Health Hazard Assessment of Nonasbestos Fibers
Vanessa T. Vu, Ph.D.
Health and Environmental Review Division
Office of Toxic Substances
U.S. Environmental Protection Agency
December 30, 1988
Final Draft
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TABLE OF CONTENTS
PAGE
ACKNOWLEDGMENTS vii
REVIEWERS viii
EXECUTIVE SUMMARY 1
I. Introduction 26
II. Man-Made Mineral Fibers 27
1.0. Fibrous Glass 28
1.1. Fiber Deposition, Clearance and Retention.... 29
1.2. Effects on Experimental Animals..... 34
1.2.1. Oncogenicity 35
1.2.2. Fibrogenicity 51
1,3. In Vitro Studies. 57
1.3.1. Genotoxicity 57
1.3.2. Cytotoxicity 63
1.4. Assessment of Health Effects 68
1.5. Recommendations. .78
2.0. Mineral Wool 79
2.1. Fiber Deposition, Clearance and Retention.... 79
2.2. Effects on Experimental Animals 82
2.2.1. Oncogenicity 82
2.2.2. Fibrogenicity. 86
2.3. In Vitro Studies 87
2.3.1. Genotoxicity 87
2.3.2. Cytotoxicity 87
2.4. Assessment of Health Effects 89
2.5. Recommendations 94
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iii
TABLE OF CONTENTS (continued)
PAGE
3.0. Ceramic Fibers 94
3.1. Fiber Deposition, Clearance and Retention.... 95
3.2. Effects on Experimental Animals 97
3.2.1. Oncogen icity 98
3.2.2. Fibrogen icity 104
3.3. In Vitro Studies 107
3.3.1. Genot ox icity 107
3.3.2. Cytotoxicity 107
3.4. Assessment of Health Effects 109
3.5. Recommendations Ill
III. Naturally Occurring Fibers Ill
1.0. Erionite Ill
1.1. Fiber Deposition, Clearance and Retention...112
1.2. Effects on Experimental Animals 113
1.2.1. Oncogen icity 113
1.2.2. Fibrogen icity 118
1.3. In Vitro Studies 119
1.3.1. Genotox icity 119
1.3.2. Cytotoxicity 122
1.4. Assessment of Health Effects 123
1.5. Recommendations 126
2.0. Wollastonite.. 126
2.1. Fiber Deposition, Clearance and Retention...127
2.2. Effects on Experimental Animals 127
2.2.1. Oncogenicity 127
2.2.2. Fibrogenicity 129
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IV
TABLE OF CONTENTS (continued)
PAGE
2.3. In Vitro Studies 129
2.3.1. Genotoxicity 129
2.3.2. Cytotoxicity 129
2.4. Assessment of Health Effects 133
2.5. Recommendations 134
3.0. Attapulgite 135
3.1. Fiber Deposition, Translocation
and Clearance 135
3.2. Effects on Experimental Animals 136
3.2.1. Oncogenicity 137
3.2.2. Fibrogenicity 141
3.3. In Vitro Studies 143
3.3.1. Genotoxicity 143
3.3.2. Cytotoxicity 144
3.4. Assessment of Health Effects 147
3.5. Recommendations 152
IV. Synthetic Fibers 152
1.0. Aramid Fibers 152
1.1. Fiber Deposition and Clearance 153
1.2. Effects on Experimental Animals 154
1.2.1. Oncogenicity 154
1.2.2. Fibrogenicity 156
1.3. In Vitro Studies 160
3.3.1. Genotoxicity 160
3.3.2. Cytotoxicity 160
1.4. Assessment of Health Effects 161
1.5. Recommendations 164
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V
TABLE OF CONTENTS (continued)
PAGE
2.0. Carbon Fibers 164
2.1. Fiber Deposition, Clearance and Retention...165
2.2. Effects on Experimental Animals 166
2.2.1. Oncogenicity 166
2.2.2. Fibrogenicity 170
2.3. In Vitro Studies 174
2.3.1. Genotoxicity 174
2.3.2. Cytotoxicity 175
2.4. Assessment of Health Effects 177
2.5. Recommendations 180
3.0. Polyolefin. Fibers 180
3.1. Fiber Deposition, Clearance and Retention...181
3.2. Effects in Experimental Animals 181
3.2.1. Oncogenicity 181
3.2.2. Fibrogenicity 183
3.3. In Vitro Studies 185
3.3.1. Genotoxicity 185
3.3.2. Cytotoxicity 185
3.4. Assessment of Health Effects 186
3.5. Recommendations 188
V. Mechanisms of Fiber-Induced Diseases: Relationship
Between Fiber Properties and Pathogenicity 188
VI. References 197
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VI
TABLE OF CONTENTS (continued)
PAGE
VII. Appendix 214
Table
Table
Table
Table
Table
Table
Table
Table
Table
1.
2.
3.
4.
5.
6.
7.
8.
9.
Summary
Summary
Summary
Summary
Summary
Summary
Summary
Summary
Summary
of
of
of
of
of
of
of
of
of
animal
animal
animal
animal
animal
animal
animal
animal
animal
studies
stud ies
studies
stud ies
stud ies
stud ies
studies
studies
studies
on
on
on
on
on
on
on
on
on
Fibrous Glass. .
Ceramic Fibers.
Aramid Fibers..
Carbon Fibers..
Polyolef in
..215
230
..234
240
243
244
..246
..248
. ,251
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Vll
ACKNOWLEDGMENTS
Dr. Kerry Dearfield, (U.S. Environmental Protection Agency) is
gratefully acknowledged for the review and evaluation of
genotoxicity data on fibers.
The author wishes to thank Mary Argus, Ph.D./ Charles Auer,
Diane Beal/ Ph.D., Karl Baetcke, Ph.D., Kerry Dearfield, Ph.D.,
Ernest Falke, Ph.D., Penelope Fenner-Crisp, Ph.D., Stephanie R.
Irene, Ph.D., Elizabeth Margoshes, Bruce Means, Karen Milne, Steven
Shapiro and Bruce Sidwell (U.S. Environmental Protection Agency) for
their critical review of the document.
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Vlll
REVIEWERS
The early draft of the document has been peer reviewed for
scientific and technical merit by the following scientists and their
valuable comments are greatly appreciated.
Dr. David L. Bayliss, Office of Health and
Environmental Assessment, U.S. Environmental
Protection Agency/ Washington, DC, U.S.A.
Dr. Steven Bayard, Office of Health and
Environmental Assessment, U.S. Environmental
Protection Agency, Washington, DC, U.S.A.
Dr. David L. Coffin, Health Effects Research
Laboratory, U.S. Environmental Protection Agency,
Research Triangle Park, NC, U.S.A.
Dr. J.M.G. Davis, Pathology Branch, Institute of
Occupational Medicine, Edingburg, Scotland, United
Kingdom
Dr. John M. Dement, National Institute of
Environmental Health Sciences, Research Triangle
Park, NC, U.S.A.
Ms. Caroline S. Freeman, Office of Standards Review,
Occupational Safety and Health Administration,
Washington, DC, U.S.A.
Dr. David Groth, National Institute for Occupational
Safety and Health, Cincinnati, OH, U.S.A.
Dr. Ulrich F. Gruber, University of Basle, Basle,
Switzerland
Dr. Peter F. Infante, Office of Standards Review,
Occupational Safety and Health Administration,
Washington, DC, U.S.A.
Dr. Jon L. Konzen, Owens Corning Fiberglass
Corporation, Toledo, OH, U.S.A. v
Dr. Aparna Koppikar, Office of Health and
Environmental Assessment, U.S. Environmental
Protection Agency, Washington, DC, U.S.A.
Dr. Dennis J. Kotchmar, Environmental Criteria and
Assessment Office, U.S. Environmental Protection
Agency, Research Triangle Park, NC, U.S.A.
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IX
REVIEWERS (continued)
Dr. Arthur Langer, Mount Sinai School of Medicine,
New York, NY, U.S.A.
Dr. William Pepelko, Office of Health and
Environmental Assessment, U.S. Environmental
Protection Agency, Washington, DC, U.S.A.
Dr. J.C. Wagner, Llandough Hospital, Pernath,
Glamorgan, United Kingdom
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EXECUTIVE SUMMARY
The inhalation of asbestos fibers including amosite,
chrysotile, and crocidolite has been associated with the
development of lung cancer, mesothelioma, pulmonary fibrosis and
other nonmalignant pleural diseases in humans. Because the
pathogenic effects of asbestos are attributed/ in general, to its
fibrous nature, human health concern extends to the use of other
fibrous substances. This document assesses the health effects of
nine non-asbestos fibers and attempts to determine the nature and
magnitude of the health hazard as compared to asbestos. The
fibers chosen for investigation were selected for one or more of
the following reasons: a) they are commercially important; b)
they are considered potential asbestos substitutes; c) they
represent fiber types with broadly different physical and
chemical characteristics; and, d) health data are available on
them. The fibers evaluated in this report include fibrous glass,
mineral wool, ceramic fibers, erionite, wollastonite,
attapulgite, aramid fibers, carbon fibers, and polyolefin fibers.
Available data suggest some similarities in the health
effects of asbestos and some nonasbestos fibers but the degree of
the health effects may differ substantially among fiber types.
The differences in the biological activity may be associated with
the specific characteristics of each fiber type including fiber
morphology, size distribution, chemical constitution, surface
properties and durability.
A basic property which allows a fiber's potential toxicity to
be expressed is its respirability, i.e., its ability to penetrate
into the smaller conducting airways of the tracheobronchilar tree
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and the alveolar region of the lung. It is clear that fiber
diameter is the most important factor in determinig the
respirability of the fiber. Fiber length and morphology also
affect the respirability of the fiber but to a lesser extent.
Also, it would appear that the fiber needs to be retained and
persist in the tissue in order to cause toxicity. Fiber length
is an important determinant of fiber retention, with shorter
fibers being cleared more readily. Fiber retention is also
determined by the biological solubility of fibers which is
directly related to their chemical composition and physical
characteristics.
To date, the exact role of various fiber properties in
relation to biological activity and pathogenicity is not clearly
understood. It is clear, however, that different types of fibers
with similar size properties (e.g. erionite and asbestos) could
have very different biological activity, although there is
increasing evidence suggesting that for a given fiber type, fiber
size is an important factor, i.e., the thinner and longer the
fiber, the more hazardous it is. Additional research is
necessary to examine further the importance of fiber properties
in mediating the induction of disease and investigate the
mechanisms by which fibrous materials cause disease.
It is difficult to definitively assess the relative
biological activity and pathogenicity of nonasbestos fibers in
comparison to asbestos because of limited data bases. Major
limitations include a lack of comparable dose-response data as
well as information available on the characteristics of the
tested fibers, particularly, fiber morphology and size
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distribution and the number of fibers in each size category.
However, on the basis of available information, it may be
concluded at this time that with the possible exception of
erionite, the other eight fibers reviewed in this report do not
pose a health hazard of similar magnitude as asbestos.
Additional studies are needed to conclusively determine the
health effects of each fiber type. Erionite, which may be more
hazardous than asbestos, is not a major concern because of its
limited production and use.
A summary of the hazard assessment of the oncogenic and
fibrogenic effects of these fibers, and the testing
recommendation(s) to fill data gaps for each fiber is presented
in the following sections. The assessment of the potential for
carcinogenicity of fibers in humans is based on the current U.S.
EPA classification system for categorizing the overall weight-of-
evidence as determined from human, animal and other supporTing
data (USEPA, 1986).
Inhalation is the major route of exposure to fibers and
exposure via this route of administration has been shown to cause
cancer in humans in the case with asbestos. Hence, it would seem
most relevant to use the inhalation route for the animal testing
of fiber carcinogenicity. Positive results from inhalation
studies in animals would be interpreted to have significant
implications for potential hazard in the human since asbestos has
also been found to induce tumors in animals following inhalation
exposure. The major pathogenic effects associated with the
inhalation of asbestos in humans including lung fibrosis, lung
cancer and mesothelioma have been replicated in rodents exposed
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to asbestos by inhalation. There are, however, shortcomings of
inhalation studies. One reason is that fiber deposition and
retention in rodents are considerably different from those in
humans. Rodents, being obligatory nose breathers, have a greater
filtering capacity than humans resulting in a lower alveolar
deposition of fibers in rodents. As a result, inhalation tests
in rodents may underestimate the hazard potential of fibers to
humans unless it is clear that the number of fibers reaching the
target tissues are comparable to the positive control.
Experimental procedures other than inhalation exposure
testing have been developed which attempt to accommodate for
these species differences and to achieve comparable target organ
doses. However, they do have their disadvantages. In these
studies, the test fiber is artificially introduced in large
"bolus" dose(s) directly into the target tissue such as the
mesothelium as in the cases with intraperitoneal and intrapleural
administrations, or near major targets including the lung and
pleural mesothelium in the case of intratracheal instillation.
Caution must be excercised in extrapolating the findings from
parental administration studies in animals to humans, since the
results from such studies may not be predictive of inhalational
hazard. Injection studies bypass the normal physiological
deposition and clearance mechanisms and lead to non-random
accumulations of test substances at the site of deposition.
Thus, respirability characteristics, which are routinely taken
into account in an inhalation study, are not operative following
injection. Nevertheless, injection studies are of value by
providing useful information regarding the intrinsic biological
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activity of the test fiber under conditions where the material is
in direct contact with the cells at risk.
1. Fibrous Glass
There is no evidence in available epidemiologic studies that
peritoneal or pleural mesotheliomas are associated with
occupational exposure to man-made mineral fibers (fibrous glass
and mineral wool). With regard to the respiratory cancer risk,
there was no excess of such cancers among continuous glass
filament workers in either the U.S. or Europe. For glass wool
production workers, there was no significant increase in
mortality from respiratory cancer (or lung cancer) compared with
regional rates in either the U.S. or European cohorts/ though
there were statistically significant small increases compared
with national rates in the U.S. study. In both investigations,
mortality from respiratory cancer increased nonsignificantly with
time from first exposure. However, it was not related to the
duration of employment or cumulative fiber exposure in the U.S.
study. Also, in the European study, it was not related to the
duration of exposure or to different technological phases
reflecting differences in the intensity and quality of
exposure. A lack of dose-related trends might be due in part to
the very low exposure experienced by the cohorts.
Among glass wool workers in the U.S. cohort who were ever
exposed to small diameter fibers (<3.0 urn)/ there was a
nonsignificant excess of respiratory cancer mortality which
increased nonsignificantly with time since first exposure,
compared to those who had never been exposed. A third study
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reported a statistically significant increase of lung cancer
mortality among Canadian glass wool workers, but this was not
related to the time since first exposure nor to the duration of
exposure.
On the basis of available information, the evidence for
carcinogenicity of small diameter glass fibers, glass wool and
glass filament from studies in humans is considered inadequate.
Still, the epidemiologic findings seem to suggest that workers
engaged in the manufacture of glass wool and small diameter
fibers might be at increased risk of developing respiratory
cancer; additional studies are necessary to clarify the health
effects of fibrous glass in humans.
A number of long-term inhalation studies have not provided
evidence of lung tumor or mesothelioma in several animal species
exposed to glasswool (typically 3-10 urn in diameter), fine fiber-
glass (1-3 urn in diameter) or to very fine fibrous glass (also
known as glass microfibers; <1 urn in diameter). Shortcomings of
these investigations include the use of small numbers of animals,
relatively short fibers, low numerical concentrations of fibers,
limited study duration, and/or inadequate positive control. In
contrast to the inhalation studies, many animal studies involving
the intrapleural injection/implantation, or intraperitoneal
injection of fine glass fibers or glass microfibers consistently
demonstrate that these fibers are capable of producing
mesothelioma in rats, hamsters, and mice when they are introduced
directly into the body cavity. Glass wool has also been shown to
produce low incidences of pleural tumors in a few intrapleural
implantation/injection studies in rats. In addition, an
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increased incidence of both lung tumors and pleural mesothelioma
has been reported in one study following intratracheal
administration of glass microfibers to hamsters; this indicates
that under certain conditions, glass fibers can pass through the
lung and incite reactions in the pleura. In another intratra-
cheal instillation study, glass microfibers also caused lung
tumors in the rat. However, several other intratracheal
instillation studies in hamsters and rats have not reported tumor
formation with glass wool, fine glass fibers or glass
microfibers.
In the absence of positive findings from available
inhalation studies, the evidence for human carcinogenicity of
very fine and fine fibrous glass and glass wool from animal
studies is considered limited because only non-physiological
routes of administration are associated with carcinogenic
findings. However, the repeated observation of tumors following
these administrations do indicate the biological activity of the
test fibers when deposited in high enough quantity at or near the
target tissue. The animal data are supported by positive
findings from a few genotoxicity studies which indicate that fine
fiberglass and glass microfibers cause similar weak genotoxic
effects (clastogenicity and cell transformation) generally seen
with asbestos. Thus, considering all available data (human,
animal and supporting evidence), the Office of Toxic Substances
(OTS) of the U.S. Environmental Protection Agency (USEPA)
proposes to classify fine and very fine fibrous glass and glass
wool in-Category C, i.e., possible human carcinogen, mainly based
on inadequate evidence of carcinogenicity in humans and
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8
limited evidence in animals. Others might interpret the same
information as supporting a B2 (probable human carcinogen)
designation/ mainly because they think the animal injection
studies should be afforded more weight. Irrespective of these
differences in classification, all would agree that the existing
evidence supporting a human carcinogen hazard for fibrous glass
is much less convincing than for asbestos.
As for the continuous glass filament (nominal diameters of
6-15 urn), there is inadequate evidence of carcinogenicity in lab-
oratory animals. The results of a few available intrapleural
implantation studies showed that large diameter glass fibers did
not induce mesothelioma in rats. Glass filament is therefore not
classifiable as to human carcinogenicity on the basis of
inadequate evidence of carcinogenicity in humans and animals
(Category D).
There does not appear to be any convincing evidence for
increased risks of non-malignant respiratory disease (NMRD) among
fibrous glass workers. In the European study/ there was no
excess mortality from NMRD in the continuous glass filament or
glass wool cohort, nor was there a trend with time since first
exposure or duration of employment. Similarly/ in the U.S.
study/ no significant excess of NMRD mortality was found among
glass filament workers compared with either local or national
rates. For U.S. glass wool workers, there was no significant
increase in NMRD mortality based on local rates though there was
a statistically significant excess compared with national
rates. Further analyses of NMRD mortality showed no apparent
dose-related trends. Among glass wool workers ever exposed to
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small diameter fibers/ no excess of NMRD mortality was observed
but there was a nonsignificant increase with time since first
exposure. The results of a respiratory morbidity study showed
some evidence of radiographic opacities in the lung of a limited
number of fibrous glass workers but there was no evidence of
pulmonary fibrosis, no increase in respiratory symptoms and no
impaired lung function.
Long-term inhalation studies have not provided definitive
evidence for the development of lung fibrosis in laboratory
animals exposed to fine glass fibers or glass wool. However, the
positive findings from several injection studies in animals and
in vitro cytotoxicity studies indicate that fine and very fine
fiberglass may be fibrogenic.
Overall, it may be concluded that a possible health hazard
exists from inhalation exposure to fine and very fine fibrous
glass, i.e., fibers with diameters consistently below 3
microns. A low health concern is also raised for exposure to
glass wool which does contain some respirable fine fibers. As
for continous glass filaments which are generally nonrespirable,
they would appear to pose little or no hazard to exposed
humans. On the basis of available experimental data, it is
concluded that fibrous glass appears to be less pathogenic than
asbestos. Although the fibrogenicity and oncogenicity of fine
fibrous glass and glass wool have been extensively investigated,
none of the available inhalation studies are considered
adequate. Furthermore, since considerable data gaps still exist,
particularly a lack of comparative dose-response effects with
pbestos, additional inhalation/injection studies would be
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10
useful. It also appears necessary to conduct additional
epidemiological studies to conclusively determine the health
hazard potential of fibrous glass in humans.
2. Mineral Wool
Small excesses of mortality due to respiratory cancer have
been observed among rock wool/slag wool workers in the U.S. and
in Europe. In the U.S. study/ the excess of respiratory cancer
mortality was statistically significant when compared to both
local and national rates. There was no clear trend with time
since first exposure and there was no relationship with duration
of exposure, cumulative fiber exposure or average intensity of
exposure. The results of a nested case-control study using cases
from the U.S. cohort showed a weak but positive trend between
mineral wool exposure and respiratory cancer when confounding by
cigarette smoking was considered.
In the European study, the lung cancer excess found among
rock wool/slag wool workers was not statistically significant
compared with either local or national mortality rates. There
was also a statistically nonsignificant increased mortality with
time since first exposure but there was no relationship between
lung cancer mortality and duration of exposure. The highest and
statistically significant lung cancer rates were found among
workers after more than 20 years first exposed in the early
technological phases, during which fiber airborne levels were
presumably higher than in later production phases. The presence
of workplace contaminants such as bitumen, pitch or asbestos
•could not explain the observed lung cancer excess.
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Overall/ the available epidemiological findings suggest that
mineral wool workers are at increased risk of respiratory
cancer. The evidence for mineral wool as an etiological agent
includes the consistent elevated risk observed in several rock
wool/slag wool facilities, and the higher cancer risks found.
among workers who had twenty or more years elapse since first
exposure. The evidence not supporting an etiological
relationship is the lack of a consistent dose-response trend.
This might be due in part to the low levels of fiber exposure and
the potential exposure misclassification. On the basis of
available information/ the evidence for carcinogenicity of
mineral wool from epidemiological studies is considered limited.
The results of three limited long-term studies showed that
mineral wool did not produce tumors in rats or hamsters when
administered by inhalation. However/ mineral wool has been shown
in a few studies to induce varying tumor yields in rats via
either the intrapleural (pleural mesothelioma) or intraperitoneal
route (peritoneal mesothelioma) of exposure. Overall, the
experimental evidence for the carcinogenic potential of mineral
wool is considered to be limited. Thus/ OTS is proposing to
classify mineral wool as a probable human carcinogen (Category
Bl) on the basis of limited evidence of carcinogenicity from
epidemiological studies and limited evidence from animal
studies. There is no genotoxicity information available on
mineral wool.
There is inadequate epidemiological evidence for an
association between the development of non-malignant respiratory
diseases (NMRD) and exposure to mineral wool. No increased
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mortality from NMRD was found for the European rock wool/slag
wool workers. In the U.S. study, a statistically nonsignificant
excess of NMRD mortality was observed among mineral wool workers
based on local or national rates. However/ there was no
relationship with time since first exposure, duration of
exposure, average intensity of exposure, or estimated cumulative
level of exposure. Furthermore, the results of a respiratory
morbidity study in the U.S. showed no evidence for impaired lung
functions or radiographic lung abnormalities associated with
mineral wool exposure.
There is little experimental evidence for the fibrogenicity
of mineral wool. Mineral wool was not found to cause lung
fibrosis in three long-term inhalation studies but focal fibrosis
was reported in a very limited inhalation study involving only
two rats. The results of two in vitro studies showed that
mineral wool was cytotoxic in cells in culture. In view of these
findings, concerns for possible development of pulmonary fibrosis
associated with mineral wool exposure cannot be entirely ruled
out at this time.
Based on the limited data base in animals, mineral wool
appears to be less biologically active and less pathogenic than
asbestos fibers. It is concluded at this time that mineral wool
fibers may present a health hazard to exposed humans but not to
the same magnitude as asbestos. Since the pathogenic effects of
mineral wool have not been adequately characterized, additional
epidemiological studies and animal testing are needed.
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3. Ceramic Fibers
There are no studies available on the potential health
effects from exposure to ceramic fibers in humans. The
pathogenicity of ceramic fibers in laboratory animals appears to
vary considerably for different fiber types which may be a
function of variation in fiber size distribution.
An increased incidence of lung tumors have been observed
after chronic inhalation exposure to ceramic aluminum silicate
glass in one study using rats. Another inhalation study produced
no tumors in rats, but one mesothelioma in a hamster. An
intratracheal instillation study conducted by the same laboratory
showed no tumor induction with refractory aluminum silicate
fibers. However, these fibers have been shown in several long-
term studies to cause mesothelioma in rats and hamsters by
intrapleural or intraperitoneal injection. Based on the
sufficient evidence of carcinogenicity in animals in multiple
experiments with different routes of administration, but in the
absence of human data, OTS proposes to classify ceramic aluminum
silicate fiber as a probable human carcinogen (Category B2).
The experimental evidence of fibrogenicity of ceramic
aluminum silicate fibers is limited. The positive results of a
chronic inhalation study suggest that long-term inhalation of
ceramic aluminum silicate glass may produce mild interstitial
lung fibrosis in humans. This finding is further supported by
positive findings from an in vitro cytotoxicity study of ceramic
aluminum silicate glass.
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In view of available findings and since ceramic aluminum
silicate fibers are respirable and durable, it may be concluded
that this ceramic fiber type may present a health hazard to the
exposed humans. Because of the variable results from available
in vivo and in vitro studies on ceramic aluminum silicate, its
relative pathogenicity in comparison to asbestos cannot yet be
made at this time. In order to further evaluate the health
effects of ceramic aluminum silicate fibers, it is recommended
that epidemiological studies of exposed workers be initiated. No
additional animal tests are recommended at this time since a
large-scale animal study by various routes of exposure is
currently being conducted at a private laboratory.
Available animal studies have not provided evidence of the
carcinogenicity and fibrogenicity for refractory alumina oxide
and zirconia oxide fibers. It has been shown in several studies
that these fibers did not produce tumors nor fibrosis in rats via
chronic inhalation exposure or by intracavitary injection. The
lack of experimental pathogenic effects of these fibers may be
attributable to the test fibers being largely nonrespirable.
Similarly, the cytotoxicity of these fibers in rat peritoneal
macrophages is low. These refractory fibers are therefore not
classifiable as to human carcinogenicity (Category D) on the
basis of inadequate evidence of carcinogenicity in animal studies
and in the absence of human data. Based on available findings,
it would appear that refractory alumina and zirconia fibrous
products containing mostly nonrespirable fibers would not pose
significant health hazard in exposed humans.
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4. Erionite
Available epidemiological data show that populations from
South Central Turkey have an excessive incidence of malignant
pleural mesothelioma and nonmalignant pleural diseases (chronic
pleurisy fibrosis, pleural thickening and pleural plaques). The
etiology of these diseases is uncertain but there is limited
evidence to indicate that erionite fibers may be the major
etiological factor. All of the experimental studies conducted to
date have confirmed that erionite from Turkey and deposits in the
U.S. causes a significant increase in malignant meseothelioma in
animals by several routes of exposure including inhalation.
Animal data are also supported by findings that erionite is
genotoxic, in causing DNA damage and repair and inducing cell
transformation in culture. Thus, OTS is proposing to classify
erionite as a probable human carcinogen (Category Bl) on the
basis of limited evidence of carcinogenicity from studies in
humans and sufficient evidence of carcinogenicity from animal
studies.
There is no information available on the ability of erionite
to induce fibrotic diseases in animals by inhalation. However,
erionite has been shown to cause fibrogenic effects in animals by
the injection method. Furthermore, available in vitro studies
demonstrate that erionite is hemolytic and highly cytotoxic.
Thus, it is concluded that erionite is potentially fibrogenic in
view of the limited evidence from epidemiological studies and
limited evidence from experimental studies.
Overall, there is sufficient evidence to conclude that
erionite potentially poses a significant health hazard to exposed
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16
humans. However, if practical, additional epidemiological
studies should be conducted to further evaluate the association
between erionite environmental exposure and development of
malignant and nonmalignant respiratory diseases. Since the
toxicological profile of erionite has been adequately
characterized in animals, no further testing is recommended.
Based on the available experimental data, erionite appears to be
at least as hazardous as asbestos.
5. Wollastonite
None of the available epidemiological studies were designed
to assess the risk of lung cancer or mesothelioma associated with
wollastonite exposure. One case of mesothelioma has been
reported in a worker who had been exposed to wollastonite, but no
cause and effect relationship can be drawn based on a single case
report. Preliminary information on an inhalation oncogenicity
study of wollastonite in rats indicates the lack of a tumorigenic
response. The results of an intrapleural implantation study
showed that wollastonite was weakly tumorigenic in rats; whereas,
in another long-term study in rats, wollastonite caused no tumors
when injected into the peritoneal cavity. Thus, based on limited
evidence of carcinogenicity in animals and inadequate human data,
OTS is proposing to classify wollastonite as a possible human
carcinogen (Category C). No other supporting evidence (e.g.,
genotoxicity data) of oncogenicity is available.
Available data are inadequate to evaluate the fibrogenic
potential of wollastonite. A preliminary report of an NTP
bioassay indicates no evidence of pulmonary fibrosis in rats
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17
following chronic inhalation of wollastonite but data are not yet
available for a full evaluation. Available epidemiological
studies indicate a possible association between wollastonite
exposure and some nonmalignant diseases such as impaired
ventilatory capacity, mild fibrosis of the lung, pleural
thickening and chronic bronchitis. However, because of a number
of limitations, they do not provide convincing evidence of a
causal relationship of nonmalignant respiratory diseases and
wollastonite exposure. Nevertheless, these epidemiological
findings do raise a health concern, particularly in view of
positive results from in vitro cytotoxicity assays which are
thought to be indicative of fibrogenic activity.
Overall, there is some evidence supporting a concern for a
possible health hazard from exposure to wollastonite. However,
it would appear that wollastonite is probably less hazardous than
asbestos since available experimental data indicate that
wollastonite is much less biologically active than asbestos. In
order to fully assess the health effects of wollastonite, it is
necessary to seek additional epidemiological studies and to fully
evaluate the results of an inhalation bioassay recently completed
by the National Toxicology Program.
6. Attapulgite
There is inadequate evidence of carcinogenicity of short-
fibered attapulgite from available studies in humans. The
results of a single small cohort study in the U.S. showed an
excess of lung cancer among some groups of attapulgite workers.
However, due to several limitations, this study did not provide
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18
convincing evidence of a fiber etiology. Several experimental
studies showed that short attapulgite fibers (<2 yum) in
commercial use from the U.S., France, and Spain did not produce
mesothelioma in rats by the intrapleural or intraperitoneal
route. In addition, short attapulgite fibers from Spain did not
induce tumors in rats following prolonged inhalation exposure.
There is also no evidence of carcinogenicity in mice following
life-time feeding with short-fibered attapulgite. These data are
supported by negative findings from a single genotoxicity study
on short attapulgite fibers. Short-fibered attapulgite is,
therefore, not classifiable as to human carcinogenicity (Category
D) on the basis of inadequate evidence of carcinogenicity from
epidemiological and animal data.
In contrast, attapulgite samples from other geographical
locations (e.g. Spain, U.K.) which contain considerable numbers
of long fibers (>5 urn) have been shown to be tumorigenic in rats,
causing the induction of lung tumors and mesotheliomas by inhala-
tion, as well as pleural mesothelioma following intrapleural
injection and abdominal tumors via the intraperitoneal route.
Therefore, based on sufficient evidence of carcinogenicity in
animals but in the absence of human data, OTS is proposing to
classify long-fibered attapulgite as a probable human carcinogen
(Category B2).
Available data have not provided evidence of fibrogenic
effects for short-fibered attapulgite. The results of three
studies in humans provide inadequate evidence of the development
of nonmalignant respiratory diseases associated with exposure to
short-fibered American attapulgite. The results of a long-term
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19
animal study showed that short attapulgite fibers from Spain did
not induce lung fibrosis in rats via inhalation. Morever, none
of the available injection studies with short-fibered attapulgite
from various geographical locations have reported any fibrotic
lesions in treated rats. However/ positive findings of several
in vitro cytotoxicity studies suggest a possible fibrogenic
concern for short-fibered attapulgite. In contrast, based on the
positive results of a chronic inhalation study in rats with long-
fibered attapulgite, it is concluded that attapulgite samples
containing long fibers (>5 urn long) may induce lung fibrosis in
humans.
In view of available findings, it would appear that the
toxicological properties of attapulgite may depend on fiber
length. Overall, there is insufficient evidence to support a
health concern for short-fibered attapulgite in commercial use in
the U.S. However, because these fibers are highly respirable,
and appear to be biologically active in in vitro, adverse health
effects remain a possibility. On the other hand, there is a
reasonable basis to support a health concern for long-fibered
attapulgite. Available animal data are not sufficient to allow a
definitive assessment on the relative pathogenicity of long-
fibered attapulgite compared to asbestos. However, since these
fibers are not widely available for commercial use, they are not '
expected to pose significant health risks to humans. In order to
fully assess the health effects of short-fibered American
attapulgite, it is necessary to obtain additional epidemiological
data and to conduct long-term inhalation studies in animals.
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7. Aramid Fibers
There is no information available on the health effects of
para-aramid fibers in humans. In the female rat, long-term
inhalation of ultrafine para-aramid (Kevlar®) fibrils caused a
dose-related production of lung tumors. Although there are no
oncogenicity data on ultrafine para-aramid in animals via the
intracavitary route, weak tumorigenic responses were observed in
rats in two intraperitoneal injection studies with Kevlar® fiber
and pulp containing a considerable number of fine fibrils. Thus,
based on the sufficient evidence of the carcinogenicity in
animals but in the absence of human data, OTS is proposing to
classify ultrafine para-aramid as a probable human carcinogen
(Category B2). There is no genotoxicity information available on
ultrafine para-aramid.
Data from the same chronic inhalation study also indicate
that ultrafine para-aramid (Kevlar®) is weakly fibrogenic in
rats. The positive findings from an in vitro cytotoxicity study
on short, thin Kevlar® fibers further support the concern for the
fibrogenic potential of ultrafine para-aramid.
In view of these findings, it may be concluded that
ultrafine para-aramid is potentially pathogenic. This fibrous
material, however, does not pose a health risk to humans because
it is not available in commerce. Available data, however, are
not sufficient to provide definitive assessment on the
comparative pathogenicity of ultrafine para-aramid to asbestos.
The positive results of two intraperitoneal injection
studies in rats indicate that para-aramid pulps or fibers may
have a low carcinogenic and fibrogenic potential. Thus, based on
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21
the limited evidence of carcinogenicity in animals and in the
absence of human data, OTS proposes to classify commercial grade
para-aramid as a possible human carcinogen (Category C). Because
of the generally nonrespirable characteristic of commercial grade
para-aramid fiber and pulp, it would appear that the hazard
potential of para-aramid is probably much lower than that of
asbestos. However, it should be pointed out that since small
numbers of para-aramid fibrils can result from peeling off the
para-aramid fiber matrix and may become airborne, a possible
health hazard may exist for exposure to para-aramid, particularly
to the pulp form. In order to further assess the potential
health effects of para-aramid, additional animal testing is
recommended.
There are insufficient data to assess the health effects of
Nomex® aramid fibers. Nomex® is not classifiable as to human
carcinogenicity because of lack of data in humans and animals
(Category D). Based on the fact that no effects were observed in
a single long-term intratracheal instillation study in the rat,
and that Nomex® is nonrespirable, it would appear that Nomex®
poses no significant health hazard to humans. Because of a low
health concern, no additional animal testing is recommended for
Nomex®.
8. Carbon Fibers
There is no information available on the potential
development of respiratory neoplasms in humans from exposure to
carbon fibers. Furthermore, no data are available on the
oncogenicity of carbon fibers in animals by inhalation. However,
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22
carbon fibers were not found to induce tumors in rats following
intratracheal instillation, intraperitoneal injection, or
intramuscular implantation. The only studies that reported
positive results were those from a subcutaneous study in which an
increased production of local sarcomas was found in rats, and
from a dermal bioassay demonstrating that benzene extracts of
pitch-based carbon fibers were weakly oncogenic in mice.
However, because there was no information available on the
characteristics of the test materials, particularly particle size
and morphology, the significance of these findings is question-
able and the overall experimental evidence of carcinogenicity is
considered to be inadequate. Carbon fibers are, therefore, not
classifiable as to human carcinogenicity (Category D) on the
basis of inadequate evidence from animal studies and in the
absence of human data. The oncogenic potential of carbon fibers,
however, is supported by available genotoxicity data which
indicate that benzene extracts of pitch-based carbon fibers are
clastogenic and induce DNA damage and repair. On the other hand,
the evidence of clastogenicity of benzene extracts of
polyacrylonitrile (PAN)-based carbon fibers is only suggestive.
There is inadequate evidence of fibrogenicity for carbon
fibers. A small cross-sectional study conducted to date showed
no evidence of pathological effects in the lungs of workers in a
PAN-based carbon fiber production plant. With regard to
experimental studies, there is no information available on the
long-term inhalation toxicity of carbon fibers in animals. With
the exception of one study which reported in an abstract that
polyacrylonitrile (PAN)-based carbon fibers induced lung fibrosis
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in rats via intratracheal instillation, several other animal
studies showed that carbon fibers did not induce fibrosis in
laboratory animals following subchronic inhalation exposure,
intratracheal instillation, or intraperitoneal injection. Most
of these studies, however, are of little value for the evaluation
of the fibrogenic potential of carbon fibers because of limited
scope, lack of particle size and morphology data of the test
materials, and/or lack of details available on study design and
findings. Furthermore, both negative and positive findings have
been reported regarding the in vitro cytotoxicity of carbon
fibers.
Although currently available data are insufficient to
evaluate the potential health effects of carbon fibers, the data
taken together suggest that carbon fibers do not appear to
present a serious health hazard. Nevertheless, the marginally
positive tumorigenic effects in a dermal study and the positive
clastogenic effects in genotoxicity tests induced by pitch-based
carbon fibers, suggest that a weak oncogenic potential for
certain types of carbon fibers may exist. Because carbon fibers
are much less respirable and less biologically active than
asbestos, it would appear that they pose a lower degree of health
hazard compared to asbestos. In order to further assess the
health hazard of carbon fibers, it is necessary to seek results
of an inhalation study now conducted at a private laboratory.
Since the endpoint of this study is fibrosis, it is further
recommended that a chronic animal study capable of detecting
oncogenic effects be conducted if carbon fibers of respirable
size enter the marketplace.
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9. Polyolefin Fibers
There are no available epidemiological studies which examine
the potential oncogenic effect of polyolefin fibers. Further-
more, there are no data available on the oncogenicity of poly-
olefin fibers in animals by inhalation. The results of an intra-
tracheal insufflation study showed that both polyethylene and
polypropylene fibers did not induce tumors in rats. However, the
lack of information on the characteristics of the fibers, the
dosages, and the specific methods of administration precludes any
definitive assessment of the oncogenicity of these fibers under
the conditions of the study. In a long-term intraperitoneal
injection study in rats, polypropylene fibers were found to be
weakly oncogenic. These results were only preliminary and a full
evaluation cannot be made at this time. Therefore, polyolefin
fibers are not classifiable as to human carcinogenicity (Category
D) on the basis of inadequate evidence of carcinogenicity in
animals and no human data.
No epidemiological studies have been conducted to determine
the nonmalignant respiratory effects in humans from exposure to
polyolefin fibers. There is no information available on the
long-term inhalation toxicity of polyolefin fibers in animals.
Available animal injection studies have provided inconclusive
results. Polyethylene and polypropylene fibers did not induce
fibrosis in rats in a long-term intratracheal insufflation study
and in a short-term intraperitoneal injection study. These
results are supported by the finding from a single in vitro study
that polyethylene and polypropylene dusts exhibited very low
cytotoxicity. However, the lack of information on the
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25
characteristics of the test materials makes it difficult to draw
any definitive conclusion on the fibrogenic potential of this
fiber category. On the other hand, preliminary results of a
long-term intraperitoneal injection study in rats with thin, long
polypropylene fibers showed a strong degree of adhesions of the
abdominal organs. However, in the absence of histological data,
a full evaluation of this study cannot be made at this time.
Overall, available data are inadequate to determine conclusively
whether polyolefin fibers are fibrogenic. However, they seem to
suggest a low fibrogenic potential for polyolefin microfibers.
In summary, available studies do not provide adequate data
for a definitive assessment of potential health effects in humans
exposed to polyolefin fibers by inhalation. However, the
inhalation of polyolefin fibers or pulp may pose little or no
health hazard because they are generally not respirable and would
not be expected to produce lung diseases even if the material has
some intrinsic activity. On the other hand, a possible health
hazard potential may exist for polyolefin microfibers since they
may be respirable. Additional animal testing is therefore
recommended for polyolefin microfibers. Because of a low concern
for the potential health effects of polyolefin fibers and pulps,
••f
further animal testing is not recommended at the present time.
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I. Introduction
Human exposure to airborne asbestos fibers including
amosite, chrysotile/ and crocidolite has been associated with the
development of malignant (e.g. lung cancer/ mesothelioma) and
nonmalignant (e.g. interstitial pulmonary fibrosis, also known as
asbestosis) diseases. These diseases have also been induced
experimentally in laboratory animals exposed to asbestos. As a
result/ concern has risen with the increasing development and use
of other respirable fibrous substances. Nonasbestos fibers have
come under considerable investigation primarily because they
possess some asbestos-like characteristics (e.g. fiberlike
morphology, dimensional range, durability) suspected to be
important factors in the initiating of diseases. The objective
of this report is to assess the human health effects associated
with exposure to nonasbestos fibers and to evaluate the
hypothesis that nonasbestos fibers may induce asbestos-like
diseases.
The fibers under review comprise three categories: man-made
mineral fibers (fibrous glass, mineral wool, ceramic fibers),
naturally occurring fibers (erionite, attapulgite, wollastonite),
and synthetic fibers (aramid fibers, carbon fibers, polyolefin
fibers). These fibers were selected because of one or more of
the following reasons: 1) they are commercially important;
2) they are considered potential asbestos substitutes; 3) they
represent fiber types with broadly different physical and
chemical characteristics; and 4) some health data are available
on them.
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This document reviews available data on pulmonary
deposition/ clearance and retention, in vivo toxicity, and in
vitro biological activity of each of the nine fibrous materials.
It also assesses the human health effects, primarily the
potential development of malignant and nonmalignant respiratory
diseases associated with inhalation exposure to each fiber, based
on the combined available epidemiological and experimental
evidence. Finally, it determines the adequacy of data for each
of these fibers and makes testing recommendations to fill data
gaps. A detailed review of the key epidemiological studies on
the health effects posed by most of these fibers is presented in
a separate document by Battelle (1988). Summaries and
conclusions regarding human data have been derived from this
report and are used in the overall hazard assessment of each
fiber. The assessment of the carcinogenicity of fibers in humans
is based on the U.S. EPA classification system for categorizing
overall weight-of-evidence for carcinogenicity from human,
animal, and supporting data (USEPA, 1986).
The last section of the document discusses overall findings
about the whole fiber category and briefly evaluates the role of
physicochemical properties of fibers in relation to biological
activity and pathogenicity.
II. Man-Made Mineral Fibers (MMMF)
MMMF comprise three groups: fibrous glass, mineral wool,
and ceramic fibers. MMMF have glassy structures rather than
crystalline. Their length and diameter distribution differ
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28
considerably and are dependent on the method of production and
the chemical composition. In general, commercially produced MMMF
are much coarser than asbestos fibers, although specialized
samples have been produced with dimensions similar to those of
asbestos. MMMF are usually coated with binding materials to
produce fabricated shapes and forms. MMMF are monofilamentous,
and thus do not split longitudinally into thinner fibrils, but
may break transversely into shorter segments (NRC, 1984). Based
on available data, the health effects of MMMF appear to vary
substantially.
II.1. Fibrous Glass
Fibrous glass is made by forcing molten glass through an
orifice, followed by air, steam, or flame attenuation. There are
three major classes of fibrous glass: wool, textile, and
special-purpose fibers. Glass wool fibers comprise approximately
90 percent of the total fibrous glass production and their major
use is in thermal and acoustical insulation. They are typically
3-10 urn diameter but may range from 1-25 um diameter, and
therefore, may generate respirable airborne fibers. Textile
fibers or continuous glass filament which account for 5-10
percent of the total fibrous glass are used in the manufacture of
textile products and as reinforcements in plastics, rubber and
paper. Textile fibers are, in general, nonrespirable because
they have fairly large diameters with nominal diameters ranging
from 6-15 um. Special-purpose fibers with small diameters,
representing less than 1 percent of fibrous glass production, are
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29
manufactured for certain highly specialized uses in thermal
insulation in aerospace vehicles and filter materials. This
group includes fine fibers which have nominal diameters of 1-3 urn
and very fine glass fibers (or microfibers) with diameters less
than 1 jam. These fibers are highly respirable (NRC, 1984).
II.1.1. Fiber Deposition, Clearance and Retention
Available information regarding the inhalation, deposition,
and clearance of glass fibers is fairly limited. The results of
available studies suggest that fiber dimension is the most
important factor in the deposition and elimination of glass
fibers. Coarse glass fibers thicker than 1.5 jum are likely to be
deposited mainly in the upper respiratory tract (nasopharyngeal
and tracheobronchial regions) and would have little chance for
alveolar deposition. Further, longer fibers (>10 jum) are less
able to penetrate the alveolar region of the lung. Like other
fibrous particles, glass fibers are probably eliminated rapidly
from the upper airway via mucociliary clearance whereas fibers
deposited in the alveolar space appear to be cleared more slowly,
primarily by phagocytosis and to a lesser extent via
translocation and possibly by dissolution. Short fibers «5 pm)
are believed to be removed mainly by macrophage uptake whereas
longer fibers may be cleared at a slower rate by dissolution. In
general, short fibers are cleared more rapidly than longer
fibers, suggesting that fiber per fiber, short fibers are less
likely to pose a toxicological concern.
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The regional deposition of inhaled glass fibers has been
studied by Morgan et al. (1980) and Morgan and Holmes (1984a).
In these studies, rats were exposed for several hours by
inhalation (nose-only) to glass fibers of different diameters
(1.5 urn or 3 pm) and lengths (5, 10/ 30 or 60 urn). The results
of these studies showed that for fibers with 1.5 urn diameter and
longer than 10 urn, fiber deposition in the lower respiratory
tract and alveolar region was low and decreased with increasing
fiber length. Moreover, alveolar deposition of thicker fibers (3
urn) was about one third of that of fibers of 1.5 urn diameter of
similar lengths. These results, together with the previously
reported data on other asbestiform mineral fibers (Morgan, 1979),
indicated that alveolar deposition of fibers in the rat was
optimal with an aerodynamics diameter of 2 urn, which is
equivalent to an actual fiber diameter of approximately 0.5 urn.
Available data also demonstrated that in general, increasing
fiber length decreases the proportion of inhaled fibers deposited
in the alveolar region (Harris and Timbrell, 1977; Harris and
Fraser, 1976).
Immediately following deposition, there is a rapid decline
in the lung content of glass fibers. Griffis et al. (1981)
reported that 41-48 percent of lung burden of glass fibers in
rats was cleared between daily exposures. The initial decline
presumably represents early clearance from the upper respiratory
airways, with a half time of less than one day. Fibers deposited
in the upper airways are cleared by mucociliary activity which
transports the fibers toward the oralpharynx. Fibers are then
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31
swallowed/ passed into the gastrointestinal tract and excreted
into the feces. It has been shown that dogs excreted
approximately 77 percent of the initial total burden of glass
fibers within 4 days after inhalation exposure (Griffis et al.,
1983). Similarily, in the rat, more than 95 percent of the total
burden of glass fibers was associated with the gastrointestinal
tract following a 2-hour exposure (nose-only), which was all
excreted in the feces two days later (Morgan et al., 1980).
The elimination of fibers from the alveolar region is much
slower than those in the upper airways via mucociliary
clearance. The half time alveolar clearance of "TEL" glass
fibers in the rat was reported to be approximately 44 days
(Friedberg and Ullmer, 1984). Short fibers appeared to be
cleared more efficiently than longer fibers. Morgan et al.
(1982) showed that in the rat, more than 80 percent of glass
fibers less than 5 urn in length were cleared by one year
following intratracheal instillation whereas no significant
clearance of fibers greater than 10 urn length could be detected
over the same period. Bellmann et al. (1986) also found that
short glass fibers (_<5 urn) cleared faster than longer fibers (>5
urn) from the rat lung following intratracheal dosing. This
study, however, showed that long glass fibers do clear from the
lung while long crocidolite asbestos fibers (>5 urn) apparently do
not clear from the rat lung over one year. On the other hand,
long chrysotile asbestos fibers appear to split into fibrils as
reflected by the observed increase in the number of fibers over a
6-month period.
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Fibers are cleared from the alveolar region by a variety of
mechanisms. The major pathway involves the removal of fibers by
macrophage uptake. It is believed that fiber-laden macrophages
(dust cells) move to the terminal bronchioles and are transported
by the mucociliary system to the upper respiratory tract. These
dust cells could then be swallowed. It would appear that the
difference in the lung clearance between short and long fibers
could be due to the fact that short fibers of less than 5 urn are
efficiently removed by phagocytosis whereas the macrophage-
mediated clearance is ineffective for fibers longer than 10 pmf
due to the inability of macrophages to completely engulf the
longer fibers (Bernstein et al., 1980; 1984; Morgan et al., 1982;
Morgan and Holmes, 1984a).
The second pathway of fiber clearance from the alveoli
involves the lymphatic system. Fibrous particles in the alveolar
space are removed, either by macrophages or by themselves via an
unknown mechanism, to the lymph nodes. The fate of the fibers in
the lymph nodes is not known although they may escape the lymph
nodes and enter the lymphatic and blood circulation, and may
migrate to other tissues. There are few data available regarding
the translocation of glass fibers. Glass fibers were found in
the tracheobronchial and mediastinal lymph nodes of animals at
different time periods after exposure to the mineral dusts by
inhalation or intratracheal instillation (Lee et al., 1981;
Bernstein et al., 1980, 1984; Wright and Kuschner, 1977).
Furthermore, it appears that short fibers are more readily
transported to the lymph nodes than longer fibers. In the study
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33
by Morgan et al. (1982), measurements of the fiber content of the
hilar lymph nodes of rats killed after one year following
intratracheal instillation showed that approximately 4 percent of
5 urn glass fibers had been transferred from the lung to the lymph
nodes. Smaller proportions of the 10 urn and 30 urn fibers had
been transported and no 60 urn fibers were detected. With regard
to the translocation of fibers to other organ tissues/ only
minimal amounts of glass fibers were found in the liver, spleen,
and blood of animals exposed to the fibrous dust by inhalation
(Lee et al., 1979, Griffis et al., 1983). Glass fibers were also
detected in the spleen of rats after 2 years following
intratracheal instillation. Further, Monchaux et al. (1982)
reported recovery of fibers from all organs (blood, liver,
kidney, brain) at 90 days after intrapleural injection of glass
microfibers. However, increased pressure caused by this method
of administration may have been partly responsible for these
results.
It has been suggested that fibrous particles may also be
cleared by dissolution. For glass fibers, the suggested evidence
comes from morphological observations showing limited breakage
and etching of the fibers retained over a long period following
dosing, and chemical analysis of the recoverd fibers showing some
changes of elemental composition (Johnson et al., 1984a; Le
Bouffant et al., 1984; Spurny et al., 1983). These processes
would result in shorter, thinner fragments which then could be
cleared more efficiently by phagocytosis. The solubility of
glass fibers in lung tissues appears to be dependent on fiber
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34
size. In studies with rats, longer glass fibers dissolved more
rapidly than shorter ones (Morgan et al., 1982; Morgan and Holmes
1984a; Bernstein et al., 1980, 1984). It has been suggested that
the dependency of dissolution on fiber length may be due to
differences in the intracellular and extracellular pH. The
shorter fibers within macrophages are exposed to a lower pH of
7.17, while those outside are exposed to a higher extracellular
pH of 7.4 (Morgan and Holmes, 1984a).
The solubility of glass fibers in lung tissues and in
physiological fluids has been shown to be greater than that of
amphibole fibers but may be similar or less then chrysotile
(Forster, 1984; Spurny, 1983a; Spurny et al., 1983). The results
of other in vitro studies also indicate that glass fibers have
marked solubility rates in physiological fluids (Griffis et al,
1981; Leineweber, 1984; Klingholz and Steinkopf, 1984). Glass
fibers of fine diameters degraded more rapidly than coarser ones
(Spurny et al., 1983; Forster, 1984). Futhermore, the
dissolution of long glass fibers (50 jum) in saline was much
faster than that of short fibers (5 urn). These results indicate
that the in vitro dissolution rate of glass fibers is
proportional to the surface area of the fibers (Leineweber,
1984).
II.1.2 Effects on Experimental Animals
Fibrous glass has been extensively tested in laboratory
animals for the ability to induce lung tumor, mesothelioma, and
fibrosis. Information on the design and results of available
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35
animal studies on glass fibers is summarized in Table 1
(pages 215-229). Such investigations have been conducted by
several routes of exposure including inhalation, intratracheal
instillation, intrapleural injection/implantation, and
intraperitoneal injection. Animal exposure by inhalation
represents the most relevant method for the assessment of risks
to man. However, because of the technical difficulties and high
costs, fewer long-term inhalation studies have been conducted in
comparison with studies using the injection or implantation
method which are more sensitive and generally more
reproducible. Injection studies are of value in screening the
test fiber for carcinogenicity and providing useful information
regarding the intrinsic biological activity and carcinogenicity
of the test fiber.
II.1.2.1 Oncogenicity
None of the available long-term studies have provided
evidence of pulmonary or mesothelial carcinogenicity in animals
exposed to fine glass fibers, glass microfibers. or larger
diameter glass fibers (e.g., glass wool) by inhalation. In
contrast, many studies involving intrapleural or intraperitoneal
administration of these fibers to animals have resulted in
increases in mesothelioma of the pleura or peritoneum,
respectively. In addition, two of several intratracheal instil-
lation studies on glass microfibers also reported tumor induction
with both lung tumors and mesothelioma in hamsters and lung
tumors alone in the rat. By using the intrapleural implantation
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36
method, Stanton and coworkers demonstrated that glass fibers less
than 0.25 urn diameter and greater than 8 urn length have
carcinogenic potential equal to that of asbestos fibers of
similar size distribution. Other investigators also found that
long, thin glass fibers are highly carcinogenic by the injection
routes of exposure but are less effective than asbestos.
II.1.2.1.1 Inhalation Studies
The earliest studies with fibrous glass were those by
Schepers and coworkers (Schepers and Delahunt, 1955; Schepers,
1955; Schepers, 1959a; Schepers, 1959b; Schepers, 1961) which
were summarized in a final report in 1976 (Schepers, 1976). In
one series of experiments, guinea pigs and rats were exposed to
fairly large diameter glass wool fibers (average diameter close
•5
to 5 urn) at an average mass concentration of 0.145 mg/m for
44 months, and at 0.03 mg/m for 28 months, respectively. In
another series of studies, guinea pigs, rabbits, rats, and
monkeys were exposed to dust from two types of glass fiber
3 3
reinforced plastics at either 3.8 mg/m or 4.6 mg/m for various
time periods ranging from 8-24 months. No pulmonary tumors were
reported in any exposed group. These studies, however, were
inadequate to determine whether the fibrous products tested were
carcinogenic in animals by inhalation due to 1) extremely low
levels of fiber exposure, particularly for glass wool;
2) insufficient information on fiber size distribution in the
dust cloud; and 3) poor survival of treated and unexposed
animals.
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Gross et al. (Gross et al., 1970; Gross, 1976) reported
studies in which rats and hamsters were exposed for 2 years to a
very high concentration of uncoated glass fibers (135 mg/irr),
glass fibers coated with a phenol-formaldehyde resin (106 mg/nr),
or glass fibers coated with a starch binder (113 mg/m^). All
three types of glass fibers in the dust cloud had an average
diameter of 0.5 jam and an average length of about 10 jum. None of
the rats or hamsters exposed to any of the fiberglass products
developed lung or pleural tumors. However/ it is not clear
whether there was a sufficient number of animals at risk from
late developing tumors due to a small number of animals and
apparent poor survival of exposed animals. The survival pattern
of unexposed control animals was not available for comparison.
Morrison et al. (1981) reported that 5 of 12 male A-strain
mice developed bronchogenic or septal cell tumors 90 days after
exposure to "crushed" glass insulation (80 percent were 6-11 jjm
long and 2-5 urn diameter) mixed in bedding material every 3 days
for 30 days. However, the results of this study were
inconclusive because of 1) insufficient information on the actual
airborne glass fiber concentration; 2) lack of control animals
caged in normal bedding; and 3) short exposure period and small
number of exposed animals.
In 1979 and subsequently in 1981, Lee et al. reported
studies in which rats and guinea pigs were exposed to glass fiber
aerosol at an extremely high dust mass of 400 mg/m for
90 days. The airborne dust particles had an average diameter of
1.2 urn and most particles were less than 2 urn long; thus, the
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38
dust particles were predominantly nonfibrous. After 18 and 24
months post exposure, 2 of 19 rats and 2 of 8 guinea pigs
developed bronchial alveolar adenoma while none of 13 rats and 6
guinea pigs exposed to clean air as controls had pulmonary
tumors. Since these findings were based on a small number of
animals, meaningful conclusions cannot be drawn from this
study. Other limitations such as short exposure period further
limit the conclusion that can be made about this study.
Goldstein et al. (1983, 1984) studied the effects of
inhalation exposure of very fine fibrous glass in male baboons
and compared them with the effects produced by crocidolite
asbestos. Animals were exposed to a blend of Johns-Manville code
102 and code 104 glass microfibers (median diameter of airborne
fiber of 0.6 urn) at a mass concentration of 7.54 mg/m (1,122
fibers/mL) for 35 months or UICC crodolite asbestos (median
diameter of airborne fiber of 0.38 urn) at a mass concentration of
15.8 mg/m3 (1,128 fibers/mL) for 40 months. A total of 10
animals were used; the numbers in glass fibers exposed or
positive control group were not specified. No neoplasms occurred
with either of the dusts at 6-7 months following the end of
exposure. Since the exposure and observation periods were short
in relation to the lifespan of baboons, this study is considered
inadequate for the evaluation of the oncogenic potential of
fibrous glass. It should also be noted that neoplasms have been
rare even in previous studies of asbestos-exposed monkeys and
baboons.
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39
Two studies by Wagner et al. (1984) and McConnell et al.
(1984) were undertaken as a joint effort to compare the
carcinogenic effects of glass microfibers with chrysotile
asbestos/ and to assess the comparability of results of similar
inhalation studies at two different locations. In the study by
Wagner et al. (1984), specific pathogen-free (SPF) male and
female Fischer 344 (F344) rats (28 of each sex per group) were
exposed for 3 or 12 months to coated or uncoated glass wool,
glass microfibers, or UICC Canadian chrysotile asbestos.
Chrysotile and glass microfibers were highly respirable with
airborne fiber diameters ranging from 0.03 urn to 2 urn (mean
diameter of 0.3 urn) while glass wool had larger airborne fiber
diameters ranging between 0.3 urn and 3 urn (mean diameter of
0.8 urn). The respirable dust mass was 10 mg/m in all cases.
The concentrations of airborne respirable fibers (diameter <3 urn,
length >5 urn) were 240 fibers/mL for uncoated glass wool,
323 fibers/mL for coated glass wool, 1436 fibers/mL for glass
microfibers, and 3822 fibers/mL for chrysotile. Pulmonary
response was assessed in rats sacrificed at 3, 12, and 24 months,
and in animals that were allowed to live out their natural
lifespan. One case of lung adenocarcinoma was found in animals
exposed to glass wool with resin (1/48) and glass microfibers
(1/48) while exposure to glass wool without resin resulted in one
case of benign lung adenoma (1/48). In contrast, a total of 12
lung tumors (11 adenocarcinoma, 1 adenoma) were produced in the
chrysotile group. All of the neoplasms were reported to occur
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40
within 500-1,000 days after the start of exposure. Unexposed
control animals developed no tumors.
Comparable results were obtained in the study by McConnell
et al. (1984). In this study, male and female SPF F344 rats were
exposed to the same glass microfibers or chrysotile asbestos
preparation as used by Wagner et al. (1984), targeted at a
respirable dust mass concentration of 10 mg/m for 1 year.
However, the actual cumulative dose of glass microfibers was
approximately one half of that in the study by Wagner et al.
(1984). Increased incidences of lung neoplasms were observed in
11 of 56 animals exposed to chrysotile but no tumors were found
in the glass microfiber group (0/55). Two of 53 unexposed
animals had lung adenocarcinoma. Most of the tumors were found
after 24 months.
Analysis of the findings from these two inhalation studies
showed that there was no statistically significant difference in
tumor incidence between the unexposed controls and rats exposed
to glass microfibers (Rossiter, 1982). In the study by Wagner et
al. (1984), there was also no significant difference in tumor
incidence between animals exposed to coated or uncoated glass
wool fibers and the negative controls. However, both studies are
limited with regard to study design including the use of a
relatively small number of animals and short duration of
exposure. Despite these limitations, these two studies
demonstrated that while glass microfibers and glass wool fibers
were not carcinogenic in rats under the conditions tested,
similar mass concentration of chrysotile asbestos produced a
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41
significant increase in the incidence of benign and malignant
pulmonary neoplasms in the rat.
Smith et al. (1984, 1986) also found that glass microfibers
and large diameter glass fibers caused neither lung tumor nor
mesothelioma when inhaled by rats and hamsters. As a part of a
comprehensive study, groups of male Syrian hamsters and female
Osborne-Mendel rats (50-70 animals/group) were exposed "nose-only"
for 24 months to one of the following dusts: (1) highly
respirable glass microfibers (fiber product with mean diameter
0.45 urn) at a mean mass concentration of 3.0 +_ 0.6 mg/m
(approximately 3,000 fibers/mL) or 0.3_+_0.1 mg/m3 (300
fibers/mL); (2) fibrous glass "blowing wool" (fiber product with
3.1 urn mean diameter) targeted at 10 mg/m (100 fibers/mL);
(3) flame attenuated fibrous glass (fiber product with 5.4 urn mean
diameter) at either 12 mg/m3 (100 fibers/mL) or 1.32 mg/m3 (10
fibers/mL); (4) fibrous glass insulation building (fiber product
with 6.1 urn mean diameter) at 9.0 mg/m (25 fibers/mL). Positive
control animals were exposed to UICC crocidolite asbestos at a
o
mass concentration of 7 mg/m (3,000 fibers/mL). One negative
control group was exposed to clean air (sham controls). Following
the exposure period, test and sham control animals were maintained
for their natural lifespans. Another negative untreated control
group remained in cages throughout their lives.
No primary lung tumors were found in rats or hamsters exposed
to any of the fibrous glass dusts. On the other hand, one
mesothelioma and two cases of bronchoalveolar tumors were detected
in 57 asbestos-exposed rats. None of the hamsters exposed to
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42
crocidolite asbestos developed lung tumors or mesothelioma.
However, bronchoalveolar metaplasia/ possibly a preneoplastic
event in the development of epithelial tumors/ was significantly
elevated in hamsters exposed to crocidolite asbestos. With the
exception of the occurrence of a bronchoalveolar tumor in a sham
control hamster/ none of the other sham control or unexposed
control animals developed lung tumors. Thus, under the conditions
of these lifetime studies there was no evidence of carcinogencity
in rats or hamsters exposed to glass microfibers or large diameter
fiberglass. The lack of significant tumorigenic response by
crocidolite asbestos observed in this study might well be due to
the use of a short-fibered material (approximately 95-97 percent
were less than 5 um long).
The long-term effects of inhalation of glass microfibers and
glass wool were also studied in rats by Le Bouffant et al.
(1984). Groups of 48 Wistar IOPS AF/Han rats (24 animals of each
sex) were exposed to French commercial resin-free glass wool
(Saint-Gobain)/ American produced glass microfibers (Johns-
Manville code 100) or Canadian chrysotile asbestos at a respirable
dust mass of approximately 5 mg/m for 12 or 24 months. Because
of differences in fiber size distribution and proportion of non-
fibrous material present in the aerosols, the numerical concentra-
tions of respirable fibers greater than 5 um length as determined
by optical microscopy were varied, ranging from 48 fibers/mL for
glass wool (68 percent <1 um diameter), 332 fibers/mL for glass
microfibers (51 percent with diameters from 0.2-0.5 um), to 5,901
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43
fibers/mL for chrysotile (fiber diameter distribution not
specified). The animals were sacrificed at 12, 24, and 28 months.
No pulmonary tumors were found in animals exposed to glass
microfibers (0/48). A single lung tumor was observed at 24 months
with the glass wool group (1/45). In contrast, nine cases of lung
tumors were detected in the positive control group exposed to
chrysotile (9/47). Negative control animals (unexposed) had no
pulmonary tumors. Although there were no significant increases in
lung tumors in rats exposed to either glass microfibers or glass
wool fibers, this study is considered limited based on small
numbers of animals and a relatively low level of fiber exposure.
This study, however, demonstrated that under similar experimental
conditions and mass concentrations, chrysotile asbestos was more
potent in inducing lung tumors in rats than glass fibers.
Mitchell et al. (1986) also reported no evidence of pulmonary
or mesothelial neoplasms in rats and monkeys following chronic
inhalation of fibrous glass of varying geometry and mass
concentrations. In this study, groups of F344 rats (50 animals of
each sex per group) and male cynomolgus monkeys (15 per group)
were exposed to (1) large diameter and long glass fibers with
binder (4-6 urn in diameter and >20 urn long) at approximately 15
mg/m (Group I); small diameter and long glass fibers with binder
(0.5-3.5 urn in diameter and >10 jam long) at 15 mg/m3 (Group II);
(3) small diameter and long uncoated glass fibers (<3.5 urn in
diameter and >10 urn long) at 5 mg/m3 (Group III); and (4) small
diameter and short uncoated glass fibers «3.5 urn and <10 urn long)
at 5 mg/m3 (Group IV). Control animals (Group V) were exposed to
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44
filtered air. The rats were exposed for a total of 86 weeks while
the monkeys were dusted for only the 72 weeks. The animals were
sacrificed following the termination of exposure.
Neither pulmonary tumors nor mesothelioma were detected in
any treated monkey or rat groups. However, short treatment and
study duration may have excluded observation of late developing
tumorigenic effects/ particularly in the monkeys. Furthermore/
there was a low survival among treated and control rats.
Approximately 37 percent of rats (187 of 500 animals) died
spontaneously or were killed in a moribund condition before the
termination of study. Many of the spontaneous early deaths were
due to mononuclear cell leukemia (MCL). It was reported that
there was a statistically increased incidence of MCL in each glass
fiber exposed rat group. However, the investigators performed
statistical analyses on the combined incidence in both males and
females rather than analyzing the incidence data for the male and
female populations separately. Reanalysis of data using Fisher
exact test showed that for the male population only Group 3
(p = 0.024) and Group 4 (p = 0.002) displayed a significant
increase in MCL. In the females/ the incidence was significant
only in Group I (p = 0.047). The biological significance of this
finding remains uncertain since spontaneous increase in MCL is
commonly seen in aged F344 rats.
II.1.2.1.2 Intrapleural Implantation/Injection Studies
Stanton and his colleagues reported a series of experiments
(Stanton and Wrench/ 1972; Stanton et al./ 1977 and 1981) in which
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45
they tested the ability of fibrous glass and other mineral fibers
(including asbestos) of diverse dimensional distributions, to
induce malignant neoplasms in female Osborne-Mendel rats by
intrapleural implantation of the mineral dusts. Pledgets of
coarse fibrous glass were coated with 40 mg of the test fibers
suspended in gelatin and the pledgets were placed over the
visceral pleura of the rats after open thoracotomy. Animals were
observed for two years at which time survived animals were
killed. The greatest increase in pleural sarcomas was observed
for fibers with diameters less than 0.25 jam and lengths greater
than 8 urn, although relatively high tumor yields were also
produced with fibers having diameters up to 1.5 urn with lengths
greater than 4 urn. These studies demonstrated that glass fiber
with dimensional distribution similar to that of asbestos was
equally carcinogenic as asbestos by intrapleural implantation.
Similar findings were obtained in the study by Smith et al.
(1980) in which the tumorigenic effects of six fiberglass samples
were tested in hamsters by intrapleural injection of a single dose
of 25 mg of the test fiber. Intrathoracic tumors occurred in 9 of
60 animals which received fibers with a mean diameter of 0.1 ium
and 82 percent longer than 20 urn. Fibers with a mean diameter of
0.33 urn and 46 percent longer than 20 urn induced tumors in 2/60.
Fibers with a mean diameter of 1.23 um and 34 percent longer than
20 um also induced tumors in 2/60. No tumors were found in groups
treated with the other three preparations containing fibers of
similar diameter range but shorter lengths with only 0-2 percent
longer than 10 um. These results suggest that carcinogenicity is
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46
associated with length and diameter of fibers; the thinner and
longer the fiber, the more tumorigenic it is.
Wagner et al. (1973, 1976, and 1984) also tested the
carcinogenicity of fiberglass of various types and size
distributions by intrapleural injection in rats and confirmed that
thin fiberglass was carcinogenic. Glass microfibers (Johns-
Manville code 100), when injected as a single dose of 20 mg into
the pleura of rats produced a significant increase in pleural
tumors. In the 1976 study, 4 of 32 Wistar rats (p = 0.01)
developed pleural mesothelioma while none of 32 control animals
had tumors. Similarly, in the 1984 study, 4 of 48 Sprague-Dawley
rats treated with glass microfibers developed mesothelioma. In
contrast, coarse glass fibers (Johns-Manville code 110) produced
no tumors in rats (Wagner et al., 1973, 1976) and only one case of
mesothelioma was found among 48 rats injected with glass wool
(Wagner et al., 1984). When comparing these results with those
obtained with various types of asbestos in earlier experiments
reported in Wagner et al. (1973) using identical intrapleural
injection technique, finer glass fibers were considerably less
carcinogenic than some of the asbestos samples, while coarse glass
fibers were not tumorgenic.
Monchaux and coworkers (Lafuma et al., 1980; Monchaux et al.,
1981) also reported induction of pleural tumors in rats following
intrapleural injection of 20 mg of fine glass fibers (JM 104).
The mean length of the test glass fibers was 5.8 urn and mean
diameter of 0.229 urn. Pleural mesotheliomas were observed in 6 of
44 (14 percent) animals. Higher tumor incidences were produced by
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47
UICC crocidolite (54 percent) and chrysotile (45 percent) asbestos
while control animals receiving saline alone had no tumors. These
findings were consistent with results of other intrapleural
studies which showed that at a similar mass dose, crocidolite and
chrysotile asbestos were more potent in inducing mesothelioma in
rats than fine fibrous glass.
II.1.2.1.3 Intraperitoneal Injection Studies
In a series of studies, Pott and coworkers investigated the
ability of fibrous glass to induce abdominal tumors in the rat by
the intraperitoneal (i.p.) route of exposure. In the first series
of experiments as reported in 1972, 1974 and 1976 (Pott and
Friedrichs, 1972; Pott et al. 1974, 1976), a dose-related tumor
induction (2.5 - 57.5 percent) was produced in female Wistar rats
(40 per group) following intraperitoneal injection of a single
dose of 2 or 10 mg, or 4 doses of 25 mg of fibrous glass (S + S
106; mean diameter 0.5 urn; 72 percent <5 um long). Positive
control animals receiving UICC chrysotile asbestos also developed
tumors in the peritoneal cavity in a dose-related manner (15-67
percent). Histologically, nearly all the tumors from fibrous
glass or chrysotile treated animals were sarcomatous
mesothelioma. In both treated groups, the latency period for
tumor development was inversely related to the dose of fibers
injected. No tumors were observed in negative control animals
receiving saline.
Similar results were obtained with uncoated glass fibers of
type MN 104 (50 percent <0.2 um in diameter; 50 percent <11 um
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48
long). This study showed a dose-related increase in mainly
peritoneal mesothelioma in Wistar rats (80 animals/group)
following intraperitoneal injection of the test fiber at a single
dose of 2 or 10 mg, or 2 doses of 25 mg. Glass fibers of type MN
112 (50 percent <1 urn in diameter; 50 percent <28 urn long)
produced a tumor incidence of 27.5 percent following an i.p. dose
of 20 mg (Pott et al. 1976).
In a subsequent study, Pott et al. (1980) reported that
intraperitoneal injection of 10 mg of glass microfibers (JM 104)
to rats of 4 different strains resulted in different tumor rates
ranging from 51 to 79.6 percent. The rat strains used in this
study included Wistar (Ivanovas)/ SIV (Ivanovas), Sprague-Dawley
(Hagemann)/ and Wistar (Hagemann). No other details of the
experiments were available.
These results were confirmed in a later study by Pott et al.
(1984) which showed a production of high incidences (40-70
percent) of abdominal tumors, primarily sarcoma or mesothelioma,
in Wistar or Sprague-Dawley rats following intraperitoneal dosing
with 2.5 or 10 mg of long glass microfibers (JM 104). Shorter
glass microfibers (JM 100) induced lower incidences of tumors (2-
10 percent).
Comparable findings were reported by other investigators
using similar injection techniques. Davis (1976) injected into
the peritoneal cavity of Balb/C mice and rats (strain unspecified)
very fine glass fibers with an average diameter of 0.05 urn as a
single dose of 10 and 25 mg, respectively. Three of 25 mice and 3
of 18 rats developed peritoneal tumors. It was reported that
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49
these tumors appeared identical to those produced in the
peritoneal cavities of rats and mice by injection of crocidolite
asbestos, as reported in earlier studies (Davis, 1974).
Recently, Smith et al. (1986) reported a 32 percent incidence
of abdominal mesothelioma (8/25) in female Osborne-Mendel rats
following an intraperitoneal injection of 25 mg of 0.45 urn mean
diameter fiber. UICC crocidolite asbestos produced tumors in 80
percent of the animals while no tumors were observed in saline
controls or untreated animals.
II.1.2.1.4. Intratracheal Instillation Studies
Variable results on the carcinogenicity of fibrous glass via
the intratracheal route have been reported. Tumor induction by
fibrous glass was reported in one study by Mohr et al. (1984). In
this study, groups of 136 male Syrian golden hamsters received
eight weekly intratracheal instillations of 1 mg of the dusts.
Thin fibrous glass (JM 104) of two different size lengths (mean
diameter of 0.3 jum, and mean length of either 7 urn or 4.2 urn) and
UICC crocidolite asbestos, were tested. Neoplasms, including lung
carcinomas (4 percent), mesothelioma (27 percent) and thoracic
sarcoma (4 percent), were found in hamsters treated with glass
fiber samples at comparable rates. Interestingly, the incidence
of mesothelioma in asbestos-treated animals was considerably lower
than that of fiberglass. Control animals treated with titanium
dioxide nonfibrous dusts developed no mesothelioma or lung
carcinomas.
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50
A subsequent intratracheal instillation study by the same
group of investigators (Pott et al., 1987a) reported a low
incidence of lung tumors in the rat treated with glass micro-
fibers. Female Wistar rats were administered 20 weekly doses of
0.05 mg of JM 104/Tempstran 475 glass fibers (50% <3.2 urn long;
50% <0.18 urn in diameter). Five cases of lung tumors (1 adenoma,
2 adenocarcinomas, 2 squamous cell carcinomas) were found among 34
treated animals. In rats treated similarly with crocidolite
asbestos (50% <2.1 urn long; 50% <0.20 urn in diameter), there were
11 cases of lung tumors out of 35 animals examined.
In contrast, several other intratracheal studies with fine
glass fibers have not produced positive results. Gross et al.
(1976) found no tumors in rats or hamsters injected
intratracheally with multiple doses of uncoated glass fibers,
glass fibers coated with resin, or starch binder. Glass fibers
tested in this study had an average diameter of 0.5 urn and
average length of 10 pm. Wright and Kuschner (1976 and 1977)
also reported no tumor induction in guinea pigs injected with
12.5 mg of either thin, long glass fibers (90 percent >10 pm in
length) or 25 mg of shorter fibers (90 percent <10 urn) of similar
diameter (mean diameter <1 urn).
Recently, Feron et al. (1985) reported no mesothelioma or
other tumors of the respiratory tract in Syrian golden hamsters
treated with JM 104 glass microfibers (31 percent <0.25 pm in
diameter; 89 percent <12 urn long) via intratracheal instillation
(1 mg every 2 weeks for 52 weeks). Smith et al. (1986) also
found no tumors in female Osborne-Mendel rats following
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51
intratracheal instillation of 0.45 urn mean diameter glass fibers
(1 mg weekly for 5 weeks).
II.1.2.2 Fibrogenicity
Fine fibrous glass and glass wool have been shown in several
animal studies to produce minimal interstitial dust cell reaction
without fibrosis following chronic inhalation. The pulmonary
responses generally consist of macrophage infiltration with
alveolar dust cell collections, alveolar proteinosis, and
granuloma formation. In one study/ fine fiberglass was reported
to produce focal fibrosis in baboons. However, the small number
of animals and the lack of unexposed animal control group limit
the conclusions which can be made from this study.
In contrast, extensive pulmonary fibrosis has been induced
in animals by intratracheal instillation and intrapleural
injection of fine fibrous glass. Furthermore, marked peritoneal
fibrosis has been produced via injection of fine glass fibers
into the abdominal cavity of animals. The results of these
injection studies showed that long, thin glass fibers are more
fibrogenic than short, thin glass fibers, while thick glass
fibers are apparently relatively inert, producing no significant
pulmonary response. Pulmonary pathology induced by glass fibers
by these routes of exposure, including inhalation, are much less
severe than that produced by asbestos fibers in concurrent
experiments.
Since the experimental details of most available studies are
already presented in the discussion of oncogenicity and are
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52
summarized in Table 1 (pages 215-229) only relevant information
and test results on the fibrogenic effects are discussed in the
following sections.
II. 1.2. 2.1 Inhalation Studies
Gross et al. (1976) found no development of pulmonary
fibrosis in rats and hamsters exposed to very high dose levels
(100 mg/m3) of uncoated or coated glass fibers (mean length of 10
urn; mean diameter of 0.5 urn). The survival rate of treated
animals/ however, was poor. Schepers et al. (1976) also reported
that glass wool and glass fiber reinforced plastics did not
induce fibrosis in rats/ guinea pigs, rabbits/ and monkeys/
following a two-year inhalation exposure to various
concentrations of the dusts (0.03-4.6 mg/m ) . This study also
had a high incidence of mortality.
In 1979 and subsequently in 1981 / Lee et al. reported that
the major pathological lesion found in rats, hamsters, and guinea
pigs which were exposed for 90 days to a very high glass fiber
dust cloud (400 mg/m3) with a full lifespan follow up, was
alveolar proteinosis. Very slight alveolar interstitial fibrosis
occurred in a few old animals. It should be noted that these
experiments used fibers of small aspect ratios (3:1) with only 7
percent of the fibers considered fibrous in shape. Furthermore,
the exposure period was relatively short.
WAGrfif, v-~ .• -
(202)200-3;},,"
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53
Morissett et al. (1979) reported that a group of 20 male
albino mice which were exposed to respirable glass fiber «3 urn
diameter and <10 urn length) at 1,070 fibers/mL for six weeks did
not develop pulmonary fibrosis. This study is considered limited
because of the short duration of exposure.
In 1980, Johnson and Wagner reported that electron
microscopic examination of lung tissues of rats (two SPF Fischer
rats/group) exposed to 10 mg/m of glass microfibers, resin
coated glass wool or uncoated glass wool for 50 weeks revealed
focal fibrosis. However, pulmonary fibrosis was not found in the
more extensive investigation by Wagner et al. (1984). Fischer
344 rats developed minimal interstitial cellular reaction (grade
3.4) following a one-year exposure to glass microfibers (10
o
mg/mj) and a one-year follow up. Animals exposed to glass wool
either with or without resin at similar mass concentration (10
mg/m3) had no significant pulmonary responses (grade 2.6 and 2.4,
respectively). On the other hand, animals exposed to UICC
Canadian chrysotile showed evidence of early interstitial
fibrosis (grade 4.1).
McConnell et al. (1984) also found no evidence of pulmonary
fibrosis in Fischer 344 rats following a one-year exposure to
very fine JM 100 glass fibers, obtained from the same source as
described in Wagner et al. (1984). Animals which were exposed to
UICC crocidolite developed mild pulmonary fibrosis. It should be
pointed out the accumulative exposure of glass fibers in this
study was only half of that achieved in Wagner's study.
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54
Le Bouffant et al. (1984) found only minimal pulmonary
response in rats after one year exposure to fine fibrous glass or
glass wool at 5 mg/m . They were limited to alveolar and
interstitial macrophage reactions, with mild septal fibrosis in
the case of glass microfibers. In the case of chrysotile fibers/
only hyperplastic changes of the alveolar lining were observed;
pulmonary fibrosis was not detected.
Smith et al. (1986) exposed groups of rats and hamsters to
fine fibrous glass (0.45 um mean diameter; 300 or 3,000
fibers/mL) and coarse fibrous glass (>3 um diameter; 25-150
fibers/mL) for 2 years. Pulmonary fibrosis was not found in any
of the treated animals (50-60 animals/group) with fibrous
glass. Many of the rats and hamsters exposed to UICC crocidolite
asbestos, however, developed prominant pulmonary fibrosis.
Baboons were reported to develop focal peribronchiolar
fibrosis following exposure to respirable glass microfiber dust
clouds for 35 months at 1,122 fibers/ml (7.54 mg/m ). The test
fibers had a mean diameter of 0.5 um and median length of 6 um.
Pulmonary lesions induced by glass microfibers were morphologi-
cally similar to those produced by crocidolite asbestos; however,
the incidence and severity in unexposed control animals were not
reported (Goldstein et al., 1983).
In the study by Mitchell et al. (1986), cynomolgus monkeys
and Fischer 344 rats were exposed via inhalation to dust clouds
of fibrous glass of varying geometry and concentrations (5 or
15 mg/m3) for 13 months and 21 months, respectively. There was
no evidence of lung fibrosis in either species. Both species had
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55
pulmonary macrophage aggregates and granulomas containing fibrous
glass. The rats had grossly visible pleural plaques which were
not seen in the monkeys. No positive controls were included in
this study.
II.1.2.2.2 Intratracheal Instillation Studies
Kuschner and Wright (1977) reported that long/ thin glass
fibers (92 percent >10 urn in length; <1 urn in diameter) produced
a marked fibrotic reaction in the guinea pigs following
intratracheal injection of a single dose of 12 mg. The
instillation of short, thin glass fibers (93 percent <10 yum) at
similar doses produced only macrophage aggregation in the
alveoli.
In the study by Pickrell et al. (1983), groups of 20 male
Syrian hamsters were intratracheally instilled with one of two
uncoated glass microfibers (2 and 7 mg; 0.1-0.2 urn diameter) or
one of three commercial glass fiber samples (17-21 mg; 2.3-4.1 um
diameter), or UICC crocidolite (6 mg; 0.24 jam diameter). The
thinner glass microfiber (0.1 um) caused deaths from pulmonary
edema shortly after instillation. Increased collagen deposition
and mild pulmonary fibrosis were observed in animals treated with
the thicker glass microfiber (0.2 um) and one type.of commercial
glass fiber (2.3 m) at 11 months after instillation. However,
the microfibers produced a greater effect than the commercial
type, while crocidolite asbestos induced the greatest response.
No pulmonary responses were observed in animals treated with the
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56
other two types of commercial glass fibers which had larger
diameter (3-4 urn).
Marked lung fibrosis was also found in 27 percent of female
Osborne-Mendel rats (7/22) treated intratracheally with 2 mg of
0.45 urn mean diameter glass fibers once a week for five weeks
compared to saline control animals. However, the incidence of
pulmonary fibrosis in positive control rats instilled with
crocidolite asbestos was much higher and the lesions were more
severe (Smith et al./ 1986).
II.1.2.2.3. Intrapleural Injection Studies
The relationship between fiber dimension and fibrogenicity
was also demonstrated by Davis (1976). Groups of 25 Balb/c mice
received 10 mg of one of 4 samples of glass fibers of varying
lengths and diameter, by the intrapleural route. Short fiber
samples «20 pm) of both large (3.5 urn) and small diameter (0.05
urn) produced only small discrete granulomas with minimal
fibrosis. Long fiber samples (>100 urn) produced massive
fibrosis, which was comparable to that induced by asbestos.
II.1.2.2.4 Intraperitoneal Injection Studies
Pott et al. (1974) reported that glass fibers (average
diameter of 0.5 urn; 72 percent less than 5 urn in length), when
injected into the abdominal cavity of rats as a single dose of
50 mg, produced marked peritoneal fibrosis. The effect was less
extensive at lower doses (2 and 10 mg). Similarly, Smith et al.
(1986) found extensive peritoneal fibrosis in female Osborne-
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57
Mendel rats injected intraperitoneally with 25 mg of 0.45 jjm mean
diameter glass fibers.
II.1.3. In Vitro studies
II.1.3.1 Genotoxicity
Several studies on glass fibers have been performed, ranging
from bacterial mutation tests to transformation studies in
mammalian cells. Most studies dealt with Code 100 and Code 110
fiberglasses of various lengths. These two glass fibers differ
in their diameters with mean diameters of roughly 0.12 urn and
1.9 jum, respectively. Glass fibers do not appear to induce gene
mutations in bacterial cells, although this evidence is very
limited. The two major effects that consistently appear with
Code 100 fiberglass are aberrations and transformation in
cultured cells. The cytogenetic effects seen by Code 100
fiberglass appear to be less effective than chrysotile asbestos,
although sometimes comparable to crocidolite asbestos. Other
cytogenetic effects, such as induction of sister chromatid
exchanges (SCE) and micronuclei, were not seen; again however,
only a very limited number of studies were available. Code 110
fiberglass does not appear to have effects comparable to Code 100
fiberglass.
II.1.3.1.1. Mutational Effects
Glass fibers and several asbestos samples were tested in two
bacterial mutation tests (Chamberlain and Tarmy, 1977). The two
glass fibers examined were Code 100 (mean length of 2.7 urn, mean
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58
diameter of 0.12 urn) and Code 110 (mean length of 26 |im, mean
diameter of l.S^m) fiberglasses. The asbestos samples included
UICC Canadian chrysotile/ UICC crocidolite as well as a "cleaned
crocidolite" (Magnetite), UICC amosite, UICC anthophyllite and
SFA chrysotile. All samples were found negative in the
Salmonella/mammalian activation test in strains TA1535 and TA1538
with and without activation. The asbestos samples were tested at
0.1 and 1.0 mg/plate, but the glass fiber concentrations were not
specifically stated. Similar negative results were found in the
_E_. coli mutation test with strains B/r, WP2, WP2 uvrA and WP2
uvrA pol A. All samples were tested up to 1,000 ug/plate in the
_E_. coli test, except for Code 110 fiberglass (100 jug/plate top
dose). The authors suggest that the negative results may be due
to a lack of phagocytosis of fibers by bacteria (bacteria
apparently do not phagocytize). Also, in general, bacteria
appear resistant to the cytotoxic effects of fibers whereas
mammalian cells are sensitive. Despite the problems of not
specifically stating the concentrations for glass fibers and the
lack of data using other strains (e.g. TA98, TAlOO) in the
Salmonella assay, it appears that bacterial systems may not be
appropriate to assay the potential mutagenicity of fibers.
II.1.3.1.2. Chromosomal Effects
Glass fibers were examined in several studies for
chromosomal effects and were compared to the effect induced by
chrysotile and/or crocidolite asbestos. The first study to
examine the potential effects of glass fiber and glass powder in
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59
Chinese hamster ovary (CHO) cells was reported by Sincock and
Seabright (1975). They found that chrysotile and crocidolite at
0.01 mg/mL both induced polyploid cells, cells with fragments/
and other chromosomal changes (such as breaks and double minutes)
as well as an increase in the percentage of abnormal cells.
Glass fiber and glass powder at 0.01 mg/mL appeared to cause no
effect different from controls. However/ an effect by
specifically sized glass fibers cannot be ruled out by this
study, as the dimensions of the glass fibers were not specified.
In subsequent studies, Sincock (1977) and Sincock et al.
(1982) examined the potential chromosomal effects of glass fibers
in CHO cells in more detail. Asbestos samples/ including
chrysotile/ crocidolite/ amosite, and anthophyllite were also
examined. Chrysotile and crocidolite up to 0.1 mg/mL for 48 or
72-hour cell exposure consistently induced high levels of
chromosome damage including increases in breaks/ dicentrics,
inversions/ rings/ percent abnormal cells/ and polyploidy. Code
100 (up to 0.1 mg/mL; lengths 2.7-26 urn) induced a significant
increase in the same parameters, but at levels usually less than
that for chrysotile and crocidolite. It produced polyploidy at
levels similar to amosite and anthophyllite. Code 110 (lengths
2.7-26 urn), glass powder (coarse borosilicate) and glass of 2 urn
diameters but of specific lengths (<10 urn, 25 urn, 50 urn and
100 urn) all had no effect.
Sincock et al. (1982) also examined the potential effect of
the asbestos and glass fiber samples (described above) on
cultured human cells. Five different fibroblast cell strains
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60
(not exceeding passage 15) and two different lymphoblastoid cell
lines were used. No increase in chromosomal damage was noted for
any sample assayed. The authors also searched for fiber-induced
micronuclei in the lymphoblastoid lines, but noted no increase
over controls. It was shown in this report that cultured CHO
cells sustained damage to fibers, but the cultured human cells
were not overtly damaged. There is no apparent explanation,
although the authors suggest that the difference may be due to
differences in excision repair, the nature of the transformed
lines, or the species of origin. The phenomenon! seems similar
for the asbestos and glass fibers tested by these authors.
Code 110 fiberglass and its respirable fraction were tested
in Chinese hamster lung (V79) cells (Brown et al., 1979b). The
fibers were milled to lengths <200 jam. The respirable fraction
was obtained from collecting respirable dust and was designated
110R. Code 110 had 9 x 109 fibers/g and 110R had 25.2 x 109
fibers/g of which a 20 ug/mL concentration for both was tested in
the V79 cells. The 110R sample presumably had similar diameters
as 110, but had shorter lengths. In comparison to a crocidolite
positive control, 110 fibers had no observed chromosomal
effect. 110R however, induced increased fragments, breaks, and
percent of cells with abnormal spreads over the negative
control. The 110 sample was weakly cytotoxic to V79 cells, but
the 110R sample induced noticeable cytotoxicity.
Oshimura et al. (1984) examined the cytogenetic effects of
several asbestos and fiberglass samples on tertiary cultures of
Syrian hamster embryos. Chrysotile induced time- and
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61
concentration-dependent increases in frequencies of cells with
numerical changes (aneuploidy and tetraploidy), chromosomal
aberrations (breaks/ fragmentation, exchanges, dicentrics),
binuclei, and micronuclei after 24- and 48-hour treatments
*\
(concentrations at 2 jjg/um1'). Code 100 fiberglass and
crocidolite had similar effects (48 hour exposure; 2 ug/^m^), but
both of these were less effective in inducing cytogenetic changes
than chrysotile. Code 110 fiberglass and alpha-quartz (non-
fibrous mineral dust) were without significant effects. Milling
of code 100 samples reduces the length (not given) as well as the
cytogenetic effect. This suggests that the appropriate length,
not the chemical composition, of Code 100 fiberglass is
responsible for the cytogenetic effects seen in this study.
Glass fiber and asbestos samples were tested for their
ability to induce sister chromatid exchanges (SCE) in CHO and
cultured human cells (Casey, 1983). Chrysotile, crocidolite,
Code 100, and Code 110 fiberglasses were added to cell cultures
under two regimes. Concentrations of 0.001, 0.01 and 0.05 mg/mL
were added to cells one hour after seeding in procedure one, and
cells in suspension were exposed to 0.01 mg/mL before seeding in
procedure two. By either treatment, no fiber tested induced SCE
over the control frequency in CHO cells, human lymphoblastoid
cells, or primary human fibroblasts (8-10 passages). No cell
cycle effect was seen in the fibroblasts under either procedure
and a mitotic delay was seen in CHO cells only with procedure two
(except for Code 110). It appears that while glass fibers may
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62
induce aberrational and ploidy type changes in cells, glass
fibers do not induce SCE, at least based on this study.
II.1.3.1.3. Transformation Effects
Two studies report results from transformation studies using
asbestos and glass fibers. In the earlier report, Sincock (1977)
described the effect of chrysotile, crocidolite, and coarse
fiberglass (Code 110) on murine 3T3 cells. The two asbestos
fibers (0.01 mg/mL) induced foci indicative of transformation
after only 7 days of exposure. Coarse fiberglass had no apparent
effect.
Hesterberg and Barrett (1984) examined the effect of many
more fiber samples on tertiary cultures of Syrian hamster
embryos. Chrysotile and crocidolite produced linear increases in
o
transformation frequency (concentrations 0.25-2 ug/cm ) with
chrysotile more potent than and twice as cytotoxic as
crocidolite. Extracted chrysotile actually induced a 3-fold
higher frequency than unextracted samples, indicating that
possible contaminating organics may not have a role in fiber-
^
induced transformation. Code 100 fiberglass (2 ug/cm ; 9.5-16 pm
length) was as active as chrysotile in transforming cells.
Milled Code 100 (0.95-1.7 urn length) and milled chrysotile both
exhibited greatly reduced transformation and cytotoxic
activities. The reduction is presumably due to the reduction in
fiber length. Code 110 fiberglass was less toxic than Code 100
and was 20-fold less potent than Code 100 for transformation.
Two nonfibrous mineral dusts (alpha-quartz and Min-U-Sil) also
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63
induced concentration dependent increases in transformation, but
at much higher concentrations (10-75 ^ug/cm ) than chrysotile and
Code 100 fiberglass. They were also much less toxic than
chrysotile. The authors suggest that the slopes of the response
curves indicate a one-hit mechanism for transformation that would
suggest a direct effect by the fibers.
II.1.3.2. Cytotoxicity
Fibrous glass was tested in several in vitro studies to
determine its cytotoxic potential in various cell culture
systems. Glass microfibers were found highly cytotoxic to lung
and peritoneal macrophages, P388D1 macrophage-like cells,
phagocytic ascites tumor cells, Chinese hamster lung fibroblast
V79-4 cells, rabbit lung fibroblasts, type II human alevolar A549
cells, and human bronchial epithelial cells. The cytotoxic
effect of thin glass fibers appears to approach that of asbestos
fibers. On the other hand, coarse fiberglass (code 110) had
little or no cytotoxic effects although its respirable fraction
was found to have some cytotoxic activities in one study. These
studies also indicated that long, thin glass fibers are more
cytotoxic than short, thin fibers. This may be due to the fact
that long fibers are incompletely phagocytized and, as a result,
may damage the cell membrane and may cause subsequent release of
enzymes, followed by cell death. The ability of fibrous glass to
cause cellular membrane damage, as measured by hemolysis of red
blood cells, has been reported, but a varying degree of hemolytic
activity was found.
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II.1.3.2.1. Erythrocytes
Available data on the hemolytic activity of glass fibers are
limited. Jaurand and Bignon (1979) reported that glass fibers
had a poor hemolytic effect, compared to UICC chrysotile, when
incubated with human red blood cells. However, the hemolytic
activity of glass fibers was similar to that of UICC crocidolite.
In contrast, Ottolenghi et al. (1983) showed that Pyrex glass
fibers (dimensions not specified) at 100 ug/mL did not cause
hemolysis in chicken erythrocytes. Amosite also had no effect,
while chrysotile asbestos induced high hemolytic effect. In an
abstract, Nadeau et al. (1983) reported that glass microfibers
(diameter of 0.2 urn; length of 221 urn) induced marked hemolytic
activity in rat erythrocytes. No further details were available
for a conclusive evaluation.
II.1.3.2.2. Phagocytic cells
Tilkes and Beck (1983a) examined the cytotoxic effects of
glass microfibers of different size distributions in guinea pig
and rat lung macrophages. The release of lactate dehydrogenase
(to demonstrate plasma membrane permeability) and beta-
glucuronidase (to indicate lysosomal permeability) were measured
as indicators of cytotoxicity. It was shown that macrophage
toxicity (100 ug/mL) was length dependent; the highest toxicity
was seen with fibers longer than 5 urn. For fibers of similar
physical size dimension, the cytotoxic effects of amosite and
crocidolite asbestos and glass fibers were equivalent when doses
were gravimetrically equivalent. Glass microfibers (JM 100) also
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65
caused a significant depression in phagocytic activity of
macrophages. Phagocytosis was assayed quantitatively by
determining the-amount of luminescence produced after the
addition of serum-opsonized zymosan A particles.
These results confirmed the earlier findings in the study by
Beck et al. (1972) showing that fine fiberglass (0.25-1.0 urn
diameter; 1-20 urn length) induced an increase in cell membrane
permeability of guinea pig alveolar and peritoneal macrophages/
as measured by increased release of lactate dehydrogenase and
lactate levels.
Pickrell et al. (1983) tested the in vitro cytotoxicity of
two uncoated glass microfiber insulation materials (0.1-0.2 urn
diameter), three types of fibrous glass-containing household
insulation (2-4 urn diameter) and crocidolite asbestos (0.25 urn
diameter) in pulmonary alveolar macrophages isolated from Beagle
dogs. It was reported that the most cytotoxic of the fibers
tested was crocidolite asbestos. Household insulations were not
cytotoxic at the highest concentration tested. Both types of
glass microfibers had cytotoxicities intermediate between
household insulation and crocidolite asbestos.
In an abstract/ Nadeau et al. (1983) also reported that long
glass microfibers (0.2 um x 221 turn) were highly cytotoxic to rat
pulmonary alveolar macrophages. However, the experimental
details were not provided in this report.
Brown et al. (1979a) studied the cytotoxicity of JM code 100
glass microfibers (nominal diameter of 0.05-0.09 um) and JM code
110 glass fibers (nominal diameter of 1.5-2.49 um) in mouse
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66
peritoneal macrophages. Code 100 microfibers were more cytotoxic
than code 110 fibers as reflected by 2-3-fold differences in the
release of lactate dehydrogenase and beta-glucuronidase levels at
160 ug/mL. Similar findings were obtained by Davies (1980) who
demonstrated that fine glass fibers (JM 100) at a concentration of
160 ug/mL were cytotoxic toward mouse peritoneal macrophages.
Coarse glass fibers code JM 110 had no cytotoxic effects but the
respirable fraction of JM 110 glass fibers had some cytotoxic
activities.
Tilkes and Beck (1980, 1983b) investigated the cytotoxicity
of fibrous glass in phagocytic ascites tumor cells derived from
Wistar rats/ as measured by the release of lactic dehydrogenase
and the inhibition of cell proliferation as determined by cell
count, DNA, RNA, and protein synthesis. It was found that for
long glass fibers (>20 urn), the thinner the fiber, the greater the
toxicity in this cell culture system. In addition, a glass fiber
fraction with comparable geometry to a UICC chrysotile asbestos
fraction exhibited the same high cytotoxicity.
In the study by Lipkin (1980), borosilicate glass fiber
(dimension unspecified) which was obtained from the same lots used
by Stanton et al. (1977) was found highly toxic to P388D1
macrophage-like cells at a concentration of 100 ug/mL. The
cytotoxicity of glass fibers in this cell culture was well
correlated with potency in pleural sarcoma induction reported by
Stanton et al. (1977) in intrapleural implantation studies.
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II.1.3.2.3. Nonphagocytic cells
Brown et al. (1979b) studied the effect of glass wool on
Chinese hamster lung fibroblasts (V79-4 cells) and human alveolar
type II (A549) cells. Respirable fractions of coated or uncoated
glass wool produced a dose-dependent inhibition of cell growth
(10-50 ug/mL) of V79-4 cells. Uncoated glass wool also produced a
significant increase in the number of giant cells when added to
the A549 cell cultures at 200 ug/mL.
Chamberlain et al. (1980) reported that code 100 glass
microfibers (dimensions and concentrations not provided) reduced
the colony forming ability of V79-4 cells and induced giant cells
in A549 cell cultures. In contrast, code 110 coarse glass fibers
had no effect. The actual data were not provided in this study to
fully evaluate the findings.
In a study by Richards and Jacoby (1976), glass fibers
(dimensions unspecified) caused a slight cytotoxicity to rabbit
lung fibroblasts when added to cell cultures at 50 jug/mL.
Fiberglass also induced morphological changes and alterations in
reticulin deposition in the fibroblast cultures. In contrast,
UICC chrysotile asbestos was highly cytotoxic to fibroblasts and
caused more extensive morphological changes in these cultures at a
similar mass concentration.
Glass fibers (1-100 ug/mL) were also found to induce a dose-
dependent inhibition of clonal growth rate of human bronchial
epithelial cells (Haugen et al., 1982). In this cell culture
system, UICC chrysotile was more cytotoxic than glass fibers by
more than 100-fold.
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II.1.4. Assessment of Health Effects
Existing studies have provided no clear evidence of a
carcinogenic or fibrogenic hazard in humans. However, available
animal studies show that fine fibrous glass is carcinogenic and
fibrogenic by the injection route of exposure. Thus, there remains
a concern for possible health hazards from inhalation exposure to
fine fibrous glass, i.e., fibers with diameters less than 3 urn. A
low health concern is also raised for exposure to glass wool, which
does contain some respirable fine fibers. As for textile fibers
(continuous glass filaments) which are generally nonrespirable,
they would appear to pose little hazard to exposed humans. On the
basis of available animal data, it is concluded that all fiberglass
categories appears to be less pathogenic than asbestos.
II.1.4.1 Oncogenicity
Available health and toxicological information seems to
indicate that the oncogenicity of fibrous glass varies for the
three major categories i.e., fine fibrous glass, glass wool, and
continuous glass filament. The variable oncogenic potential for
these classes of fibrous glass appear to be related to their
different fiber size distributions.
By using the U.S. EPA weight-of-evidence criteria for car-
cinogenicity (USEPA, 1986), fine fibrous glass and glass wool may
be categorized as possible human carcinogens (Category C) on the
basis of inadequate evidence of carcinogenicity in humans and
limited evidence in animal studies. On the other hand, continuous
glass filament is not classifiable as to human carcinogenicity
(Category D) due to inadequate evidence of carcinogenicity from
epidemiological and animal data.
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69
Available data from recent cohort studies suggest that
workers engaged in the manufacture of glass wool and small
diameter fibers might be at increased risk of developing
respiratory cancer. Small excesses of respiratory cancer death
have been observed among workers exposed to glass wool and small
diameter glass fibers but no excess of respiratory cancer has
been found among glass filament workers. A dose-related trend
has not been found although it should be noted that exposure to
fibrous glass has been extremely low. The causal relationship
between fibrous glass exposure and the development of respiratory
cancer is therefore not considered credible at this time. There
is also inadequate evidence of an increased mortality from
mesothelioma in available MMMF cohorts. On the basis of
available information, the weight of evidence of carcinogenicity
of fibrous glass, i.e., glass wool, continuous glass filament,
and small diameter fibers (fine fiberglass), from studies in
humans is considered inadequate. Since the results of relevant
epidemiological studies on fibrous glass have been reviewed in
details and assessed in a report by Battelle (1988), only a brief
description of the study design and findings are presented here.
Enterline et al. conducted a large cohort study on fibrous
glass workers from 11 plants in the U.S.. These workers had at
least one year exposure between 1945 and 1963. For those working
in facilities where small diameter fibers were prevalent, the
criterion was greater than six months of exposure. The cohort's
mortality experience was traced through 1977 in the early study
(Enterline et al, 1983) and in the subsequent studies mortality
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70
was followed to 1982 (Enterline et al., 1986; 1987). The average
level of exposure to glass fibers (<3 urn in diameter) for all
fiberglass plants was 0.039 fibers/mL.
In this study/ a slight excess of mortality from respiratory
cancer was observed among glass wool workers which was
nonsignificant based on local rates but was statistically
significant compared to national rates. Mortality from
respiratory cancer increased nonsignificantly with time from
exposure but was not related to duration of exposure/ cumulative
exposure, or average intensity of exposure. In the glass
filament subcohort, there was no excess of respiratory cancer and
no upward trend with time since first exposure, duration of
exposure, or average intensity of exposure. Among workers in 4
fiberglass plants ever exposed to small diameter glass fibers (<3
urn), there was a nonsignificant excess of respiratory cancer
mortality which increased nonsignificantly with more than 30
years since onset of exposure. However, the small number of
deaths limits any definitive conclusion regarding the
relationship between fine fiberglass exposure and respiratory
cancer. The results of a nested-case control study using
respiratory cancer cases among fibrous glass (type unspecified)
workers showed a statistically significant association between
respiratory cancer and smoking but not between respiratory cancer
and cumulative fiber dose (Enterline et al., 1986; 1987).
Similar results were obtained in the European study.
Simonato et al. (1985; 1986a; 1986b) also performed a historic
cohort investigation of glass wool workers from five plants and
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continuous glass filament workers from two facilities in Europe.
This study cohort consisted of men and women employed with at
least one year of employment from 1933-46. Mortality was
followed to 1982 and risks were also examined for early, middle
and late production phases. In the glass wool cohort/ there was
no overall excess of lung cancer deaths by using the local
mortality rates but there was a small nonsignificant excess when
compared to national rates. Mortality from lung cancer increased
nonsignificantly with time since first exposure but was not
related to duration of exposure or to different technological
phases, reflecting differences in the intensity and quality of
exposure. Among glass filament workers there was no excess of
lung cancer and no upward trend with time since first exposure or
duration of exposure.
A third study by Shannon et al. (1986) reported a
significantly elevated risk for lung cancer in a small Canadian
glass wool cohort. However, analyses of lung cancer deaths by
duration of employment and time since first exposure indicated no
consistent dose-related trends.
There were no excessive mesothelioma deaths reported in the
two large cohort studies on MMMF workers exposed to fiberglass and
mineral wool. Simonato et al. (1985) observed one death due to
mesothelioma in the European study of 24,000 workers. Enterline
et al. (1986) reported two mesothelioma deaths in a cohort of
16,000 workers followed for 36 years. However, an investigation
by Engholm et al. (1986) reported an excess number of mesothelioma
in the Swedish construction industry. The study population
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consisted of 135,000 male workers exposed to MMMF (no distinction
between exposure to fibrous glass and mineral wool). There was a
significantly increased mortality from pleural- mesothelioma in the
Swedish cohort. However/ possible confounding by asbestos
exposure and several limitations of the study (e.g. exposure
defined by job category and no monitoring data to define
categories) limit the conclusions that can be made about this
finding.
Experimentally, there is insufficient evidence for the
carcinogenesis of fibrous glass in animals by inhalation. Fine
fibrous glass (including glass microfibers) and glass wool have
been tested in several long-term inhalation studies, in several
animal species including the rat (Wagner et al., 1984; McConnell
et al., 1984; Le Bouffant et al., 1984; Smith et al., 1986),
hamster (Smith et al., 1986), monkey (Mitchell et al., 1986) and
baboon (Goldstein et al., 1983). There was no statistically
significant increase in the incidence of lung tumors or pleural
mesothelioma in any of these studies; only a few tumors of the
respiratory tract occurred in some experiments in rats (Wagner et
al., 1984; Le Bouffant et al., 1984). Although none of the
available inhalation bioassays is considered adequately studied,
collectively they do demonstrate that at equal mass concentrations
and similar experimental conditions, chrysotile asbestos generally
induced significant increases in lung tumors while fine fibrous
glass and glass wool did not cause significant tumorigenic
responses in laboratory animals following chronic inhalation
exposure.
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However, data from studies in which glass fibers were
administered by nonphysiological routes indicate that a carcino-
genic hazard potential does exist for glass wool and fine fibrous
glass, in particular, for glass microfibers which contain a
considerable number of long, thin fibers. Glass wool, fine
fibrous glass and glass microfibers were not found to cause tumors
in a number of intratracheal instillation studies in rats (Smith
et al. 1986; Gross et al., 1976), hamsters (Feron et al., 1985;
Gross et al., 1976) and guinea pigs (Wright and Kuschner, 1976,
1977). However, in one study, lung tumors and pleural mesotheli-
omas were observed in hamsters by intratracheal instillation of
glass fibers with a median diameter of 0.3 urn in hamsters (Mohr et
al., 1984). In another study by the same laboratory, lung tumors
were also induced in rats instilled intratracheally with glass
microfibers (Pott et. al., 1987a). In studies where various
samples of glass microfibers «1 urn diameter) were tested by
intrapleural implantation (Stanton et al., 1977, 1981) or
injection (Smith et al., 1980; Wagner et al., 1976, 1984; Monchaux
et al., 1981) variable incidences of pleural tumors were induced
in rats. Furthermore, peritoneal mesotheliomas or sarcomas were
found in the abdominal cavity in rats following intraperitoneal
injection of glass microfibers (Davis, 1976; Pott et al., 1974,
1976, 1980, 1984). By the intrepleural route, glass wool also
caused low incidences of mesothelioma in a few studies (Stanton et
al., 1981, 1977; Wagner et al., 1984) while other studies have
produced no mesothelioma (Wagner et al., 1973; 1976). Stanton and
coworkers also demonstrated that glass fibers less than 0.25 urn
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74
diameter and greater than 8 urn length have carcinogenic potential
equal to that of asbestos fibers. Similarly, other investigators
found that long/ thin gl-ass fibers are highly carcinogenic by the
injection routes of exposure but are generally less effective than
asbestos at equal mass doses.
The relevance of the injection method with regard to human
exposure is considered questionable considering that it bypasses
normal physiological deposition and clearance mechanisms in the
respiratory tract. Positive results from studies using
intrapleural or intraperitoneal injection/implantation method in
the absence of positive findings from inhalation experiments do
not indicate that these fibers will produce tumors in man upon
inhalation. However, positive results from such injection studies
as found in the case of fine glass fibers and glass wool indicate
that they have the potential to induce tumors when introduced to
the target tissues in sufficient quantity. Furthermore, the fact
that in two studies involving intratracheal instillation of small
doses of glass microfibers (to mimic the inhalation exposure
condition) resulted in the induction of tumors distal to the
administration site (lung tumors and mesothelioma) indicate that
fine fiberglass can reach the critical target tissues (lung and
pleural mesothelium) if a sufficient amount of fibers can
penetrate the upper respiratory airways. Whether or not these
materials when inhaled will indeed reach the target tissues in
sufficient quantity to cause tumors depends on the respirability
characteristics of the fibers, which are not operative in the
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75
injection study. Thus, in the absence of positive findings from
available inhalation studies, the weight-of-evidence for the
carcinogenicity -of fine fibrous glass and glass wool in animal
studies is considered limited.
In vivo animal data are supported by positive findings from a
few genotoxicity studies showing that fine glass fibers appear to
have similar genotoxic effects (clastogenicity and transformation)
as asbestos (Sincock et al., 1982; Oshimura et al., 1984;
Hesterberg and Barrett, 1984).
There are no studies available that examined the
carcinogenicity of glass filaments in animals via inhalation.
Moreover, large diameter glass fibers did not produce mesothelioma
in rats via the intrapleural route (Stanton and Wrench, 1972;
Stanton et al., 1977; 1981). Thus, the weight-of-evidence of
carcinogenicity for glass filament in animal studies is considered
inadequate.
II.1.4.2. Fibrogenicity
There does not appear to be any convincing evidence for
increased risks of non-malignant respiratory disease (NMRD) from
exopsure to fibrous glass. There is also no definitive evidence
for the development of lung fibrosis in animals inhalation.
However, the positive findings from several injection studies in
animals and in vitro cytotoxicity studies indicate that fine
fibrous glass may be fibrogenic.
Available epidemiological studies have provided weak or no
evidence of excess mortality from NMRD in fibrous glass workers.
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In the large cohort study in the U.S. (Enterline et al., 1986;
1987; Enterline/ 1987)/ there was no significant excess mortality
from NMRD among glass wool workers compared with local rates,
although there was a statistically excess based on national
rates. However, there was no relationship with time from first
exposure, or duration of exposure. Among glass wool workers "ever
exposed" to small diameter fibers, there was no excess of NMRD
mortality but there was a slight nonsignificant increase with time
since first exposure. In the continuous glass filament cohort, no
excess NMRD mortality was observed based on either local or
national rates.
Other investigators have not observed an association of NMRD
and fibrous glass exposure. In the large European study (Simonato
et al., 1985; 1986a; 1986b), there was no excess mortality from
NMRD in the glass wool or continuous filament cohort, nor was
there a relationship with time from first exposure or duration of
exposure. Shannon et al. (1986) also did not find an excess risk
of NMRD in their study of Canadian glass wool workers. A deficit
in risk for NMRD was reported by Engholm et al. (1986) in their
study of Swedish workers exposed to MMMF (fibrous glass and
mineral wool).
The results of a respiratory morbidity study (Weil et al.,
1983) showed some evidence of radiographic opacities in the lung
of a limited number of fibrous glass workers. However, this study
showed no evidence of pulmonary fibrosis, no increase in
respiratory symptoms, and no impaired lung function.
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Overall/ there is inadequate experimental evidence of
fibrogenicity for fine fiberglass and glass wool via inhalation
exposure. It has been shown in several studies that chronic
inhalation exposure to fine glass fibers or glass wool produced
only minimal interstitial dust cell reaction without fibrosis in
rats (Wagner et al., 1984; Smith et al., 1986; McConnell et al.,
1984; Mitchell et al., 1986; Le Bouffant et al., 1984), hamsters
(Smith et al. 1986) and monkeys (Mitchell et al., 1986). One
study reported the development of focal fibrosis in baboons
exposed to fine glass fibers (Goldstein et al., 1983). However,
the small number of animals and the lack of unexposed control
animals limit the conclusions that can be made from this study.
In contrast, more extensive pulmonary fibrosis was induced in
animals by intratracheal instillation (Wright and Kuscher, 1977),
Pickrell et al., 1983; Smith et al., 1986) or intrapleural
injection (Davis, 1976). Furthermore, intraperitoneal injection
of fine glass fibers generally resulted in marked peritoneal
fibrosis (Pott et al., 1974; Smith et al., 1986). The results of
these injection studies also indicate that long, thin glass fibers
are more fibrogenic than short, thin fibers, while thick glass
fibers (>3 urn diameter) are relatively inert. In general, glass
fibers produced less severe and less progressive pulmonary lesions
than those induced by asbestos via either inhalation or injection
at equal mass concentrations or doses.
The in vivo findings are further supported by results from
several in vitro studies showing that fibrous glass is cytotoxic
to various cell types in culture. The cytotoxicity of fibrous
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glass was found to be a function of fiber dimension, with longer
(>10 urn), thinner (<1 urn) fibers being most cytotoxic/ whereas
coarse fibrous glass with fairly large diameter fibers (>3 urn)
were less cytotoxic (Tilkes and Beck, 1980, 1983a, 1983b; Brown et
al., 1979a; Davies, 1980; Pickrell et al., 1983).
II.1.5. Recommendations
Although glass wool and fine fibrous glass have been tested
extensively, none of available inhalation studies are considered
to be adequate. In addition, there are no data available
regarding the comparative dose-response effects with asbestos.
Thus, it would be useful to conduct additional long-term animal
inhalation or injection studies on fibrous glass. Further
epidemiological studies are also necessary to clarify the
pathogenicity of fibrous glass in humans.
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II.2. Mineral Wool
There are two major types of mineral wool, i.e., rock wool
and slag wool. Rock wool is made by melting natural igneous rocks
and then drawing, blowing, or centrifuging the melts into
fibers. Slag wool is produced by a similar process from blast
furnace slag. Mineral wools are primarily used for thermal
insulation but are also used for sound dampening and reinforcement
of other materials. Slag and rock wools have nominal diameters
ranging from 6-9 um, but also contain a relatively high proportion
of respirable fibers (diameter _<3 um). Thus, mineral wools are
likely to generate respirable airborne fibers during production
and processing (ICF, 1986).
II.2.1. Fiber Deposition, Clearance and Retention
There is limited information on the pulmonary deposition,
clearance, and retention of mineral wool fibers. However, the
results of available animal studies suggest that mineral wool
deposition and clearance are dependent on both fiber length and
diameter. The lung clearance of mineral wools appears to be rapid
soon after inhalation, presumably via the mucocillary system and
by phagocytosis. Translocation of inhaled mineral wool fibers to
regional lymph nodes and abdominal organs appears to be limited.
During later periods, mineral wools are eliminated slowly,
presumably by dissolution.
Hammad (1984) studied the pulmonary deposition and clearance
of mineral wool in the rat. A group of 49 male rats were exposed
"nose only" to aerosol of mineral wool (fiber type not specified)
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at 300 fibers/mL for 6 consecutive days. Count median length and
median diameter of airborne fibers were 13 urn and 1.2 urn,
respectively. Rats in groups of seven were sacrificed at 5, 30/
90, 180, and 270 days after the last day of exposure. The
pulmonary deposition of fibers, as approximated by fiber retention
after 5 days of clearance, appeared to be dependent on both fiber
length and diameter. Fibers of diameters less than 1.3 urn and
shorter than 50 urn were found much more frequently in the lung
than thicker and longer fibers. The pulmonary clearance of
mineral wools was multiphasic. During the 5-30 and 30-90 day
periods, mineral wool had a half-life of 38 days, whereas the
half-lives increased to 68 days and 175 days for the 90-180 and
180-270 day periods, respectively. Approximately 3-7 percent of
mineral wool fibers deposited in the lung were retained after 270
days. Most of the fibers which were retained in the lung had
fairly large diameters (1.0-1.3 urn) and were relatively short
«5 jam).
Fiber retention has also been demonstrated in the rat lung
following long term inhalation exposure to mineral wools (Johnson
et al., 1984a; Le Bouffant et al., 1984). In the lung, rock wool
fibers were found predominantly in the alveolar or interstitial
macrophages (Johnson et al., 1984a). Fiber translocation from the
lung to the tracheobronchial glands and diaphragm has been
observed for rock wool as evidenced by the presence of small
amounts of fibers in these organs (Le Bouffant et al., 1984).
Migration of slag wool fibers outside the lung to the abdominal
organs including the spleen, liver, and diaphragm have also been
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reported after instillation of fibers into the trachea of rats,
hamsters, and rabbits (Spurny et al., 1984).
Mineral wool fibers appear to dissolve in the rat lung after
a long period of a time (1-2 years) following inhalation exposure
(Hammad et al., 1985; Johnson et al., 1984a; Wagner et al., 1984),
or via inoculation into the trachea (Morgan and Holmes, 1984b;
Spurny et al., 1984). Apparent fiber dissolution in abdominal
tissues has also been observed after injection of mineral wool
fibers into the peritoneum of various rodent species (Pott et al.,
1984; Spurny et al., 1984).
Slag and rock wools appear to have different solubility
properties. Morgan and Holmes (1984b) showed that rock wool
appeared to dissolve relatively slowly in the lung and that
dissolution apparently occurred more rapidly at the end of fibers
than in the middle, where the diameter was essentially
unchanged. Similar findings have been obtained by other
investigators reporting that etching of fibers in the lung was
minimal for rock wool (Johnson et al., 1984a; Wagner et al,
1984). On the other hand, slag wool fibers in the lung (Spurny et
al., 1984) and in abdominal tissues (Pott et al., 1984; Spurny et
al., 1984) showed a considerable degree of corrosion. Analyses of
the retained slag wool fibers by various spectroscopic methods
revealed a partial to complete loss of alkali metals and alkaline
earth ions (Spurny et al., 1984).
Results from in vitro experiments which studied the
dissolution of mineral wools in simulated physiological fluid, are
in agreement with the in vivo observations on fiber durability.
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Slag wool fibers have been shown to undergo rapid and extensive
leaching in physiological fluid, while the leaching of rock wool
fibers was much less extensive (Forster, 1984; Klingholz and
Steinkopf, 1984). Leineweber (1984) also demonstrated that in
physiological saline, mineral wool fibers dissolved at a slow
rate, but it is not clear whether the tested fibers in this study
were rock wool or slag wool.
II.2.2. Effects on Experimental Animals
A number of studies have been conducted to evaluate the
tumorigenic and fibrogenic effects of mineral wools in laboratory
animals. The experimental protocols and findings of available
studies are summarized in Table 2 (pages 230-233).
II.2.2.1. Oncogenicity
The results of available long-term studies have not provided
evidence of pulmonary or mesothelial carcinogenicity in rats or
hamsters exposed to mineral wool fibers by inhalation (Wagner et
al., 1984; Le Bouffant et al., 1984; Smith et al., 1986). On the
other hand, malignant mesothelioma of the pleura or peritoneum
have been produced in rats following either intrapleural (Wagner
et al., 1984) or intraperitoneal (Pott et al., 1984, 1987b)
injection of various types of mineral wool at varying yields.
However, significantly more neoplasms were found in animals
exposed to asbestos fibers by either inhalation or injection route
of exposure at equal mass concentrations or doses.
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II.2.2.1.1. Inhalation studies
In the study by Wagner et al. (1984), a group of 56 SPF
Fischer 344 male and female rats were exposed to a dust cloud of
rock wool (58 percent <1 urn diameter; 64 percent >10 um long) at a
mass concentration of 10 mg/m (equivalent to approximately 227
fibers/mL) for 12 months. Of the 48 exposed animals which were
allowed to live out their full lifespans, there were two cases of
lung tumors (one benign adenoma and one adenoma with some
malignant features). Unexposed control animals had no tumors.
Taking into account the known occurrence of spontaneous species-
specific lung neoplasms in F344 rats, there were no significant
differences in tumor incidence between unexposed and exposed
rats. In contrast, UICC chrysotile asbestos produced 12 cases of
lung neoplasms (11 adenocarcinomas, 1 adenoma with some malignant
features).
In a limited inhalation study by Le Bouffant et al. (1984), a
group of male and female Wistar IOPS rats were exposed to rock
wool at concentration of 5 mg/m of dust for 24 months. The rock
wool fibers had fairly large diameters (only 22.7 percent <1
um). Because the rock wool fiber dust also contained a large
proportion of nonfibrous particles and fragments that did not
conform with the definition of a fiber, the numerical rock wool
fiber concentration was very low (11 fibers/mL) in comparison with
that of Canadian chrysotile (9,978 fibers/mL) used as control. No
tumors were found in the exposed males (0/24) or female (0/23)
rats. On the other hand, nine cases of lung tumors were observed
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in the chrysotile exposed animals at 24 months. Unexposed control
animals had no lung tumors.
In a study reported by Smith et al. (1986) , -female Osborne-
Mendel rats and male Syrian hamsters were exposed "nose-only" to a
mineral wool dust cloud at a mass concentration of 12 mg/m (200
fibers/mL) for 24 months. The tested mineral wool fibers had
fairly large diameters with a median value of 2.7 urn. No primary
lung tumors were found in the exposed hamsters (0/69) and rats
(0/55). Tumors were not observed in any of the untreated control
rats (0/125) or hamsters (0/112) nor in rats exposed to clean air
(0/59), and only one bronchoalveolar tumor (1/58) was found in the
control hamsters group exposed to air. No significant production
of neoplasms were found in positive control hamsters (0/58) or
rats (3/57; 1 mesothelioma, 2 bronchoalveolar tumors) exposed to
UICC crocidolite asbestos. It was believed that the lack of a
significant tumorigenic response by crocidolite asbestos observed
in this study could have been due to the use of relatively short-
fibered material (95 percent <5 im long).
II. 2. 2. 1.2. Intrapleural Injection Studies
Wagner et al. (1984) injected 20 mg of either rock wool (with
or without resin) or slag wool (with or without resin) into the
pleural cavity of groups of 48 SPF Fischer 344 rats.
Approximately 70-80 percent of rock wool and slag wool, either
with or without resin, were less than 5 urn long and less than
1 urn diameter. Three cases of mesotheliomas were produced in the
animal group treated with rock wool with resin, and two cases by
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rock wool without resin. The slag wool produced no mesotheliomas
while UICC chrysotile asbestos induced mesothelioma in six
animals. It should be pointed out th-at the injected rock wool and
slag wool dusts contained more nonfibrous particles (i.e., aspect
ratio less than 3) than fibrous particles.
II.2.2.1.2. Intraperitoneal Injection Studies
Pott et al. (1984) reported very low tumor yields in female
Sprague-Dawley and Wistar rats (40-60 animals per group) following
intraperitoneal injection of mineral wools. A single dose of 5 mg
of slag wool containing a high proportion of very thin fibers (90
percent <0.28 urn diameter) and long fibers (9 percent >10 urn
length) produced only a tumor rate (sarcoma or mesothelioma) of 5
percent, which was not statistically different from zero. Rock
wool of fairly large diameter fibers (50 percent <1.9 urn diameter)
produced a 16 percent incidence of sarcoma/mesothelioma of the
peritoneum of rats treated with three doses of 25 mg of dust,
while no neoplasms were observed in rats after 15 months following
a single dose of 10 mg of thin rock fibers (50 percent <0.64 urn in
diameter). Basalt wool (50 percent <0.52 urn diameter, 50 percent
<5.8 urn long) also did not produce neoplasms in female Wistar rats
after 15 months following a single i.p. dose of 5 mg.
Recently, Pott et al. (1987b) reported that relatively thick
basalt wool produced a high incidence of abdominal tumors in rats
following repeated intraperitoneal injections. In this study,
female Wistar rats received five weekly injections of 15 mg of
basalt wool (50 percent <1.8 urn diameter; 50 percent <20 yam
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long) suspended in saline. The animals were kept for their entire
lifespan. Peritoneal mesothelioma/sarcoma were found in 30 of 53
treated animals. High tumor yields were also obtained with
UlCC/Canadian chrysotile asbestos at considerably lower doses,
11/36 at 0.05 mg, 21/34 at 0.25 rag, and 30/36 at 1.0 ing). The
tumor incidence in negative saline controls was 1/102.
II.2.2.2. Fibrogenicity
The experimental data on the fibrogenic effect of mineral
wools are limited. The majority of studies showed a lack of
fibrogenic response following chronic inhalation exposure.
However, the results of a limited inhalation study suggest that a
low fibrogenic potential may exist for mineral wools.
In a limited study by Johnson and Wagner (1980), groups of
two SPF Fischer 344 rats were exposed to dust clouds of either
respirable rock wool (length >5 urn) or UICC chrysotile B asbestos,
•j
at 10 mg/m for 50 weeks. The animals were sacrificed 4 months
following the inhalation period. Rock wool and chrysotile
asbestos produced focal fibrosis. However, the effect was more
marked following inhalation of chrysotile than after exposure to
rock wool. Two unexposed rats had normal lungs.
On the other hand, lung fibrosis was not observed in the more
extensive study subsequently reported by Wagner et al. (1984).
Rats which were exposed to rock wool dust clouds (10 mg/m3) for 12
months developed interstitial cellular reactions to the dusts
without fibrosis (grade 3) at 12 and 24 months upon sacrifice or
following spontaneous death. In contrast, animals which were
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exposed to UICC chrysotile asbestos showed evidence of early
interstitial fibrosis (grade 4) similar to those seen in human
asbestosis. U-nexposed control animals had normal lungs (grade 1).
A lack of fibrogenic effects was also reported in the chronic
inhalation study by Smith et al. (1986). Hamsters and rats did
not develop lung fibrosis following a 2-year "nose-only" exposure
to mineral wool fibers (12 mg/m ). Similarly/ there was no
evidence of lung damage in rats exposed to Saint-Gobain rock wool
q
for 24 months at 5 mg/mj as reported by Le Bouffant et al. (1984).
II.2.3. In Vitro Studies
II.2.3.1. Genotoxicity
There is no information available on the genotoxicity of
mineral wools. Thus, the genotoxic potential of mineral wools
cannot be assessed at the present time.
II.2.3.2. Cytotoxicity
The results from two in vitro studies indicate that rock wool
and slag wool are cytotoxic to phagocytic and nonphagocytic
cells. In general, mineral wools appear to be less cytotoxic than
crocidolite asbestos.
Davies (1980) studied the cytotoxic effect of rock wool, slag
wool, and UICC crocidolite asbestos on mouse peritoneal
macrophages. The macrophages were exposed to 160 ug/mL of the
respirable fraction of the test fibers (fiber dimension
unspecified). Cytotoxicity was measured by determining the
release of lysozomal enzyme beta-glucuronidase (BGD) and
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cytoplasraic enzyme lactic dehydrogenase (LDH). Both slag wool and
rock wool caused a significant release of BCD (2.5- and 1.8-fold,
respectively) when added to the cell culture. Rock wool also
induced a 1.7-fold increase in the release of LDH, while UICC
crocidolite asbestos produced a 3.2- and 2.9-fold increase in LDH
and BCD levels, respectively. It was also reported that removal
of binder material from rock and slag wools had no effect on their
activity; however, no data were presented to support this
conclusion.
Brown et al. (1979b) studied the effects of respirable
fractions of rock and slag wools (size distribution unspecified)
on Chinese hamster (V79-4) lung cells and human alveolar
epithelial type II lung tumor cells (A549). Both slag and rock
wools, with or without resin (10-50 ug/mL) caused a dose-dependent
cytotoxic response toward V79-4 cells, but the uncoated samples
were slightly more cytotoxic than the equivalent resin coated
samples. Uncoated slag and rock wools, when added to the A549
cell cultures at 200 ug/mL, produced a significant increase in the
formation of giant cells, i.e., clusters of 200 cells or more.
The effect of UICC crocidolite asbestos on A549 cells, however,
was much greater than that of mineral wools.
Nadeau et al. (1983) reported in an abstract that mineral
wools were more or less unreactive toward rat pulmonary alveolar
macrophages and rat erythrocytes. However, no other information
was provided to evaluate these findings.
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II.2.4. Assessment of Health Effects
Data from available epidemiological and experimental studies
indicate that mineral wools are potentially carcinogenic and
possibly fibrogenic. Thus, there is a reasonable basis to
conclude that mineral wool fibers may present a health hazard to
exposed humans. However, based on available experimental data,
mineral wools appear to be much less biologically active than
crocidolite asbestos in a few cytotoxicity studies and less
carcinogenic than chrysotile asbestos fibers in a few limited
inhalation studies, and therefore would pose a health hazard of
less magnitude than that of asbestos.
II.2.4.1. Oncogenicity
By using the weight-of-evidence criteria for carcinogenicity,
mineral wool may be classified as a probable human carcinogen
(Category Bl) on the basis of limited evidence of carcinogenicity
from epidemiological studies and limited evidence from animal
studies.
The earlier epidemiological evidence relating mineral wool
exposure as reviewed by the National Research Council (NRC, 1984)
suggests an association with respiratory cancer. More recent data
from two large cohort mortality studies (Enterline et al., 1986;
1987; Simonato et al., 1985; 1986a; 1986b) now indicate that
mineral wool workers are at increased risk of developing
respiratory cancer. Overall, there are no large excesses of
deaths from respiratory cancer in any of available studies.
Evidence supporting an etiological relationship between respira-
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tory cancer and mineral wool exposure includes the consistently
elevated respiratory cancer risks seen in several mineral wool
plants from different countries, and the higher risks in workers
who have had 20 or more years elapse since first exposure. In
addition/ in a nested-case control study in which confounding by
smoking was controlled/ there was a weak but significant trend
observed between mineral wool exposure and respiratory cancer.
However/ consistent dose-response relationships have not been
observed among available studies. It should be pointed out that
the low levels of exposure in nearly all plants studied and the
potential exposure misclassification could have contributed to the
apparent lack of dose-response relationships. On the basis of
available findings, the weight-of-evidence for a causal
association between exposure to mineral wool and occurrence of
respiratory cancer is considered limited (Battelle/ 1988).
The results of key epidemiological studies on mineral wools
have been reviewed in detail in a report by Battelle (1988).
Briefly/ the studies by Enterline et al. examined deaths due to
respiratory cancer (malignant neoplasms of the bronchus/ trachea
and lung) among male mineral workers from 6 plants in the United
States. These workers were employed for at least 1 year from
1941-63. In the early study (Enterline et al., 1983), the cohort
was followed from 1941-1977. An update of the study included a 5
additional years of follow up from 1946 through 1982 (Enterline et
al./ 1986; 1987). The mean fiber exposure level in the mineral
wool plants was 0.3 fibers/mL. It was found that respiratory
cancer death was significantly elevated using both national and
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local mortality rates. Analyses of data by duration of exposue,
cumulative exposure and average intensity of exposure showed no
dose-related trend. However, a significant excess was observed
for 20 or more years from first exposure. The investigators also
conducted a small case-referent study which controlled for
cigarette smoking. It was found that there was a statistically
significant relationship between fiber exposure and respiratory
cancer for mineral wools even after smoking was considered
(Enterline et al., 1987).
Simonato et al. (1985; 1986a; 1986b) conducted an historical
cohort study on mineral wool workers from seven rock/slag wool
facilities in 4 European countries. The study was followed from
the time that production started (1937-1943) through 1982. The
study cohort consisted of men and women with at least one year
employment. There was a nonsignificant elevated increased risk of
lung cancer mortality rates among rock/slag wool workers compared
to national and regional rates. There was no relationship between
mortality from lung cancer and duration of exposure. However/
significant excess of lung cancer death was found after more than
20 years follow up among workers first exposed during the early
technological phase, i.e., before the introduction of oil binders
and presumably dustier conditions existed. Exposure such as
smoking or other occupational substances are considered unlikely
to provide a sufficient explanation for the excess of lung cancer
risk. However, possible effects of such exposure either alone or
in combination with fiber exposure cannot be excluded on the basis
of available information.
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The experimental evidence for the oncogenicity of mineral
wool is considered to be limited. In two long-term inhalation
studies in which rats were exposed to rock wool, no statistically
significant increase in lung tumor incidence was observed (Wagner
et al., 1984; Le Bouffant et al.f 1984). In a third study in
which rats and hamsters were exposed chronically to mineral wool
(fiber type not specified) containing fairly large diameter
fibers, no lung tumors were found (Smith et al., 1986). Although
available studies have not provided evidence of oncogenicity via
inhalation exposure, it should be noted that due to a number of
experimental limitations, none of the studies on mineral wool are
considered adequately studied. However, rock wool was shown to
produce a low incidence of pleural mesothelioma in rats via
intrapleural injection (Wagner et al., 1984) and both rock wool
and basalt wool induced abdominal tumors following intraperitoneal
injection (Pott et al., 1984, 19875). Slag wool, on the other
hand, produced no pleural tumors in rats by intrapleural
inoculation (Wagner et al., 1984) and only a statistically
nonsignificant increase in peritoneal tumors via intraperitoneal
injection (Pott et al., 1984). In contrast, at equal mass
concentrations or doses chrysotile asbestos induced high
incidences of lung tumors in rats via inhalation (Le Bouffant et
al., 1984; Wagner et al., 1984) and pleural mesothelioma by
intrapleural injection (Wagner et al., 1984).
There were no reports available that examined the
genotoxicity of mineral wools.
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II.2.4.2. Fibrogenicity
The epidemiological evidence of an association between
increased risks of nonmalignant respiratory diseases and mineral
wool exposure is considered inadequate. However, since there is
limited evidence from experimental studies indicating that mineral
wool may have some cytotoxic and fibrogenic effects, there remains
a concern for possible development of pulmonary fibrosis
associated with mineral wool exposure.
No increased mortality from nonmalignant respiratory diseases
was found for the European rock wool workers (Simonato et al.,
1985, 1986a, 1986b). However, in the U.S. study (Enterline et
al., 1986; 1987; Enterline, 1987), a statistically nonsignificant
excess of deaths from nonmalignant respiratory diseases was
observed among mineral wool workers based on local or national
rates, but the data did not establish a relationship with interval
from onset of employment nor was there a dose-related trend using
exposure indices including duration of employment, cumulative
level of exposure, and average intensity of exposure.
Furthermore, the results of a morbidity study (Weill et al., 1983)
showed no evidence for impaired lung functions or radiographic
lung abnormalities associated with exposure to mineral wools.
The experimental evidence for the fibrogenic potential is
limited. Three inhalation studies showed that mineral wools did
not produce pulmonary fibrosis in rats or hamsters following
chronic inhalation exposure (Wagner et al., 1984; Le Bouffant et
al., 1984; Smith et al., 1986), whereas chrysotile asbestos used
as the positive control induced extensive lung fibrosis in the
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exposed rats (Wagner et al., 1984). However, the results of a
limited inhalation study involving two rats which showed a
production of focal fibrosis following chronic exposure to rock
wool, provided suggestive evidence of a fibrogenic potential
(Johnson and Wagner, 1980). The fibrogenic concern is further
supported by the findings that respirable fractions of mineral
wools were cytotoxic to cells in culture (Brown et al., 1979b;
Davies, 1980). However, mineral wools were less cytotoxic than
crocidolite asbestos.
II.2.5. Recommendations
Since the effects of mineral wools have not been adequately
tested in animals, additional long-term inhalation studies on
mineral wools are recommended. Additional epidemiological studies
are also needed in order to fully assess the health hazard
potential of mineral wools in humans.
II.3. Ceramic Fibers
Ceramic aluminum silicate glasses are vitreous substances,
made by melting kaolin clay or a mixture of alumina and silica,
and then blowing the melt to form the fibers. Alumina and
zirconia fibers are monocrystalline substances, composed mainly of
aluminum oxide and zirconium oxide, respectively. Ceramic fibers
have high temperature resistance, and for that reason are often
referred to as refractory ceramic fibers. Ceramic products are
primarily used in industrial settings as high temperature
insulation. The desired range of fiber diameters for industrial
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applications is 2-3.5 urn/ but the diameters can range from less
than 1 urn to 12 jum. Thus, ceramic fibers are likely to generate
respirable airborne fibers (NRC, 1984).
II.3.1. Fiber Deposition/ Clearance, and Retention
Very limited information is available on the lung deposition,
clearance and retention of ceramic fibers. The results of
available studies indicate that only a small fraction of inhaled
ceramic aluminosilicate fibers was deposited in the rat lung.
Fibers deposited in the lung were predominantly short «10 jum) and
thin (<1 jum). Ceramic fibers were found to be cleared slowly from
the rat lung. Like other fibrous materials, ceramic fibers are
presumably cleared by macrophage uptake, transport to the
lymphatic system and possibly by slow dissolution and
fragmentation.
The pulmonary deposition of ceramic fibers has been studied
in the rat. Rowani and Hammad (1984) exposed 19 albino male rats
(nose-only) to a ceramic aluminium silicate dust cloud with an
average concentration of 709 fibers/mL for 5 consecutive days.
The airborne fibers had a median length of 3.7 pn and a median
diameter of 0.53 pm. The pulmonary deposition of fibers was
measured 5 days after the last day of exposure; this period was
allowed for clearance of approximately 95 percent of fibers
deposited in the ciliated airways. Fiber deposition of the entire
lung was 6.7 percent. Fibers that were deposited in all
lobes were predominantly thin (<1 urn) and short (<10 urn). Large
diameter and long fibers which constituted only a small fraction
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96
of total lung deposition, were found to be higher in the lobes
with relatively short path length from the trachea to the terminal
bronchioles (left lung and right apical lobe). However, the
overall fiber size distributions in the various lobes were not
significantly different.
In another study, Hammad (1984) studied the clearance of
ceramic fibers from the rat lung. In this study, a group of 49
male rats were exposed by "nose-only" to ceramic fiber (aluminum
silicate) dust clouds with a mean concentration of 300 fibers/mL
for five consecutive days. The mean diameter and length of
airborne fibers were 0.7 and 9.0 urn, respectively. Rats in groups
of seven were sacrificed 5, 30, 90, 180, and 270 days after the
last day of exposure. The clearance of ceramic fibers from lung
tissues was determined by the percentage of initial fiber
retention at day 5 after exposure. The results of this study
indicate that ceramic fibers are cleared slowly from the rat
lung. The fiber clearance during the 5-30 and 30-90 day periods
had the same half-lives of 85 days. The fiber clearance for the
90-180 and 180-270 day periods was much slower, with half-lives of
157 and 196 days, respectively. After 270 days following
exposure, about 25 percent of the ceramic fibers were still
present in the lung tissue.
There is very limited information on the clearance mechanisms
of ceramic fibers. In the rat, alumina fibers were detected in
the alveolar macrophages and in the mediastinal lymph nodes
following inhalation exposure. These results suggest that these
fibers may be transported from the lung via macrophages into the
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lymphatic system (Pigott et al., 1981). Furthermore, large
number of fibers were found in the sternal and mesenteric lymph
nodes following injection of alumina or zirconia fibers into the
abdominal cavity of rats. These findings also indicate that
these fibers can migrate from the peritoneum into the lymph nodes
and can be subsequently removed by the lymphatic system (Pigott
and Ishmael, 1981; Styles and Wilson, 1976).
Ceramic fibers may also be cleared by dissolution and
fragmentation. Hammad et al. (1985) reported that considerable
alterations in the elemental composition were found in ceramic
fibers (aluminum silicate) recovered from the rat lung after a
long period of 270 days following short-term exposure to the
fibers via inhalation. Furthermore, Pigott et al. (1981)
observed that alumina fibers retained in the rat lung showed a
high degree of fragmentation. These in vivo observations are
consistent with results obtained from an in vitro study which
showed considerable dissolution of ceramic fibers in
physiological saline solution. However, ceramic fibers are
relatively more resistant to solvent attack in comparison with
other man-made mineral fibers including fibrous glass and mineral
wools (Leineweber, 1984).
II.3.2. Effects on Experimental Animals
The potential oncogenic and fibrogenic effects of ceramic
fibers have been evaluated in several animal studies via
inhalation and injection routes of exposure. The experimental
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design and results of available studies are summarized in Table 3
(pages 234-239).
II.3.2.1. Oncogenicity
The oncogenicity of ceramic fibers in laboratory animals
appears to vary considerably for different fiber types. In one
inhalation study (Davis et al., 1984), an increased incidence of
lung tumors was observed in rats after chronic exposure to
ceramic aluminum silicate glass. In another inhalation study, no
lung tumors were produced in rats, but a single case of malignant
mesothelioma was found in hamsters (Smith et al., 1986). Alumi-
num silicate fibers also produced mesothelioma in rats and ham-
sters by intrapleural or intraperitoneal injection (Davis et al.,
1984; Smith et al., 1986; Wagner et al., 1973; Pott et al.,
1987). In contrast, refractory alumina oxide and zirconia oxide
fibers did not induce tumors in rats by either inhalation or
intrapleural implantation (Pigott et al., 1981; Stanton et al.,
1981).
II.3.2.1.1. Inhalation studies
Davis et al. (1984) studied the effects of long-term inhala-
tion exposure to ceramic aluminum silicate glass in rats. In
this study, a group of 48 SPF Wistar rats of the AF/HAN strain
were exposed to the test dust cloud at a mass concentration of
8.4 mg/m3 for 12 months. Approximately 95 fibers/mL were longer
than 5 urn and less than 3 urn in diameter. Animals were sacri-
ficed at 12, 18, and 36 months. The survival of treated and
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control groups was similar. Eight exposed animals developed
pulmonary neoplasms (1 adenoma, 3 carcinomas, 4 malignant histi-
ocytomas). It should be noted that the pattern of tumor develop-
ment appeared to be different than that for asbestos exposure
since malignant histiocytomas have not generally been associated
with asbestos exposure. One case of peritoneal mesothelioma was
also observed in the exposed group. No pulmonary tumors of any
types were found in the 40 unexposed control animals.
Smith et al. (1986) also studied the long-term health
effects of refractory ceramic fibers in rats and hamsters. Male
Syrian hamsters and female Osborne-Mendel rats were exposed
"nose-only" to dust cloud of refractory ceramic fibers at a mass
concentration of 12 mg/m3 (equivalent to 200 fibers/mL) for 24
months. Approximately 83 percent of the exposure aerosol was
greater than 10 ^um long and 86 percent less than 2 urn in diameter
(69 percent >10 pm long and <2 urn in diameter). The ceramic
fiber type was not specified in the report but it was presumed to
be aluminum silicate fibers (Kaolin) similar to the type that was
tested by Davis et al. (1984).
In contrast to the test results of the study by Davis et al.
(1984), no pulmonary neoplasms were observed in the exposed rats
(0/55) in this study. None of the exposed hamsters developed
primary lung tumors (0/70) but malignant mesothelioma was found
in one hamster (1/70). This finding was not statistically
significant although the possibility that the tumor was
associated with ceramic fiber exposure could not be ruled out,
since positive tumor responses have been observed in rats and
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hamsters by the injection routes of exposure. With the exception
of one bronchoalveolar tumor in a sham control hamster (1/58),
none of the other sham controls or unexposed control animals
developed pulmonary or pleural tumors. Thus, under the experi-
mental conditions of this study, there was no evidence of carci-
nogenicity in rats exposed to refractory ceramic fibers and there
was only suggestive evidence of carcinogenicity in exposed ham-
sters. It should be noted that in this study UICC crocidolite
asbestos only produced a low tumor incidence in rats (3/57; 1
mesothelioma, 2 bronchoalveolar tumors) and no tumor response in
hamsters. It was suggested that the lack of significant tumori-
genic effects of crocidolite asbestos observed in this study
could be due to the use of relatively short fibers (95-97 percent
<5 jjm long).
Pigott et al. (1981) investigated the effects of chronic
inhalation exposure to refractory alumina fibers in rats and
reported that they were not carcinogenic. Groups of 50 albino
Wistar derived rats (25 of each sex) were exposed by inhalation
to dust cloud of refractory alumina fibers (Saffil fibers),
either as manufactured or in a thermally aged form at a mean
respirable dust concentration of 2.18 and 2.45 mg/m , respec-
tively, for 86 weeks, after which the animals were maintained to
85 percent mortality. No pulmonary tumors were reported in
either animal groups exposed to manufactured Saffil fibers (0/42)
or aged Saffil fibers (0/38). It should be pointed out that a
major limitation of this study was the low levels of respirable
dust clouds. Furthermore, both types of Saffil fibers had fairly
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large diameters with median value of around 3 urn. The tumor
incidence found in positive control animals exposed to UICC
chrysotile A asbestos at 4.54 mg/m3 was comparable with those
reported in other studies. Pulmonary neoplasms were found in 9
of 38 animals (5 adenomas/ 3 squamous-cell carcinomas,
1 adenocarcinoma).
II.3.2.1.2. Intrapleural Injection/Implantation Studies
Wagner et al. (1973) found that the carcinogenic potency of
ceramic aluminum silicate fibers, when administered via the
intrapleural route, was considerably less than that of SFA chry-
sotile asbestos. Groups of 36 SPF Wistar rats (24 males and 12
females) were administered a single dose of 20 mg of ceramic or
chrysotile fibers via intrapleural inoculation. The diameters of
the tested ceramic fibers were between 0.5 and 1.0 um (lengths
unspecified). Pleural mesotheliomas were observed in 3 of 31
rats treated with ceramic fibers. The survival time to the first
mesothelioma was 743 days. In contrast, significantly higher
incidences of mesothelioma were detected in rats treated with SFA
chrysotile samples (21/32 with one sample and 23/36 in a second
sample) as early as 325 days after injection. A concurrent
vehicle control was not used.
Stanton et al. (1981) tested two ceramic glasses (presumably
alumina and zirconia ceramic fibers) for carcinogenicity after
intrapleural implantation (40 mg) into rats (50 female Osborne-
Mendel rats/group). These were large diameter fibers, with
microcrystalline aluminum oxide content >80 percent (glass 21),
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and with microcrystalline zirconia oxide content greater than 90
percent (glass 22). Both ceramic fiber types were considered
noncarcinogenic; 2/47 rats receiving glass 21 and 1/45 treated
with glass 22 developed pleural neoplasms, compared to 3/491
untreated controls and 17/615 negative controls receiving
noncarcinogenic pleural implants. As concluded by the
investigators, the carcinogenicity of fibrous dust appeared to be
related to fiber size; the lack of tumorigenic responses seen
with the two ceramic glasses samples were probably due to the
fact that they were composed of large diameter fibers.
II.3.2.1.3. Intraperitoneal Injection Studies
Davis et al. (1984) found that ceramic aluminum silicate
glass was carcinogenic in rats by the intraperitoneal route. In
this study, a group of 32 SPF Wistar rats of the AF/HAN strain
(sex unspecified) received a single intraperitoneal injection of
25 mg of ceramic fibers. The injected fibers which were col-
lected from the inhalation exposure system were predominantly
short and thin (90 percent <3 urn long and <0.3 jurn in diameter).
Three animals developed peritoneal tumors (1 mesothelioma, 2
fibrosarcomas) approximately 850 days after injection. Negative
control animals were not included in this study.
Smith et al. (1986) also reported that refractory ceramic
fibers were carcinogenic in male Syrian hamsters and female
Osborne-Mendel rats when injected as a single dose of 25 mg into
the abdominal cavity of the animals. Fibers used for injections
were collected airborne materials from the inhalation exposure
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chambers with mean diameter of 1.8 urn. The incidences of peri-
toneal mesbthelioma in hamsters injected with refractory ceramic
fibers were 13 percent (2/15) in one group and 24 percent (5/21)
in a second group. The incidence of abdominal tumors in treated
rats was 83 percent (19/23). On the other hand, 40 percent
(8/25) of the hamsters and 80 percent (20/25) of the rats
injected with crocidolite asbestos had abdominal mesotheliomas at
their deaths. Negative saline controls and unmanipulated control
animals had no tumors.
A recent study by Pott et al. (1987b) also showed that
ceramic aluminum silicate fibers are highly carcinogenic in rats
via the intraperitoneal route. Two ceramic fibrous samples were
tested in this study. Suspensions of either Ceramic "Fiberfrax"
dust (50 percent <8.3 jam in length; 50 percent <0.91 urn in
diameter) or ceramic "MAN" (50 percent <6.9 urn in length; 50
percent <1.1 urn in diameter) were injected into the abdominal
cavity of female Wistar rats at 5 weekly doses of 9 mg (a total
dose of 45 mg) and 15 mg, (a total dose of 75 mg), respectively.
High incidences of abdominal tumors were observed in both animal
groups treated with ceramic Fiberfrax (33/47) and ceramic MAN
(11/54). Under similar experimental conditions, UICC chrysotile
asbestos induced comparable incidences of peritoneal tumors in a
dose-related manner but at considerably lower doses, (11/36,
21/34, 30/36 at 6.05, 0.25, 1.0 mg, respectively). The saline
control group had one tumor (1/102).
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II.3.2.1.4. Intratracheal Instillation Studies
Smith et al. (1986) also tested the carcinogenicity of
refractory ceramic fibers in male Syrian hamsters and female
Osborne-Mendel rats via intratracheal instillation of 2 mg of the
test fiber (mean diameter of 1.8 jum) once a week for 5 weeks (a
total dose of 10 mg). All animals were maintained for the dura-
tion of their lives. Six of the 22 rats had bronchoalveolar
metaplasia but none of the rats (0/22) nor hamsters (0/25)
instilled intratracheally with refractory ceramic fibers developed
primary tumors. In contrast, 74 percent (20/27) of the hamsters
and 8 percent (2/25) of the rats instilled intratracheally with
crocidolite asbestos developed bronchoalveolar tumors.
II.3.2.2. Fibrogenicity
The experimental data on the fibrogenicity of ceramic
aluminum silicate glass are limited but suggestive of a
fibrogenic potential. This ceramic fiber type was shown in one
limited study to cause mild interstitial pulmonary fibrosis in
rats by inhalation exposure. In contrast/ available evidence
indicates that large diameter alumina and zirconia fibers do not
appear to cause fibrosis in rats via inhalation or by injection.
II.3.2.2.1. Inhalation Studies
In an inhalation study by Davis et al. (1984), as discussed
under "Oncogenicity", ceramic aluminum silicate glass was found
to induce low levels of interstitial pulmonary fibrosis in rats.
Large areas of alveolar proteinosis and small amounts of inter-
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stitial fibrosis were detected in the lungs of rats killed at the
end of the 12 months exposure period and 6 months later (at 18
months). The fibrotic lesions were~more severe and extensive
(0.2 - 14.5 percent of total lung area) in older rats killed at
32 months, while only two of the control animals had very small
areas of interstitial fibrosis (<0.01 percent of total lung
tissue area).
Smith et al. (1986)/ however, did not observe lung fibrosis
induction in rats or hamsters chronically inhaling (nose-only)
refractory ceramic fibers for 24 months. In contrast, the number
of hamsters and rats in the crocidolite asbestos exposure group
with fibrous pulmonary lesions was statistically higher than
either that of chamber or unmanipulated control group.
As discussed under "Oncogenicity", Pigott et al. (1981)
reported that inhalation of Saffil or "aged" Saffil fibers
(refractory alumina fibers) did not produce pulmonary fibrosis in
the rat. Pulmonary reactions to both forms of alumina fibers
were confined to minimal alveolar epithelialization. On the
other hand, moderate fibrosis was produced in most rats exposed
to UICC chrysotile asbestos. These results are not surprising
considering that the tested ceramic fibers were relatively thick
and contained low respirable fractions. Furthermore, the
exposure concentrations of alumina fibers were low and almost
twofold less than that of chrysotile.
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II.3.2.2.2. Intraperitoneal Injection Studies
In a study by Pigott and Ishmael (1981), groups of 24 SPF
Wistar rats (12 of each-sex) were each injected intraperitoneally
with 20 mg of refractory alumina fibers, either of Saffil type A
(15.5 x 2.75 jjm) or type B (17 x 3.7 yum), or UICC chrysotile
asbestos (7.7 x 1.1 urn). Rats which were treated with either
alumina fibers showed mild chronic inflammatory reactions and
deposition of small amounts of collagen in the abdominal tissues
after 3, 6, and 12 months following treatment. There was no
evidence of progressive peritoneal fibrosis in these animals. In
contrast, marked fibrosis was observed in rats given chrysotile
at 6 and 12 months, whereas animals which were injected with
vehicle control (saline) showed normal findings.
Styles and Wilson (1976) tested the fibrogenic potential of
Saffil alumina and Saffil zirconia fibers (median diameter of 3.6
and 2.5 urn, respectively) and found that under the experimental
conditions, these fibers were not fibrogenic in the rat. Groups
of 40 Wistar rats (20 of each sex) were each injected intraperi-
toneally with a single 20 mg dose of either test materials or
UICC chrysotile asbestos in saline (mean diameter of 1.1 urn).
Control animals received saline only. All animals were killed 6
months after injection. Considerable number of white nodules
containing fibroblasts and mononuclear cells and small amounts of
collagen were detected in the abdominal cavity of 36 rats which
were dosed with either Saffil zirconia or Saffil alumina
fibers. However, there was slightly more collagen in animals
treated with alumina fibers than in those dosed with zirconia
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fibers. In contrast/ animals which were treated with chrysotile
showed evidence of marked peritoneal fibrosis.
II.3.2.2.3. Intrathoracic Injection Studies
In a short-term study by Davis et al. (1970), guinea pigs
(number, sex and strain unspecified) were each administered by
intrathoracic injection with 25 mg of ceramic aluminum silicate
glass (mean diameter of 2 urn; 50 percent <75 jam in length).
After 6 weeks following treatment there was considerable
formation of ferrunginous bodies and large granulomas consisting
of macrophages, giant cells and fibroblasts, in treated
animals. These pulmonary reactions appeared similar to those
induced by asbestos reported in other previous studies.
Induction of lung fibrosis by ceramic fibers was not observed in
this study. This finding is certainly not unexpected since the
observation period of this study was quite short. In general,
fibrotic lesions are produced by most mineral fibers including
asbestos only after a minimum of 6 months following treatment.
II.3.3. In Vitro Studies
II.3.3.1. Genotoxicity
There is no information available with regard to the
genotoxicity of ceramic fibers.
II.3.3.2. Cytotoxicity
Available in vitro data indicate that fibrous ceramic
aluminum silicate is not cytotoxic to macrophage-like cells
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(P388D1) and lung fibroblasts (V79/4 cells) but is active toward
the human alveolar tumor cell line (A549). The results of a
^single study showed that alumina and zirconia ceramic fibers are
slightly toxic to macrophages.
A respirable sample of ceramic aluminum silicate fibers
collected from the inhalation chambers by an elutriation process
was not found to affect the viability of P388D1 cells following a
48 h treatment at 50 mg/mL of the dust (Gormley et al., 1985).
In contrast, almost all asbestos samples tested showed a wide
range of cytotoxicity in this assay.
In a subsequent study (Brown et al., 1986), the same group
of investigators tested the same ceramic fiber sample in two
nonphagocytic assays. In the assay using Chinese hamster lung
fibroblast (V79/4) cell line, respirable fibrous ceramic aluminum
silicate was found to be inactive; the ED^Q, the concentration of
dust causing a 50 percent reduction in the cloning efficiency of
V79/4 cells was greater than 100 mg dust/mL. On the other hand,
the same fiber sample displayed some activity in the assay using
human alveolar type II lung tumor cell line, as measured by the
induction of growth and giant cell formation at 25 and 50 mg
dust/mL. Ceramic aluminum silicate fibers ranked in the mid
range in this assay; it was slightly more active than some of the
amphibole asbestos tested but much less active than several
chrysotile samples.
Styles and Wilson (1976) reported that Saffil alumina and
Saffil zirconia induced low cytotoxicity in rat peritoneal
macrophages whereas UICC chrysotile asbestos was highly
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cytotoxic. It should be noted that both types of ceramic fibers
contained predominantly large fibers (2-6 urn in diameter) while
UICC chrysotile asbestos contained thin fibers (median diameter
of 1.1 urn). The experimental details were not provided in this
report.
II.3.4. Assessment of Health Effects
Available experimental studies indicate that ceramic
aluminum silicate glass is carcinogenic and weakly fibrogenic in
animals whereas large diameter refractory aluminum oxide and
zirconia oxide do not appear to be tumorigenic nor fibrogenic.
Therefore, it is concluded that ceramic aluminum silicate fibers
may present a health hazard to exposed humans. Because of the
variable results seen in available animal studies/ a comparison
of the carcinogenicty between ceramic aluminum silicate and
asbestos cannot yet be determined. Based on available
information/ it would appear that refactory zirconia oxide and
alumina oxide fibers would not pose significant health hazard in
humans. The discrepant results concerning the pathogenicity of
various types of ceramic fibers may be a function of variation in
fiber size distribution.
There are no epidemiological studies available on the health
effects from exposure to ceramic fibers. Available experimental
studies indicate that ceramic aluminum silicate glass is
carcinogenic in laboratory animals. The results of a study by
Davis et al. (1984) showed that chronic inhalation exposure to
ceramic aluminum silicate glass produced an increased incidence
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of lung tumors in rats. In addition, injection of these fibers
into the pleural cavity or abdomen of rats or hamsters have
resulted in the production of mesothelioma of the pleura or
peritoneum, respectively (Wagner et al., 1973; Davis et al.f
1984; Smith et al., 1986; Pott et al., 1987b). Thus, based on
sufficient evidence of carcinogenicity of ceramic aluminum
silicate glass in multiple experiments with different routes of
administration, but in the absence of human data, this ceramic
fiber type may be categorized as a probable human carcinogen
(Category B2).
Experimental evidence of fibrogenicity of ceramic aluminum
silicate fibers is limited. However, the results of one chronic
inhalation study by Davis et al. (1984) which showed low levels
of lung fibrosis in the exposed rats suggest a low fibrogenic
potential for ceramic aluminum silicate fibers. This finding is
supported by in vitro test data showing that ceramic aluminum
silicate is active toward the human cell line A549 (Brown et al.,
1986).
With regard to other ceramic fiber types, refractory alumina
oxide and zirconia fibers did not cause tumor or fibrosis in rats
via inhalation exposure (Pigott et al., 1981) or intracavitary
injection (Stanton et al., 1981; Pigott and Ishamael, 1981;
Styles and Wilson, 1976). Similarly, the cytotoxicity of these
fibers is low (Styles and Wilson, 1976). On the basis of
available information, refractory alumina oxide and refractory,
zirconia fibers are not classifiable as to human carcinogenicity
due to inadequate evidence of carcinogenicity in animals and no
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Ill
human data (Category D). A lack of pathogenic effects of these
fibers may be because test fibers were largely nonrespirable.
II.3.5. Recommendations
It is recommended that epidemiological studies of exposed
workers be initiated. No additional animal tests are recommended
at this time. A large-scale animal study sponsored by industry
is being conducted at a private laboratory. The study is
designed to subject rats and hamsters to common types of ceramic
fibers for long periods by inhalation and injection methods.
Ill. Naturally-Occurring Mineral Fibers
III.l. Erionite
Erionite is a naturally-occurring mineral of the fibrous
zeolite class. Erionite and other natural zeolites are crystal-
line minerals that contain alkaline metal and alkaline earth
elements in a hydrated aluminium silicate structure. In the
United States, fibrous erionite is found in several well-defined
deposits in Arizopa, Nevada, Oregon, and Utah, where it occurs as
thin, pure beds with sedimentary tuft sequences or as outcrops in
the desert valleys of the intermountain region (Rom et al.,
1983). Fibrous erionite has also been identified in the volcanic
tuft located in the central region of Turkey (Spurny, 1983b).
Erionite can occur as either single needles or in
clusters. Erionite fibers are, on the average, shorter than
asbestos fibers with a maximum length of approximately 50 urn.
Fiber diameter generally ranges from 0.25 urn-to 1.5 )im (Wright et
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al., 1983) although fibers with diameters of 0.01 to 5 urn have
been reported (Suzuki, 1982). Airborne erionite fibers are
generally respirable.
Erionite is rarely rained and has very limited commercial
uses, mainly as a molecular sieve in ion-exchange processes.
Erionite was once, but is no longer, used as a catalyst in
petroleum cracking. Instead, synthetic nonfibrous zeolites are
used extensively for these types of applications (ICF, 1986).
III.1.1. Fiber Deposition, Clearance and Retention
Little is known about the lung deposition of erionite
fibers. A number of epidemiological studies have reported the
detection of erionite in the pleural and parenchymal tissues in
some Turkish villagers exposed to low ambient erionite
concentrations (Baris et al., 1978; Rohl et al., 1982; Sebastien
et al., 1981). Most of the erionite fibers found in the lung
tissues were uncoated, with a mean diameter of 0.3 urn and maximum
length of approximately 9 urn. Some ferrunginous bodies
containing erionite fibers (zeolite bodies) which were similar to
typical asbestos bodies were also detected (Sebastien et al.,
1981). Experimentally, it was reported in an abstract that
erionite fibers were well distributed in the rat lung soon after
intratracheal instillation, followed by the development of
macrophage and giant cell granulomatous reactions, and the
production of ferrunginous bodies after 1 week (Moatamed et al.,
1981). These findings taken together indicate that airborne
erionite fibers can penetrate the lung and pleura and appear to
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elicit early lung tissue responses similar to those induced by
asbestos. There is no information available on the clearance of
erionite.
III.1.2. Effects on Experimental Animals
Erionite has been evaluated in several studies for potential
carcinogenic and fibrogenic effects in animals by several routes
of exposure. Table 4 (pages 240-242) summarizes the experimental
protocols and results of available studies on erionite.
III.1.2.1. Oncogenicity
Erionite from different geographical sources has been shown
to be extremely carcinogenic in rats by inhalation/ and in both
rats and mice following injection. Erionite appears to be more
potent in inducing mesothelioma than either crocidolite or
chrysotile asbestos.
III.1.2.1.1. Inhalation Studies
Wagner et al. (1985) tested samples of natural erionite and
synthetic nonfibrous erionite for carcinogenicity in Fischer 344
rats via inhalation. Groups of 20 male and 20 female rats were
exposed to mean respirable dust concentrations of 10 mg/m for
7 hours/day/ 5 days/week for 12 months. The tested dusts
included Oregon erionite (86 percent <0.4 urn in diameter;
92 percent <10 um long) at 354 fibers/mL, synthetic nonfibrous
Zeolite (>0.5 jjm) of similar chemical composition to erionite at
1040 particles/mL, and UICC crocidolite asbestos (95 percent <0.4
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114
urn in diameter; 86 percent <10 urn long) at 1,630 fibers/mL.
Twelve rats in each group were sacrificed at 12 months to study
dust accumulation. The remaining animals were observed until
death. An extremely high incidence of pleural mesothelioma was
induced in rats (27/28) exposed to Oregon erionite. The average
induction time was 580 days. One mesothelioma (1/28) and one
adenocarcinoma (1/28) occurred in the rats exposed to the
synthetic nonfibrous zeolite. It is interesting to note that no
mesotheliomas were produced in any of the positive control rats
exposed to crocidolite, and only one squamous carcinoma of the
lung was observed (1/28). Unexposed control rats had no tumors
(0/28).
Johnson et al. (1984b) examined the histopathology and
ultrastructure of seven pleural tumors that had been induced in
rats by inhalation to Oregon erionite. The tumors were
epithelial, fibrosarcomatous, or mixed epithelial/sarcomatous in
form. However, the majority of tumors were of mixed features
with either the fibrous or epithelial component being more
prominent. In general, erionite-induced mesothelioma appeared to
be morphologically similar to human mesothelioma and to
experimentally induced mesothelioma in rats by inoculation of
asbestos into the pleural or peritoneal cavity.
III.1.2.1.2. Intrapleural Injection Studies
Three intrapleural studies also document the oncogenicity of
/
erionite in rats. In the study by Wagner et al. (1985), groups
of 40 Fischer 344 rats (20 of each sex) were each inoculated
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intrapleurally with 20 mg of Oregon erionite (75 percent
<6 jLim long; 92 percent <0.2 /jm in diameter), Turkish (Karain)
rock fiber (91 percent <0.2 ^im in diameter; 86 percent
<6 jum long), synthetic nonfibrous zeolite or chrysotile
asbestos. The test dusts were suspended in saline. A negative
control group received only saline. All of the rats treated with
Oregon erionite developed mesothelioma (40/40 rats). Karain rock
fiber induced 38 mesotheliomas (38/40) while only two
mesothelioma (2/40) occurred with the nonfibrous zeolite, which
had similar chemical composition as erionite. Chrysotile
asbestos produced a total of 19 mesotheliomas and one
mesothelioma was found in the negative control group. The mean
survival times in the Oregon erionite group (390 days) and Karain
rock fiber (435 days) were considerably shorter than that in the
chrysotile group (678 days).
Maltoni et al. (1982a) also reported induction of pleural
mesothelioma in rats by erionite by intrapleural injection.
Groups of 40 Sprague-Dawley rats (20 of each sex) received a
25 mg dose of either erionite or crocidolite asbestos in water.
The dimensions of tested fibers were not specified. Among the 40
rats treated with erionite, 10 animals died within 53 weeks, 9
with pleural mesotheliomas. No pleural tumors were found in the
crocidolite group after 53 weeks. None of the vehicle controls
developed tumors. Followup data on the study have not been
published.
Preliminary results from intrapleural studies by Palekar and
Coffin (1986) showed that erionite induced pleural mesothelioma
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in a dose-related manner in Fischer 344 rats (25 animals/dose
level). A dose response (0.5-32 mg) was obtained for two samples
of erionite tested, erionite I (mean length of 2.2 urn; mean width
of 0.25 urn) and erionite II (mean length of 1.4 urn; mean diameter
of 0.17 urn). The tumor response of both erionite samples was
much greater than that of chrysotile and crocidolite when the
data were expressed as the mass or the number of fibers.
III.1.2.1.3. Intraperitoneal Injection Studies
The evidence of the carcinogenicity of erionite following
intraperitoneal injection is demonstrated by three studies in
mice. Suzuki (1982) studied the carcinogenicity of erionite
after a single intraperitoneal injection in male Swiss albino
mice. In the first experiment, a group of 12 mice were each
treated with 10 mg of erionite (20 percent <1 urn and 95 percent
<8 urn in length; 19 percent <0.1 urn and 94 percent <1 urn in
diameter). Seven mice served as untreated controls. Six treated
mice were sacrificed at 2-3 months after injection to determine
early pathological lesions. One treated mouse died from
intestinal obstruction due to severe peritoneal fibrosis. Among
the remaining five animals which died between 8 and 15 months
after treatment, two had malignant peritoneal tumors. No tumors
were found in untreated control animals. In a second experiment,
groups of five mice received either 10 or 30 mg of erionite. A
positive control group that also consisted of 5 animals were
treated with 10 mg of chrysotile asbestos. A negative control
group of 6 animals remained untreated. Four of five mice in the
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low dose erionite group and 2/5 in the chrysotile group developed
malignant peritoneal tumors. All mice in the high dose erionite
group died with intestinal obstructions due to adhesion of tfhe
intestine. Untreated control mice had no tumors.
Suzuki and Kohyama (1984) subsequently reported a high
incidence of peritoneal tumors, mainly malignant mesotheliomas,
in male Balb/c mice treated with a single intraperitoneal dose of
erionite. Two samples of erionite were tested. A group of 50
mice were administered 10 mg of erionite I (90 percent <8 jjm and
6 percent >9.5 jjm in length; 85 percent <1 pm and 8.7 percent
>1.4 um in diameter) while groups of 20, 50 and 75 mice received
a single dose of 0.5, 2, or 10 mg of erionite II (95 percent
<8 um and 4 percent >9.5 um in length; 82 percent <0.5 um and 100
percent <1 um in diameter), respectively. In the animal group
treated with erionite I, 21 of 42 (50 percent) had malignant
peritoneal tumors. Of the three groups treated with erionite II,
6 of 18 (33 percent), 24 of 44 (55 percent) and
3 of 8 (37.5 percent) had malignant tumors, respectively.
Animals treated with 2 mg of chrysotile had no tumors (0/22)
while 6 of 32 (18 percent) animals treated with 20 mg of
chrysotile developed malignant peritoneal tumors. The erionite-
induced mesotheliomas were similar to those induced by chrysotile
asbestos in gross appearance and histology. Saline controls and
untreated controls had no tumors (0/118 and 0/37, respectively).
Ozesmi et al. (1985) also tested dust from the village of
Karain (Turkey) containing both fibrous and nonfibrous erionite
for induction of tumors in Swiss albino mice using the
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intraperitoneal route. Groups of Swiss albino mice (37-98/group)
received a 5, 10, 15, 20, 30 or 40 mg dose of Karain dust in
saline and were followed until death (up to 32 Inonths).
Mesothelioma developed in 41/321 of the dosed mice, malignant
lymphomas in 31 and both lymphomas and mesothelioma in 11
animals, within 9 to 32 months after injection of dust. The
incidence of tumors did not appear to be dose-related. Three
mesotheliomas and one lymphoma occurred in 55 saline controls.
III.1.2.2. Fibrogenicity
There is no information available on the ability of erionite
to induce fibrotic disease in animals by inhalation. However,
erionite has been shown to cause fibrogenic effects in animals by
the injection method.
III.1.2.2.1. Intrapleural Injection Studies
Erionite has been reported to produce a fibrogenic reaction
when administered by intrapleural injection. In the study by
Maltoni et al. (1982a), Sprague-Dawley rats were injected
intrapleurally with 25 mg of erionite (dimension unspecified).
Among the 40 treated animals, 10 died within 53 weeks, 9 with
pleural mesotheliomas. Upon gross examination, the visceral,
parietal, and diaphragmatic pleura appeared thickened and
whitish. In addition, several hard, whitish or yellowish nodules
from 2-10 mm in diameter were found scattered at different sites
of the serosal surfaces. Deposits of erionite surrounded by
granulomatous reaction were seen within the neoplastic tissue.
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III.1.2.2.2. Intraperitoneal Injection Studies
Erionite has been shown to possess fibrogenic properties
similar to asbestos following intraperitoneal injection. Severe
fibrotic lesions were observed in the peritoneum of Swiss albino
mice treated with single intraperitoneal injections of either 10
or 30 mg of erionite (Suzuki, 1982). Similar findings were
observed in a followup study by Suzuki and Kohyama (1984), which
reported that two different samples of erionite produced marked
peritoneal fibrosis in mice by intraperitoneal injection, with a
severity similar to that produced by chrysotile asbestos. The
experimental details of these two studies are presented in the
oncogenicity section.
III.1.3. In Vitro Studies
III.1.3.1. Genotoxicity
Available data indicate that erionite is genotoxic. The
major genotoxic effects seen with erionite include DNA damage and
repair, induction of cell transformation, clastogenicity and
aneuploidy. Like asbestos fibers, erionite does not appear to
cause detectable gene mutations.
Fibrous erionite (Oregon origin) was tested in CSHIOT1/^ cells
for transformation and unscheduled DNA synthesis (UDS) and in a
human lung cell line (A549) for UDS (Poole et al., 1983b). The
count median length was 1.7 ^am and diameter was 0.2 urn. Erionite
induced the appearance of transformed type III foci at
concentrations >10 ug/mL (up to 30 ug/mL). These same
investigators report that while erionite is not more cytotoxic
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than asbestos, in another article they demonstrate that
crocidolite and amosite asbestos do not transform 101^ cells
(Poole et al., 1983a).
Erionite was examined by two methods for UDS, the
autoradiographic method with 10T^ cells and the liquid
scintillation method with lOT^/2and A549 cells (Poole et al.,
1983b). With the autoradiographic method, erionite induced a
significant increase in UDS over controls at 100, 150 and
200 ug/mL. However, at higher concentrations (250 and 500
pg/mL), no increases were seen, suggesting a cytopathic effect
not measured in this study as no apparent cytotoxicity was
noted. UDS was induced at all concentrations (50, 100, and 200
jug/mL) in both cell types with the scintillation method. The
authors favored this method for use with fibers for two
reasons: 1) fibers can obscure the nucleus in the
autoradiographic method and therefore not allow a truly random
selection of nuclei for counting; and 2) the scintillation method
allows a larger number of cells to be assayed. This may reduce
variability seen in autoradiographic UDS as cells do not receive
a homogenous exposure to similar fiber lengths and diameters.
Overall, erionite produced a significant level of UDS in two
different cultured cell types indicating induced DNA damage and
repair.
Palekar et al. (1987) reported that erionite fibers were at
least as effective as, if not more than, asbestos in producing
aneuploidy in exposed V79-4 cells. A comparable or lesser
clastogenic effect than asbestos was also noted. A significant
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reduction in diploid cells and a parallel increase over controls
in aneuploid and polyploid cells were observed in cultures
treated with erionite at all concentration levels ranging from
10-100 ug/mL, whereas in UICC crocidolite and UICC chrysotile-
treated cultures, significant increases in aneuploidy were
observed at all exposure levels except the low concentration, 10
ug/mL. When the effects were compared on the basis of number of
fibers per dose, fewer erionite fibers than those of crocidolite
and chrysotile were required to produce similar aneuploidy.
Erionite treatment at 100 ug/mL also produced chromatid
aberrations but the clastogenic effect of erionite was comparable
to that of crocidolite, but weaker than that of chrysotile
asbestos.
Further evidence that erionite fibers are clastogens and are
capable of altering the ploidy of cultured cells is provided by
Kelsey et al. (1986). These investigators studied the
cytogenetic effects of Oregon erionite and crocidolite asbestos
in Chinese hamster ovary (CHO) fibroblasts. Treatment with
erionite at concentrations of 5-50 ug/mL induced a slight but
significant elevation in sister chromatid exchanges (SCE) in
cultures of synchronous CHO cells, while crocidolite at the same
concentrations failed to significantly increase the frequency of
SCE. However, both fiber types induced a low level of
chromosomal aberrations in CHO cells. In addition, an increase
in the relative percent of tetraploid CHO cells after treatment
with either erionite or crocidolite was observed.
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Kelsey et al. (1986) also tested the mutagenicity of
erionite and crocidolite fibers in a human lymphoblastoid cell
line (TK6) at either the HGPRT (hypoxanthine guanine
phosphoribosyl transferase) or thymidine kinase loci. Both
erionite and crocidolite were negative in these assays.
III.1.3.2. Cytotoxicity
Experimental evidence has demonstrated that erionite is
hemolytic and cytotoxic to various cell types. In an abstract,
Nadeau et al. (1983) reported that erionite caused hemolysis to
rat erythrocytes. The hemolytic activity of erionite was lower
than that of chrysotile but higher than that of amphibole
asbestos (crocidolite/ amosite, anthophyllite). It was also
reported that erionite was cytotoxic to rat pulmonary alveolar
macrophages in a dose-related manner. However, the experimental
details including fiber dimensions and dose levels were not
reported.
Palekar et al. (1985) studied the cytotoxicity of erionite
and asbestos fibers in Chinese hamster ovary (CHO) and Chinese
hamster lung V79-4 cell cultures at concentrations of 10-100
jug/mL during a 6-day exposure. In CHO cells, erionite and
chrysotile asbestos were cytotoxic at 20 ug/mL and crocidolite
asbestos was cytotoxic at 40 ug/mL. Similarly, V79 cytotoxicity
was induced by erionite and chrysotile at 40 jLig/mL while
crocidolite was cytotoxic at 100 ^ag/mL.
Subsequent findings by Palekar and Coffin (1987) confirmed
their previous results that erionite was cytotoxic to V79
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cells. Erionite samples containing long erionite fibers (median
length of 1.6 ^im) exhibited similar cytotoxicity to UICC
chrysotile asbestos by weight while shorter erionite fibers
(median length of 0.99 urn) were less cytotoxic than chrysotile.
However, both erionite samples were more cytotoxic to V79-4 cells
than chrysotile when the cytotoxicity was expressed as a function
of number of fibers. Both erionite samples were more cytotoxic
to V79-4 cells than UICC crocidolite asbestos by either methods
of data analysis.
III.1.4. Assessment of Health Effects
Erionite has been shown to be a potent carcinogen in animals
and is potentially fibrogenic. Thus, there is sufficient
evidence to conclude that erionite potentially poses a
significant health hazard to the exposed humans. Based on
experimental data, erionite appears to be at least as hazardous
as asbestos.
III.1.4.1. Oncogenicity
Erionite may be categorized as a probable human carcinogen
(Category Bl) based on limited evidence of carcinogenicity from
studies in humans and sufficient evidence from experimental
studies.
Available epidemiological studies have shown that
populations from several locations in South Central Turkey have a
large excess incidence of malignant mesothelioma (Baris et al.,
1978, 1981; Artvinli and Baris, 1979, 1982; Rohl et al., 1982).
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There is limited evidence to suggest that erionite may be the
major etiological factor. This is based on the findings that
erionite was the major fibrous material present in the
surroundings and in the air of these affected areas, and in the
pleural and parenchymal tissues of individuals with pleural
disease(s). However, since asbestos and other zeolite fibers
were also found in environmental and tissues samples taken in one
of the affected villages (Rohl et al., 1982; Baris et al., 1978;
Boman et al., 1982), it is possible that asbestos and other
fibrous agents could also be involved in the etiology of this
malignant mesothelioma (Battelle, 1988).
Experimental studies have confirmed that erionite from
Turkey and the United States is extremely carcinogenic in animals
by several routes of exposure. In an inhalation study, a 96
percent incidence of malignant mesothelioma of the pleura was
produced in rats following 1-year exposure to Oregon erionite
(Wagner et al., 1985). Intrapleural inoculation of Oregon or
Karain erionite also produced very high incidences of pleural
mesothelioma (53-100 percent) in rats (Maltoni et al., 1982a;
Wagner et al., 1985; Palekar and Coffin, 1986). In these
studies, erionite caused more mesothelioma than either
crocidolite or chrysotile asbestos by inhalation or intrapleural
inoculation. Furthermore, the latency periods for mesothelioma
induced by erionite were much shorter than those induced by
asbestos. In mice, intraperitoneal injection of erionite
resulted in the production of malignant mesotheliomas of the
peritoneum at high yields, comparable to those induced by
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asbestos (Suzuki, 1982; Suzuki and Kohyama, 1984; Ozesmi et al.,
1985).
Positive findings from a few genotoxicity studies further
support a carcinogenic concern. Erionite has been shown to cause
DNA damage and repair (Poole et al., 1983b), cytogenetic changes
including aneuploidy, chromosomal aberrations, sister chromatid
exchanges (Kelsey et al., 1986; Palekar et al., 1987) and
morphologic transformation of cells in culture (Poole et al.,
1983b).
III.1.4.2. Fibrogenicity
In view of limited evidence from epidemiological studies and
limited evidence from experimental studies, erionite is
considered to be potentially fibrogenic.
Epidemiological evidence collected over the past several
years from a limited geographical area in South Central Turkey
where erionite was present indicated significant incidences of
nonmalignant pleural diseases as well as malignant pleural
mesothelioma. These nonmalignant chest diseases included
calcified plaques, chronic pleural fibrosis, and pleural
thickening (Baris et al., 1978, 1981; Artvinli and Baris, 1979,
1982). The evidence for erionite as the major etiological factor
is considered to be limited because possible exposure to asbestos
and other fibrous material cannot be excluded (Battelle, 1988).
No information is available on the ability of erionite to
induce fibrotic diseases in animals by inhalation. However,
erionite has been shown to cause fibrogenic effects in animals by
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injection. Whitish or yellowish nodules and plaques associated
with the visceral, parietal and diaphragmatic pleura, and pleural
thickening were observed in rats given an intrapleural dose of
erionite (Maltoni et al., 1982a). In mice, intraperitoneal
injection of erionite produced severe peritoneal fibrosis which
was intimately associated with the observed peritoneal tumors
(Suzuki, 1982; Suzuki and Kohyama, 1984). The in vivo results
are further supported by positive findings from in vitro studies
showing that erionite is hemolytic and highly cytotoxic (Nadeau
et al., 1983; Palekar et al., 1985; Palekar and Coffin, 1987).
III.1.5. Recommendations
Since erionite has been adequately tested in animals, no
v,
further animal testings are thought necessary. However,
additional epidemiological studies should be conducted, if
practical, to further evaluate the association between erionite
environmental exposure and development of malignant and
nonmalignant respiratory diseases.
III.2. Wollastonite
Wollastonite is an acicular or fibrous natural monocalcium
silicate mineral. The largest deposits of Wollastonite are
located in the United States, Mexico and Finland. Wollastonite
is widely used in ceramics, and as a substitute for asbestos in
insulation, wallboard, and brake linings. Wollastonite exhibits
similar heat resistance properties as asbestos but has lower
tensile strength. Wollastonite fibers range from 1 to 10 urn in
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diameter with an average diameter of 3.5 urn. The median fiber
size of airborne wollastonite is 0.22 urn in diameter and 2.5 urn
in length. Approximately" 92-97 percent of total airborne fibers
during mining and milling operations are considered respirable
(ICF, 1986).
III.2.1. Fiber Deposition, Clearance and Retention
No information is available on the deposition, clearance,
and retention of wollastonite.
III.2.2. Effects on Experimental Animals
Very few studies have been conducted to examine the
oncogenic and fibrogenic effects of wollastonite in animals.
Table 5 (page 243) summarizes the experimental protocols and test
findings of these studies.
III.2.2.1. Oncogenicity
There is no information available regarding the oncogenicity
of wollastonite in animals via inhalation exposure. However,
wollastonite has been shown to be weakly tumorigenic by intra-
pleural implantation and nontumorigenic by the intraperitoneal
route in rats.
III.2.2.1.1. Inhalation Studies
Recently, a chronic inhalation study in male Fischer 344
rats was conducted by the National Toxicology Program (NTP) to
test for the oncogenicity of wollastonite. The experiment has
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been completed but full results are not yet available. However,
the authors reported that inhalation exposure to wollastonite
produced no adverse effects on the animal survival (Adkins and
McConnell, 1985) and no tumorigenic response (McConnell, 1988).
III.2.2.1.2. Intrapleural Implantation Studies
Stanton et al. (1981) showed that wollastonite was weakly
carcinogenic in rats following intrapleural implantation with a
40 mg dose of particles. Four samples of wollastonite from a
Canadian mine were tested. These fibers were relatively large
and only one of these samples was completely fibrous. The
incidences of pleural sarcoma observed at 2 years following
treatment were: grade 1, 5/20; grade 2, 2/25; grade 3, 3/21;
grade 4, 0/24. The tumor incidence in groups receiving grades 1
and 3 was statistically significantly higher (p <0.05, Fisher
exact test) than that of control animals implanted with
noncarcinogenic materials (17/615).
III.2.2.1.3. Intraperitoneal Injection Studies
Pott et al. (1987b) recently reported that wollastonite was
not tumorigenic in rats following intraperitoneal injection. In
this study, female Wistar rats were injected intraperitoneally
with 5 weekly 20 mg doses of wollastonite in saline. The test
dust was obtained from India, with 50 percent of the fibers
having diameters less than 1.1 pm and lengths less than 5.2 ^am.
The animals were observed for full life span. No peritoneal
tumors (0/54) were found.
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III.2.2.2. Fibrogenicity
There are no data available for evaluating the fibrogenic
potential of wollastonite in laboratory animals. As mentioned
above, a 2-year inhalation study of wollastonite has been
completed to study the development of chronic respiratory disease
in rats (Adkins and McConnell/ 1985). According to a preliminary
report, no evidence of pulmonary fibrosis was found in this study
(McConnell, 1988) but data are not yet available for a full
evaluation of the study. In the long-term intraperitoneal
injection study by Pott et al. (1987b), wollastonite from India
was found to cause a low degree of adhesions of abdominal organs
as observed macroscopically in rats. However, it was not clear
whether there were any developments of fibrosis in treated
rats. Histological data are not yet available for a complete
evaluation of this preliminary finding.
III.2.3. In Vitro Studies
III.2.3.1. Genotoxicity
There are no genotoxicity data available on wollastonite.
III.2.3.2. Cytotoxicity
Several in vitro studies have been conducted to compare the
biological effects of wollastonite with asbestos with regard to
the hemolytic activity to erythrocytes and cytotoxicity to
macrophages. A number of investigators have shown that wollasto-
nite was weakly to moderately hemolytic to human and rat
erythrocytes while others have reported that wollastonite was
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more or less unreactive to rat erythrocytes. Similarly,
wollastonite was found to induce varying degrees of cytotoxicity
in rat or rabbit alveolar macrophages, ranging from noncytotoxic
to moderately cytotoxic. However, wollastonite was far less
hemolytic and cytotoxic than asbestos. The conflicting in vitro
results with wollastonite appeared to be related to different
experimental conditions and the nature of the materials tested,
especially particle morphology and size distribution.
III.2.3.2.1. Erythrocytes
Skaug and Gylseth (1983) tested the hemolytic activity of
two samples of naturally-occurring wollastonite and three samples
of synthetic nonfibrous calcium silicate in human red blood
cells. Both wollastonite samples {one fibrous and the other
mostly nonfibrous) were found to be weakly hemolytic while
synthetic compounds were far more reactive. The particle size
distribution of the tested fibers and dusts were not specified.
Hefner and Gehring (1975) studied the hemolytic activity of
two wollastonite samples using rat erythrocytes. One sample was
fibrous with a mean fiber length of 200 urn and the other sample
was nonfibrous with a mean particle size of 4 pm. Both wollasto-
nite samples were hemolytic but the large nonrespirable 200 pm
wollastonite (fiber diameter not specified) had a much slower
rate of hemolysis.
Similar results were obtained in a study by Potts et al.
(1978) who studied the ability of two wollastonite samples to
induce hemolysis in rat red blood cells. Large particle
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wollastonite (200 pm) induced weak hemolytic activity whereas
small particle wollastonite (6.73 jam) was moderately hemolytic.
In contrast, chrysotile asbestos was found to be strongly
hemolytic in this in vitro system.
In an abstract, Vallyathan et al. (1984) also reported that
wollastonite is moderately hemolytic. Wollastonite fibers tested
had lengths less than 10 jam. The hemolytic effects of chrysotile
«21 jjm), amosite (41 jam), and crocidolite «10 jum) were more
pronounced than that of wollastonite. The source of red blood
cells used in this assay was not specified.
In constrast, Nadeau et al. (1983) reported in an abstract
that wollastonite was more or less unreactive in hemolytic assays
using rat erythrocytes, whereas crocidolite asbestos was highly
hemolytic followed by anthophyllite, amosite, and crocidolite.
No other experimental details were provided in this report for
evaluation.
III.2.3.2.2. Macrophages
Pailes et al. (1984) found that wollastonite had no
cytotoxic activity in rabbit alveolar macrophages whereas
chrysotile was strongly cytotoxic. Exposure of alveolar
macrophages to wollastonite (fiber size distribution not
specified) as much as 250 ug/mL did not induce lysosomal enzyme
release (beta-glucuronidase, beta-galactosidase, acid
phosphatase, and N[-acetylglucosaminidase) or alter membrane
integrity as measured by trypan blue exclusion and the release of
the cytosolic enzyme, lactate dehydrogenase (LDH). On the other
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hand, treatment of alveolar macrophages with as little as 25
|jg/mL of chrysotile asbestos caused the release of lysosomal
enzymes and decreased membrane integrity.
Similarly, Nadeau et al. (1983) reported in an abstract that
wollastonite (fiber size distribution unspecified) was unreactive
to rat pulmonary alveolar macrophages whereas dose-response
relationships for cytotoxicity were observed with all asbestos
samples. Cytotoxicity was evaluated by the release of
cytoplasmic LDH and lysosomal alpha-galactosidase enzymes.
Warheit et al. (1984) also found that exposure of rat
pulmonary macrophages to wollastonite did not affect cell
viability or morphology but wollastonite exposure did result in a
diminished phagocytic capacity of the cells. On the other hand,
crocidolite asbestos affected both macrophage morphology and
phagocytic activity without affecting macrophage viability.
Wollastonite fibers were large and long compared to crocidolite
fibers which were short and thin.
Vallyathan et al. (1984) reported in an abstract that the
cytotoxicity of wollastonite appeared to be dependent on fiber
length. Wollastonite containing fibers less than 10 urn long was
moderately cytotoxic in macrophage enzyme release studies (LDH,
beta-glucuronidase, beta-H-acetylglucosaminidase) whereas shorter
fibers (<5 urn) were only mildly cytotoxic. The cytotoxic effects
of long-fibered chrysotile (<21 pm), crocodolite (<10 /am) and
amosite «41 ^jm) in alveolar macrophages were more pronounced
than those of both wollastonite samples.
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III.2.4. Assessment of Health Effects
Overall, there is some evidence to support a possible health
hazard from exposure to wollastonite. However, results from
available experimental studies indicate that wollastonite is much
less biologically active than asbestos, suggesting that
wollastonite may pose a lesser health hazard than asbestos.
III.2.4.1. Oncogenicity
Wollastonite may be classified as a possible human
carcinogen (Category C) on the basis of limited experimental
evidence of carcinogenicity and inadequate human data.
None of available epidemiological studies were designed to
assess the risk of lung cancer or mesothelioma associated with
wollastonite exposure. One case of retroperitoneal malignant
mesothelioma has been reported in Finland in one worker who had
been exposed to wollastonite for twenty years (Huusk.onnen et al.,
1983). However/ no cause and effect relationship can be drawn
based on a single case report. Preliminary information on an
inhalation study of wallastonite in rats indicates the lack of
tumorigenic response (McConnell, 1988). However, wollastonite
has been shown in one study to produce weak tumorigenic response
in rats via intrapleural implantation (Stanton et al., 1981) but
does not induce tumors in rats via the intraperitoneal route
(Pott et al., 1987b).
III.2.4.2. Fibrogenicity
Available data are inadequate to assess the fibrogenic
potential of wollastonite. There were no reports available that
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examined the fibrogenicity of wollastonite in animals. Limited
epidemiological studies conducted to date on quarry workers in
the U.S. (Shasby et al., 1977, 1979; Hanke et al., 1984) and
Finland (Huuskonen et al. 1983, 1984) indicate a possible
association between wollastonite exposure and some nonmalignant
diseases such as impaired ventilatory capacity, mild fibrosis of
the lung, pleural thickening, and chronic bronchitis. However,
these studies do not provide conclusive evidence of nonmalignant
respiratory disease following exposure since the sample size was
small and exposure was relatively short (Battelle, 1988).
Nevertheless, available epidemiological findings do raise a
concern for potential fibrogenicity of wollastonite, particularly
in light of positive results from in vitro cytotoxicity assays,
which are thought to be indicative of fibrogenic activity.
Wollastonite has been shown to induce varying degrees of
hemolytic and cytotoxic activity although it is far less active
than asbestos (Skaug and Gylseth, 1983; Hefner and Gehring, 1975;
Potts et al., 1978; Vallyathan et al., 1984). These in vitro
findings suggest that wollastonite may be considerably less
fibrogenic than asbestos.
III.2.5. Recommendations
In order to fully assess the health effect of wollastonite,
additional epidemiological studies are needed. In addition, the
results of the NTP inhalation bioassay should be evaluated.
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III.3. Attapulgite
Attapulgite is a naturally-occurring sorptive and gelling
clay made up of fibrous aluminum and magnesium silicate.
Although attapulgite is mined commercially in several countries,
the United States is a leading producer of attapulgite, the
majority of which is mined in the areas of Quincy, FL and
Attapulgus, GA. Attapulgite is used in a wide variety of
applications as an absorbent and thickening agent, and to a
lesser extent as a substitute for asbestos in friction products
and other materials (NRC, 1984).
Attapulgite morphology can vary greatly depending on where
the material is mined. The attapulgite in commercial use in the
United States consists of short fibers (0.1-2.5 jam) with mean
diameter of 0.07 jum (0.02 - 0.1 pm) (Zumwalde, 1977). French
attapulgite fibers are also short «1.2 jum) (Bignon et al., 1980)
while attapulgite samples from Spain can either be long or short
(Wagner, et al., 1987). All attapulgite fiber types are of
respirable size.
III.3.1. Fiber Deposition, Translocation, and Clearance
There is very little information available on the
deposition, translocation, and clearance of attapulgite. The
results of two limited case studies suggest that attapulgite
fibers are capable of penetrating into the alveolar spaces
following inhalation, and that after ingestion, attapulgite can
be transported to the kidney and excreted in the urine. There is
also some experimental evidence suggesting that short attapulgite
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fibers are readily cleared from the lung while longer attapulgite
fibers appear to be retained longer in the lung.
Bignon et al. (1980) reported the findings of two case
studies. In the first case, a high concentration of attapulgite
fibers (42,000 fibers/mL) were found in lung washing fluid
recovered by bronchoalveolar lavage from a 41-year-old patient
with lung fibrosis, who had been exposed to attapulgite for 3
years during mining and processing of attapulgite. Mean length
and diameter of the attapulgite fibers in lung washing fluids
were 1.5 urn and 0.11 urn, respectively. In a second case, a very
high concentration of attapulgite was found in the urine of a 60-
year-old woman treated orally for 6 months with an attapulgite-
containing drug at a fairly large dosage (6-9 g/day).
Wagner et al. (1987) examined the recovered dusts from the
lungs of rats following 12 months exposure to two attapulgite
dusts at 10 mg/m . Examination of both macerated lung tissue and
ashed lung sections from animals exposed to short-fibered
attapulgite (all fibers <2 pm long) from Lebrija (Spain) showed a
complete absence of short fibers. On the other hand, in animals
exposed to long-fibered attapulgite (palygorskite from Leicester,
U.K.), fibers up to 25 jam in length and with diameters less than
0.2 jum were found in the macerated lung and ashed sections.
III.3.2. Effects on Experimental Animals
There is considerable information available on the effects
of attapulgite in laboratory animals. The experimental protocols
and results of available studies are summarized in Table 6 (pages
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244-245). Attapulgite fibers from various geographical locations
appear to have different pathogenic potential which may be
related to differences in fiber size distribution.
III.3.2.1. Oncogenicity
A number of studies have been conducted to evaluate the
oncogenic potential of attapulgite by different routes of
administration. In a long-term inhalation study, attapulgite
from Spain (Lebrija) which consisted of short fibers (all <2 ^im)
did not induce tumors in rats. Several injection studies also
showed that short attapulgite fibers (<2 pm) from the United
States (U.S.), Spain (Lebrija), and France did not cause
mesothelioma in rats by the intrapleural or intraperitoneal
routes of administration. Tumors were also not observed in mice
following lifetime feeding with short-fibered attapulgite. In
contrast, inhalation exposure to attapulgite (also known as
palygorskite) from the United Kingdom (Leicester) which contained
a considerable number of long-fibers (>6 urn) resulted in low
incidences of lung tumors and mesothelioma in rats. In addition,
long-fibered attapulgite samples from the U.K. (Leicester), Spain
(Torrejon) and an unknown source produced high incidences of
mesothelioma in rats via intrapleural or intraperitoneal
injection.
III.3.2.1.1 Inhalation Studies
In a recent report, Wagner et al. (1987) provided the
completed findings of a series of inhalation experiments on
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attapulgite and asbestos. Two samples of attapulgite were
tested/ Lebrija attapulgite from Southern Spain, and palygorskite
(synonymous to attapulgite) from the U.K. (Leicester). All
fibers in the Lebrija attapulgite sample were less than 2 yum in
length whereas the palygorskite sample from Leicester also
consisted of long, thin fibers (18 percent >6 urn in length and
•_•» ^
<2.0 urn in diameter). In this study, groups of 40 SPF Fischer
rats (20 of each sex) were exposed to a dust cloud of either
attapulgite sample or UICC crocidolite asbestos at 10 mg/rrr for 6
hours a day, five days a week for up to 12 months. Four animals
(2 of each sex) were sacrificed after 3, 6 and 12 months of
exposure to assess the severity of pulmonary fibrosis. The
remaining 28 animals were allowed to live out their normal life
span.
No significant tumor response was found in the animal group
exposed to short-fibered attapulgite from Lebrija. Among the 40
exposed animals, there was only one peritoneal mesothelioma and 3
bronchoalveolar hyperplasia (BAH). It should be noted that BAH
is considered to be a reaction to an irritant and not a tumor.
In contrast, there was some evidence of carcinogenicity for the
long-fiber palygorskite sample from Leicester in rats. Three
mesotheliomas (two pleural and one peritoneal), one malignant
alveolar tumor (MAT, accepted as an early carcinoma), two benign
alveolar tumors (BAT) and 8 BAH (one BAH with MAT) were found
among the 40 animals exposed to the palygorskite sample. A
comparison of the carcinogenic potency between this attapulgite
sample and asbestos could not be made based on the results of
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this study alone because of the lack of significant tumorigenic
response in the positive control group exposed to UICC
crocidolite asbestos (1/40 adenocarcinoma/ 2/40 BAH, 1/40 BAH
with adenocarcinoma). No tumors were found in the unexposed
controls (0/40) and the negative controls exposed to nonfibrous
kaolin dust (0/40).
III.3.2.1.2. Intrapleural Injection Studies
Stanton et al. (1981) tested two samples of American
attapulgite (Attapulgus, GA) for carcinogenicity in female
Osborne-Mendel rats using an intrapleural implantation method.
Both samples were composed of small-diameter short fibers. No
excess of tumors was found in animals treated with 40 mg of
either sample (2/29 for both samples) compared to untreated
animals (3/491) and negative controls treated with noncarcino-
genic implants (17/615).
Renier et al. (1987) also found no tumorigenic response with
short, thin attapulgite from France in an oncogenic intrapleural
bioassay. In this study, 20 mg of attapulgite fibers suspended
in saline were injected into the pleural cavity of Sprague-Dawley
rats (sex and number of animals not specified). The test fibers
had a mean diameter of 0.06 urn and a mean length of 0.77 jum.
After 24 months of treatment, no pleural tumors were found.
Positive control animals treated with UICC chrysotile or Canadian
chrysotile asbestos had a 19 percent and 48 percent mesothelioma
incidence, respectively. Vehicle control animals injected with
saline had no tumors.
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Wagner et al. (1982, 1987) conducted a series of injection
studies with three samples of attapulgite and showed that two
attapulgite samples which consisted of variable proportions of
long fibers were highly carcinogenic by the intrapleural route
whereas no excess tumors were produced by short attapulgite
fibers. Forty SPF Fischer 344 rats, 20 of each sex, were
inoculated with a single injection of one of the following dusts
suspended in saline (dose unspecified) including Lebrija (Spain)
attapulgite (<2 jam long), Torrejon (Spain) attapulgite (0.54
percent _>L 6 jum long and <0.5 jam in diameter), palygorskite (18
percent _>. 6 jam in length and <0.2 jam in diameter) from Leicester
(U.K.), UICC crocidolite asbestos and chrysotile B asbestos.
High incidences of pleural mesothelioma were found among animals
treated with the palygorskite sample (30/32) and Torrejon
attapulgite (14/40). These long-fibered attapulgite samples
appeared to have comparable carcinogenic potency as UICC
crocidolite and chrysotile B asbestos which induced 34/40 and
19/40 cases of mesothelioma, respectively. In the group treated
with short-fibered attapulgite from Lebrija there were two
mesotheliomas (2/40), one pleural and one peritoneal. The saline
control^group had one pleural mesothelioma (1/40).
III.3.2.1.3. Intraperitoneal Injection Studies
Pott et al. (1974) found that attapulgite from an unknown
source which contained a large proportion of long fibers (30
percent >5 um long) was tumorigenic when injected
intraperitoneally in rats. In this study, a group of 40 Wistar
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rats received three doses of 25 mg of attapulgite dusts at weekly
intervals. A tumor incidence of 65 percent (peritoneal
mesothelioma) was found for the attapulgite group, and the first
tumor appeared at day 275. In animals treated with chrysotile
asbestos/ 30-67 percent had mesotheliomas. No peritoneal tumors
were reported for saline control animals.
More recently Pott et al. (1985) reported that short, thin
attapulgite fibers from France, Spain, and the United States
induced no excess tumors in rats after intraperitoneal
injection. However, no experimental details and results were
available for evaluation.
III.3.2.1.4. Oral Studies
Brune and Deutsch-Wenzel (1983) reported that attapulgite
was not tumorigenic in mice following lifespan feeding. In this
study, groups of 60 male and 60 female NMRI mice were fed for 25
months with 1 percent or 3 percent of attapulgite (mean length
<1 pm) admixed in a pelleted diet. Untreated animals served as
controls. The animals were sacrificed at the end of the
treatment period. Mortality rates were not influenced by the
treatment of attapulgite. No toxic effects nor increase of
tumors in any organs were observed.
III.3.2.2. Fibrogenicity
The results of a recent inhalation study indicates that
long-fibered palygorskite (attapulgite) is fibrogenic in rats
following long-term exposure. Short-fibered attapulgite, on the
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other hand/ appears to be nonfibrogenic under the same
experimental conditions.
In the study by Wagner et al. (1987), 40 SPF Fischer 344
rats (20 of each sex) were exposed to either palygorskite fibrous
dust from Leicester (U.K.) which contained a considerable
proportion of long, thin fibers (18 percent _>6 urn in length and
<0.2 urn in diameter) or short attapulgite fibers (all <2 urn long)
from Lebrija (Spain) at 10 mg/m^ for 6 hours daily, five days a
week for up to 12 months. A group of 40 positive control animals
were exposed to UICC crocidolite asbestos at similar experimental
conditions. Four animals (two of each sex) were sacrificed after
3, 6, 12 and 24 months to assess the severity of pulmonary
fibrosis. The remaining animals were allowed to live out their
normal life span and the oncogenic response was then evaluated
upon sacrifice.
The mean fibrosis gradings evaluated from four animals
killed at 3, 6 and 12 months after exposure to the long-fibered
palygorskite were 3.0, 3.1, 4.0, respectively. Since a grading
of 4.0 represents first signs of fibrosis, these results indicate
that this palygorskite sample should be considered to be
potentially fibrogenic in humans. It should be noted that a
conclusive evaluation of the extent and progression of pulmonary
fibrosis induced by this attapulgite sample in comparison to
asbestos could not yet be made because (1) the gradings of
pulmonary responses were not done for the palygorskite sample at
24 months; and (2) the low fibrogenic response in crocidolite
asbestos exposed animals. In the majority of inhalation studies
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with asbestos, extensive lung fibrosis with gradings greater than
4.0 is generally seen in exposed animals. In this study,
however, the mean fibrosis gradings at 3, 6, 12 and 24 months for
crocidolite exposed animals were only 4.1, 3.3, 3.1 and 3.8,
respectively.
In contrast, the pulmonary response to short-fibered
attapulgite from Spain was confined to the presence of dust-laden
macrophages (grade 2) and early interstitial reaction (grade
3). The mean gradings of tissue response in the lungs of rats
exposed to Lebrija attapulgite at 3, 6, 12, and 24 months were
reported to be 3.1, 2.6, 3.2, and 3.2 respectively. Unexposed
animals had normal lungs throughout the study period (gradings of
1.25-1.75).
III.3.3. In Vitro Studies
III.3.3.1. Genotoxicity
Little information is available for the genotoxicity of
attapulgite. In one study, short attapulgite fibers were not
found to induce unscheduled DNA synthesis (UDS) in primary
cultures of rat hepatocytes.
Denizeau et al. (1985) tested the ability of short, thin
attapulgite to induce DNA damage in primary rat hepatocyte
cultures by measuring its capacity to induce UDS. Ninety-six
percent of the attapulgite fiber had a diameter between 0.01 and
0.1 pm with an average length of 0.8 urn. The liquid
scintillation UDS method was used. Attapulgite produced no UDS
effect over controls at 10 ug/mL. The fiber did not induce
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cytotoxicity, as assessed by the release of lactate
dehydrogenase.
III.3.3.2. Cytotoxicity
In general/ attapulgite from various sources was hemolytic
to red blood cells and cytotoxic to macrophages; these in vitro
effects were somewhat comparable to those induced by asbestos.
Long-fibered attapulgite was found to induce cytotoxicity in
nonmacrophage cells, whereas short attapulgite fibers were
relatively inert. However, short attapulgite fibers were found
to cause a nonsignificant increase in squamous metaplasia of
hamster tracheal organ cultures.
III.3.3.2.1. Erythrocytes
A number of studies have shown that attapulgite was
hemolytic to red blood cells from humans and animals. Jaurand
and Bignon (1979) reported that palygorskite (attapulgite) was
highly hemolytic. However, the information on the source and
fiber size distribution of the attapulgite tested was not
provided. Bignon et al. (1980) subsequently reported that long-
fibered Spanish attapulgite (unspecified fiber length
distribution) was more hemolytic to human red blood cells than
UICC chrysotile asbestos. Three drugs containing short French
attapulgite (mean length of 0.8 pn) were weakly hemolytic to
human red blood cells. Other investigators found that
attapulgite was as hemolytic as chrysotile asbestos to rat
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erythrocytes (Nadeau et al., 1983) and sheep erythrocytes (Harvey
et al., 1984).
III.3.3.2.2. Phagocytic cells
In an abstract, Nadeau et al. (1983) reported that
attapulgite induced cytotoxicity in a dose-related manner to rat
pulmonary alveolar macrophages similar to that induced by
asbestos fibers. Cytotoxicity was evaluated by the release of
cytoplasmic enzyme lactate dehydrogenase (LDH) and lysosomal
enzyme alpha-galactosidase. Fiber dimensions and dose levels
were not reported.
Similar findings were reported by Bignon et al. (1980) who
studied the cytotoxicity of two drugs containing short
attapulgite fibers (mean length of 0.6 urn) in rabbit alveolar
macrophages. Both drugs produced a 39-45 percent of LDH and 24-
31 percent of beta-galactosidase release at 300 or 200 ug/mL.
Chamberlain et al. (1982) found that both short-fibered
attapulgite and long-fibered attapulgite were cytotoxic to rat
peritoneal macrophages. Treatment of cell culture with short-
fibered attapulgite at 150 ug/mL caused a 58 percent of LDH
release/ while after treatment with long-fibered attapulgite
there was a 29 percent of LDH release. Specific fiber dimensions
were not provided in this study.
By using P388D1 macrophage-like cells/ Harvey et al. (1984)
found that attapulgite treatment at a relatively high
concentration (1 mg/mL) for 4 hours caused considerable
cytoxicity. However, attapulgite was slightly less cytotoxic
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than UICC chrysotile A or Canadian chrysotile asbestos but was
markedly more cytotoxic than crocidolite asbestos. This study
did not provide the fiber size distribution of the attapulgite
sample.
In contrast, Lipkin (1985) found no evidence of cytotoxicity
of short-fibered French or American attapulgite in P388D1
macrophage-like cells. The maximum fiber length of both
attapulgite samples was 1.2 and 1.6 urn, respectively. UICC
amosite asbestos showed a dose-dependent cytotoxic effect on the
macrophage system while both attapulgite samples had no effect at
10, 50 or 100 ug/mL, as measured by reduction in cell number over
a 72-hour period.
III.3.3.2.3. Nonphagocytic cells
Chamberlain et al. (1982) reported that short fibered
attapulgite at concentrations greater than 100 pg/mL induced no
effect on colony formation of Chinese hamsters of V79-4 cells nor
on the ability of human type II alveolar tumor (A549) cells to
form giant cells, i.e., colonies containing more than 200
cells. Long-fibered attapulgite, on the other hand, reduced
cloning efficiency of V79-4 cells by 50 percent at 52 ug/mL.
UICC crocidolite asbestos was more potent than either attapulgite
samples in inducing cytotoxic effects in both cell types.
Using 1-407 human embryo cells, Reiss et al. (1980) found
that short-fibered attapulgite from the United States
(Attapulgus/ GA) caused only minimal inhibition of colony
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formation. At equal doses, amosite asbestos was considerably
more cytotoxic than attapulgite.
III.3.3.2.3.4. Tracheal Organ Cultures
Woodworth et al. (1983) examined the ability of short
attapulgite fibers to induce metaplastic changes in trachea
mucosa of the Syrian hamster. Ninty four percent of attapulgite
fibers were shorter than 1 pm long. The investigators reported
that attapulgite treated explants underwent proliferative and
metaplastic alterations. However, metaplastic changes were not
statistically significant at 1, 4 or 16 mg/mL of attapulgite. In
contrast, both long and short fibers of chrysotile asbestos
induced a significant increase in metaplasia at low concen-
trations (1.0, 4.0 mg/mL).
III.3.4. Assessment of Health Effects
The toxicological properties of attapulgite may depend on
fiber length. There is inadequate evidence of carcinogenicity
and fibrogenicity of short attapulgite fibers «2 urn long) in
humans and animals. Based on an apparent lack of significant
effects from long-term animal studies via inhalation and by the
intrapleural or intraperitoneal route, it would appear that
short-fibered attapulgite from commercial deposits in the United
States is less hazardous than asbestos. In contrast, there is
sufficient experimental evidence of carcinogenicity and
fibrogenicity for attapulgite samples containing long fibers (>5
urn in length). Available data bases, however, are not sufficient
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to provide a definitive assessment with regard to the comparative
pathogenicity between long-fibered attapulgite and asbestos.
Fortunately, one of -the samples (palygorskite from the U.K.) is
of no commercial interest and the other sample is a Spanish
product (Torrejon attapulgite) and is being used in the
preparation of drilling mud in the exploration of oil deposits in
the North Sea and Persian Gulf.
III.3.4.1. Oncogenicity
With regard to human carcinogenicity, short-fibered
attapulgite «2 pm in length) from the United States, France, and
Spain, is not classifiable (Category D) because of inadequate
evidence from epidemiological studies and insufficient evidence
from animal studies. On the other hand, attapulgite containing
long fibers (>5 urn in length) from Spain, and the U.K. may be
categorized as a probable human carcinogen (Category B2) based on
sufficient evidence of carcinogenicity in animal studies in the
absence of human data.
The results of a single available cohort study (Waxweiler et
al.f 1985) provide inadequate evidence of human carcinogenicity
of short-fibered attapulgite. This study examined the mortality
trends among workers at one Georgia attapulgite operation. Lung
cancer mortality in the total cohort was slightly elevated but a
statistically significant excess of mortality due to lung cancer
was observed among white workers while a deficit of risk was
found in the nonwhite subgroup. The excess risk among white
employees could have been related to exposure to attapulgite
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because there was an increased risk among employees with presumed
highest exposure levels, and an increased risk among those with
longer duration of employment and time since first exposure.
However, the relatively small size of the cohort and several
other limitations such as the inability to confirm the
completeness of the cohort, limit the conclusions that can be
made about this study (Battelle, 1988).
Experimental studies indicate that short-fibered attapulgite
fibers (<2 jam long) did not induce tumors in rats following
chronic inhalation (Wagner et al., 1987) or by the intrapleural
route (Stanton et al., 1981; Renier et al., 1987; Wagner et al.,
1987), or intraperitoneal route (Pott et al., 1985). Short-
fibered attapulgite also did not induce tumors in mice following
lifetime feeding (Brune and Deutsch-Wenzel, 1983).
The negative results from a genotoxicity study provide
supporting evidence for a lack of tumorigenic effect of short-
fibered attapulgite. These fibers did not induce DNA damage in
primary rat hepatocytes as reflected by a lack of an induction of
unscheduled DNA synthesis (Denizeau et al., 1985).
In contrast, materials containing long attapulgite (>5 jum in
length) have tested positive in long-term animal studies via
various routes of exposure. Palygorskite from the U.K.
(Leicester) was shown to induce low incidences of lung tumors and
mesothelioma in rats following chronic inhalation and very high
incidences of pleural mesothelioma by intrapleural injection
(Wagner et al., 1987). Other attapulgite samples containing long
fibers such as the one from a small deposit in Torrejon, Spain,
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and an unknown source were also found to induce pleural
mesothelioma by intrapleural injection (Wagner et al., 1987), and
abdominal tumors by intraperitoneal injection (Pott et al.,
1974), respectively. In all of these studies, the tumorigenic
responses of long-fibered attapulgite were comparable to those
induced by chrysotile and crocidolite asbestos.
III.3.4.2. Fibrogenicity
In view of inadequate evidence of fibrogenicity in humans
and laboratory animals, there is an insufficient basis to support
a health hazard concern for potential fibrogenic effects of
short-fibered attapulgite. However, positive findings of several
in vitro cytotoxicity studies on these fibers suggest a
possibility of a fibrogenic hazard. As for the long-fibered
attapulgite, there is sufficient evidence to conclude that
prolonged exposure to the dust may cause the development of lung
fibrosis in humans.
The results of three available studies reporting the effects
of attapulgite exposure provide inadequate evidence of fibro-
genicity of short-fibered attapulgite in humans (Battelle,
1988). One case of lung fibrosis in a worker who had been
exposed to attapulgite for two years was reported, indicating a
possible link between occupational exposure and fibrosis (Sors et
al., 1979). However, the results of a morbidity study showed no
consistent relationship between attapulgite exposure and
respiratory symptoms (Gamble et al., 1985). Furthermore,
Waxweiler et al. (1985) reported a deficit mortality risk for
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nonmalignant respiratory diseases among attapulgite workers in a
Georgia plant.
Experimentally, there are no studies available that examined
the ability of short-fibered attapulgite in commercial use in the
United States in inducing lung fibrosis in animals via
inhalation. However, the results of a long-term inhalation study
showed that attapulgite from Lebrija (Spain) which consisted of
only short fibers did not induce fibrosis in rats (Wagner et al.
1987). Furthermore, none of the available injection studies with
short-fibered attapulgite have reported the production of
fibrotic lesions in rats via the intrapleural route (Stanton et
al., 1981; Renier et al., 1987; Wagner et al., 1987) or
intraperitoneal route (Pott et al., 1985). These results taken
together suggest that short-fibered attapulgite is not likely to
induce severe fibrogenic effects in humans. On the other hand,
the fact that these fibers are hemolytic (Bignon et al., 1980;
Jaurand and Bignon, 1979; Harvey et al., 1984; Nadeau et al.,
1983) and cytotoxic to macrophages (Chamberlain et al., 1982;
Bignon et al., 1980; Nadeau et al., 1983) suggests that a
fibrogenic potential may exist.
With regard to long-fibered attapulgite, the results from a
recent inhalation study (Wagner, et al., 1987) showed that the
palygorskite from the U.K. (Leicester) that contained a
considerable number of long particles caused lung fibrosis in
rats following 12 months of exposure, comparable to that induced
by crocidolite asbestos. These findings indicate that long-
fibered attapulgite is potentially fibrogenic.
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III.3.5. Recommendations
A long-term inhalation study in animals should be conducted
to fully assess the chronic toxicity and oncogenic effects of
attapulgite from a United States commercial deposit. Additional
epidemiological studies should also be performed to further
determine the health effects of attapulgite in humans.
IV. Synthetic Fibers
IV.1. Aramid Fibers
These synthetic fibers are formed from aromatic
polyamides. Aramid fibers are characterized by high tensile
strength, and chemical and flame resistance. They are used as
replacements for asbestos in a number of applications such as
insulation, flame barriers, thermal protective clothing and
friction products.
There are two major types of aramid fibers produced in the
United States, Kevlar® and Nomex®. Para-aramid Kevlar® is
4
produced as continuous filament yarn, staple fiber (38-100 mm),
short fiber (6-12 mm) or pulp (2-4 mm), with a nominal diameter
of 12 urn. Thus, Kevlar® fibers generally tend to fall outside of
the respirable range. However, Kevlar® pulp, which is frequently
used to replace asbestos, has fine curled or tangled fibrils «1
urn in diameter) attached to the surface of the core fiber, and
these fibrils may break off and potentially become airborne upon
abrasion during the manufacturing processes. Nomex® is
manufactured as continuous filament, staple fiber and short
fiber, with a nominal diameter of 12 urn. However, unlike
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Kevlar®, Noraex® does not have the tendency to form fine fibrils
and therefore is not respirable (ICF, 1986).
IV.1.1. Fiber Deposition and Clearance
Available information on the pulmonary deposition and
clearance of aramid fibers is very limited. Results of
intratracheal instillation and inhalation studies indicate that
the deposition of aramid fibers is dependent on fiber dimension
and is dose-related. Short aramid fibers are mostly phagocytized
by alveolar macrophages which are cleared from the lung via
transport to the lymph nodes.
Reinhart (1980) reported that following intratracheal
instillation (25 mg of Kevlar® polymer dust), large para-aramid
fibers (100-150 urn in diameter) remained in the terminal
bronchioles whereas small particulates (approximately 5 urn)
penetrated deep in the aleveolar region of the rat lung.
Following inhalation exposure to 0.1-18 mg/m3 of ultrafine
Kevlar® fibrils for 2 weeks, fiber deposition and macrophage
response in the rat lung were found to be dose-related (Lee et
al., 1983). At high concentrations, fiber dust and fiber-laden
macrophages (dust cells) accumulated in the respiratory
bronchioles and alveolar region immediately following exposure.
Some dust cells containing short fibers «2 urn long) were found
in the peribronchial lymphoid tissue or tracheobronchial lymph
nodes by 6 months post exposure. These results suggest that
short Kevlar® fibers are cleared via phagocytosis followed by
transport to the lymphatic system.
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IV.1.2. Effects on Experimental Animals
The pathogenic potential of aramid fibers has been
investigated in a single long-term inhalation study an-d a number
of short-term inhalation studies as well as injection studies.
The experimental protocols and results of available studies are
summarized in Table 7 (pages 246-247).
IV.1.2.1. Oncogenicity
It has been shown that chronic inhalation to a dust cloud of
ultrafine para-aramid (Kevlar®) fibrils resulted in increased
lung tumor formation in rats. In addition, intraperitoneal
injection of para-aramid (Kevlar®) pulp or fibers caused low
incidences of peritoneal tumors in rats.
IV.1.2.1.1. Inhalation Studies
The results of a long-term inhalation study which
investigated the oncogenic potential of ultrafine Kevlar® fibrils
in rats are summarized in an unpublished report by Reinhardt
(1986). In this study, 5 groups of male and female Sprague-
Dawley rats (100 of each sex per group) were exposed to dust
clouds containing ultrafine Kevlar® fibrils (90 percent <1.5 urn
in width; more than 75 percent less than 20 pm long) at targeted
concentrations of 2.5, 25, 100, or 400 fibrils/mL. The means of
weekly Kevlar® fibril counts during the exposure period were 2.4,
25.4, 112.2 or 435.5 fibrils/mL, respectively (approximately
equivalent to 0.08, 0.32, 0.63 or 2.23 mg/m3, respectively).
Rats were exposed for two years (6 hours/day, 5 days/week) with
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the exception of males and females in the highest dose group
which were exposed for only one year and then maintained for one
year without exposure. This was due to high mortality and
apparent lung toxicity found following one year of exposure at
the highest dose. By the end of first year of exposure, 34 males
and 15 females in the high dose group were found dead or were
sacrificed in extremis.
Lung tumors identified as cystic keratinizing squamous cell
carcinomas were observed in rats exposed to the two highest dose
levels; in the group exposed to 400 fibrils/mL, 1 of 36 males
(3%) and 6/56 females (11%) developed lung tumors. At 100
fibrils/mL, none of the exposed males had tumors (0/68) but lung
tumors were found in 4 of 69 females (6%). Squamous cell
metaplasias were also observed in 6 females exposed to 100
fibrils/mL. Control animals had no lung tumors.
IV.1.2.1.2. Intraperitoneal Injection Studies
Two intraperitoneal injection studies have also been
conducted to determine the oncogenic potential of Kevlar® in
laboratory animals. Pott et al. (1987b) reported a low tumor
yield with Kevlar® in rats. Female Wistar rats (8 weeks of age)
were administered 4 weekly intraperitoneal doses of 5 mg of
Kevlar® (50% <3.9 urn and 90% <11 jum long; 50% <0.47^um and 90%
<0.75 urn in diameter) suspended in saline. Surviving animals
were sacrificed at 130 weeks after first treatment. Three of 53
animals were found to have peritoneal tumors. The tumor
incidence in the vehicle controls was 1/102.
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The results of another intraperitoneal study conducted by
Davis (1987) also showed a low tumor yield in rats with Kevlar®
pulp. Three groups of male A-F/Han strain rats (3 months of age)
received a single intraperitoneal injection of a preparation of
disaggregated filaments of Kevlar® pulp suspended in phosphate
buffered saline at either 25, 2.5, or 0.25 mg of the test
material. By mass the bulk of the injected material consisted of
aggregates of large fibers. However, a small proportion of the
injected sample was composed of free fibrils which were within
the respirable range (96 percent <1 pm and 56 percent <0.25 /am in
diameter). A group of untreated animals were maintained as
controls. There were no significant differences in the survival
between the treated and untreated groups. More than 50 percent
of animals survived for more than 800 days and the oldest
survivors exceeding the age of three years. Two animals in the
high dose group consisting of 32 animals which received 25 mg of
Kevlar® developed peritoneal mesothelioma. Both mesotheliomas
were typical of those induced by asbestos. No peritoneal
mesotheliomas were found in the two low dose treated group (0/32
in the 2.5 mg and 0/48 in the 0.25 mg dose groups) and the
untreated controls (0/48).
IV.1.2.2. Fibrogenicity
Results of two inhalation studies indicate that ultrafine
para-aramid (Kevlar®) fibrils induced low fibrogenic activity in
rats. Animal studies with commercial grade para-aramid (Kevlar®)
by inhalation and intratracheal instillation and Nomex® by the
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intratracheal route did not produce lung fibrosis in rats.
However, injection of para-aramid (Kevlar®) pulp into the
peritoneal cavity of rats produced strong tissue reactions and a
minimal degree of fibrosis.
IV.1.2.2.1. Inhalation Studies
Lee et al. (1983) studied the pulmonary response of male
Crl:CD rats exposed by inhalation to ultrafine Kevlar® fibrils at
O.I/ 0.5, 3.0 or 18 mg/m and commercial Kevlar® fiber at 18
mg/m for 2 weeks. Fiber length distribution at different
exposure concentrations of ultrafine Kevlar fibers showed 60-70
percent of fibers were 10-30 jam in length and less than 1 urn in
diameter. Only 13 percent of airborne commercial Kevlar® fibers
were respirable. Five rats from each group were sacrificed at
the end of 2 weeks of exposure. Subsequently, 5 rats from each
group at 0.1, 0.5, 3.0 mg/m exposed to ultrafine Kevlar®, and 5
rats exposed to commercial Kevlar® at 18 mg/m were killed at 2
weeks, 3 months and 6 months post exposure. Five rats at 18
mg/m exposure were sacrificed at 4 and 14 days, 3 and 6 months
after exposure. Control animals exposed to air alone were
sacrificed at the same intervals as the exposed rats.
The pulmonary response in rats exposed to commercial Kevlar®
at 18 mg/m3 and ultrafine Kevlar® at 0.1, 0.5, and 3.0 mg/m3
essentially satisfied biological criteria for nuisance dusts,
i.e., they did not produce significant collagen formation or
permanent alteration of basic lung structure, and tissue
reactions were reversible. However, ultrafine Kevlar® fibrils at
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concentrations of 18 mg/m produced minimal collagen fiber
formation in the alveolar duct region where dust particles
accumulated. It should be noted that this study was an
assessment of the effects of short-term exposure and the results
alone cannot be extrapolated to assess long-term hazard.
Reinhardt (1986) also reported a low level of lung fibrosis
in rats chronically exposed to ultrafine Kevlar® at 2.5, 25 or
100 fibers/mL for 104 weeks or 400 fibers/mL for 52 weeks. Lung
lesions observed in male and female rats included alveolar type
II cell hyperplasia, bronchoalveolar hyperplasia, collagen fiber
granulomas, cholesterol-containing granulomas, and formation of
ciliated columnar cells in the alveolar ducts (alveolar
bronchiolarization). A dose-response trend was evident with
fewer, less severe lesions occurring in groups exposed to 25
fibers/mL and the highest incidences and most severe lesions
present in rats exposed to 400 fibers/mL. No pathological events
were evident in rats exposed to 2.5 fibers/mL. Experimental
details of the study are provided in Section IV.1.2.1.1.
IV.1.2.2.2. Intratracheal Instillation Study
Reinhardt (1980) reported that intratracheal instillation of
Kevlar® polymer dust produced only a non-specific dust cell
reaction in rats. Rats (strain, sex, and total number of animals
unspecified) were treated intratracheally with 25 mg of the
polymer dust which contained a low proportion of respirable
fibrous particles (<1.5 ^im in diameter and between 5-60 urn in
length) and a large proportion of larger nonrespirable particles
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ranging up to 150 urn in diameter. Rats were maintained without
further treatment and were sacrificed at 2, 1 and 49 days and 3,
6, 12 and 21 months after treatment. A group of control rats
received saline only. No differences in mortality rates,
clinical observations and gross autopsy results were observed
throughout the study. Initially there was a nonspecific
inflammatory response in the rat lung which then subsided within
one week. In later sacrifices, however, foreign body granulomas
containing dust particles were found along with a negligible
amount of collagen. All tissue responses to dust particles
decreased with increasing recovery periods.
Similarly, Reinhardt (1980) reported that intratracheal
instillation of fibrous dust of Nomex® did not show any
progressive pulmonary fibrosis in rats. Rats (strain, sex, and
total number not specified) were instilled intratracheally with
2.5 mg of Nomex® suspended in physiological saline. The test
material contained circular, oblong or rod-shaped particles
varying in size from 2-100 urn in length and 2-30 urn in
diameter. Groups of rats (number unspecified) were sacrificed at
2 and 7 days, 3 and 6 months, and 1 and 2 years following
exposure. Initial transitory acute inflammation followed by
foreign body granuloma formation was produced by larger
nonrespirable particles (3-100 jam). Respirable particles
«10 urn) produced only negligible dust cell reaction similar to
that seen with nuisance particulates. After 2 years post-
exposure, lungs appeared normal. It should be pointed out that
the actual data of both intratracheal instillation studies were
not provided in the report.
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IV.1.2.2.3. Intraperitoneal Injection Study
In a long-term intraperitoneal injection study by Davis
(1987) / Kevlar® pulp was found to cause a low level of peritoneal
fibrosis in rats. Histological examination of peritoneal tissues
from rats injected with 25 mg disaggregated Kevlar® pulp taken at
varying time periods between one week and 9 months after
injection showed the formation of cellular granulomas. These
granulomas consisted of macrophages and fibroblasts and foreign
giant cells. There was also a small amount of fibrosis with
deposition of reticulin and collagen fibers.
IV.1.3. In Vitro Studies
IV.1.3.1. Genotoxicity
There is no information available on the genotoxicity of
aramid fibers.
IV.1.3.2. Cytotoxicity
The results of an in vitro study by Dunnigan et al. (1984)
indicate that short, thin aramid fibers are at least as cytotoxic
as chrysotile asbestos to rat pulmonary alveolar macrophages.
Short, thin aramid fibers were extracted from commercial grade
Kevlar®. Ninty percent of the counted fibers were less than 5 jam
long and smaller than 0.25 pm in diameter. Average fiber length
and diameter were 2.72 pi and 0.138 jLtm, respectively. The test
fibers were added to freshly harvested pulmonary alveolar
macrophages or cultured macrophages obtained from adult male
Long-Evans black hooded rats, at concentrations of 0, 25, 50,
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100, or 200 ug/mL. After an 18-hour incubation period,
cytotoxicity was assessed by measuring lactate dehydrogenase
(LDH) and beta-galactosidase enzyme released into the incubation
medium. Releases of LDH (10-55%) and beta-galactosidase (0-48%)
from pulmonary alveolar macrophages were essentially identical
when either aramid or chrysotile fibers were incubated with
freshly harvested cells. With cultured macrophages, the
cytotoxic response was even higher with aramid fibers than
chrysotile.
IV.1.4 Assessment of Health Effects
There is sufficient experimental evidence to conclude that
ultrafine para-aramid is potentially carcinogenic and
fibrogenic. Due to limited comparative data bases, it is not
possible at this time to definitively assess the pathogenicity of
ultrafine para-aramid relative to that of asbestos. This
material, however, does not pose a health risk to humans because
it is not available in commerce. For the commercial grades of
para-aramid fiber and pulp to which humans are exposed, there is
limited experimental evidence suggesting that they may have a
low oncogenic and fibrogenic potential. Thus, a possible health
hazard exists from exposure to commercial grade para-aramid
particularly the pulp form which may generate respirable airborne
fine fibrils upon abraison.
Nomex® aramid which contains mainly nonrespirable fibers do
not appear to pose a significant health hazard to humans.
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IV.1.4.1. Oncoqenicity
Ultrafine para-aramid may be classified as a probable human
carcinogen (category B2) on the basis of sufficient evidence of
para-aramid carcinogenicity in animal studies and in the absence
of human data.
There is no information available on the oncogenicity of
para-aramid fibers in humans. The results of an inhalation study
indicate that ultrafine para-aramid (Kevlar®) is tumorigenic in
rats via inhalation (Reinhardt, 1986). It was shown that chronic
inhalation exposure to ultrafine Kevlar® resulted in the
development of malignant lung tumors in female rats in a dose-
related manner (100 and 400 fibers/mL). No injection data are
available on ultrafine Kevlar® to further assess its relative
carcinogenic potency in comparison with asbestos. However/ the
positive findings from the inhalation bioassay are further
supported by the weak tumorigenic responses observed in rats
treated intraperitoneally with commercial grade para-aramid
(Kevlar®) fibers (Pott et al., 1987b) and pulp (Davis, 1987)
which contained small numbers of thin fibrils.
In the absence of epidemiological data and based on the
limited evidence of carcinogenicity in animals, commercial grade
para-aramid may be classified as a possible human carcinogen
(Category C). The limited evidence of carcinogenicity in
laboratory animals is provided by the positive results of two
intraperitoneal injection studies which showed that Kevlar® fiber
and pulp induced low incidences of peritoneal tumors in rats
(Pott et al., 1987b; Davis, 1987). The authors attributed the
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low tumorigenic responses of aramid fibers and pulps to technical
difficulty in administering the test fibers, since they tend to
aggregrate and form large clumps.
No experimental studies were available that evaluated the
oncogenic potential of Nomex® aramid fibers. Thus/ Nomex® is not
classifiable as to human carcinogenicity (category D) due to
inadequate data in humans and animals.
IV.1.4.2. Fibrogenicity
There were no epidemiological studies available that
examined the potential fibrogenicity of aramid fibers. Results
of two inhalation studies showed that ultrafine para-aramid
(Kevlar®) is weakly fibrogenic in rats. Minimal pulmonary
fibrosis was induced in rats by 6 months following a 2-week
inhalation exposure to high concentrations (18 mg/m3) of
ultrafine Kevlar® fibrils (Lee et al., 1983). Furthermore, dose-
related pathological lung effects including alveolar type II
hyperplasia, alveolar broncholarization, and collagenized
fibrosis were also observed in rats following long-term
inhalation exposure to ultrafine Kevlar® at 25, 100 and 400
fibrils/mL (equivalent to approximately 0.3, 0.6 and 2.23 mg/m3,
respectively (Reinhardt, 1986). The concern for the fibrogenic
potential of ultrafine Kevlar® is further supported by findings
of an in vitro study demonstrating that short, thin aramid fibers
extracted from commercial grade Kevlar® are as cytotoxic as
chrysotile asbestos to rat pulmonary macrophages (Dunnigan et
al., 1984).
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Lung fibrosis was not found for commercial Kevlar® in a
short-term inhalation study in rats (Lee et al., 1983). However,
a low fibrogenic effect has been demonstrated for commercial
Kevlar® pulp via injection. Davis (1987) showed that inoculation
of Kevlar® pulp into the abdominal cavity of rats resulted in a
low level of peritoneal fibrosis. On the other hand, no fibrogenic
effects were observed in rats instilled intratracheally with large
nonrespirable Kevlar® or Nomex® aramid fibers (Reinhardt, 1980).
IV.1.5. Recommendations
In order to fully assess the potential health effects of
para-aramid fibers or pulps, additional animal testings by
inhalation or injection appear necessary. Because of a low
health concern, no further testing is recommended for Nomex®.
IV.2. Carbon Fibers
Carbon fibers are synthetic fibers which are characterized
by light weight, high tensile strength, flexibility, good
electrical conductivity, thermal resistance, and chemical
inertness (except to oxidation). Carbon fibers are mainly used
as reinforcing materials in structural composites. They are
currently not used as asbestos substitutes but may replace
asbestos in thermal and electrical insulation, textiles, and
friction products.
Carbon fibers (92 percent carbon by weight) are made by the
carbonization (i.e., pyrolysis) of precursor polyacrylonitrile
(PAN), rayon, or pitch fibers, with PAN-based carbon fibers being
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the most common. Carbon fibers are manufactured as continuous or
chopped fibers. The nominal diameter of carbon fibers range from
5-8 urn, which fall outside the resprrable range. However, less
than 25 percent of these fibers have diameters less than 3 pm and
shorter than 80 jam, which are considered respirable.
Furthermore, upon mechanical or thermal stress, carbon fibers may
split longitudinally to finer respirable fibers (ICF, 1986).
IV.2.1. Fiber Deposition, Clearance and Retention
There is very limited information on the deposition and
clearance of carbon fibers. Results of available inhalation
studies in guinea pigs indicate that inhaled carbon fibers are
capable of penetrating the alveoli. In the lung, nonfibrous
carbon particles are phagocytized by alveolar macrophages while
uncoated carbon fibers longer than 5 jjm are found in the
extracellular matrix. Carbon fibers appear to be cleared from
the lung slowly as evidenced by the detection of uncoated carbon
fibers and dust-laden macrophages in the lung even after 6 months
to 2 years following exposure.
Holt and Horne (1978) exposed guinea pigs to high
concentrations of a respirable dust cloud of carbon fibers for
7-24 hours. Most of the respirable dust (99 percent) was
nonfibrous (370 particles/mL) and the airborne concentration of
respirable fibers (1-2.5 urn in diameter and lengths up to 15 urn)
was very low (2.9 fibers/mL). Examination of lung tissues
revealed the presence of carbon particles to be intracellular in
the cytoplasm of macrophages. The few carbon fibers found in the
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lung that were longer than 5 urn were still extracellular after 27
weeks post-exposure. These fibers were uncoated.
In a subsequent experiment, Holt (1982) exposed guinea pigs
to dust of carbon fibers for 100 hours. The carbon dust was
reported to be submicron in size and mainly nonfibrous. However,
dust concentration and particle dimensions were not given. It
was reported that phagocytosis of the dust particles commenced
immediately one day after exposure but proceeded slowly, with the
number of dust-laden macrophages continuing to increase up to 400
days post exposure. Macrophages containing dust began to decline
after that but were still evident even after 2 years following
exposure.
IV.2.2. Effects on Experimental Animals
A number of studies have been conducted to evaluate the
oncogenic and fibrogenic potential of carbon fibers in laboratory
animals via various routes of exposure. Table 8 (pages 248-250)
summarizes the experimental protocols and findings of relevant
studies on carbon fibers.
s~
IV.2.2.1. Oncogenicity
No information is available on the oncogenicity of carbon
fibers in animals via inhalation. Studies of carbon fibers in
rats by intratracheal instillation, intraperitoneal injection,
and intramuscular implantation have reported no tumorigenic
response. Petroleum pitch-based continuous fibers were reported
to be weakly oncogenic in mice by the dermal route, and
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subcutaneous implantation of carbon fibers were reported to
produce local sarcomas in rats. However, the results of these
studies are questionable in view of inadequate reporting of the
test results and/or the nature of the materials tested.
IV.2.2.1.1. Intratracheal Instillation Studies
A small intratracheal instillation study was conducted at
the U.S. Air Force Aerospace Materials Research Laboratory by C.
Olson. Carbon fibers were reduced to respirable size (20 percent
<1 pm in diameter/ with varying lengths) by partial oxidation at
a high temperature and then injected intratracheally into the
lungs of male Fischer rats. The rats were maintained over a
2-year period. As reported by Parnell (1987), no lung tumors
were found at 200 days, 1 year or 2 years after treatment. This
was a preliminary report and details of the study design (e.g.,
dosage, number of animals) and results were not given for full
evaluation.
IV.2.2.1.2. Intraperitoneal Injection Studies
Parnell (1987) also reported that no tumor response was
observed in male Fischer rats treated intraperitoneally with
respirable carbon fibers. Mesotheliomas were not found in any of
the treated rats at 200 days or 2 years post-treatment. No other
experimental details were provided.
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IV.2.2.1.3. Intramuscular Studies
Tayton et al. (1982) investigated the carcinogenic potential
of intramuscular implantation of carbon fiber in strand and
powdered forms in rats and found no signs of any malignant
changes. In one experiment, a 1.5 urn length carbon fiber
Graffil®, was inserted intramuscularly into the left gluteal
muscle of 50 rats (unspecified sex and strain). A group of 50
control animals received an implant of black braided silk suture
material. In a second experiment, groups of 10 rats had either a
5 jjm length of carbon fiber (Graffil®) or the black silk (for
control) tied around the periosteum of the left femur. In a
third study, a group of 50 rats each received intragluteal
injection of a suspension of powdered carbon fibers (unspecified
particle size). All surviving animals were sacrificed at 18
months and morphological and histological examinations of the
implants were performed. In all cases, minimal tissue reactions
were observed and there was no evidence of malignant changes. It
should be noted that the route of administration used in this
study may not be relevant in providing information with regard to
the potential of carbon fibers in inducing lung toxicity and
carcinogenicity via inhalation.
IV.2.2.1.4. Subcutaneous Implantation Studies
In 1982, Maltoni et al. (1982b) reported initiation of
testing of carbon fibers for oncogenicity in rats by subcutaneous
implantation. Male and female Sprague-Dawley rats (40 per sex)
were each subjected to subcutaneous implantation of a 2 cm
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diameter disc containing 25 rag of carbon fibers (fiber dimension
not specified). Animals were to be kept under observation until
spontaneous death and a complete necropsy and histopathologic
evaluation of the tissues were to be performed. Recently,
Maltoni et al. (1987) reported in an abstract that the
preliminary results of this study showed an induction of local
sarcomas in carbon fiber treated rats, but no other details
regarding the nature of the test material and test results were
available for a full evaluation of the findings.
IV.2.2.1.5. Dermal Studies
DePass (1982) evaluated the potential of carbon fibers in
inducing cancer of the skin in mice. Four types of carbon fibers
were tested: (1) continuous filament (CF) pitch-based, (2)
pitch-based carbon fiber mat (MAT), (3) polyacrylonitrile
continuous fibers (PAN-based), and (4) oxidized PAN-based (PAN-
oxidized) fibers. No tumorigenic response appeared to be
elicited by PAN-based, MAT, or PAN-oxidized fibers. The CF
pitched-based, however, were judged to produce a weak tumorigenic
response.
Groups of 40 male C3H/HeJ mice each received a 25 uL
application of the test material suspended in benzene (10% w/v),
to the clipped skin of the back three times weekly until death.
Each of the four fiber types was ground by mortar and pestle
(particle size not specified). A group of negative controls
received benzene only while positive control animals were treated
with 0.1 percent methylcholanthrene in acetone. No skin tumors
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were found in the groups treated with PAN-based fibers or vehicle
control (benzene). In the CF pitch-based group, one papilloma
(1/40) and one squamous cell carcinoma (1/40) of the skin at the
application sites were found. Because of extremely low
historical control incidence (0/285 in C3H/HeJ mice used as
benzene controls at that laboratory), CF pitch-based fibers were
considered to be marginally oncogenic under the conditions of the
study. A very low incidence of various types of skin tumors were
found in rats treated with MAT or PAN-oxidized fibers. However,
MAT and PAN-oxidized fibers were considered to have questionable
oncogenic potential because the tumors observed were distal to
the application site.
IV.2.2.2. Fibrogenicity
A number of studies have been conducted to determine the
fibrogenic potential of carbon fibers by various routes of
exposure. With the exception of a report that carbon fiber is
fibrogenic in rats via intratracheal instillation, other studies
have not produced positive results. It should be noted, however,
that available studies are of little value in evaluating the
fibrogenicity of carbon fibers because of their limited scope or
experimental design, and/or lack of information on the test
material or test results.
IV.2.2.2.1. Inhalation Studies
Two inhalation studies were conducted in an attempt to
evaluate the effects of short-term exposure to chopped PAN-
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oxidized carbon fibers in guinea pigs. In the first study, Holt
and Home (1978) exposed 13 specific pathogen-free guinea pigs to
carbon dusts for up to 104 hours. No pathological effects were
found in the lung of exposed guinea pigs examined at 1-144 days
post-exposure. It should be pointed out that 99 percent of the
respirable dust generated was nonfibrous (370 particles/mL) and
the levels of respirable carbon fibers were extremely low (2.9
fibers/mL). These fibers had diameters of 1.0-2.5 urn and lengths
up to 15 urn.
In a subsequent study, Holt (1982) also reported no evidence
of pathological changes in the lungs of guinea pigs exposed to
submicron carbon dusts. Specific pathogen-free guinea pigs (2-9
per group) were exposed to carbon dust for 7-12 hours or 100
hours and single animals were killed at intervals after one to
720 days. The dust was reported to be submicron in size and
mainly nonfibrous. Dimensional characterization of the dust was
not provided, nor were dust concentrations reported. Exposed
guinea pigs showed no lung fibrosis nor other pathology.
However, it should be pointed out that these two studies only
demonstrated that short-term inhalation of mostly nonfibrous
respirable fragments of carbon fibers caused no adverse effects
to guinea pigs.
Recently, Owen et al. (1986) conducted a subchronic
inhalation toxicity study on PAN-based carbon fibers and reported
no systemic toxicity nor progressive pulmonary dysfunction in the
exposed rats. Four groups of 10 male Sprague-Dawley rats were
exposed to carbon fibers for 6 hours daily, five days a week for
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4, 8, 12, or 16 weeks and were sacrificed at the end of the
exposure. A fifth group consisting of 20 animals were exposed
for 16 weeks and were kept for 32 weeks post-exposure. The mean
atmospheric concentration of carbon fibers was 20 mg/m , with a
range of 16-23 mg/m . Carbon fibers had a mean diameter of 7 urn
and lengths ranging from 20-60 urn. A similar number of control
rats were exposed to air only and were sacrificed at similar
schedules. One death occurred during the sixth week of exposure
but was not considered related to treatment. Pulmonary function
tests conducted prior to animal sacrifice did not show any
significant or consistent changes in airway resistance.
Histologic examination revealed no inflammatory or fibrogenic
reaction in the lungs of exposed rats. A lack of an effect was
not unexpected considering that the dust cloud contained mostly
large nonrespirable fibers.
IV.2.2.2.2. Intratracheal Instillation
Troitskaya et al. (1984) reported findings on comparative
fibrogenicity of carbon fibers and asbestos. Rats each received
a single intratracheal administration of either chrysotile
asbestos or one of two preparations of polyacrylonitrile-
reinforced carbon fibers. The animals were examined 1-9 months
after the administration of the dust. It was reported that
chrysotile asbestos was several-fold more fibrogenic than either
of the carbon fiber samples. No further details were provided.
In a study by Swensson (1979), as reported by Gross and
Braun (1984), a mixture of carbon fibers (size distribution not
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specified) and unspecified plastic was injected intratracheally
into Sprague-Dawley rats (dose and number of animals not
specified). The animals were mainta-ined for eight months. Aside
from an acute foreign body reaction during the first month after
instillation/ there was no indication of obstructive lung disease
at 8 months as judged by analysis of collagen content in the
lungs. No other details were given for conclusive evaluation.
Parnell (1987) recently reported that there was no evidence
of any adverse effects in male Fischer 344 rats following
intratracheal instillation of respirable carbon fibers. No
treatment-related degenerative lesions of the lungs were observed
in this long-term study. This was only a preliminary report and
full results were not available for evaluation.
IV.2.2.2.3. Intraperitoneal Injection Studies
Styles and Wilson (1973) reported that carbon fiber was not
fibrogenic in rats following intraperitoneal injection. A group
of 6 male and 6 female SPF albino Wistar rats (200-250g) were
injected intraperitoneally with carbon fibers at a dose of 50
mg/kg (10-15 mg per animal). Particle size of the test material
ranged from 0.2-15 urn in diameter. No pathological lesions were
found at 1 and 3 months after treatment. On the other hand, rats
injected with chrysotile asbestos developed diffuse fibrosis of
the peritoneum after 1-3 months post-treatment. It should be
noted that a major limitation of this study was the short
observation period and the use of a small number of animals. It
was also not clear as to whether the test carbon dust was in
fibrous or nonfibrous form.
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Parnell (1987) also reported negative findings with two
samples of respirable carbon fibers following injection into the
peritoneal cavity of male Fischer 344 rats. No treatment-related
degenerative lesions were observed in either treated animal group
at 200 days or 2 years after treatment. This was only a
preliminary report and full results were not available for
evaluation.
IV.2.2.2.4. Other Studies
Neugebauer et al. (1981) conducted a series of experiments
to determine the reaction of tissues to carbon fibers. In this
study/ 50 mg of carbon fiber reinforced carbon (CFRC) fragments
(diameter of 7 um and lengths between 20-100 urn) were injected
into the femoral medullary canal of 16 rabbits of the CHBB:CH
strain. Tissue reactions were evaluated at 2 and 12 weeks post-
treatment. A small amount of fibrosis and foreign body giant
cell reactions were found in the medullary cavity. It was also
reported that previous experiments in rats involving intravenous,
intraperitoneal or intra-articular injections of carbon fiber
particles (1-8 um) also showed no evidence of tissue reaction.
No additional details were available.
IV.2.3. In Vitro Studies
IV.2.3.1. Genotoxicity
Genotoxicity tests have been conducted on two types of
carbon fibers. The carbon fibers are the acetone reconstituted
benzene extracts of pitch-based carbon fibers and poly-
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acrylonitrile (PAN)-based carbon fibers. Available data indicate
that neither type of carbon fiber appears to cause gene
mutations. - However, pitch-based carbon fibers appear to be
clastogenic while a clastogenic mechanism cannot be entirely
ruled out for PAN-based carbon fibers.
Both carbon fibers were negative in the Salmonella/mammalian
activation assay and the Chinese hamster ovary/hypoxanthine-
guanine-phosphoribosyltransferase (CHO/HPRT) mutation assay
(Litton Bionetics, 1980; Union Carbide, 1983a, 1983b, 1983c,
1983d). Pitch-based carbon fibers induced significant
concentration dependent increases of sister chromatid exchanges
(SCE) in CHO cells and unscheduled DNA synthesis (UDS) in primary
rat hepatocytes (Union Carbide, 1983c). In the SCE assay,
chromosomal aberrations were also noted for this carbon fiber.
On the other hand, PAN-based carbon fiber did not induce
significant increases in UDS in primary rat hepatocytes and the
frequency of SCE in CHO cells. However, several types of
chromosomal aberrations were observed in the SCE assay (Union
Carbide, 1983d). These results are consistent with other fiber
studies where mineral fibers do not appear to cause gene
mutations, but are clastogenic.
IV.2.3.2. Cytotoxicity
Both positive and negative results were obtained from in
vitro cytotoxicity studies on carbon fibers. Carbon fibers were
reported in one study to be non-hemolytic to rabbit erythrocytes
but highly cytotoxic to rabbit alveolar macrophages. However, in
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another study, carbon fibers were found to cause no cytotoxic
effects to either rat alveolar or peritoneal macrophages. Carbon
fibers also did not affect rabbit lung fibroblast cultures. It
would appear that the discrepancy in the observed in vitro
biological activity of carbon fibers might be related to
differences in fiber type and/or size distribution of the test
materials.
IV.2.3.2.1. Erythrocytes
Richards and Hunt (1983) reported that carbon fibers had
little or no hemolytic activity in rabbit erythrocytes. The test
fibers were obtained by grinding carbon fiber cloth. Ninety
percent of the fibers were less than 10 urn in length. Hemolysis
was observed only at a relatively high dose compared to
chrysotile asbestos. No other details were available.
IV.2.3.2.2. Phagocytic Cells
Richards and Hunt (1983) also reported that carbon fibers
(90 percent <10 um long) were highly cytotoxic to rabbit alveolar
macrophages following one hour of incubation. Experimental
details were not provided for full evaluation.
On the other hand, Styles and Wilson (1973) found that
carbon dusts (0.2-15 jam in diameter) were not cytotoxic to rat
peritoneal macrophages or alveolar macrophages. The test dusts
were incubated with cells for 2 hours and cell viability was
assessed at 0, 1 and 2 hours after addition of dust. Less than
2-5 percent of cells were killed following phagocytosis of carbon
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dust. In contrast, chrysotile asbestos induced a high degree of
cytotoxicity.
IV.2.3.2.3. Fibroblasts
Richards and Hunt (1983) tested the effect of ground carbon
fiber cloth (90 percent <10 pm long) on rabbit lung fibroblast in
culture. The amount of DNA and hydroxyproline levels in the
culture were measured after 24 days of exposure. Treatment of
fibroblast cultures with carbon fibers affected neither parameter.
IV.2.4. Assessment of Health Effects
Currently available data provide inadequate evidence of
carcinogenicity and fibrogenicity for carbon fibers. However/
based on suggestive evidence from a dermal study and positive
clastogenic effects in genotoxicity tests with pitch-based carbon
fibers, a weak oncogenic potential for certain types of respirable
carbon fibers may exist. Overall, carbon fibers appear to pose a
lower degree of health hazard compared to asbestos because they
are less respirable, and less biologically active than asbestos as
demonstrated in the few available comparative studies.
IV.2.4.1. Oncogenicity
Carbon fiber is not classifiable as a human carcinogen
(Category D) based on inadequate evidence of carcinogenicity from
animal studies and in the absence of human data.
No information is available on the potential development of
respiratory malignant diseases in humans from exposure to carbon
fibers. Moreover, there are no animal data on the oncogenic
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potential of carbon fibers via inhalation. However, negative
results have been reported in rats via intratracheal instillation
(Parnell, 1987), intraperitoneal injection (Parnell, 1987), and
intramuscular implantation (Tayton et al., 1982). The studies
that reported positive results were those of a subcutaneous study
with carbon fibers in which an increased production of local
sarcomas were found in rats (Maltoni et al., 1987) and a lifetime
skin painting study with pitch-based carbon fibers showing a
nonstatistically significant increase of skin tumors in mice
(DePass, 1982). The biological significance of these findings
remains uncertain in light of the absence of particle size and
morphology data, the weak tumorigenic response in the dermal
study, the lack of data reported in the subcutaneous injection
study as well as the questionable relevance of its method of
administration to human exposure at the workplace. On the other
hand, the positive clastogenic effects of benzene-extracts of
pitch-based carbon fibers (Union Carbide, 1983c) tend to support
an oncogenicity concern for this carbon fiber type. Additional
data are needed to conclusively evaluate the oncogenicity of
carbon fibers.
IV.2.4.2. Fibrogenicity
Available data are insufficient to evaluate the fibrogenic
potential of carbon fibers. There is one single small cross-
sectional study which showed no evidence of pathological effects
in the lungs of workers in a PAN-based carbon fiber production
plant, based on respiratory symptoms, spirometric and chest
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radiographic data (Jones et al., 1982). It should be noted,
however, that respirable fiber concentrations in this facility
were low and that the duration of exposure to carbon fibe-rs was
relatively short. Thus, the results of this study do not provide
conclusive evidence of a negative effect (Battelle, 1988).
With regard to experimental studies, there are no data
available on the long-term effects of inhalation of respirable
carbon fibers in animals. The results of a subchronic inhalation
toxicity study showed no evidence of lung pathology in rats
exposed to large diameter carbon fibers (Owen et al., 1986). In
addition, several studies have reported that carbon fibers were
not fibrogenic in rats via intratracheal instillation (Parnell,
1987; Swenson, 1979), intraperitoneal injection (Parnell, 1987;
Styles and Wilson, 1973) or injection into the medullary cavity
of femur bone (Neugebauer et al., 1981). On the other hand, it
was reported that PAN-based carbon fibers induced lung fibrosis
in rats following intratracheal instillation (Troitskaya et al.,
1984). Most of these studies, however, are of little value for
the evaluation of the fibrogenic potential of carbon fibers
because of limited scope, lack of particle size and morphology
data of the test materials, and/or no details available on study
design and findings. Furthermore, both negative and positive
findings have been reported regarding the in vitro cytotoxicity
of carbon fibers (Styles and Wilson, 1973; Richards and Hunt,
1983). Thus, available animal and in vitro studies do not
provide conclusive evidence for or against a fibrogenic effect
for carbon fibers. They do suggest, however, that carbon fibers
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at most have low fibrogenic potential, as supported by results of
a few studies showing that chrysotile asbestos was more
fibrogenic, hemolytic and cytotoxic than c-arbon dust fibers under
the same experimental conditions (Troitskaya et al., 1984; Styles
and Wilson, 1973; Richards and Hunt, 1983).
IV.2.5. Recommendations
A chronic inhalation toxicity study was recently conducted
at a private laboratory. When results become available, they
should be assessed to see if further study is warranted on this
fiber.
IV.3. Polyolefin Fibers
Polyolefin fibers are manufactured from long-chain,
synthetic polymers of ethylene, propylene or other olefin
units. Approximately 95 percent of polyolefin fibers are made
from polypropylene, while most of the rest is from polyethylene.
Polyolefins are manufactured as monofilament yarn (greater than
153 urn in diameter), multifilament yarn (5-20 urn in diameter),
tape and fibrillated film yarn (continuous sheet), spun-bonded
fabric, staple fiber (chopped multifilament), synthetic pulp
(5-40 urn in diameter, 2.5-3 mm long), and microfiber (1-5 urn in
diameter). Applications of polyolefin fibers and pulp as
substitutes for asbestos include roof sealant, asphalt solvent,
caulks, joint cement, adhesive, textile compounds, filter,
flooring felts, and roofing felts. With the possible exception
of polyolefin microfibers, the likelihood that polyolefin fibers
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and pulp generate airborne respirable fibers appears small since
they generally fall outside the respirable range. Furthermore/
it is unlikely that polyolefin fibers and pulp would split
longitudinally to produce finer respirable fibers (ICF, 1986).
IV.3.1. Fiber Deposition, Clearance and Retention
There is no information available on the lung deposition,
clearance and retention of polyolefin fibers.
IV.3.2. Effects on Experimental Animals
Very few studies have been conducted to determine the
oncogenic and fibrogenic potential of polyolefin fibers in
animals. Table 9 (page 251) summarizes the experimental
protocols and results of available animal studies on polyolefin
fibers.
IV.3.2.1. Oncogenicity
There is no information available on the oncogenic potential
of polyolefin fibers in animals via inhalation. Preliminary
results of an intraperitoneal injection study showed that
polypropylene fibers induced a low incidence of peritoneal tumors
in rats. In a limited intratracheal insufflation study, both
polyethylene and polypropylene fibers were not tumorigenic in
rats. Other forms of polyethylene and polypropylene including
disc, film, rod fragment and powder produced local sarcomas in
mice and rats following subcutaneous or intraperitoneal
implantation (as reported in IARC, 1979).
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IV.3.2.1.1. Intraperitoneal Injection Studies
Pott et al. (1987b) recently reported preliminary findings
of a study of polypropylene fibers in rats via intraperitoneal
injection. Female Wistar rats received 5 weekly injections of 10
mg of polypropylene fibers in saline. Ninety percent of the test
fibers were less than 2.1 urn in diameter and less than 23 urn
long. The animals were observed for full lifespan. Peritoneal
tumors were found in 2/53 treated animals compared to 1/102
negative controls (saline). In contrast, animals treated with
chrysotile asbestos showed a dose-dependent tumorigenic response
at extremely low doses. The tumor incidences (identified as
mesothelioma or sarcoma) in the chrysotile group were 11/36,
21/34, and 30/36 at a single dose of 0.05, 0.25, and 1.0 mg,
respectively.
IV.3.2.1.2. Intratracheal Insufflation Studies
MB Research Laboratories (1980) conducted a long-term study
of the effects of intratracheal insufflation of polyolefin fibers
in rats. Groups of 40 male Long-Evans rats were administered a
single dose of ozonized polyethylene SHFF, ozonized polypropylene
SHFF, or HHF polypropylene. Control animals received vehicle
only (Tween 60). All surviving animals were sacrificed at 21
months following administration of the test material. A number
of deaths were observed in both control and treated groups. The
cause of early deaths was attributed to dosing technique and that
of later deaths to infectious diseases. Histologic examinations
showed the development of lung granulomas in all treatment
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groups. No lung tumors were found in any test groups. It should
be pointed out that in the absence of available information on
the characteristics of the test materials, specific dosages and
methods of administration, this study is of little value for the
evaluation of the oncogenic potential of polyolefin fibers.
IV.3.2.2. Fibrogenicity
There is no information available on the fibrogenic effects
of polyolefin fibers in animals via inhalation. In a 3-month
study, peritoneal fibrosis was not observed in rats following a
single intraperitoneal dosing of polyethylene or polypropylene
dusts. In a limited intratracheal study, lung fibrosis was not
produced in rats treated with either polyethlyene or poly-
propylene fibers. However, preliminary results of a lifespan
study in rats reported a strong degree of adhesions of the
abdominal organs following intraperitoneal injection of
polypropylene fibers.
IV.3.2.2.1. Intraperitoneal Injection Studies
In the study by Pott et al. (1987b) that was described in
the oncogenicity section, a strong degree of adhesions of
abdominal organs was observed macroscopically in rats treated
with 5 weekly doses of 10 mg of polypropylene fibers (90 percent
<2.1 um in diameter; 90 percent <23 um long). It was not clear
whether there were any developments of fibrosis in treated
rats. Histological data are not yet available for a full
evaluation of this preliminary finding.
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Styles and Wilson (1973) reported that polyethylene and
polypropylene dusts were not fibrogenic in rats via the intraper-
itoneal route of exposure. In this study, groups of 6 male and 6
female albino Wistar rats (200-250g) were intraperitoneally
administered a single dose of either polyethylene (3-75 urn in
diameter) or polypropylene (4-50 jum in diameter) dusts at 50
mg/kg (10-15 mg/animal). No fibrosis were observed at 1 or 3
months after treatment in either treated group. On the other
hand, chrysotile asbestos at lower doses produced characteristics
of fibrotic nodules after 1 month and diffuse fibrosis by 3
months. It is difficult to evaluate these findings in view of
the small numbers of animals used in this study and short
duration of the study. Moreover, it was not clear whether the
test dusts were fibrous or nonfibrous.
IV.3.2.2.2. Intratracheal Insufflation Studies
In the long-term study by MB Research Laboratories (1980)
that was described in the oncogenicity section, lung fibrosis was
not found in rats at 21 months following intratracheal insuffla-
tion of ozonized polyethylene SHFF, ozonized polypropylene SHFF,
or HHF polypropylene. No information with regard to the charac-
teristics of the test materials, the particle size distribution
and administered doses was provided. These findings are therefore
inadequate for definitive assessment.
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IV.3.3. In Vitro Studies
IV.3.3.1. genotoxicity
Polyethylene extracts were tested in the Salmonella/mamma-
liam activation assay in strains TA98, TA100 and TA1537 (Fevolden
and Holler, 1978). This report is an abstract that provides no
details, therefore it is not completely adequate for assessment.
IV.3.3.2. Cytotoxicity
Results of a single in vitro study showed that polypropylene
and polyethylene dusts were significantly less cytotoxic to
alveolar or peritoneal macrophages than was chrysotile
asbestos. However, the authors did not specify whether the
materials tested were fibrous or nonfibrous.
In the study by Styles and Wilson (1973), peritoneal and
pulmonary macrophages (10 cells/mL) obtained from male and
female Wistar rats were treated with either polyethylene or
polypropylene dust at 500 ug/mL. The particle size of poly-
ethylene and polypropylene dusts ranged between 3-75 urn and 4-50
urn in diameter, respectively. Negative control cultures were
untreated while positive controls were treated similarly with
chrysotile asbestos. Results of cell culture experiments indi-
cated that cells treated with asbestos had the highest mortality
(10-60 percent) while those tested with either polyethylene or
polypropylene dust had the lowest mortality (less than 2 percent
to 5 percent), as measured by the ratio of percentage of living
to dead cells after 1 and 2 hours post-incubation.
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IV.3.4. Assessment of Health Effects
Available data are inadequate for a conclusive assessment of
potential carcinogenic and fibrogenic effects of pblyolefin
fibers, but they do suggest that polyolefin microfibers may have
low fibrogenic potentials. Because polyolefin fibers or pulp are
generally not respirable, inhalation of these fibrous materials
would pose little or no health hazard to humans. On the other
hand/ a health hazard potential for polyolefin microfibers may
exist since these may be respirable.
IV.3.4.1. Oncogenicity
Polyolefin fibers are not classifiable as to human carcino-
genicity (Category D) on the basis of inadequate evidence of
carcinogenicity in animal studies and no human data.
There are no available epidemiological or animal inhalation
studies that examine the oncogenic potential of polyolefin
fibers. The results of a limited intratracheal insufflation and
an apparently well-conducted intraperitoneal injection
oncogenicity study have not provided conclusive evidence of
carcinogenicity for polyolefin fibers in animals. In the long-
term intratracheal insufflation study, both polyethylene and
polypropylene fibers did not induce tumor in rats (MB Research
Laboratories, 1980). However, the lack of information on the
nature, size distribution and dosage of the test materials
precludes any definitive assessment of the oncogenicity of these
fibers under the conditions of the study. In the long-term
intraperitoneal injection study in rats, a low tumor incidence
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was obtained with polypropylene microfibers (Pott et al.,
1987b). These results, however, were only preliminary and a full
evaluation cannot yet be made.
In contrast, the results of subcutaneous or intraperitoneal
implantation studies showed that polyethylene/polypropylene disc,
film, rod or fragments cause local sarcomas in mice and rats
(IARC, 1979). However, because the test materials were not in
fibrous form, these findings are not considered relevant to the
assessment of the oncogenicity of fibrous polyolefin per se.
IV.3.4.2. Fibrogenicity
There is no information available on the fibrogenic effects
of polyolefin fibers in humans and animals via inhalation
exposure. Available animal studies by the injection/insufflation
method and a single in vitro cytotoxicity study provide
inconclusive data, and thus definitive assessment of the
fibrogenic potential of polyolefin fibers cannot be made,
although these studies seem to suggest a lower fibrogenic
potential than that of asbestos.
In a long-term intratracheal study with polyethylene and
polypropylene fibers, lung fibrosis was not observed in rats
following 21 months (MB Research Laboratories, 1980). In a
short-term study, peritoneal fibrosis was not found in rats
treated with either polyethylene or polypropylene dusts, whereas
under similar experimental conditions but at lower doses,
chrysotile asbestos induced a low level of fibrosis after 3
months (Styles and Wilson, 1973). These in vitro results are
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supported by the finding of a single in vitro study that both
polypropylene and polypropylene dusts had significantly lower
cytotoxicity in rat alveolar/peritone.al macrophages than did
chrysotile asbestos (Styles and Wilson, 1973). However, the lack
of information on the characteristics of the tested fibers makes
it difficult to draw any definitive conclusions for this fiber
category. On the other hand, preliminary results of an
apparently well-conducted long-term intraperitoneal injection
study in rats with long, thin polypropylene fibers showed a
strong degree of adhesions of the abdominal organs. However,
without histological data, it is not yet known whether or not
fibrosis was also induced by polypropylene fibers (Pott et al.,
1987b).
IV.3.5. Recommendations
A chronic inhalation study is recommended to further
evaluate the oncogenic and fibrogenic potential of polyolefin
microfibers. Because of a low health hazard associated with
inhalation exposure to polyolefin fibers and pulps, additional
animal tests do not appear necessary at this time.
V. Mechanisms of Fiber-Induced Diseases: Relationships between
Fiber Properties and Pathogenicity
Epidemiological and experimental evidence accumulated thus
far suggests that inhalation of fibrous dust other than asbestos
might also be associated with malignant and nonmalignant
pulmonary diseases in humans. However, the carcinogenicity and
fibrogenicity of nonasbestos fibers appear to be variable. While
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erionite seems to be at least as potent as asbestos, if not more
so, fibrous glass and mineral wools are probably less hazardous
than asbestos. On the o_ther hand, available experimental data
suggest that ceramic aluminum silicate glass, ultrafine aramid
(Kevlar®) fibrils, and long-fibered attapulgite are potentially
pathogenic, but conclusive assessment of the comparative
oncogenic potential of these fibers and that of asbestos cannot
yet be determined. As for wollastonite, short-fibered
attapulgite, carbon fibers, and polyolefin fibers, these fibers
appear to exhibit considerably lower pathogenic potential than
asbestos. It should be stressed, however, that these assessments
are by no means definitive because of incomplete data bases.
Although it seems that certain asbestiform fibers can cause
asbestos-related diseases, there is some evidence suggesting that
the pattern of diseases may vary with different fiber types. For
example, available epidemiological evidence suggests that
erionite exposure appears to be associated mainly with malignant
mesothelioma of the pleura and peritoneum. This is consistent
with animal evidence showing that inhalation exposure to erionite
produces very high rates of mesothelioma in animals. The
development of lung cancer, however, has not been demonstrated
experimentally nor has it been conclusively established in human
studies. On the other hand, for man-made mineral fibers, there
is some epidemiological evidence for a possible association of
lung cancer and occupational exposure to fibrous glass or mineral
wool, but a risk of mesothelioma is not apparent.
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An explanation of these differences may lie in the different
intrinsic fiber properties which may control biological
activity.- It should be pointed out, however, that mechanisms by
which mineral fibers, including asbestos, produce pathogenicity
are not understood. Furthermore, little is known of the
physicochemical properties that determine pathogenicity.
However, it is still important to briefly discuss the
relationships of fiber characteristics with possible mechanisms
of fiber-induced diseases so that speculation about their
importance can be focused in terms of research needs, and
qualitative ranking of the hazard of fibers.
Clearly, fiber dimension is an important determinant for the
development of any type of fiber-induced disease because it
governs the entry and bioavailability of a fiber at target
tissues. Fiber diameter is the most important factor in
determining the respirability of the fiber. The thinner the
fiber, the more respirable it is and the more easily it can
penetrate into the lung. Fiber length and shape also affect the
respirability and pulmonary deposition of the fiber but to a
lesser degree. However, fiber length is more important in terms
of fiber retention. Short fibers «5 jum) are readily cleared by
macrophage uptake while long fibers (>20 pm) which are not
efficiently removed by phagocytosis may be retained long enough
to cause diseases.
Fiber retention is probably also determined by the
biological solubility of the fiber. In the lung, asbestos and
nonasbestos fibers may undergo physicochemical alterations to
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varying degrees, which could result in fragmentation and
dissolution. Thus, it would appear that fibers which have low
solubility, i.e., more durable fibers, are potentially more
hazardous because of their long retention at target tissues. It
has therefore been suggested that ceramic fibers are of
considerable concern because they are relatively durable. On the
other hand, the lower hazard potential of mineral wool and
fibrous glass might be due to their high solubility. It should
be noted that the solubility of a fiber is probably largely
determined by fiber chemical characteristics.
With respect to the role of fiber properties in mediating
biological effects and the development of diseases, fiber size
also appears important for the pathogenesis of malignant
mesothelioma. In a series of studies by Stanton and co-workers
(Stanton et al., 1977, 1981) involving intrapleural implantation
of various fibrous dusts of diversified chemical, crystallo-
graphic and morphological structures, a correlation was
demonstrated between tumor incidence and the number of fibers
present with lengths greater than 8 ^im and diameters less than
0.25 jjm. These studies provided the foundation for the "long,
thin" hypothesis (also known as the Stanton's hypothesis) for the
pathogenesis of mesothelioma. This hypothesis is supported by
most of the experiments conducted to date by other investigators,
showing that regardless of fiber characteristics, longer, thinner
fibers are more carcinogenic than short, thick fibers by a
variety of intracavitary injection methods. Furthermore, for a
given fiber type, samples containing more long, thin fibers are
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considerably more carcinogenic than those with mostly shorter
thin fibers.
Bertrand and Pezerat (1980) statistically reanalyzed the
data obtained from Stanton's studies and showed that
carcinogenesis is a result of a continuous function of the aspect
ratio (ratio of fiber length to fiber diameter), and the effects
of fiber length and diameter cannot be separated. Most of the
fibrous dusts which have been reported to be carcinogenic have
high aspect ratios, and therefore, tend to support this
hypothesis. However, this hypothesis does not explain the fact
that short, thin attapulgite fibers from various sources with
high aspect ratios are not carcinogenic in animals by either the
intrapleural or intraperitoneal injection method. The only
attapulgite samples which have been shown to be carcinogenic are
those containing considerable amounts of long, thin fibers. This
finding appears to argue against the Betrand and Pezerat
hypothesis but does support the role of fiber length in fiber
carcinogenesis.
The fiber size hypothesis, however, cannot explain the
differential carcinogenic responses observed for various fiber
types with similar fiber size distributions. A most notable
example is that of erionite, which has comparable fiber size
distribution as that of asbestos, yet is more potent in inducing
mesothelioma in animals fiber per fiber than asbestos by either
inhalation or injection methods. Thus, it would appear that
other fiber properties such as chemical constitution and/or
surface properties are also important in the development of
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mesothelioma. However, the fact that synthetic nonfibrous
erionite, which has identical chemical composition as naturally-
occurring fibrous erionite, is not carcinogenic argues against
the direct role of chemical constitution but rather supports the
importance of fiber morphology in fiber carcinogenesis. It
should also be noted that other nonfibrous particles do not
generally cause mesothelioma.
Mesothelioma, which is not known to be associated with
cigarette smoking, could be mediated by different mechanism(s)
than those by lung cancer. It has been postulated that mineral
fibers may behave as complete carcinogens in mesothelial cells
and fibroblasts, the progenitors of mesotheliomas and pleural
sarcomas (Mossman et al., 1983). This hypothesis is supported by
the observation that erionite, which is the most potent
mesothelioma-inducing fibrous agent, is highly genotoxic while
asbestos and other fibers such as glass fibers are only weakly
genotoxic. Based on the limited data base, the genotoxicity of
fibers also appear to be influenced by fiber dimension. Thin
fibers (e.g., fibrous glass) generally show some degree of
clastogenicity and cell transformation, whereas coarse fibers
have little or no activity. Fiber length also appears to affect
not only the ability of fibers to be phagocytized but also the
ability of intracellular fibers to induce cytogenetic damage and
cell transformation.
There is also evidence to indicate that fiber size appears
to be important in the induction of lung cancer. Davis et al.
(1986, 1987) recently demonstrated that long, thin amosite and
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chrysotile asbestos fibers are more potent than short/ thin
fibers in inducing lung tumors in rats via inhalation. It would
appear that the different tumorigenic responses between short
versus long fibers could be explained by their differences in the
lung residence time and biological activity. Long fibers of a
number of mineral fibers have been shown to be retained longer in
the lung than short fibers and, moreover, long fibers are
generally more cytotoxic and genotoxic than short fibers.
Emphasis has also been placed on the importance of surface
properties of asbestos regarding the cocarcinogenic or
promotional ability of asbestos in the development of lung
cancer. In humans, a potentiating increase in lung cancer risk
associated with asbestos exposure among cigarette smokers has
been well documented. A synergistic effect has also been
\
demonstrated experimentally in animals exposed by intratracheal
instillation to a combination of asbestos and chemical
carcinogens such as polycyclic hydrocarbons (PAHs) found in
cigarette smoke. It has been hypothesized that asbestos fibers
might serve as a physical carrier of chemical carcinogens,
providing a means for cellular transport and uptake (Mossman and
Craighead, 1979). It would appear that while the surface area
would influence the quantity of chemical carcinogen adsorbing to
the fiber, the parameters which actually determine the adsorption
of chemical carcinogens onto the fiber, would most likely be the
specific surface chemical characteristics of the fiber.
It should be noted that a synergistic effect in the
induction of lung cancer has not yet been observed between
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cigarette smoke and exposure to other asbestiforra fibers (e.g.,
fibrous glass, mineral wool). Furthermore, unlike asbestos,
erionite does not increase the genotoxicity-of chemical
carcinogens (e.g., benzo[a]pyrene), and extraction of erionite
with organic solvent to remove potential organic contaminants
does not reduce its in vitro genotoxicity (Brown et al., 1987).
These findings suggest that asbestos fibers might have different
adsorptive properties that are not shared by other fibers, which
enable them to act as promotional agents in the development of
lung cancer.
Fiber length also appears to be an important determinant in
the development of lung fibrosis. Available experimental studies
have shown that long, thin asbestos fibers are more fibrogenic
than short, thin fibers in animals via inhalation or
intratracheal instillation. It has been postulated that the
sequence of cellular events leading to fibrosis probably involves
first the interaction between the fiber and macrophage followed
by a macrophage-fibroblast direct interaction and/or via effects
on an intermediary cell type (NRC, 1984). If the theory is
correct, i.e., at least with regard to the initial step, then the
observation that long fibers are generally more cytotoxic to
macrophages than are short fibers does indeed support the
importance of fiber length in the development of fibrosis.
However, the fact that long, thin fibers of various types, such
as those of asbestos and fibrous glass, do not necessarily have
comparable fibrogenic activity, and that respirable nonfibrous
particles (e.g., silica) are also fibrogenic indicate that dust
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particle characteristics other than morphology and size may also
play an important role in the induction of fibrosis.
In conclusion, it is now recognized that the inhalation of
durable fibers of certain diameter and length size range may be
associated with the development of malignant and nonmalignant
lung diseases. However/ the pathogenic response may vary
depending on the nature of the fibrous dustf including chemical
constitution, solubility, surface charge, surface area, fiber
size and morphology. Because these properties are probably
interrelated, elucidation of the pathogenicity and mechanisms of
fiber-induced diseases has been difficult. To increase our
understanding of the health hazards of fibrous dusts, it is
therefore necessary to study the common physical and chemical
properties of these fibers in relation to their biological
activity. This could lead to modifications of the
physicochemical properties of fibers in order to minimize the
production of adverse effects without affecting the desired
properties necessary for industrial and commercial usage. Until
the gaps in knowledge of this subject are filled, the fiber size
model remains useful for further experimental studies, as well as
environmental and epidemiological studies. Additional studies
should also be conducted to elucidate the mechanisms for fiber-
induced cytotoxicity, genotoxicity, and pathogenicity. Further
studies investigating the relationship between fibrogenicity and
carcinogenicity are also needed.
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bacterial mutagenicity assay by W.C. Hengler and R.S. Slesinski
(10/21/82); (3) material safety data sheet- carbon fibers.
Washington, DC: Office of Toxic Substances, U.S. Environmental
Protection Agency.
Union Carbide. 1983b. 8EHQ-0483-0423 Supplement. Polyacrylo-
itrile (PAN)- based carbon fibers (benzene extract)
Salmonella/microsome (AMES) bacterial mutagenicity assay by
Hengler WC, Slesinki RS, et al. (10/21/82) Washington, DC:
Office of Toxic Substances, U.S. Environmental Protection Agency.
Union Carbide. 1983c. Union Carbide Corporation. 8EHQ-1285-
0423 FLWP. Benzene extract of pitch-based carbon fibers in
vitro mutagenesis studies: 3-test battery. By Slesinski RS, et
al. (1/14/83) Washington, DC: Office of Toxic Substances, U.S.
Environmental Protection Agency.
Union Carbide. 1983d. Union Carbide Corporation. 8EHQ-0483-
0423 Supp. Benzene extract of polyacrylontrile (PAN)-based carbon
fibers in vitro mutagenesis studies: 3-test battery by Slesinski
RS, et al. (12/22/82) Washington DC: Office of Toxic
Substances, U.S. Environmental Protection Agency.
USEPA. 1986. Guidelines for carcinogenic risk assessment.
Federal Register 51:33992-34003.
Vallyathan V, Robinson V, Reasor M, Stettler L. 1984.
Wollastonite and asbestos cytotoxicity. Ann Rev Resp Dis
129:A178.
Wagner JC. 1982. Health hazards of substitutes. In:
Proceedings of the World Symposium of Asbestos. May 25-27.
Montreal, Canada, pp. 244-266.
Wagner JC, Berry G, Timbrell V. 1973. Mesothelioma in rats
after inoculation with asbestos and other minerals. Br J Cancer
28:173-185.
-------
213
Wagner JC, Berry GB, Skidmore JW. 1976. Studies on the
carcinogenic effects of fiberglass of different diameters
following intrapleural inoculation in experimental animals.
In: Occupational exposure to fibrous glass. Proceedings of a
Symposium. Washington, DC. US Dept. Health, Education and
Welfare. NIOSH Publication No. 76-151. pp. 193-197.
Wagner JC, Berry GB, Hiu RJ, Munday DE, Skidmore JW. 1984.
Animal experiments with MMM(V) fiber-effects on inhalation and
intrapleural inoculation in rats. In: Biological effects of
man-made mineral fibers. Proceedings of a WHO/IARC Conference,
Volume 2, Copenhagen, Denmark, April 20-22, 1982, Copenhagen,
WHO Regional Office for Europe; pp. 209-233.
Wagner JC, Skidmore JW, Hill RJ, Griffiths DM. 1985: Erionite
exposure and mesotheliomas in rats. Br J Cancer. 51:727-730.
Wagner JC, Griffiths DM and Munday DE. 1987. Experimental
studies with palygorskite dusts. Br. J. Ind. Med. 44:749-763.
Warheit DB, Hill LH, Brody AR. 1984. In vitro effects of
crocidolite asbestos and wollastonite on pulmonary macrophages
and serum complement. Scanning Electron Microscopy 2:919-926.
Waxweiller RJ, Zumwalde RD, Ness GO, Brown DP. 1985. Mortality
among persons mining and milling attapulgite clay. Division of
Surveillance, Hazard Evaluations and Field Studies and Division
of Standards Development and Technology Transfer, National
Institute for Occupational Safety and Health. Presented at
International Symposium on Inhaled Particles, Cambridge, England.
Weill H, Hughes JM, Hammad YY, et al. 1983. Respiratory health
in workers exposed to man-made vitreous fibers. Am Rev Resp Dis
28:104-112.
Woodworth GD, Mossman BT, Craighead JE. 1983. Induction of
squamous metaplasia in organ cultures of hamster trachea by
naturally occurring and synthetic fibers. Cancer Res 43:4906-
4912.
Wright G, Kuschner M. 1976. The effects of intratracheal
instillation of glass fiber of varying sizes in guinea pigs.
Proceedings of a symposium, U.S. Department of Health, Education,
and Welfare. NIOSH Publication No. 76-151; pp. 151-156.
Wright GW, Kuschner M. 1977. The influence of varying lengths
of glass and asbestos fibers on tissue response in guinea pigs.
Inhaled particles. Watton WH, ed. New York: Pergamon Press,
pp. 455-474.
-------
214
Wright WE, Rom WN/ Moatamed F. 1983. Characterization of
zeolite fiber sizes using scanning electron microscopy. Arch
Environ Health 38:99-103.
Zumwalde, R. 1977. Industrial hygiene study of the Englehard
Minerals and Chemicals Corporation, Attapulgus, Georgia. NIOSH
Report, April 29, 1977.
VII. APPENDIX
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON FIBROUS GLASS
Fiber Type
Glass Moot
Coated Glass
Fibers (calcium
carbonate)
Coated Glass
Fibers (calcium
sulfate)
Glass Fibers
(uncoated)
Coated Glass
Fibers (Phenol
formaldehyde
resin)
Coated Glass
Fibers (starch
binder)
Fiber Dimension
i
Species
20) <2 fat ' Guinea Pigs
diameter; average Rats
diameter near
5 fm; 70K >5 um long
Not specified
Not specified
Average d 1 ameter
0. 5 jjn; average
length 10 urn
(5-20 urn)
As Above
As Above
Monkeys
Guinea Pigs
Rabbits
Rats
Guinea Pigs
Rabbits
Rats
Rats
Hamsters
Rats
Hamsters
Rats
Hamsters
Number
of
Animals
too
50
5
40
18
30
63
18
20
30
30
30
30
30
30
Route Dose/ Frequency/
of Admin 1- Concentra- Treatment
stratlon tlon Duration
Inhalation 0.145 mg/m3 44 mo
0.03 mg/m3 28 mo
Inhalation 4.6 mg/m 8 mo
24 mo
18 mo
18 mo
Inhalation 3.8 mg/m3 15 mo
19 mo
9 mo
Inhalation 135 ng/m3 2 yr
Inhalation 106 mg/m3 2 yr
Inhalation 1 13 mg/m3 2 yr
Duration Results Remarks References
of Study
44 mo Little evidence of dust Poor animal survival; Ion Schepers (1955), I959a.
28 mo reaction In any species; No concentration level 1959b, 1961)
fibres Is; no pulmonary tumors Schepers and Delahunt
(1955); Schepers (1976)
8 mo As above No Information on dust cloud As above-
24 mo
18 mo
18 mo
15 mo As above No Information on dust cloud As above
15 mo
9mo «
Ul
Llfespan No flbrosts or tumors; hlsto- Poor survival Gross et al. (1970)
logical changes limited to Gross (1976)
those seen from Inert dusts
Llfespan As above As above
Llfespan As above As above
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON FIBROUS_GLASS (CONTINUED)
Fiber Type
Fibrous Glass
Fiberglass
Insulation
Fiberglass
Fiber Dimension
801 3
Species
Male Albino
Mice (Charles
River, CDR-t)
Male A-straln
Mice
Male
Charles River
Sprague-Oawley
Rats
Male Albino
Guinea Pigs
Number Route
of of Admin 1-
Anlmals stratlon
20 Inhalation
12 Mixed In
bedding
material
(Inhalation)
46 Inhalation
32 Inhalation
Dose/
Concentra-
tion
1070
f 1 bers/mL
300 mg/
100 mg
bedding
400 mg/m3
(700
fibers/Hi)
400 mg/m3
(700
Frequency/
Treatment Duration Results
Duration of Study
6 veeks 6 weeks No lung damage; no f Ibrosls
30 days 90 days Bronchogenlc tumor (3/12);
septal cell tumor (2/12)
90 days 18-24 mo Bronchoalveolar adenoma (2/19);
control rats had no tumors
(0/13); No flbrosls
90 days 18-24 mo Bronchoalveolar adenoma (2/8);
control animals had no tumor*
Remarks
Short exposure
No unexposed controls; short
exposure; small number of
exposed animals; atypical
method of administration
Short exposure; small number of
animals; mostly nonflbrous
material
References
Mori s jet et al. (1979)
Morrison et al.
(1981)
Lee et al. (1979)
tee et at. (1981)
K>
O*
As above
fIbers/mL)
(0/6); no flbrosls
Glass Fibers
(Johns-ManvlIle
Code 100)
Uncoated Glass
Wool
Coated Glass MooI
Not specified
SPF Fischer Rats 2/group Inhalation 10 mg/m
SO weeks 16 mo Focal flbrosls was evident with
all the dusts but more marked
with chrysotlle; noncoated glass
wool more reactive than uncoated
glass wool
Smalt number of animals
Johnson and Wagner
(1980)
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON FIBRQyUtLASS (CONTINUED)
Fiber Type
Glass Micro-
fibers (A blend
of JM CI02 and
JM C104)
Glass Micro-
fibers (Johns-
Manvllle
Coda 100)
Glass Moot
(uncoated)
Glass Wool
(coated)
Glass Micro-
fibers
(JM Cod* 100)
Fiber Dimension
Median diameter
0.6 urn; iMdlan
length 6. 25 urn
Mean diameter
0.3 fm; 71)
10 pi long
1
0.2-3 urn
diameter; 57 J
>10 um long
Not available
but presumably
similar to that
used In Wagner
et al. (1984)
Number Route
Species of of Admin 1-
Anlmals stratlon
Male Baboons Not Inhalation
(Paplo urslnus) speci-
fied
(10
animals
In total
Including
positive
contro 1 s )
Male and Female 28 of Inhalation
Fischer 344 Rats each sex
Male and Female 28 of Inhalation
Fischer 344 Rats each sex
Male and Female 28 of Inhalation
Fischer 344 Rats each sex
Male and Female Unspe- Inhalation
Fischer 344 Rats clfled
Dose/
Concentra-
tion
7.54 mg/m3
(1122
f Iber/mL)
10 mg/m1
(1436
f Ibers/mL)
10 mg/m3
(240
f Ibers/mL)
10 mg/m3
(323
f Ibers/mL)
10 mg/m3
Frequency/
Treatment Duration Results Remarks
Duration of Study
35 mo 41-42 mo Fibres Is after 18 and 30 mo Short exposure In relation to
exposure; however, lesions llfespan of baboons; no un-
less severe than those In exposed controls
animals exposed to crocl-
dollte; no evidence of
malignancy
12 mo Llfespan No f Ibrosls at 24 mo; No tumors In unexposed controls;
lung adenocarclnoma (1/48) 12 tumors In 48 chrysotlle
exposed animals (It lung
. adenocarclnomas; 1 adenoma)
12 mo Llfespan No f Ibrosls; lung adenocarclnoma
( 1/48)
12 mo Llfespan No f Ibrosls; lung adenoma (1/48)
12 mo Llfespan No f Ibrosls; no neoplasms . Lung tumors In 11 of 56 chryso-
(0/55); lung adenocarclnoma tile exposed rats (7 adenocarcl-
In 2 of 53 negative controls noma; 4 adenoma)
References
Goldstein et al. (1983)
Goldstein et al. (1984)
Wagner et el. (1984)
M
*4
As above
As above
McConnell et al. (1984)
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON FIBRQUSrfSLASS (CONTINUED)
Fiber Type
31 as* Micro-
fibers
(JM Cod* 100)
Slass Moot
(uncoated)
3 lass Mlcro-
f 1 bers
Number Route DOS*/ Frequency/
Fiber Dimension Species of of Admlnl- Concentre- Treatment Duration
Animals stratlon tlon Duration of Study
51* with 0.2-O.J Male and Female 24 of Inhalation 5 mg/m3 12 or 24 24 mo
un diameter IOPS AF/Han Rats each sex (332 mo
f Ibers/mL)
68*
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON FIBRO^B^ASS (CONTINUED)
Number
rltwr Type Fiber 01 mansion Species of
An Ima Is
3lass Wool 3.1 urn mean Male Syrian 60
diameter Hamsters
Female Osborne- 52
Mendel Rats
;lass Wool 5.4 pm mean Male Syrian 66/69
d 1 ameter Hamsters
Female Osborne- 57/61
Mendel Rats
•lass Moot 6.1 pm mean Male Syrian 99
diameter Hamsters
Female Osborne- 58
Mendel Rats
Route Dose/ Frequency/
of Admlnl- Concentre- Treatment Duration Results Remarks References
strati on tlon Duration of Study
Inhalation 10 mg/m 24 mo Llfespan No f Ibrosls or lung neoplasms Glass wool aerosol dusts had a Smith et al. (1986)
(100 In exposed rats or hamsters large proportion of nonflbroos
flbers/mL) material
Inhalation 12 mg/m 24 mo Llfespan No f Ibrosls or lung neoplasms As above
(100 In exposed rats or hamsters
fibers/mo or
1.2 mg/m3
(10 flbers/mL)
i K>
Inhalation 9 mg/«r 24 mo Llfespan No f Ibrosls or lung neoplasms As above —
(25 In exposed rats or hamsters • "°
flbers/mL)
-------
TABLE
SUMMARY OF ANIMAL STUDIES ON Fl
SS (CONTINUED)
Fiber Type Flbar Dimension Species
Number
of
Animals
Rout*
of Admini-
stration
Dose/
Concentra-
tion
Frequency/
Treatment
Duration
Duration Results
of Study
Remarks References
Fibrous Glass 4.6 um diameter;
(Red Binder; >20 um long
Group I)
Male and Female 50/5ex Inhalation IS mg/m3
Fischer 344 Rats
Male Cynomolgus IS
Monkeys
Inhalation II mg/«
86 weeks 86 weeks
72 weeks
72 weeks
No fibres Is; no pul nonary
tumors or mesothel Ionia In any
treated rat or monkey groups;
statistical Increase In mono-
nuclear cell leukemia In Group I
female rats (p-0.047; Fisher
exact test). Group III (p-0.024)
and Group IV (p-0.002) male rats.
Early death In 37* rats In Mitchell et al. (1986)
treated and control group; short
treatment and study duration
Fibrous Glass 0.5-5.5 um Male and Female
(Yellow Binder; diameter; >10 urn Fischer 344 Rats 50/sex Inhalation 15 mg/m
(Group II) long
Male Cynomolgus 15
Monkeys
Inhalation IS mg/mj
86 weeks 86 weeks
72 weeks 72 weeks
As above
Fibrous Glass <3.5 um diameter; Male and Female SO/sax Inhalation 5 mg/m
(Uncoated;
Group III)
>IO fm long
Fischer 344 Rats
Male Cynomolgus
Monkeys
15
Inhalation 5 mg/m
86 weeks 86 weeks
72 weeks 72 weeks
As above
Fibrous Glass <3.S um diameter; Male and Female 50/sex Inhalation 5 mg/m
(Uncoated;
Group IV)
<10 um long
Fischer 344 Rats
Male Cynomolgus 15
Monkeys
86* weeks 86 weeks
Inhalation 5 mg/m3 72 weeks 72 weeks
As above
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON Fl
SS (CONTINUED)
Iber Type Fiber Dimension
Ibrous Glass 6 samples of vary-
ing fiber size
distributions
Species
Female pathogen-
free Osborne-
Mendel Rats
Number Route Dose/
of of Admlnl- Concentra-
Anlmals stratlon tlon
Not Intrapleural 40 mg
sped- Implantation
fled
Frequency/
Treatment Duration Results
Duration of Study
Single dose 2 yrs Moderately high Incidence of
mesothelloma In two samples of
fine fiberglass milled to
approach length of asbestos
fibers
Remarks
High Incidence of mesothellom
In amoslte, chrysotlle, and
croc 1 do lite exposed group
References
Stanton and wrench (1972)
I berg I ass
Code 110)
30} <2.5 urn
diameter; 60)
>20 pm long
SPF Wlstar Rats 36
(sex unspecified)
Intrapleural 20 mg
Injection
Single dose Llfespan No mesothelloma
Mesothelloma In 23/36 rats
treated with SFA chrysotlle
Wagner et a I. (1973)
• lass Fibers
3.; pm diameter;
<20 pm long
3.5 urn diameter;
>100 pm long
0.05 pn diameter;
<20 |M long
0.05 pm diameter;
»00 pn long
Balb/C Mice 25/group Intrapleural 10 mg
Injection
Single dose 18 mo
Long fiber samples produced
mass Ive fIbrosIs while short
flbered samples produced only
discrete granulomas with minimal
fIbrosIs
Davis (1976)
Ibrous Glass 17 samples of Female Osborne- 30 In Intrapleural 40 mg
diverse dimensional Mendel Rats each Implantation
distributions treated
group
Single dose 2 yrs
Highest yield of pleura! sar-
coma with fibers <1.S urn In
diameter and >8 urn In length
Stanton et al. (1977)
-------
TABLE
SUMMARY OF ANIMAL STUDIES ON FIB
|SS (CONTINUED)
Iber
Mass
Code
• lass
Type
Fiber
MO)
'Icrof Iber
Code
100)
Fiber Dimension
17) <1 urn diameter
median dlametef
1.8 urn; median
length 22 urn
99) 20 pi long
Ibrous Glass Mean diameter Male Syrian 60
0.1 urn; S2t >20 \n Golden Hamsters
long
Median diameter
0.09 LMI; 0-2)
>20 urn long
Mean diameter 0.33
urn; 46) >20 |M long
Mean diameter 0.41
)«; 0-2% >20 |im long
Mean diameter 1.23
urn; 34) >20 \m long
Mean diameter 1.49
urn; 0-2) >20 Mm long
IntrapI euro I 25 mg
Injections
Single dose Not Intrathoraclc tumors (9/60)
specified
No tumors
Intrathoraclc tumors (2/60)
No tumors
Intrathoraclc tumors (2/60)
No tumors
Histology not provided; no
control group reported
Smith at al. (1980)
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON Fl«"
•SS (CONTINUED)
Iber Type Fiber Dimension
*lne Glass Mean diameter
"Ibers 0.229 urn; mean
length 5.8 urn
fibrous Glass 22 samples of
diverse dimension-
Species
Male Sprague-
Dawley Rats
Female Osborne-
Mendel Rats
Number Route Dose/
of of Admlnl- Concentra-
Anlmals stratlon tlon
45 Intrapleural 20 mg
Injection
30-50 Intrapleural 40 mg
Implantation
Frequency/
Treatment Duration Results
Duration of Study
Single dose Llfespan 13) Incidence of pleura! tumors
(6/44)
Single dose 2 years Probability of pleura! sarcoma
best correlated with the number
Remarks
No tumors In vehicle controls
(saline); high Incidence of
mesothel loma In chrysotlle (4S)>
and crocldollte (54)) treated
animals
References
Lafuma et al. (1980);
Monchaux et al. (1981)
Stantcm et al. (1981)
al distributions
of fibers with diameters
<0.25 urn and length >8 urn;
relatively high correlations
also noted for fibers with
diameters up to 1.5 urn and
length >4 urn
Slass Micro-
fibers (Johns-
lanvllle
Code 100)
86) <0.6 pm
diameter;
88) <5 urn long
SPF Sprague-
Dawley Rats
48
Intrapleural
Injection
20 mg
Single dose Llfespan
Pleura!
rats
mesothel loma In 4 of 48
Six cases of pleura I tumors
48 rats treated with UICC
chrysotlle asbestos
In Wagner et at. (1984)
Slass Moot
(uncoated)
85)
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON FIBRCj
(CONTINUED)
Number Route Dose/ Frequency/
Iber Type Fiber Dimension Species of of Admin 1- Concentre- Treatment Duration Results
Animals stratlon tlon Duration of Study
Ibrous Glass Mean diameter 0.5 Female Wlstar 40 Intraperl- 2 mg Single dose Not
Abdominal tumors (mostly
S + SI06) urn; 72.6) <5 urn Rats toneal specified mesothel loma) 2.5) at 2 mg,
long Injection 10 mg Single dose
4x25 mg Four doses
at weekly
Intervals
10) at 10 mg and 57) at
100 mg; f Ibrosls In
animals receiving 100 mg
of glass fibers; less
severe lesions at 10 mg and
2 mg dose levels
Remarks
Tumor rates of 15-67) In UICC
chysot 1 1 e asbestos treated
group at similar dosing regimen;
latency period Inversely related
to dose; no tumors In saline
treated controls
References
Pott and Frledrlchs
(1972); Pott et al.
(1974) and (1976)
I berg I ass
:MNI04)
50) <0.2 urn
diameter; 50)
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON Fl
iSS (CONTINUED)
Fiber Type
Glass
Mlcrof Ibers
Glass Fibers
(JM 104)
Glass
Mlcrof Ibers
(JM 104)
Glass
Mlcrof (bars
(JM 100)
Fibrous Glass
Fiber Dimension Species
Average diameter Balb/c
of 0.05 urn nice
Rats
(unspecified
strain)
Not specified Wlstar Rats
( Ivanovas)
SIV Rats
( Ivanovas)
Sprague-Oawley
Rats (Hagenann)
Ml star Rats
(Hagemann)
501 <0.3 urn Wlstar/Sprague-
dlaneter; Daw lay Rats
90| <13 urn long
501 <0.3 pn Wlstar/Sprague-
dlameter; Daw ley Rats
90S <7 urn long
0.45 urn mean Female Osborne-
dlameter Mendel Rats
Number Route Dose/
of of Admin)- Concentra-
Anlmals strut Ion tlon
25 Intraperl- 25 ng
tonea 1
Injection
18 Intraperl- 10 mg
tonea 1 «
Injection
50 Intraperl- 10 mg
tonea 1
Injection
50
50
50
40-60 Intraperl- 2 or 10 mg
group tonea 1
Injection
40-60 Intraperl- 2, 5, or
group tonea 1 10 mg
Injection
25 Intraperl- 25 mg
tonea 1
Injection
Frequency/
Treatment Duration
Duration of Study
Single dose Not
Specified
Single dose Not
Specified
Single dose Not
specified
Single dose Not
specified
Single dose Not
specified
Single dose Not
specified
Results Remarks References
Peritoneal tumors (3/25) Davis (1976)
Peritoneal tumors (3/28)
Abdominal tumors (25/49; 5t)> No experimental details Pott et al. (1980)
Abdominal tumors (36/50; 721)
to
to
Abdominal tumors (29/49; 59.2)) "
Abdominal tumors
(39/49; 79.6J)
Peritoneal sarcoma and Pott et al. (1984)
mesothelloma ( 40-70* )
Peritoneal sarcoma and As above
mesothelloma (2-IOf)
Abdominal mesothelloma (8/25); Tumor Incidence of 80$ (20/25); Smith et al. (1986)
Abdominal reactive tissue/ In positive controls treated with
fibres Is In 13/17 animals UICC croc 1 do lite asbestos; no
untreated animals
-------
TABLE I. SIMMARY OF ANIMAL STUDIES ON FIG
6S (CONTINUED)
Iber Type
"Ibrous Glass
(Uncoated)
~ Ibrous Glass
(Coated with
;esln)
Fibrous Glass
(Coated with
Starch Binder)
Fiber Dimension
Average d 1 ameter
0.5 um; average
length 10 um
Average diameter
0.5 urn; average
length 10 um
Average diameter
0.5 um; average
length 10 |m
Number Route
Species of of Admlnl-
Anlmals stratlon
Rats (strain I5/
unspecified) 30
Hamsters (strain 12
unspecified)
Rats 30
Hamsters 12
12
12
Rats 15
30
Hamsters 12
Intratra-
cheal In-
stillation
Intratra-
cheal In-
stillation
Intratra-
chea 1 1 n-
stl nation
Dosa/ Frequency/
Concentra- Treatment Duration Results
tlon Duration of Study
3 x
3.5 mg or Not Llfespan No tumors In any treated rat
10 x 3.5 mg specified or hamster group
3 x
3 x
or
10 x
1 x
2 x
3 x
3 x
10 x
3 x
3.5 mg
3.5 mg As above As above
3.5 mg
3.5 mg
1.75 mg
3.5 mg
3.5 mg
3.5 mg
3.5 mg
Remarks References
Experimental details not avail- Gross (1976)
able; no positive controls;
small number of animals
As above As above
As above
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON Fl
S (CONTINUED)
Fiber Type
Fiber Dimension Species
Number Route Dose/ Frequency/
of of Admlnl- Concentra- Treatment Duration
Animals stratlon tlon Duration of Study
Results
Remark*
References
-lass Fibers Diameter <1 pm; Guinea Pigs
(Thin Fibers) 93* <10 urn long
Diameter <1 urn; Guinea Pigs
921 >IO in long
I: lass Fibers
JVery Thin)
3 lass Fibers
(Thick)
Diameter <0.3 urn
and <5 urn long
Diameter <0.3 urn;
50* >IO urn long
Diameter 2 um;
88) IO um long
30 Intratra- 2 x 12.? mg Biweekly 2 years No fIbrosls nor tumors
cheal
Instillation
30 3 x 4 mg Biweekly 2 years Flbrosls; no tumors
30 Intratra- 2 x 12.5 mg Biweekly 2 years No f Ibrosls nor tumors
cheal
Instillation
30 2 x 6 mg Biweekly 2 years Flbrosls; no tumors
30 Intratra- 2 x 12. $ mg Biweekly 2 years No f Ibrosls nor neoplasms
cheal
Instillation
30
2 x 12.5 mg Biweekly 2 years No f Ibrosls nor neoplasms
Long fibers O10 um) of croc I do- Wright and Kuschner
lite asbestos produced fIbrosls; (1976, 1977)
short fibers «IO um) did not
produce fIbrosls
As above
As above
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON Fl
S (CONTINUED)
Iber Type Fiber Dimension Species
tacoated Glass O.I um man Male Syrian
"Icroflbers diameter Hamsters
0.25 |M mean
d 1 ameter '
household 2.3 ym mean diameter
nsulat Ion
•lass fibers 3.0 um mean diameter
4.1 pm mean dlamater
3lass SO) <0.3 |m Male Syrian
'Icroflbers diameter; Golden Hamsters
(JM Code 104) 50) <7 um long
SO) <0.3 pm
diameter;
50) <4.2 M«
long
Number Route Dose/
of of Admlnl- Concentra-
Anlmals stratlon tlon
20 Intratra- A total of
cheal In- 7 mg
stl Nation
20 2 mg
20 21 mg
20 18 mg
20 17 mg
136 Intratra- 8 x 1 mg
cheal
Instillation
138 Intratra- 8 x 1 mg
cheal
Instillation
Frequency/
Treatment Duration
Duration of Study
Biweekly It months
Meekly
Not specified
Not specified
Not specified
Weekly 136 weeks
Meekly 136 weeks
Results Remarks References
Mild flbrosls In glass micro- Ptckrell et al. (1983)
fibers treated group at 11
months after Instillation
No flbrosls As above
No flbrosls
No flbrosls
K>
Lung carcinoma (5/136) Tumors In croc 1 do lite asbestos Mohr et al. (1984) £
Pleura! mesothel loma (37/136) positive controls
Thoracic sarcomas (6/136) Lung carcinoma (9/142)
Mesothel loma (8/142)
Thoracic sarcoma (1/142)
Lung carcinoma (6/138) 2 cases of thoracic sarcoma
Mesothel loma (26/138) (2/135) In titanium dioxide
Thoracic sarcomas (6/138) treated group but no
mesothel loma or lung
neoplasms; no saline
control group
-------
TABLE I. SUMMARY OF ANIMAL STUDIES ON Fl
S (CONTINUED)
Iber Type
• lass
Mcrof Ibers
JM Code 104)
Ibrous Glass
-lass
Mcrof Ibers
JM 104/
Fiber Dimension
31} <0.25 urn
diameter; 58*
<5 urn long
0.45 v» mean
d 1 ameter
50* <3.2 urn
length; 50*
<0. 12 urn
Species
Mala and Female
Syrian Golden
Hamsters
Female Osborne-
Mendal Rats
Female
Wlstar
Rats
Number Route Dose/
of of Admin 1- Concentra-
Anlmals stratlon tlon
35/sex Intratra- 26 x 1 mg
cheat
Instillation
32 Intratra- 5 x 2 mg
cheat
Instillation
34 Intratra- 20 x 0.05 mg
cheat
0.5 mg
Frequency/
Treatment Duration
Duration of Study
Biweekly 85 weeks
for 52
weeks
Meekly Llfespan
Weekly Llfespan
Results
No tumors (0/34 males; 0/30
females)
Slgnf leant f Ibrosls (7/22);
no tumors
Lung tumors In 5/34 animals
(1 adenoma, 2 adenocarclnoma,
2 squamous cell carcinomas)
Remarks
No positive control animals
No lesions In saline controls
and untreated animals
Positive control animals
treated with croc 1 do lite
had 11/35 lung tumor
References
Feroo et al. (1985)
Smith et al. (1986)
Pott et al. (1987a)
Instilla-
tion
and 9/142 lung cancer
-------
Table 2. SLMMARY OF ANIMAL
FON MINERAL WOOL
Fiber
Type
Rock wool
Salnt-Gobaln
rock wool
Fiber
Dimension
58$ IO |im long
22.71 IO um long
Species
Male and
Female
F344 rats
Male and
Female
Wlstar IOPS
rats
Number of Route of Dose/ Frequency/ Duration of
Animals Administration Concentration Treatment Study
Duration
56 Inhalation 10 mg/m3 12 mo Llfespan
(227 flbers/mL;
for d <3 (•»;
and 1 >5 um)
48 Inhalation 5 mg/m3 24 mo 24 mo
(It flbers/mL;
for J^>5 um)
Results
No lung fibres Is;
lung adenoma (2/48)
No pulmonary
changes; no
lung tumors
(0/24 males;
Remarks References
No tumors In Wagner et at. (1984)
unexposed controls;
lung adenocarclnoma
(11/48) and adenoma
(1/48) In chrysotlle
asbestos positive
controls
Very low fiber con- Le Bouffant et al.
centratlon; dust (1984)
cloud contained
mostly nonflbrous
particles; nine
cases of lung tumors
In Canadian chryso-
tlle asbestos control
group (males, 9/24;
females. 4/23); no
tumors In unexposed
control animal (0/27)
-------
Table 2. SUMMARY OF ANIMAL STUOI9
ERAL WOOL (CONTINUED)
Fiber
Type
Mineral
Wool
Fiber
Dimension
mean diameter
2.7 urn; 75*
>10 urn long
Number of Route of Dose/ Frequency/ Duration of
Species Animals Administration Concentration Treatment Study Results
Duration
Female Osborne- 55 Inhalation 12 mg/m (200 24 mo Llfespan No pulmonary
Mendel rats flbers/mL; flbrosls; No lung
76 flbers/mL tumors (0/55)
for fibers
longer than
10 urn with
diameters
<1 pm)
Remarks References
3/57 UICC crocodo- Smith et al. (1986)
lite positive control
rats developed tumors
(1 mesothel loma.
2 bronchoalveolar
tumors); No tumors
In sham controls
(0/59) and
unexposed rats
(0/125)
Male Syrian
hamsters
69
InhaI at I on
as above
24 mo
Llfespan
No lung flbrosls;
no lung tumors
(0/69)
No tumors In UICC
crocodoIIte asbestos
exposed group (0/58)
or In unexposed
controls (0/112);
one bronchoalveolar
tumor (1/58) In
sham control group
-------
Table 2. SLMMARY OF ANIMAL STUDIt
INERAL WOOL (CONTINUED)
Fiber
Type
Rock Wool
(with resin)
Rock wool
(without
resin)
Slag Wool
(with resin)
Slag Wool
(without
resin)
Fiber
Dimension
77$ <1 ftm In
diameter; 10%
<5 urn long
82$ <1 urn In
diameter; 69$
<5 pm long
10%
-------
Table 2. SIMMARY OF ANIMAL STUD IE
NERAL WOOL (CONTINUED)
Fiber
Type
Rock Wool
Rock Wool
Slag Wool
Basalt Wool
Basalt Wool
Fiber Species Number of
Dimension Animals
SO) <0.64 urn In Female Sprague- 45
diameter; 50) ' Daw ley rats
<4.l urn long
SO) <1.90 urn Female Sprague- 63
diameter; 50) Daw ley rats
<23 urn long
90) <0.28 urn Female Wlstar 41
diameter; 9) rats
<10 urn long
SO) <0.52 |im Female Wlstar 45
diameter; 50) rats
<58 pm long
50) <1.8 urn Female Wlstar S3
diameter, 50) rats
<20 urn long
Route of Dose/
Administration Concentration
Intraperltoneal 10 mg
Injection
Intraperltoneal 25 mg
1 n ject 1 on
Intraperltoneal 5 mg
Injection
Intraperltoneal 5 mg
Injection
Intraperltoneal 15 mg
Injection
Frequency/ Duration of Results
Treatment Study
Duration
Single dose 15 mo No peritoneal tumors
3 x 25 mg Llfespan Peritoneal sarcoma/
mesothelloma (16))
Single dose Llfespan Peritoneal tumors
(5))
Single dose 15 mo No peritoneal tumors
5 weekly Llfespan Peritoneal tumors
doses In 30/53; negative
sat Ine control had
a tumor Incidence
of 1/102; UICC/
Canadian chrysotlle
produced high
Incidence of tumor
at much lower
doses
Remarks References
Short observation Pott et al. (1984)
period (ongoing
study)
No positive As above
control group*
Small dose; tumor As above
yield not
statistically
significant
Relatively small As above
dose; short
observation period
Relatively large Pott et al. (1987b)
fibers; very
high dose level ;
preliminary
results only
-------
Table 3. SUMMARY OF ANIMAL
CERAMIC FIBERS
Fiber
Type
Ceramic
Aluminum
Silicate
Gists
Fiber Number of Rout* of Dose/ Frequency/ Duration of
Dimension Species Animals Administration Concentration Treatment Study Results Remarks References
Duration
90% <3 urn long SPF Wlstar rats 48 Inhalation 8.4 mg/m1 12 mo Up to Interstitial f 1 broils Dust cloud contained Davis et al. (1984)
and <0.3 urn (AF/HAN strain; (95 f Ibers/mL; 32 mo occurred to a loiter mostly short, thin
diameter sex unspecified d <3 urn, 1 but not significantly fibers
>5 urn) different degree than
that for chrysotlle
asbestos animals ob-
served In other
studies; lung
tumors In 8 animals
(1 adenoma.
3 carcinomas.
4 mal Ignant
hlstlocytomas); no
tumors In 40
unexposed control
animals
-------
Table 3. SUMMARY OF ANIMAL STUOIEl
4IC FIBERS (CONTINUED)
Fiber Fiber
Type Dimension
Refractory 83f> 10 Urn long
Ceramic Fiber and 86} <2 urn
diameter
Number of
Species Animals
Female Osborne- ' 55
Mendel rats
Mole Syrian 70
hamsters
Route of Dose/
Administration Concentration
Inhalation ' 12 mg/m3
(200 flbers/mL)
Inhalation 12 mg/m5
(200 ftbers/mL)
Frequency/ Duration of
Treatment Study
Duration
24 mo Llfespan
24 mo Llfespan
Results
No lung flbrosls; no
lung tumors; no tumors
In sham or unexposed
control
No lung flbrosls;
one mesothel loma;
Remarks References
Low tumorlgenlc re- Smith et al. (1986)
ponse In UICC crocldo-
1 Ite asbestos control
rats (3/59;
1 mesothel loma.
2 bronchoalveolar
tumor)
No tumors (0/58)
In positive control
no primary lung
tumors; no tumors
In unexposed
control; one case
of bronchoalveolar
tumor In sham
controI
hamsters exposed to
UICC crocldollte
asbestos
-------
Table 3. SUMMARY OF ANIMAL STUDIES
1C FIBERS (CONTINUED)
Fiber
Type
Refractory
Alumina Fibers
(a* manufac-
tured or
"thermally
aged")
Synthetic
Aluminum
Silicate
Fibers
Fiber
Dimension
Median diameter of
3.0 urn; median
length 10.9-62 pm
D 1 ameter between
0.9 and 1.0 |M;
1 ength
unspecified
Number of
Spec 1 es An 1 ma 1 s
Mala and female 25 of each
albino rats of sex/group
the Alder ly
Park (Wlstar
derived strain)
SPF Wlstar 24 males
rats 12 females
Route of Dose/ Frequency/ Duration of
Administration Concentration Treatment Study Results
Duration
Inhalation 2.18-2.45 mg/m 86 weeks >B6 weeks Pulmonary reaction to
both forms of Saff II
was minimal ; no
pulmonary neoplasms
Intrapleural 20 mg Single dose Lifetime Masothel loma In
Inoculation 3/31 rats
Remarks References
Levels of resplrable Plgott et al. (1981)
dust In the atmos-
pheres were low;
positive control
animals exposed to
UICC chrysotlle
asbestos developed
pulmonary neoplasms
(9/38)
Carcinogenic poten- Wagner et al. (1973)
cy of ceramic
fibers were consi-
derably less than
SFA chrysotlle
asbestos
-------
Table 3. SLMMARY OF ANIMAL STUD IE
1AMIC FIBERS (CONTINUED)
Fiber
Type
Alumina
Oxide Fibers
(glass 21)
Zlrconla oxide
fibers
(glass 22)
Refractory
Alumina
Fiber
(Saffll)
Fiber
Dimension
Not specified
Not specified
Type A:
median diameter
2.75 um;
median length
15.5 um
Type B:
median diameter
3.7 um; median
length 17 um
Species Number of
Animals
Female Osborne- 50
Mendel rats
Female Osborne- 50
Mendel rats
SPF Mlstar 22 males and
rats (Alderley 12 females
Park Strain) per group
Route of Dose/
Administration Concentration
Intrapleural 40 mg
Implantation
Intrapleural 40 mg
Implantation
Intraperltoneal 20 mg
Injection
__ ^
Frequency/ Duration of Results
Treatment Study
Duration
Single dose 2 yr Pleura! neoplasms
In 2/47 rats
Single dose 2 yr Pleura! neoplasm
In 1/45
Single dose up to 12 mo Mild chronic
Inflammatory
response with a
ml Id amount of
cot lagen In the
abdominal tissues
Remarks References
Tumor Incidence Stanton et al.
not statistically (1981)
significant
Tumor Incidence
not statistically
significant
Progressive Plgott and Ishmael
peritoneal fibres Is (1981)
In rats receiving
UICC Rhodes Ian
chrysotlle asbestos
-------
Table 3. SUMMARY OF ANIMAL STUD I?
t RAM 1C FIBERS (CONTINUED)
Fiber
Type
Saffll
Alumina
Fibers
Satf II
Z 1 rcon 1 a
Fibers
Ceramic
Aluminum
Silicate
Glass
Ceramic
"Flberfrax"
Fiber
Dimension ,
median diameter
3.6 urn; median
length 17 urn
median diameter
2.5 urn; median
1 ength 1 1 urn
90S <3 urn long and
<0.3 urn
diameter
50* <8.3 ym long;
50* <0.9I um
In diameter
Number of
Spec 1 es An 1 ma 1 s
SPF albino 40 (20 of
Wtstar rats each sex)
(Alderley
Park Strain)
SPF albino 40 (20 of
Mlstar rats each sex)
(Alderley
Park Stain)
SPF HI star rats 32
of AF/HAN
stain (sex
unspecified)
Female HI star 47
rats
Route of Dose/ Frequency/ Duration of
Administration Concentration Treatment Study
Duration
Intraperltoneal 20 mg (0.2 mL Single dose 6 mo
Injection of a 10)
suspension of
fibers)
Intraperltoneal 20 ng Single dose 6 mo
Injection
Intraperltoneal 25 mg Single dose Lifetime
Injection
Intraperltoneal 9 mg 5 weekly Llfespan
Injection doses
Results
Nodular deposit of
connective tissue;
no f 1 bros 1 s
Nodular deposit of
connective tissue
conta 1 n 1 ng co 1 1 agen
Peritoneal neoplasms
In 3/32 animals;
first tumor occurred
850 days after
Injection
Abdominal tumors In
33/47 animals; total
number of fibers In-
Remarks References
Harked peritoneal Styles and Ml (son
flbrosls In rats (1976)
treated with UICC
chrysot Me
asbestos
As above
•o
No vehicle control Davis et al. (1984) <"
group
Preliminary results; Pott et al. (1987b>
UICC chrysotlle
Induced dose-related
Jected (173 x10°) «er
comparable to that
of chrysot11• at
0.25 mg (202 x 106)
Increase In peritoneal
tumors at much lower
doses (11/36, 21/34.
30/36 at 0.0$, 0.25;
and 1.0 mg, respec-
tively
-------
Table 3. SIMMARY OF ANIMAL STUD IE
ERAM 1C FIBERS (CONTINUED)
Flb«r Fiber
Type Dimension
Ceramic 50% < 6.9 pi In
HAN length; 50*
-------
Table 4. SIMMARY OF AN I
IES ON ERIONITE
Fiber
Typ.
Oregon
Erlonlte
-
Oregon
Erlonlte
•
Kara In
Rock fiber
Erlonlte
Fiber
Dimension
86$ <0.4 urn
diameter;
92$
-------
Table 4. SUMMARY OF ANIMAL STI
ERIONITE (CONTINUED)
Fiber
Type
Erlonlte
Fiber Number of Route of Dose/ Frequency/ Duration of
Dlrmnslon Species Animals Administration Concentration Treatment Study
Duration
201 <1 urn and Male Swiss 12 Intraperltoneal 10 mg Single dose Six animals
95$ <8 urn albino mice Injection sacrificed at
long; 19$ 2-3 months;
<0.l pm and 95$ remaining 6
<1 pm diameter animals were
maintained
until death
(up to 15
months
Male 5*1 ss 5/group Intraperltoneal 10 mg or 30 mg Single dose Not Specified
albino mice Injection
Results Remarks References
Malignant peritoneal Suzuki (1982)
tumors In 2/5 animals
after 15 months;
flbrotlc lesions
presented at
neoplastlc tissues
Significant flbrosls; Chrysotlle (10 mg)
malignant peritoneal produced
tumors In 4/5 animals peritoneal tumors
receiving 10 mg of In 2/5 animals;
erlonlte; animals no tumors In
receiving 30 mg untreated controls
erlonlte died with
Intestinal
obstruction
-------
Table 4. SUMMARY OF ANIMAL STI
ERIONITE (CONTINUED)
Fiber
Type
Erlonlte 1
(Colorado)
Erlonlta 1 1
(Nevada)
Karaln
(Turkey)
dust
arlonlte
Fiber
Dimension Species
90% <8 urn and male Balb/C
6} >9.5 urn mice
long; 85| 1.4 urn
diameter
95) <8 urn and Male Balb/C
4J >9. 5 |im mice
length; 82) <0.5
urn and IOOK
-------
Table 5. SUMMARY OF AN I MALI
ES ON WOLLASTONITE
Fiber
Type
Wollastonlte
Wo II as ton Ita
(Canada)
Wollastonlte
(India)
Fiber Number of
Dimension Species Animals
Not specified Male Fischer Not
344 rats specified
4 samples Female Osborne- 20-2 5/
consisting of Mendel rats group
most 1 y 1 arge
fibers; only
one sample
was completely
fibrous
10< <2.4 urn and Female Wlstar 94
90} < 13 urn long; rats
\0t <0.62 urn
and 90( <2.3 urn
diameter
Route of Dose/ Frequency/ Duration of
Administration Concentration Treatment Study Results Remarks
Duration
Inhalation to mg/m 12 or 24 Up to 120 Results not yet
mo weeks available; no
adverse effects
on survival
Intrapleural 40 mg Single dose 2 yr Pleura! tumors In
Implantation 0/24, 2/25, 3/21,
5/20 animals
Intraperltoneal 20 mg 5 weekly 130 weeks No peritoneal tumors; Preliminary
Injection doses low degree of findings only; no
adhesion of hlstologlcal data
abdominal organs
References
AdKlns and
McDonnell (198$)
Stanton et al.
(1981)
Pott et al. (1987b)
-------
TABLE 6. SUMMARY OF AN IN
lES ON ATTW>ULGITE
Fiber
Type
Attapulglte
(LebrIJa, Spain)
Attapulglte/
Palygorsklte
(Leicester, U.K.)
Attapulglte
(U.S.)
Attapulglte
(French)
Fiber
Dimension
All fibers
<2 urn
long
18* of fibers
_>6 p« In length
and <0.2 um In
d 1 ameter
I
Two samples
composed
entirely of
short fibers
of smell
d 1 ameters
Mean diameter
0.06 um;
mean length
0.77 pm
Species
SPF Fischer
344 rats
SPF F344
rats
Female
Os borne-
Mendel
Sprague-
Dawley rats
(sex unspe-
cified)
Number Route Frequency/ Duration
of of Dose/ Treatment of
Animals Administration Concentration Duration Study
40 Inhalation 10 mg/m3 12 months Llfespan
(20 of
each sex)
40 Inhalation 10 mg/m3 12 months Llfespan
(20 of
each sex)
30-50 Intrapleural 40 mg Single dose 2 years
group Implantation
Not Intrapleural 20 mg Single dose 2 years
specified Injection
Results
No flbrosls; peritoneal
mesothelloma (1/40)
Flbrosls; mesothelloma
(3/40); malignant alveolar
ttmor (2/40); bronchoal velar
hyperplasla (8/40; 1 BAH
with MAT); UICC cradollte
produced 1/40 adenocarc 1 noma
and 3 BAH (1 BAH with
adenocarc 1 noma )
Pleura! tumor Incidence
2/29 for both samples
No mesothel loma; UICC
and Canadian chrysotlle
asbestos produced I9{
and 48< mesothel loma
Remarks Reference
No significant Wagner et al.
excess of tumors (1987)
Some evldlence of Wagner et al. (1987)
carcinogenic I ty
*>
^
Tumor Incidence Stanton et al.
not statistically (1981)
significant
compared with
controls
treated with
noncarc 1 nogen 1 c
materials (17/61))
Abstract only; Renler et al.
actual data (1987)
not aval (able
Incidence, respectively
-------
TABLE 6. SUMMARY OF ANl!
IIES ON ATTAPULGITE (CONTINUED)
Fiber
Type
Attapulglte
(LebrIJa,
Spain)
Attapulglte
(Torrejon,
Spain)
Attapulglte/
palygorsklte
(Leicester,
U.K.)
Attapulglte
(palygorsklte)
Attapulglte
(France,
Spain,
U.S.)
Attapulglte
Fiber Species
Dimension
Al 1 fibers SPF F344
<2 fM long rats
0.54J of fibers SPF F344
(by mass) j>6 pm rats
In length and
<0.5 urn In
d 1 anwter
18( Of fibers SPF F344
(by mass) >6 urn rats
In length and
<0.2 urn In
d 1 ameter
37.5JC <2um Wlstar
long; 70J <5um Rats
Not specified; Rats
composed of
the short,
thin fibers
mean > NMRI
length <1 pm mice
Number
of
Animals
20 of
each
sex
20 of
each
sex
32 (16 of
each
sex)
40
Not speci-
fied
60 of
each
sex
Route
of Dose/
Administration Concentration
Intrapleural Not specified
Injection
Intrapleural Not specified
Injection
Intrapleural Not specified
Injection
1 ntraper 1 tonea 1 3 x 25 mg
Injection
1 ntraper 1 tonea 1 Not specified
Injection
Feeding If or 3)
Frequency/
Treatment
Duration
Single
dose
Single
dose
Single
dose
Weekly
Single
dose
25 mo
Duration
of Results Remarks Reference
Study
Llfespan Peritoneal mesothel loma Tumor Incidence Wagner et al.
(1/40); Pleural not significant (1987)
mesothel lorn (1/40)
Llfespan Pleural mesothel loma As above
(14/40)
Llfespan Pleural mesothel loma As above
30/32; UICC
Croc 1 do lite produced M
34/40 mesothel loma; »
chrysotlle produced ""
19/40 pleural tumors
Llfespan 65< of animals developed Chrysotlle Pott et al.
peritoneal mesothel lorn; asbestos produced (1974)
first tumor appeared at 30-671 tumor
day 275 Incidence
Not specified No excess tumors observed No experimental Pott et al. (1985)
with 3 types of attapul- details or data re-
glte ported
25 mo No toxlcltles; no Brune and Deutsch-
tumors Wenzel (1983)
-------
Table 7. SUMMARY OF ANIMAL S
ARAMIO FIBERS
Iber
ype
Utraf Ina
.evlar*
Mtraflne
:evlar«
;evlar*
Ibers
.evlar*
(bars
Flbar
Dlmanslon
90< <1.5 urn
d 1 amater ;
>75J lass
than 20 fim
long
60-70)
-------
TABLE 7. SUMMARY OF ANIMAL STUDIES ON ARAM ID FIBERS (CONTINUED)
Fiber
Type
Kevlar*
pulp
Kevlar*
polymer
dust
Nomex*
aramld
Fiber
Dimension
Mostly aggregates
of large fibers;
a small proportion
composed of f 1 ne
fibrils; (96J of
these fibrils
-------
Table 8. SUMMARY OF ANIMAL S
CARBON FIBERS
ber
-pe
•.N-based
-rbon
ber
.opped
rbon
Ibers
.opped
-rbon
Ibers
rbon
ISt
-rbon
Ibers
Fiber
Dimension
7 urn
diameter
20-60 urn
long
99$ nonflbrous ,
0.8$ carbon
fibers with
1-2.5 urn
diameter and up
up to 15 urn
long
Not specified
0.2-15 urn
diameter
20$ <1 um and
35-40$ <2 (Mi
d 1 ameter
Species
Male albino
rats of the
CO BR sprague
Daw ley Strain
SPF guinea
pigs
SPF
guinea
pig*
Male and
female
SPF Wlstar
rats
Male Fischer
344 rats
Number Duration/ Duration
of Route of Dose/ Frequency of of
Animals Administration Concentration Treatment Study
10-20 animals Inhalation 20 mg/m3 4,8,12, or Up to 32
per group (16-23 mg/m ) 16 weeks weeks after
16 wk of
exposure
A total of Inhalation 370 nonflbrous 7-104 hr 1-144 days
13 exposed particles/ml after exposure
animals; 2.9 fibers/ml
2 negative
controls
2-9 animals Inhalation Not specified 7-100 hr Up to
per group 2 yr
12 Intraperltoneal 50 mg/kg Single 1 or
Injection (10-15 mg/ dose 3 mo
rat)
Not Intraperltoneal Not 1 single l.p. Up to
reported Injection/ reported dose; 2 Intra- 2 yr
Intratracheal trachea) doses
Instillation
Results
No lung pathology
No pathological
effects observed
In animals at
Interval sacrifice
No evidence of
pathological changes
In the lungs
No evidence
of flbrosls; positive
control animals re-
ceiving chrysotlle
asbestos (2.5 mg)
showed diffuse flbro-
sls by 3 months;
No tumors or toxlclty
Remarks
Large diameter
fibers
Oust cloud was
predominantly
nonflbrous;
short exposure;
small number
of animals
Short exposure;
resplrable fraction
was mainly non-
fibrous
particles
Short observation
period
Prel 1 ml nary oral
report only
References
Owen et al.
( 1986)
Holt and Home
(1978)
to
Holt (1982)
Styles and
Wilson (1973)
Parnell (1987)
-------
TABLE 8. SUMMARY OF ANIMAL STUDIES
FIBERS (CONTINUED)
ber Fiber Species
pe Dimension
•lyacryl- Not reported Rats
Itrlle (strain, sex
AN) -based - not specified
rbon fibers
Number
of
Animals
Not
reported
Duration/ Duration
Route of Dose/ Frequency of of
Administration Concentration Treatment Study
Intratracheal Not Single 1-9 mo
Instillation reported dose
Results
Both preparations
of carbon fibers Induced
lung f Ibrosls; the
flbrogenlclty of
chrysotlle asbestos
was several -fold
higher than that of
carbon fibers
Remarks References
No experimental Troltskaya et al.
details were (1984)
provided
mixture
carbon
bers and
•specified
astlc
rbon
bers
-rbon
!ber
lament
Not
reported
Not
reported
1.5 cm long
or 5 cm
long; diameter
not specified
Sprague
Daw 1 ay
rats
(sex unspeci-
fied)
Male & Fe-
male Sprague-
Dawley rats
Wlstar rats
(sex not
specified)
!
Not Intratracheal
reported Injection
4 0/5 ex Subcutaneous
Implantation
10 or 50 rats/ Intramuscular
group Implantation
Not
reported
25 mg
In a
2 cm disc
Not
specified
Not
specified
Single dose
Single dose
rbon
•n f 1 brous
•wder
Life span
18
particle
sIze not spec I-
fled
Wlstar Rats
50 rats
Intramuscular
implantatlon
Not
specified
Single dose 18 months
No lung fIbrosls; only
moderate foreign body
reaction
Local sarcoma
(tumor Incidence not
specified)
No malignant
change
No malignant
change
Experimental details
and results were not
not avallable for
evaluation
Details of findings
not available
Test materials were
either nonflbrous or
large filament; route
of exposure not rele-
vant to evaluation of
of lung carclnogenlclty
Swensson (1979)
(as reported by
Gross, and Braun,
1984)
Ma I too I et al.
(1982b, 1987)
Tayton et al.
(1982)
-------
TABLE 8. SLMMARY OF ANIMAL STUOIE
FIBERS (CONTINUED)
Number
'Iber Fiber Species of
'ype Dimension Animals
Jarbon 7 put CHB8:CH B per
:lber r»ln- diameter; rabbits group
orced 20-100 out (sax not
:arbon long specified)
•found Not specified Hale 40 per
:arbon fib- C3H/HeJ group
>ers of 4 types nice
a) continuous
(lament (CF)-
i Itch-based
b) short -fl fa-
ired pltch-
ias«d (MAT)
c) polyacrylc—
iltrlle (PAN)-
lased
d) oxidized
'AN- based
Duration/ Duration
Route of Dose/ Frequency of of Results
Administration Concentration Treatment Study
1 ntramedu 1 1 ary 50 mg Single 2 or Small amount of
Implantation dose 12 weeks H broils around some
carbon fibers
Skin painting 2.5 mg 3 times Llfespan
(25 pL of veekly
10* w/v
f Iber suspen-
sion) Skin tumors at site of
application; squamous
cell carcinoma (1/40);
papllloma (1/40)
Flbrosarcoma (1/40);
hemanglosarcoma (1/40)
No tumors (0/40)
Lelyonyosarcoma (0/40)
Remarks References
Method of exposure Neugebauer
not relevant to the et al. (1981)
determination of the
potential Induction of
lung toxlclty and
flbrosls
In the CF treated group, DePass (1982)
neither tumor Incidence nor
time to onset of tumors was
significant compared to ben-
zene-treated control animals
(0/40) In this study but
were judged to be weakly
oncogen Ic using historical
benzene controls (0/281); "
positive controls receiving 0
O.t( methylenolantnrene
had Increased Incidence
of squamous cell carcinoma
and papllloma (33/38)
-------
TABLE 9.
F ANIMAL STUDIES ON POLYOLEFIN FIBERS
Fiber Type
Polypropylene
Polyethylene
dust
Polypropylene
dust
Ozon 1 zed
Polyethylene
SHFF
Ozon 1 zed
Polypropylene
SHFF
HFF
Polypropylene
Fiber Dimension
90S <2.l u«
and 50«
number of animals
'
M
Ml
Limited study'; No MB Research
data available Laboratories
on .the choree- ' . (1980)
terlsltlc on the \
test materials, >
dose and detalls'on
the method of
administration'' . •
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