Bignon J , Baris YL , Awad L , Petit G . (1984) . Ferruginous

bodies in sputum as an indication of exposure to airborne mineral fi bers

in the mesothelioma villages of Cappadocia . Arch Environ Health , 39 ,

18 – 23 .

Sebastien P , Armstrong B , Case B , Barwick H , Keskula H , McDonald

JC . (1988) . Estimation of amphibole exposure from asbestos Body and

macrophage counts in sputum: A survey in vermiculite miners . Ann

Occup Hyg , 32 , 195 – 201 .

Seidman H , Selikoff IJ , Hammond EC . (1979) . Short term asbestos work

exposure and long term observation . Ann NY Acad Sci , 330 , 61 – 90 .

Selikoff IJ , Churg J , Hammond EC . (1964).) . Asbestos exposure and

neoplasia . JAMA , 188 , 142 – 6 .

Selikoff IJ , Hammond EC , Seidman H . (1979) . Mortality experience of

insulation workers in the United States and Canada: 1943 – 1976 . Ann

NY Acad Sci , 330 , 91 – 116 .

Selikoff IJ , Nicholson WJ , Langer AM . (1972) . Asbestos air pollution .

Arch Environ Health , 25 , 1 – 13 .

Shannon HS , Jamieson E , Julian JA , Muir DCF , Walsh C . (1987) .

Mortality experience of Ontario glass fi ber workers – extended follow-

up . Ann Occup Hyg , 31 , 657 – 62 .

Shannon H , Hayes M , Julian J , Muir D . (1984) . Mortality experience

of glass fi bre workers. In: Biological Eff ects of Man-Made Mineral

Fibers. Copenhagen: World Health Organization, pp. 347 – 9.

Shannahan JH , Nyska A , Cesta M , Schadweiler MCJ , Vallant BD ,

Ward WOI , et al . (2012) . Subchronic pulmonary pathology, iron

overload, and transcriptional activity after Libby amphibole exposure

in rat models of cardiovascular disease . Environ Health Perspect , 120 ,

85 – 91 .

Shukla A , Gulumian M , Hei TK , Kamp D , Rahman Q , Mossman BT .

(2003) . Multiple roles of oxidants in the pathogenesis of asbestos-

induced diseases . Free Radical Biol Med , 34 , 1117 – 29 .

Simonato L , Fletcher AC , Cherrie J , Andersen A , Bertazzi PA , Charney

N , et al . (1986) . Updating lung cancer mortality among a cohort of

man-made mineral fi bre production workers in seven European

countries . Cancer Lett , 30 , 189 – 200 .

Cri

tical

Rev

iew

s in

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f M

aryl

and

on 1

0/14

/14

For

pers

onal

use

onl

y.


Smith AH , Wright CC . (1996) . Chrysotile asbestos is the main cause of

pleural mesothelioma . Am J Ind Med , 30 , 252 – 66 .

Spengler JD , Ozkaynak H , McCarthy JF , Lee H . (1989) . Summary of

symposium on health aspects of exposure to asbestos in buildings . In :

Symposium on Health Aspects of Exposure to Asbestos in Buildings,

Cambridge, MA: Harvard University Kennedy School of Government ,

pp. 1 – 26 .

Stanton MF , Wrench C . (1972) . Mechanisms of mesothelioma induction

with asbestos and fi brous glass . J Natl Cancer Inst , 48 , 797 – 821 .

Stanton MF , Layard M , Tegeris A , Miller E , May M , Kent E . (1977) .

Carcinogenicity of fi brous glass: Pleural response in the rat in relation

to fi ber dimension . J Natl Cancer Inst , 58 , 587 – 603 .

Stayner LT , Dankovic DA , Lemon RA . (1996) . Occupational exposure

to chrysotile asbestos and cancer risk: a review of the amphibole

hypothesis . Am J Public Health , 86 , 179 – 86 .

St ö ber W , Flachsbart H , Hochrainer D . (1970) . Der aerodynamische

Durchmesser von Latexaggregaten und Asbestfasern . Staub-Reinhalt

Luft , 30 , 277 – 85 .

Stone RA , Youk AO , Marsh GM , Buchanich JM , Smith TJ . (2004) .

Historical cohort study of U.S. man-made vitreous fi ber production

workers IX: Summary of 1992 mortality follow up and analysis of

respiratory system cancer among female workers . J Occup Environ

Med , 46 , 55 – 67 .

Stone RA , Youk AO , Marsh GM , Buchanich JM , McHenry MB , Smith

TJ . (2001) . Historical cohort study of US man-made vitreous fi ber

production: IV. Quantitative exposure-response analysis of the nested

case-control study of respiratory system cancer . J Occup Environ Med ,

43 , 779 – 92 .

Su W-C , Cheng YS . (2006) . Fiber deposition pattern in two human

respiratory tract replicas . Inhal Toxicol , 18 , 749 – 60 .

Sussman RG , Cohen BS , Lippmann M . (1991a) . Asbestos fi ber deposition

in a human tracheobronchial cast . I. Experimental. Inhal Toxicol , 3 ,

145 – 60 .

Sussman RG , Cohen BS , Lippmann M . (1991b) . Asbestos fi ber deposition

in a human tracheobronchial cast . II. Empirical model. Inhal Toxicol ,

3 , 161 – 79 .

Timbrell V . (1972) . An aerosol spectrometer and its applications . In:

Mercer TT , Morrow PE , St ö ber W , Eds. Assessment of Airborne

Particles Springfi eld, IL: Charles C . Thomas , pp. 290 – 330 .

Timbrell V . (1982) . Deposition and retention of fi bers in the human lung .

Ann. Occup. Hyg , 26 , 347 – 69 .

Timbrell V . (1983) . Fibers and carcinogenesis . J Occup Health Soc , 3 , 3 – 12 .

Timbrell V . (1984) . Pulmonary deposition and retention of South

African amphibole fi bers: Identifi cation of asbestosis-related

measure of fi ber concentration . In: Proceedings of VIth International

Pneumoconiosis Conference, Bochum, 1983, Vol. 2. Geneva: ILO ,

pp. 998 – 1008 .

Timbrell V , Ashcroft T , Goldstein B , Heyworth F , Meurman LO , Rendall

REG , et al . (1987) . Relationships between retained amphibole fi bers

and fi brosis in human lung tissue specimens . In: Walton WH , Ed.

Inhaled Particles VI Oxford: Pergamon Press .

Tran CL , Jones AD , Cullen RT , Donaldson K . (1997) . Overloading of

clearance of particles and fi bres . Ann Occup Hyg , 41 , 237 – 243 .

Trethowan WN , Burge PS , Rossiter CE , Harrington JM , Calvert IA .

(1995) . Study of the respiratory health of employees in seven European

plants that manufacture ceramic fi bres . Occup Environ Med , 52 ,

97 – 104 .

Utidjian HMD , deTreville RTP . (1970) . Fibrous glass manufacturing

and health: Report of an epidemiological study. Parts I and II.

Proceedings of the 35th Annual Meeting of the Industrial Health

Foundation. October 13 – 14, 1970. Pittsburgh, PA. IHF Bulletin No.

44 ., pp. 98 – 102 .

Veblen DR . (1980) . Anthophyllite asbestos: Microstructures, intergrown

sheet silicates and mechanisms of fi ber formation . Am Mineral , 65 ,

1075 – 86 .

Viallat JR , Rayhuad F , Passeral M , Boutin C . (1986) . Pleural migration

of chrysotile fi bers after intratracheal injection in rats . Arch Environ

Health , 41 , 282 – 6 .

Vincent JH , Johnston AM , Jones AD , Bolton RE , Addison J . (1985) .

Kinetics of deposition and clearance of inhaled mineral dusts during

chronic exposure . Br J Ind Med , 42 , 707 – 15 .

Vincent JH . (1999) . Particle Size-Selective Sampling for Particulate

Air Contaminants. American Conference of Governmental Industrial

Hygienists, Cincinnati, OH.

Wagner JC , Pooley FD . (1986) . Mineral fi bers and mesothelioma . Thorax ,

41 , 161 – 6 .

Wagner JC , Skidmore JW . (1965) . Asbestos dust deposition and retention

in rats . Ann NY Acad Sci , 132 , 77 – 86 .

Wagner JC , Steggs A , Marchand P . (1960) . Diff use pleural mesothelioma

and asbestos exposure in northwestern Cape Province . Br J Ind Med ,

17 , 260 – 71 .

Wagner JC , Pooley FD , Barry G , Seal RME , Munday DE , Morgan

J , Clark NJ . (1982) . A pathological and mineralogical study of

asbestos-related deaths in the United Kingdom . Ann Occup Hyg ,

26 , 417 – 22 .

Wagner JC , Berry G , Skidmore JW . (1976) . Studies of the carcinogenic

eff ects of fi ber glass of diff erent diameters following intrapleural

innoculation in experimental animals. In: Occupational Exposure to

Fibrous Glass, HEW Publ. No. (NIOSH) 76 – 151, pp. 193 – 7.

Wagner JC , Berry G , Skidmore JW , Timbrell V . (1974) . The eff ects of the

inhalation of asbestos in rats . Br J Cancer , 29 , 252 – 69 .

Wagner JC , Skidmore JW , Hill RJ , Griffi ths DW . (1985) . Erionite

exposure and mesotheliomas in rats . Br J Cancer , 51 , 727 – 30 .

Walker AM . (1984) . Declining relative risks for lung cancer after

cessation of asbestos exposure . J Occup Med , 2 , 422 – 6 .

Walton WH . (1982) . The nature, hazards and assessment of occupational

exposure to airborne asbestos dust: a review . Ann Occup Hyg , 25 ,

117 – 247 .

Warheit DB , Hartsky MA . (1990) . Species comparisons of alveolar

deposition patterns of inhaled particles . Exp Lung Res , 16 , 83 – 99 .

Webber JS , Blake DJ , Ward TJ , Pfau JC . (2008) . Separation and

characterization of respirable amphibole fi bers from Libby, Montana .

Inhal Toxicol , 20 , 733 – 40 .

Weill D , Dhillon G , Freyder L , Lefante J , Glindmeyer H . (2011) . Lung

function, radiological changes and exposure: analysis of ATSDR data

from Libby, MT, USA . Eur Resp J , 38 , 376 – 83 .

Weitzman SA , Graceff a P . (1984) . Asbestos catalyzes hydroxyl and

superoxide radical release from hydrogen peroxide . Arch Biochem

Biophys , 288 , 373 – 6 .

Whittaker EJW , Zussman J . (1956) . The characterization of serpentine

minerals by X-ray diff raction . MinMag , 32 , 107 – 15 .

WHO . (1997) . Determination of Airborne Fibre Number Concentrations .

Geneva: World Health Organization, 53pp .

Wong O , Musselman RP . (1994) . An epidemiological and toxicological

evaluation of the carcinogenicity of man-made vitreous fi ber, with a

consideration of coexposures . J Environ Pathol Toxicol Oncol , 13 ,

169 – 80 .

Wright GW , Kuschner M . (1977) . The infl uence of varying lengths of

glass and asbestos fi bers on tissue response in guinea pigs . In: Walton

WH , Ed. Inhaled Particles IV, Part 2 . New York: Pergamon Press , pp.

455 – 72 .

Yada K . (1967) . Study of chrysotile asbestos by a high resolution electron

microscope . Acta Crystallogr , 23 , 704 – 7 .

Yarborough CM . (2006) . Chrysotile as a cause of mesothelioma: An

assessment based on epidemiology . Crit Rev Toxicol , 36 , 165 – 87 .

Yu CP , Asgharian B , Abraham JL . (1990) . Mathematical modeling of

alveolar clearance of chrysotile asbestos fi bers from the rat lings . J

Aerosol Med , 21 , 587 – 94 .

Zalma R , Guignard J , Copin E , Pezzarat H . (1987) . Studies of surface

properties of asbestos . Env Res , 41 , 296 – 301 .

Cri

tical

Rev

iew

s in

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f M

aryl

and

on 1

0/14

/14

For

pers

onal

use

onl

y.

Toxicological and epidemiological studies on effects of airborne fibers: Coherence and public health...

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