PRELIMINARY DRAFT ECAO-R-053
DO NOT QUOTE OR CITE JULY 1988
WORKSHOP REVIEW DRAFT
SUMMARY REVIEW OF HEALTH EFFECTS ASSOCIATED WITH
MANMADE MINERAL FIBERS OTHER THAN ASBESTOS, SYNTHETIC FIBERS,
AND SELECTED MINERALS: HEALTH ISSUE ASSESSMENT
NOTICE
This document is a preliminary draft and .is intended
for internal Agency use only. It has not been formally
released by the U.S. Environmental Protection Agency
and should not at this stage be construed to represent
Agency policy. It is being circulated for comments on
its technical merit and policy implications.
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NC 27711
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DISCLAIMER
This document is a preliminary draft and is intended for internal Agency
use only. It has not been formally released by the U.S. Environmental Protec-
tion Agency and should not at this stage be construed to represent Agency
policy. It is being circulated for comments on its technical merit and policy
implications. Mention of trade names or commercial products does not consti-
tute endorsement or recommendation for use.
ii
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CONTENTS
Page
LIST OF FIGURES x
LIST OF TABLES xi
AUTHORS, CONTRIBUTORS, AND REVIEWERS xv
1. SUMMARY 1-1
1.1 MANMADE MINERAL FIBERS 1-2
1.1.1 Fibrous Glass 1-2
1.1.2 Mineral Wool 1-9
1.1.3 Ceramic Fibers 1-11
1.2 SYNTHETIC FIBERS 1-13
1.2.1 Aramid Fibers 1-13
1.2.2 Carbon Fibers 1-15
1.2.3 Polyolefin Fibers 1-17
1.3 MINERALS 1-18
1.3.1 Attapulgite 1-19
1.3.2 Erionite 1-21
1.3.3 Talc 1-23
1.3.4 Vermiculite 1-25
1.4 REFERENCES : 1-27
2. BACKGROUND INFORMATION 2-1
2.1 PHYSICAL AND CHEMICAL PROPERTIES 2-1
2.1.1 Manmade Mineral Fibers ' 2-2
2.1.1.1 Fibrous Glass 2-2
2.1.1.2 Mineral Wool 2-3
2.1.1.3 Ceramic Fibers 2-4
2.1.2 Synthetic Fibers : 2-5
2.1.2.1 Aramid Fibers 2-5
2.1.2.2 Carbon Fibers 2-6
2.1.2.3 Polyolefin Fibers 2-7
2.1.3 Minerals 2-7
2.1.3.1 Attapulgite • 2-7
2.1.3.2 Zeolites 2-8
2.1.3.2.1 Erionite 2-9
2.1.3.3 Talc 2-9
2.1.3.4 Vermiculite 2-10
2.2 PRODUCTION AND INDUSTRIAL USES 2-10
2.2.1 Manmade Mineral Fibers 2-10
2.2.1.1 Fibrous Glass 2-12
2.2.1.2 Mineral Wool 2-12
2.2.1.3 Ceramic Fibers 2-12
2.2.2 Synthetic Fibers 2-14
2.2.2.1 Aramid Fibers 2-14
2.2.2.2 Carbon Fibers 2-16
2.2.2.3 Polyolefin Fibers 2-18
2.2.3 Minerals 2-19
2.2.3.1 Attapulgite 2-19
2.2.3.2 Zeolites 2-21
2.2.3.3 Talc 2-21
2.2.3.4 Vermiculite 2-22
iii
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CONTENTS (continued)
Page
2. 3 REFERENCES 2-24
SOURCES OF EMISSIONS, AMBIENT LEVELS, AND ENVIRONMENTAL FATE ... 3-1
3.1 SOURCES OF EMISSIONS • 3-1
3.2 EXPOSURE 3-2
3.2.1 Manmade Mineral Fibers 3-3
3.2.2 Synthetic Fibers 3-8
3.2.3 Minerals 3-9
3.3 AMBIENT LEVELS 3-13
3.4 ENVIRONMENTAL FATE 3-16
3.5 ANALYTICAL METHODS 3-17
3.6 REFERENCES 3-21
RETENTION AND B10D1SPOSIT10N 4-1
4.1 INTRODUCTION 4-1
4.1.1 Host Entry and Retention 4-1
4.1.2 Translocation and Clearance 4-6
4.2 MANDMADE MINERAL FIBERS 4-7
4.2.1 Glass Fibers 4-7
4.2.1.1 Host Entry and Retention 4-7
4.2.1.2 Translocation and Clearance 4-11
4.2.2 Mineral Wool 4-16
4.2.2.1 Rock Wool 4-17
4.2.3 Ceramic Fibers 4-18
4.3 SYNTHETIC FIBERS 4-20
4.3.1 Aramid Fibers 4-20
4.3.2 Carbon Fibers 4-21
4.3.3 Polyolefin Fibers 4-23
4.4 MINERALS 4-23
4.4.1 Erionite 4-23
4.4.2 Attapulgite 4-24
4.4.3 Talc 4-25
4.4.4 Vermiculite 4-29
4.5 REFERENCES 4-29
ACUTE, SUBCHRONIC, AND CHRONIC TOXICITY IN ANIMALS 5-1
5.1 ACUTE TOXICITY 5-1
5.1.1 Manmade Mineral Fibers '.. 5-1
5.1.1.1 Fibrous Glass 5-1
5.1.1.2 Mineral Wool 5-2
5.1.1.3 Ceramic Fibers 5-2
5.1.2 Synthetic Fibers 5-2
5.1.2.1 Aramid Fibers 5-2
5.1.2.2 Carbon and Polyolefin Fibers 5-4
5.1.3 Minerals 5-5
5.1.3.1 Attapulgite 5-5
5.1.3.2 Erionite 5-5
5.1.3.3 Talc 5-5
5.1.3.4 Vermiculite 5-6
5.2 SUBCHRONIC AND CHRONIC TOXICITY 5-6
5.2.1 Mandmade Mineral Fibers 5-6
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CONTENTS (continued)
Paoe
5.2.1.1 Fibrous Glass 5-6
5.2.1.1.1 Oral 5-6
5.2.1.1.2 Inhalation 5-6
5.2.1.1.3 Intratracheal 5-18
5.2.1.1.4 Intrapleural 5-20
5.2.1.2 Mineral Wool 5-20
5.2.1.3 Ceramic Fibers 5-22
5.2.1.4 Other Manmade Mineral Fibers 5-25
5.2.2 Synthetic Fibers 5-28
5.2.2.1 Aramid Fibers 5-28
5.2.2.2 Carbon Fibers 5-29
5.2.2.3 Polyolefin Fibers 5-30
5.2.3 Minerals 5-31
5.2.3.1 Attapulgite 5-31
5.2.3.2 Erionite and Other Zeolites 5-31
5.2.3.3 Talc 5-32
5.2.3.4 Vermiculite 5-35
5.3 REFERENCES 5-35
DEVELOPMENTAL AND REPRODUCTIVE TOXICITY 6-1
6.1 MANMADE MINERAL FIBERS 6-1
6.2 SYNTHETIC FIBERS 6-2
6.3 MINERALS 6-2
6.4 REFERENCES 6-2
MUTAGENICITY, CYTOTOXICITY, AND CARCINOGENICITY 7-1
7.1 MUTAGENICITY 7-1
7-1
7-2
7-2
7-2
7-2
7-2
7-2
7-3
7-3
7-3
7.2 IN VITRO CYTOTOXICITY 7-4
772.1 Introduction 7-4
7.2.1.1 Procedures Available To Measure
Cytotoxicity 7-4
7.2.1.2 Test Material Composition 7-5
7.2.2 Manmade Mineral Fibers 7-6
7.2.2.1 Glass Fibers 7-6
7.2.2.2 Mineral Wool/Rock Wool/Slag Wool 7-13
7.2.2.3 Ceramic Fibers 7-14
7.2.3 Synthetic Fibers 7-14
7.2.3.1 Aramid Fibers 7-14
7.2.3.2 Carbon Fibers 7-15
7.2.3.3 Polyolefin Fibers "7-15
7.1.1
7.1.2
7.1.3
7.1.4
7.1.5
IN VIT
Manmade Mineral Fibers
7.1.1.1 Fibrous Glass
7.1.1.2 Mineral Wool
7.1.1.3 Ceramic Fibers
Synthetic Fibers
Minerals ......
7.1 3.1 Erionite
7.1.3.2 Attapulgite
Talc
Vermiculite
RO CYTOTOXICITY
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CONTENTS (continued)
Pace
7.2.4 Minerals 7-16
7.2.4.1 Attapulgite/Sepiolite 7-16
7.2.4.2 Erionite 7-17
7.2.5 Talc 7-1E
7.2.6 Venrn'culite 7-1S
,7.2.7 Mode of Action 7-19
7.2.7.1 Cellular Responses 7-19
7.2.7.1.1 Development of ferruginous
bodies 7-19
7.2.7.1.2 Effects of mineral fibers on
cell membranes 7-20
7.2.7.1.3 Release of superoxide 7-21
7.2.7.1.4 Development of proteinosis 7-22
7.2.7.2 Physical Properties of Fibers 7-22
7.3 CARCINDGENICITY 7-25
7.3.1 Manmade Mineral Fibers 7-25
7.3.1.1 Fibrous Glass 7-25
7.3.1.1.1 Inhalation 7-25
7.3.1.1.2 Intratracheal 7-2E
7.3.1.1.3 Intrapleural 7-30
7.3.1.1.4 Intraperitoneal 7-32
7.3.1.2 Mineral Wool 7-34
7.3.1.3 Ceramic Fibers 7-35
7.3.2 Synthetic Fibers 7-41
7.3.2.1 Aramid and Polyolefin Fibers 7-41
7.3.2.2 Carbon Fibers 7-43
7.3.3 Minerals 7-43
7.3.3.1 Attapulgite 7-43
7.3.3.2 Erionite and Other Zeolites 7-44
7.3.3.3 Talc 7-45
7.3.3.4 Vermiculite '. 7-49
7.3.4 Other Fibers 7-49
7.3.5 Summary 7-64
7.4 REFERENCES 7-66
8. EFFECTS ON HUMANS 6-1
8.1 MANMADE MINERAL FIBERS :. 6-1
8.1.1 Glass Fibers and Mineral Wool 8-1
8.1.1.1 Cross-Sectional Studies, Clinical
Evaluations, and Case Reports 8-1
8.1.1.1.1 Eye and skin irritation 8-1
8.1.1.1.2 Respiratory effects 8-4
8.1.1.2 Epidemiological Studies 8-9
8.1.1.2.1 Epidemiological studies in
U.S. workers 8-10
8.1.1.2.2 Epidemiological studies in
Canadian workers 6-29
8.1.1.2.3 Epidemiological studies in
European workers
VI
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CONTENTS (continued)
Page
8.1.1.2.4 Epidemiologies'! study combining
U.S., Canadian, and European
workers 8* 73
r 8.1.1.2.5 Integration of'tiuman health
effects data by fiber and by
carcinogenic and noncarcino-
genic effects 8-53
8.1.2 Ceramic Fibers 8-102
8.1.2.1 Cross-Sectional Studies, Clinical
Evaluations, and Case Reports 6-1C2
8.1.2.1.1 Respiratory effects 8-1C2
8.2 SYNTHETIC FIBERS 8-102
8.2.1 Aramid Fibers 8-1C2
8.2.2 ^Carbon Fibers 6-102
8.2.2.1 Cross-Sectional Studies, Clinical
Evaluations, and Case Reports £-102
8.2.2.1.1 Respiratory effects E-1D3
8.2.2.1.2 Effects from surgical
introduction £-102
8.2.3: Polyolefin Fibers £-iC2
6.3 MINERALS .". 6-102
8.3.1 Attapulgite and Sepiolite 8-102
8.3.1.1 Cross-Sectional Studies, Clinical
: Evaluations, and Case Reports 8-103
8.3.1.1.1 Respiratory effects 8-103
;, 8.3.1.2 Epidemiological Studies 8-105
8.3.2 Erionite 6-106
I? 8.3.2.1 Cross-Sectional Studi-es, Clinical
a Evaluations, and Case Reports 8-107
f 8.3.2.1.1 Respiratory effects 8-107
i. 8.3.2.1.2 Immunological effects 6-117
V8.3.2.2 Epidemiological Studies ! 8-118
8. 3.3%7alc 8-116
''"8.3.3.1 Cross-Sectional Studies, Clinical
Evaluations, and Case Reports 8-116
8.3.3.1.1 Respiratory effects 8-116
8.3.3.1.2 Effects from dermal
appl ication 8-121
8.3.3.1.3 Effects from intrapleural
instillation 8-122
8.3.3.1.4 Effects from surgical
: introduction 8-123
8.3.3.1.5 Effects from intravenous
administration. 8-123
8.3.3.2 Epidemiological Studies 6-124
8.3.4 Vermiculite 8-133
8.3.4.1 Cross-Sectional Studies, Clinical
Evaluations, and Case Reports 6-133
vn
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CONTENTS (continued)
Page
8.3.4.1.1 Respiratory effects 8-133
8.3.4.2 Epidemiological Studies 8-13*
8.4 REFERENCES 8-135
9. QUANTIFICATION OF TOXICOLOGICAL EFFECTS 9-1
9.1 PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS .... 9-1
9.1.1 Noncarcinogenic Effects 9-1
9.1.2 Carcinogenic Effects 9-3
9.1.2.1 Studies in Humans 9-3
9.1.2.2 Studies in Animals 9-4
9.2 MANMADE MINERAL FIBERS 9-6
9.2.1 Human Health Effects 9-6
9.2.1.1 Fibrous Glass 9-7
9.2.1.1.1 Qualitative evaluation of
noncarcinogenic effects 9-7
9.2.1.1.2 Characterization of carcino-
genic effects 9-9
9.2.1.2 Mineral Wool 9-13
9.2.1.2.1 Qualitative evaluation of
noncarcinogenic effects 9-13
9.2.1.2.2 Characterization of carcino-
genic effects 9-13
9.2.1.3 Ceramic Fibers 9-17
9.2.1.4 Quantification of Carcinogenic Effects
of Manmade Mineral Fibers 9-17
9.2.2 Animal Toxicity 9-20
9.2.2.1 Characterization of Noncarcinogenic
Effects S-20
9.2.2.2 Quantification of Noncarcinogenic
Effects 9-21
9.2.2.2.1 Fibrous glass 9-21
9.2.2.2.2 Mineral wool 9-24
9.2.2.2.3 Ceramic fibers 9-26
9.2.2.3 Characterization of Carcinogenic Effects .. 9-28
9.2.2.3.1 Fibrous glass 9-29
9.2.2.3.2 Mineral wool 9-30
9.2.2.3.3 Ceramic fibers 9-31
9.2.3 Characterization of Carcinogenic Potential Based
on Human and Animal Data 9-32
9.3 SYNTHETIC FIBERS 9-32
9.3.1 Human Health Effects 9-32
9.3.2 Animal Toxicity 9-33
9.3.2.1 Characterization of Noncarcinogenic
Effects 9-33
9.3.2.2 Quantification of Noncarcinogenic
Effects 9-33
9.3.2.2.1 Aramid fibers 5-33
9.3.2.2.2 Carbon fibers 9-34
9.3.2.2.3 Polyolefin fibers 9-34
V111
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CONTENTS (continued)
9.3.2.3 Characterization and Quantification of
Carcinogenic Effects 9-34
9.3.2.3.1 Aramid fibers 9-34
9.3.2.3.2 Carbon fibers 9-35
9.3.2.3.3 Polyolefin fibers 9-35
9.3.3 Characterization of Carcinogenic Potential Based
on Human and Animal Data 9-36
9.4 MINERALS 9-36
9.4.1 Human Health Effects 9-36
9.4.1.1 Attapulgite . 9-36
9.4.1.1.1 Qualitative evaluation of
noncarcinogenic and carcino-
genic effects 9-3£
9.4.1.2 Erionite 9-37
9.4.1.2.1 Qualitative evaluation of
noncarcinogenic and carcino-
genic, effects 9-37
9.4.1.3 Talc 9-37
9.4.1.3.1 Qualitative evaluation of
noncarcinogenic and carcino-
genic effects 9-37
9.4.1.4 Vermiculite 9-36
9.4.1.4.1 Qualitative evaluation of
noncarcinogenic and carcino-
genic effects 9-36
9.4.2 Animal Toxicity 9-3S
9.4.2.1 Quantification of Noncarcinogenic Effects . 9-3B
9.4.2.1.1 Attapulgite 9-38
9.4.2.1.2 Erionite 9-36
9.4.2.1.3 Talc 9-38
9.4.2.1.4 Vermiculite '. 9-39
9.4.2.2 Characterization and Quantification of
Carcinogenic Effects 9-39
9.4.2.2.1 Attapulgite 9-39
9.4.2.2.2 Erionite 9-39
9.4.2.2.3 Talc 9-40
9.4.2.2.4 Vermiculite 9-40
9.4.3 Characterization of Carcinogenic Potential Based
on Human and Animal Data 9-41
9.5 SUMMARY OF CARCINOGENIC AND NONCARCINOGENIC EVIDENCE 9-41
9.6 REFERENCES 9-43
IX
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FIGURES
Page
The relationship of glass fiber diameter and length to
aerodynamic equivalent diameter (D ) 4-3
4-2 The relationship of alveolar deposition to the diameter
and length of glass fibers 4-4
4-3 Bivariate distribution of fiber deposition in the alveoli
following nose-only breathing by humans 4-5
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TABLES
Number Page
2-1 Mineral and vitreous fibers 2-2
2-2 Major U.S. producers of textile glass fibers 2-11
2-3 U.S. consumption of textile glass fibers, 1983 2-12
2*4 Major U.S. alumina-silica producers 2-13
2-5 U.S. consumption of alumina-silica fiber products by
industry, 1983 2-13
2-6 Representative applications for ceramic, alumina, zirconia
and silica fiber products 2-15
2-7 U.S. demand for high-performance carbon fibers 2-17
2-8 Major U.S. producers of carbon fibers 2-17
2-9 Major U.S. producers of polyolefin fibers 2-20
2-10 Fuller's earth sold or used by U.S. producers in 1984,
by use 2-22
2-11 U.S. production of crude talc and pyrophyllite in 1984 2-23
2-12 End uses for ground talc and pyrophyllite 2-23
3-1 Releases of vermiculite into the environment 3-2
3-2 Airborne concentrations of manmade mineral fibers in
manufacturing plants 3-5
3-3 NOHS estimates of exposure to mineral fibers 3-7
3-4 Occupational exposure to airborne concentrations of
asbestos in processing plants 3-11
3-5 Summary of occupational and nonoccupational inhalation
exposure to asbestos In vermiculite 3-12
3-6 Asbestiform fiber measurement methods 3-15
4-1 The number and size of nonasbestos fibers in the lungs
of 20 subjects 4-25
£
5-1 Mass and concentrations of Kevlar fibers used in an
inhalation study in male rats 5-3
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TABLES (continued)
Number Page
5-2 The histologic grading system of pulmonary changes in rats
related to the inhalation of fibers 5-10
5-3 Dimensions and concentrations of glass fibers used in a
chronic inhalation study with F344 rats and cynomolgus
monkeys , 5-12
5-4 Dimensions, aerosol concentrations, and particle ratios of
fibers used in 2-year inhalation studies with Osborne-
Mendel rats and Syrian hamsters 5-15
5-5 Incidences of pulmonary lesions noted in Osborne-Mendel
(OK) rats and Syrian hamsters exposed to various glass
fibers by inhalation for 24 months 5-16
5-6 Type, diameter, and dose of glass fibers intratracheally
injected in Syrian hamsters 5-18
7-1 Size distribution of some asbestiform fibers used in
ID vitro cytotoxicity studies 7-9
7-2 Neoplasms and hyperplasia in the lungs of rats after
inhalation exposure to various MMMF 7-27
7-3 Incidence of mononuclear cell leukemia in F344 rats
exposed to fibrous glass insulation via inhalation for
2 years 7-26
7-4 Tumors in Syrian hamsters after intratracheal-instillation
of glass fibers or crocidolite 7-30
7-5 Size distribution, tumor incidence, and lifespan
following intraperitoneal administration of manmade and
naturally occurring fibers to female Wistar rats 7-25
7-6 Size distribution and number of manmade and naturally
occurring fibers administered intrapen'toneally to female
Wistar rats 7-36
7-7 Lifespan and tumor incidences in female Wistar rats after
intraperitoneal administration of manmade and naturally
occurring fibers 7-36
7-8 Incidences of lung mesotheliomas in rats after intrapleural
instillation of various MMMF "
XI 1
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TABLES (continued)
Number
7-9
7-10
7-11
7-12
7-13
8-1
8-2
8-3
8-4
8-5
6-6
8-7
8-8
8-9
8-10
8-11
Peritoneal tumor incidences in mice after intraperitoneal
injection of Karain dust
Selected data on carcinogenicity of different fibrous
materials following intrapleural implantation in rats
Incidence of pleural tumors induced in F344 rats by
ferroactinolite and amosite
Sizes of mineral fibers retained in the lungs of rats
at various intervals after intratracheal instillation
Summary of carcinogenicity studies on MMMF, synthetic
fibers, and minerals
Significantly elevated SMRs by cause for all MMMF workers
between 1978 and 1982
Significantly elevated SMRs by cause for all MMMF workers
between 1946 and 1982
Significantly decreased SMRs by cause for all MMMF workers
between 1946 and 1982
Cancer incidence analysis by site and duration of
exposure
Selected cause-specific mortality for production workers
from the U.S., Canadian, European, and combined cohorts ....
Comparison between U.S. and European SMRs for lung cancer
derived from national and local rates
Lung cancer mortality by process .
Lung cancer mortality among the three combined cohorts by
process and time since first exposure
Respiratory cancer mortality by exposure to small-diameter
glass wool fibers and time since first employment
Selected cancer mortality for U.S. and European cohorts
Mortality from NMRD by cohort
Page
7-4£
7-52
7-54
7-54
7-55
8- IS
e-19
8-20
8-71
8-75
8-76
8-77
8-77
8-78
8-80
8-81
xm
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TABLES (continued)
Number Page
8-12 Summary of carcinogenic and noncarcinogenic effects from
historical prospective morbidity and mortality studies in
workers exposed to MMMF 8-84
9-1 Summary of the weight of evidence for causal relationships
between exposure to MMMF and carcinogenic and noncarcino-
genic effects 9-8
9-2 Summary of long-term inhalation studies considered for
derivation of the RfD for fibrous glass 9-22
9-3 Summary of long-term inhalation studies considered for
derivation of the RfD for rock wool 9-25
9-4 Summary of long-term inhalation studies considered for
derivation of the RfD for ceramic fibers £-27
S-5 Sijfr.-ary of carcinogenic and noncarcinogenic effects from
animal and human data 9-42
xiv
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
The following Dynamac Corporation personnel were involved in the prepara-
tion of this document: Nicolas P. Hajjar, Ph.D. (Project Manager/Principal
Author); Barrett N. Fountos, Claire Kruger-McOermott, Ph.D., Patricia Turck,
Mary E. Cerny, Dawn Webb, Brion Cook, Nancy McCarroll, William McLellan, Ph.D.,
Christian Alexander, John Bruno, Ph.D., Edward Flynn, Charles Rothwell, Ph.D.,
Janice Range, and Sharon Segal, Ph.D. (Authors); Karen Swetlow (Technical
Editor); and Sanjivani Diwan, Ph.D. and Gloria Fine (Information Specialists).
This document was prepared by Dynamac Corporation under contract to the
Environmental Criteria and Assessment Office, Research Triangle Park, NC
(Dennis J. Kotchmar, M.D., Project Manager).
xv
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1. SUMMARY
Concern surrounding the possible inhalation associated health effects of
asbestos on the general population stimulated interest on the potential health
effects of other natural and manmade fibers.' This document discusses the
health effects of the manmade mineral fibers (MMMFs) (fibrous glass, mineral
wool, and ceramic fibers), the synthetic fibers (aramid, carbon, and polyolefin
'fibers), and the naturally occurring fibers attapulgite and erionite, as well
as the health effects related to the nonfibrous silicate minerals talc and
vermiculite, which have multiple consumer uses and have been shown to contain
various concentrations of asbestiform fibers. Data for other fibers a-'i 'cr
minerals are also discussed, primarily for comparative purposes, in various
parts of this report.
Chapter 2 of this document presents background information on physical ar.s
chemical properties, production volumes, and uses of each of the 10 fibers.
The sources of emissions, ambient levels, worker and consumer exposure, envi-
ronmental fate, and analytical procedures used to identify and quantitate each
fiber are discussed in Chapter 3. Chapter 4 discusses^the aerodynamic factors
governing host entry, retention, and biodisposition. Chapter 5 provides acute,
subchronic, and chronic toxicity data for laboratory animals as the data relate
to noncarcinogenic or systemic effects. Two teratogenicity studies are dis-
cussed in Chapter 6. Mutagenicity, cytotoxicity, mode of action, and animal
carcinogenicity studies are presented in Chapter 7. Chapter 8 discusses human
health effects data obtained from cross-sectional, clinical, and retrospective
mortality studies and case reports.
The carcinogenic and/or noncarcinogenic effects of each fiber are charac-
terized from both animal toxicity and human health effects data in Chapter 9.
Quantification of noncarcinogenic effects was conducted by calculating a
Reference Dose (RfD) based on systemic No-Observed-Adverse- Effect Levels
(NOAELs) or Lowest-Observed-Adverse-Effect Levels (LOAELs) from chronic animal
toxicity data. When carcinogenicity was demonstrated, estimates of carcinogenic
i i. ir.rr, 1.1 nPirr.-nn W.T n".-f- n; r'~~
-------
risk were calculated. The carcinogenic potential of each fiber was categorizes
based on evidence from human and animal studies. Summaries for each fiber are
presented in the following sections.
1.1 MANMADE MINERAL FIBERS
MMMFs are groups of amorphous silicates that are not discrete entities
(such as minerals) definable by a fixed chemical composition. They are manu-
factured by various techniques from a molten mass of raw material, and their
properties depend on their chemical composition.
1.1.1 Fibrous Glass
Fibrous glass is composed primarily of the oxides of silicon (SiO.),
aluminum (Al-O^), and boron (ELO,). The physical and chemical properties of
glass fibers depend on the aspects of their chemical composition that can be
manipulated during production to promote specific properties. Three ma'ir,
classes of glass fibers are available: textile, wool, and fine fibers, witr,
typical fiber diameters of 10 to 15 um, 3 to 10 urn, and <_! um, respectively.
Approximately 1200 and 3000 million pounds of textile fibers and insulaticr
glass wool, respectively, were produced in 1983. Textile fibers are produced
in various forms, and about 50 percent of the amount produced is used in
reinforced plastics. Approximately 80 percent of the insulation glass fibers
are used in structural insulation. Fibrous glass wools and filaments are
relatively more water-soluble and less chemical- resistant than mineral wool,
although both are susceptible, in varying degrees, to acid and base attack.
The physical changes that affect mineral fibers are not homogeneous, since
considerable variation in composition exists along the length of a fiber and
between fibers.
Environmental Release and Fate
Environmental release of MMMFs occurs during manufacture, handling, use,
and disposal. However, estimates are not available. The principal route of
exposure to fibers is inhalation. Measurements of airborne concentrations of
glass fibers in the workplace vary greatly with sampling location within the
same plant and among plants performing similar processing operations. The,
range of average concentrations of fibrous glass found in several plants was
-------
reported to be 0.0024 to 0/78 total fibers/cm3 and 0.002 to 0.08 respirable
fibers/cm (i.e., with nominal diameters <3 urn).
The highest fiber concentrations were detected in the production and
manufacturing areas. Estimates of respirable fiber concentrations in the
European glass wool industry during the early technological phase (see
section 3.2.1) indicate that they were similar to current concentrations of
about 0.1 fibers/cm or less.
Occupational exposure also depends upon working habits, the processes
involved, physical characteristics of the fibers, and the availability of
control measures. The National Occupational Hazard Survey (NOHS) provided the
following estimates of the number of workers potentially exposed to MMMF for
1972-74: glass fibers, 62,811; glass wool, 57; fiberglass insulation, 80,629.
The National Occupational Exposure Survey (NOES) reported no information for
these fibers. Consumer exposure to MMMF is expected to be low except during
periods when insulating material is being handled, but estimates were not found
in the available literature.
Limited information is available on ambient levels for glass fibers,
although their presence appears to be ubiquitous. Concentrations of glass
fibers found in ambient air samples collected in California were reported to be
0.87 ± 0.48 fibers/L with an average diameter of 3.7 urn (range 0.1 to 17.7 prr).
A survey of several schools for MMMF indicated concentrations ranging frorr. 0 to
0.087 fibers/L, whereas concentrations in office tuildings ranged from 0.380 to
10 fibers/L. Mineral fibers have also been found in aquatic environments and
drinking water supplies.
This report discusses the environmental fate of mineral fibers with a
focus on glass fibers and compares the Information presented with data avail*
able on the environmental fate of asbestos fibers. Glass fibers can undergo
both chemical and physical changes under various environmental conditions.
These include changes in fiber size, chemistry, and crystalline structure. The
major environmental fate of minerals and mineral fibers is probably deposition,
especially of longer fibers, and eventual burial in soils and sediments.
Various methods have been used to analyze and quantitate fibers. Earlier
methods measured mass, and x-ray diffraction techniques provided identifica-
tion. Counting methods are used for samples that are too small to be weighed.
Light microscopy methods are limited in resolution. Both scanning and trans-
mission electron microscopy can be used with x-ray analytical methods to
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provide for better mineralogic identification of fibers. Another recer.t
analytical method is the LAMMA procedure, which combines a high-energy laser
beam with mass spectroscopic analysis.
Metabolism
Various factors influence the deposition of inhaled particles in the
respiratory tract; for fibers, these include the aerodynamic equivalent diame-
ter (D.D) and aspect ratio. Several studies indicate that glass fibers with a
fl C
D larger than 3.5 urn have little chance of alveolar deposition; most are
OC
deposited above the trachea and in nasal hairs. In contrast, maximum alveolar
deposition in rats and dogs occurs for glass fibers with an actual diameter of
<0.1 um and a length of about 10 urn or a D of approximately 1 to 2 um.
However, only a small percentage of these fibers are retained (7 to 16 per-
cent), and most are exhaled without being deposited. Alveolar deposition was
reported to follow a similar pattern in man, but absolute volumes are greater
than those observed in rats. Alveolar deposition declines steeply to about
3 percent of a D of 3.4, i.e., a count median diameter of 1.1 pm. The rete~-
o 6
tion of glass fibers following repeated or chronic-inhalation exposures is
similar to that observed following single exposures. Retention decreases with
increasing diameter and length, and increases with repeated dosing. In rats,
most of the retained fibers are found in the right upper and left lobes follow-
ing long-term exposure. The fibers retained in the lung were less than 5 um
long. Female rats apparently tend to have slightly higher tissue levels of
•
fibers than males following chronic inhalation exposure.
Several mechanisms are Involved in clearing fibrous materials from the
lung. These include removal by mucociliary activity, transport by alveolar
macrophages to regional lymph nodes, uptake by epithelial cells, and direct
translocation of fibers between the epithelial cells to the interstitium and
the pleura. However, transport via the blood circulation has also been demon-
strated. As indicated above, microfibers are readily eliminated following
single inhalation exposures. However, the fibers retained following single or
repeated inhalation exposure, including those with larger diameters (<3 um),
are cleared slowly with a half-life of about 44 days. The half-life clearance
value following chronic exposure was about 600 days. The rates of clearance
following intratracheal administration in rats and guinea pigs decrease with
increased fiber length (^10 pm) and dose. Short fibers are phagocytized by
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alveolar macrophages and cleared to the lymph nodes. Long fibers are usually
partially phagocytized. Fiber type and composition, which affect solubility
and fragmentation, also influence the rates of fiber retention in the lung. In
this respect, glass fibers behave differently from amphibole asbestos fibers,
which are essentially insoluble u> vitro and split longitudinally into thinner
fibers and thus are not cleared as readily from the lungs. Following intra-
pleural injection in rats, fibers were found in various organs; translocation
apparently occurred via the blood capillaries.
Animal Toxicity
Limited information was available on the acute toxicity of fibrous glass.
Fibrous glass causes dermal irritation in rabbits and guinea pigs following
repeated application for 1 month. Mild inflammatory reaction was noted in male
rats, hamsters, and guinea pigs following 20 days of exposure to fiberglass.
Inhalation exposure to glass fibers of varying diameters and lengths for
up to 2 years generally failed to show any substantial pulmonary damage or
carcinogenic response in several experimental species. In contrast, asbestos
exposure results in collagen formation and development of pulmonary tumors.
Pulmonary responses to glass fibers generally consisted of macrophage infiltra-
tion, alveolar dust-laden macrophage aggregation, and alveolar proteinosis
resulting in some alteration of lung architecture in rats, guinea pigs, and
hamsters. The tissue response appeared to be influenced by the physical
dimensions of the fibers. In general, exposure to long (>20 urn), thick (>5 prr.)
fibers resulted in a minimal reaction characterized 'by sparse dust-laden
macrophage accumulation in the alveoli. By contrast, exposure to long, thin
(<3 urn) fibers resulted in alveolar proteinosis, development of reticulin fiber
networks, and some fibrosis. Short (<5 urn), thin fibers caused a severe
inflammatory response resulting in dense dust-laden macrophage aggregation, and
in some cases, enlargement of adjacent lymph nodes due to macrophage migration.
However, very little alteration of the lung architecture was observed:
When the results of these studies are considered collectively, it is
evident that inhalation of glass microfibers results in mild cellular reactions
at exposure levels of <3.0 mg/m . Higher concentrations of microfibers or
fibrous glass (diameter <3 um) result in more pronounced pulmonary manifesta-
tions. Using a grading system to score these lesions, a NOAEL of 3.0 mg/ir, and
a LOAEL of 100 mg/m were identified in rats and hamsters for microfibers with
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diameters <0.5 urn. The RfD is 0.03 mg/m3. For thicker fibers (>0.5 to
<3.5 pin), a LOAEl of 5 mg/m3 was identified in rats, and the RfD value was
calculated to be 0.005 mg/m .
Intratracheal instillation of glass fibers into several species results in
pulmonary manifestations similar to those observed following inhalation expo-
sure. Very short (<5 pm), very thin (<0.3 pm) fibers apparently cause no
pulmonary response. Short (<10 pm), thin (<2 urn) fibers elicit simple macro-
phage response. Longer (>10 pm) or thicker fibers (<3 ym) result in a more
pronounced response and some fibrosis. However, results from the same studies
provide equivocal evidence on the carcinogenic potential of glass fibers
following intratracheal administration. Results from studies with rats anci
hamsters indicate that microfibers (diameter £0.5 urn, length >10 ym) induce
pulmonary tumors, whereas other studies with the same species exposed to fibers
with similar dimensions provided negative results. Unlike inhalation or
intratracheal instillation into the lungs, the direct application of glass
fibers with varying diameters and lengths (and especially microfibers) onto the
pleura! surface of rats and hamsters or the peritoneum of rats has been shown
to result in the development of mesothelial and lung tumors. The tumorigenic
response was more pronounced and was elicited by lower doses following intra-
peritoneal administration than following administration via the intrapleural
route. Results from one study with BALB/c mice indicate that glass fibers were
not carcinogenic following intrapleural administration. Similarly, intraperi-
toneal administration of glass microfibers to hamsters in another study was
also negative. Quantification of cancer risk could not be determined since
there are no methodologies for the intraperitoneal or intrapleural route, and
inhalation exposure was negative. Fibrous glass is not mutagenic in Salmonella
strains or Escherichia coVj WP 2 with or without S9 activation. However, these
systems may not be appropriate for assaying the mutagenicity of fibers and
other particles. Long fibers (10 ym) of small diameter (0.13 yrn) cause chromo-
somal aberrations in cultured Chinese hamster ovary cells at 0.01 mg/mL and
induce transformation in cultured Syrian hamster embryo cells.
Several in vitro cytotoxicity tests have been developed to determine the
mechanism of action of mineral fibers and to predict the fibrogenic and/or
carcinogenic potential of specific fibers. These include cultures of 3T3 or
BHK21 fibroblasts; guinea pig, rat, and mouse macrophages; Chinese hamster
V79-4 lung cells; Syrian hamster embryo cells; phagocytic epitheloid asciteB
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tumor cells; and a human tumor line of type 11 alveolar cell origin. The
cytotoxicity of glass fibers has been confirmed in several studies. Equivalent
masses and numbers of various glass and asbestos fibers induced comparable cell
responses, but the extent of toxicity was primarily dependent on fiber size.
Long, thin glass fibers (diameter £0.3 urn and length 10 to 40 urn for 83 and
74 percent of the fibers, respectively) and long, very thin glass fibers
(diameter <0.2 pm and length 10 to 60 urn for 98.1 and 50 percent, respectively)
were as cytotoxic to epitheloid ascites tumor cells, mouse peritoneal macro-
phages, hamster embryo cells, and guinea pig, rat, and dog lung macrophages as
were similar-sized chrysotile, crocidolite, amosite, and synthetic fluoramphi-
boles. Long, thin asbestos and glass fibers also reduced the phagocytic
ability of macrophages and inhibited DNA, RNA, and protein synthesis in the
above-mentioned cells. These glass fibers (mean diameters between 0.12 and
1.9 pm) also slowed the growth of adult and fetal human fibroblasts and human
bronchial epithelial cells. The cytotoxic behavior of the long, thin glass
fibers corresponds to results of j_n vitro studies in which rats and hamsters
treated intrapleurally and rats treated intraperitoneally showed an increased
incidence of mesotheliomas.
The results of an oral teratogenicity study with a food-grade sodiuir.
aluminosilicate indicate no clear compound-related effects on reproductive
indexes, maternal and fetal toxicity, or soft and skeletal tissue abnormali-
ties. The fiber was administered to pregnant Wistar rats, CD-I mice,
Dutch-belted rabbits, and Syrian Golden hamsters beginning on day 6 of gesta-
tion for 9 to 13 consecutive days at doses up to 1600 mg/kg. The available
literature contained no information on reproductive effects.
Human Health Effects
Skin and eye irritation have been associated with occupational exposure to
fibrous glass. Mechanical irritation of the skin and eye is common, although
immunologic effects in a small number of exposed workers have also been
observed. Respiratory manifestations including bronchitis, pharyngitis, rhini-
tis, asthma, laryngitis, and sinusitis have also been associated with exposure
to glass fibers. These effects are apparently reversible when exposure to
fibrous glass is discontinued. Although no clear evidence of pulmonary abnor-
malities among exposed workers was found in several cross-sectional studies,
small lung opacities and higher incidences of chronic and dysplastic
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pharyngolaryngitis have been noted in a few workers exposed to fibrous glass
for more than 5 years.
The weight of evidence from several epidemiclogical studies for a caused
relationship between exposure to microfibers having diameters similar to
asbestos and nonmalignant respiratory disease (NMRD) or respiratory cancer in
U.S. workers is inadequate. The absence of risk is limited by the small number
of deaths and low power to detect NMRD in these studies.
The weight of evidence is limited for a causal relationship, associated
with latency and duration of exposure, between exposure to glass wool fibers
and NMRD and lung cancer in U.S., Canadian, and European workers. The strong-
est evidence for a causal relationship between exposure to glass wool fibers
and NMRD comes from a study conducted in the United States (Bayliss et a!.,
•1976), whereas the evidence for lung cancer comes from a Canadian study
(Shannon et a!., 1986, 1987) comparing data to provincial mortality rates.
Several studies provide limited evidence regarding a causal relationship
between laryngeal cancer in European (especially Italian) workers and exposure
to glass wool fibers. Although only nine laryngeal cancer deaths were reports
the strength of this association is based on the large SMRs that increased
with increasing latency and length of exposure, the significant findings after
comparison with high local rates, and the identification of cases in separate
studies. In France, a threefold excess in the incidence of buccal cavity
cancer was noted among production workers with 10 to 19 or ^20 years of expo-
sure when compared to regional rates. However, since the evidence comes from
*
only one study, the weight of evidence for a causal relationship between
exposure to glass wool ffbers and buccal cavity cancer is limited.
The weight of evidence for a causal relationship between NMRD or lung
cancer and continuous filament (textile fibers) among exposed workers is
inadequate. The abse.rce of a risk is limited by the small number of deaths and
low power to detect NMRD or lung cancer in several U.S. and European studies.
A quantification of cancer risk or NMRD based on epidemiological evidence could
not be made because exposure levels existing during the early technological
phase were not available.
Based on the weight of evidence from human health effects data and animal
toxicity data summarized in Chapter 9 (see Table 9-5), the carcinogenicity
classification for fibrous glass is Bl and for glass microfibers is B2.
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1.1.2 Mineral Wool
Mineral wools also consist predominantly of SiD2, A1203, and B203, but
they differ from fibrous glass in that they contain greater amounts of CaO,
MgO, Fe203, and Ti02, and 1esser amounts of Ba and the oxides of the alkali
metals. Two types of mineral wool fibers are available: rock wool and slag
wool. Rock wool is formed by melting natural igneous rocks, whereas slag wool
is produced from material consisting of premelted slag from iron blast furnaces
or from other metal-slagging processes. Slag and rock wools are generally
formed into fibers with diameters of 1 to 6 urn, which provide optimal thermal
conductivity. These wools have many of the same uses as fibrous glass, primar-
ily in insulation. Approximately 200,000 metric tons of mineral wool were
produced in 1983. Mineral wool is relatively less water-soluble and more
chemical-resistant than glass fibers, but both are susceptible to varying
degrees in acids and bases.
Environmental Release and Fate
Estimates of the environmental release of mineral wool are not available.
Similar to glass fibers, airborne concentrations of mineral wool in the
workplace vary greatly with sampling location within the same plant and among
plants performing similar operations. The range of average concentrations of
mineral wool found in air samples from several plants were reported to be 0.024
to 0.34 total fibers/cm and 0.001 to 0.463 respirable fibers/cm . The highest
fiber concentrations were detected in the production and manufacturing areas.
Estimates of respirable fiber concentrations in the European mineral wool
industry during the early technological phase ranged from 1 to 10 fibers/cm as
compared to current levels of about 0.03 to 0.12 fibers/cm . NOHS estimated
that 5079 workers were exposed to mineral wool in 1972-74. No information was
reported by NOES. Estimates for consumer exposure were not available. Simi-
larly, ambient levels for mineral wool were not found in the available litera-
ture, except for those reported above for fibrous glass; the concentration of
MMMF ranged from 0 to 10 fibers/L. The environmental fate and analytical
methods used to identify and quantitate mineral wool are similar to those
described for fibrous glass.
Metabolism
Factors affecting retention and clearance of mineral wool fibers are
similar to those discussed for fibrous glass with similar dimensions.
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Retention of fibers decreases with increased diameter and length and increases
with repeated dosing. Retention was highest for fibers with a length of 11 pm
and a diameter of 0.5 pm. Clearance was faster for fibers with diameters less
than 0.5 pm and decreased with increased fiber diameter. The rates of clear-
ance of retained fibers following repeated and chronic inhalation exposure are
similar to those observed for glass fibers. Nearly all the fibers retained
were less than 5 pm long. Short fibers- are phagocytized by alveolar and
interstitial macrophages and cleared to lymph nodes. Fragmented and partially
dissolved fibers have also been detected. In hamsters dosed intratracheally
with rock wool (1.1 x 27 pm), pseudoasbestos bodies were detected in the lungs
after 2 months.
Animal Toxicity
No information was found on the acute toxicity of mineral wool. Inhala-
tion exposure to respirable mineral wool in hamsters and rats for periods of
12 to 24 months elicits pulmonary responses comparable to those observed with
glass fibers having similar dimensions. Pulmonary responses elicited were
mainly dust-laden macrophage aggregation with only -slight changes in lung
architecture. The results from two studies indicate a NOAEL of 5 mg/rr for
rock wool, whereas one study with slag wool identified a LOAEL of 10 mg/rr, .
The corresponding RfD values were 0.05 and 0.01 mg/m . Investigators found no
evidence of a carcinogenic response following inhalation exposure to slag wool
(diameter 2.7 pm, length 40 pm) or rock wool (diameter <3 pm, length >5 pm).
Unlike inhalation studies, increased incidences of mesotheliomas and sarcomas
were noted in rats following intrapleural or intraperitoneal administration of
rock wool. The carcinogenic evidence for slag wool administered via either
route to rats was weaker (i.e., equivocal). The tumor incidences were low
(0 to 6 percent). When compared to asbestos, the carcinogenic potential of
rock wool is much lower. Quantification of carcinogenic risk was not possible.
Genotoxicity studies were not found in the available literature. Rock
wool and slag wool can induce considerable cytotoxicity in V79-4 Chinese
hamster lung cells, A549 human tumor cells, and mouse peritoneal macrophages.
Limited data suggest that the cytotoxic effects of rock wool and slag wool are
comparable to those of similar-sized fibrous glass. In contrast, long, rela-
tively thin (diameter 3.3 pm, length 221 pm) mineral wool fibers do not appear
to be cytotoxic to rat pulmonary alveolar macrophages or erythrocytes.
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Studies describing the teratogenicity and reproductive effects of mineral
wool or slag wool and rock wool were not found.
Human Health Effects
Cross-sectional studies with workers exposed to mineral wool indicate
skin, eye, and respiratory manifestations similar to those observed in workers
exposed to glass fibers. Several epidemiologic studies did not detect, or
provided limited evidence for, an association between exposure to mineral wool
and NMRD, especially when the data were analyzed by latency. Similar to the
studies with glass fibers, the absence of risk was limited by the small number
of deaths and low power to detect NMRD in multiple cohorts.
Significant excess mortalities from various carcinogenic effects were
noted in workers exposed to mineral wool. These included respiratory, lung,
digestive system, stomach, and buccal cavity and pharyngeal cancers. The
weight of evidence for a causal relationship from several studies was limited.
A quantification of cancer risk or NMRD based on epidemiologic evidence ccuOd
not be made because exposure levels existing during the early technological
phase were not available.
Based on the weight of evidence from human health effects and animal
toxicity data summarized in Chapter 9 (see Table 9-5), the carcinogenicity
classification of mineral wool is 61.
1.1.3 Ceramic Fibers
Ceramic fibers are produced by combining kaolin'clay or a mixture of
alumina and silica to form aluminosilicate glasses. The melted compound is
blown to form fibers used primarily for high-temperature insulation. Approxi-
mately 100 million pounds were produced 1n 1983. Alumina and zirconia are two
other types of ceramic fibers that possess strong physical and chemical refrac-
tory qualities used for even higher temperature applications. The fibers
produced for industrial applications have a desired diameter range of 2 to
3.5 pm and a length ranging from a few micrometers to several centimeters.
Alumina fibers are imported from the United Kingdom; in 1983, 150,000 pounds
were imported and consumed in the United States. The annual production capacity
of zirconia fibers in the United States for 1983 was about 10,000 to 12,000
pounds. Ceramic fibers exhibit good chemical stability and resist oxidation,
reduction, and attack from most corrosive agents, but they are not resistant to
strong acids and alkalies.
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Environmental Release and Fate
Estimates of the environmental release of ceramic fibers are not
available. The range of average ceramic fiber concentration in air samples
from three plants was reported to be 0.049 to 2.6 fibers/cm and 0.21 to
2.6 respirable fibers/cm . No information was found on ambient concentrations
or NOHS and NOES estimates of worker exposure. The specialized applications of
ceramic fibers limit their potential for consumer exposure, but no estimates
were available. Similarly, no information was found on the environmental fate
of ceramic fibers. The analytical methods used to identify and quantitate
ceramic fibers are similar to those described for fibrous glass.
Metabolism
Limited information is available on the pulmonary deposition, transloce-
tion, and clearance of ceramic fibers. Results from a few available studies
indicate that pulmonary retention and clearance of ceramic fibers are similar
to the pulmonary retention and clearance observed for glass and mineral wed
fibers. Following repeated and chronic inhalation exposure, most of the
retained fibers were <_5 urn in length. However, slight differences were noted
in the distribution of fibers deposited within the various pulmonary lobes when
compared to glass fibers. Retained fibers are cleared slowly from the lung.
and clearance rates decreased with increased fiber lengths. Fragmentation of
ceramic fibers, as well as phagocytosis by alveolar macrophages and clearance
to lymph nodes, have also been reported. Migration of Ceramic fibers from the
peritoneum to the lymph nodes of rats injected intraperitoneally has been
observed.
Animal Toxicity
No information was found on the acute toxicity of ceramic fibers. Similar
to other vitreous fibers, the chronic inhalation of ceramic fibers by rats has
been shown to result in little pulmonary manifestation other than dust-laden
macrophage aggregation. Using a grading system to score the results of three
chronic inhalation toxicity studies, a NOAEL of 2.45 mg/m was identified for
refractory Al.O, fibers (Saffil ), and a LOAEL of 8.4 mg/m3 was identified for
aluminum silicate ceramic microfibers.
Intraperitoneal administration of ceramic fibers resulted in fibrosis in
rats. However, the fibrosis contained little or no collagen and was in no way
comparable to the fibrosis elicited by asbestos. The results fror seve-el
i i ,^.» T.IO nD'fT__nr. »'~T rvi-Tr r.r
-------
studies suggest that the carcinogenic potential of ceramic fibers is similar to
that observed for other vitreous fibers. Chronic inhalation toxicity studies
with rats and hamsters exposed to aluminum silicate ceramic fibers and the
refractory ceramic fibers Fiberfrax® and Saffil*1 were negative. Similarly,
inlratracheal administration of Fiberfrax® to rats and hamsters produced
negative results.
In contrast, Fiberfrax*1 was found to be very carcinogenic following
intraperitoneal administration (20 to 80 percent incidence), and the evidence
for the aluminum silicate microfibers was equivocal. Considerably lower
incidences of tumors (2 to 4 percent) were noted for large-diameter alumina and
zirconium oxide fibers following intrapleural administration. Similarly, low
incidences of mesothelial tumors (10 percent) were noted for the aluminurr.
silicate fibers. Quantification of cancer risk was not possible.
Genotoxicity studies were not found in the available literature. Several
cytotoxicity studies indicate that ceramic fibers with various diameters
(0.2 to 5 ^m) and lengths are not hemolytic to erythrocytes or cytotoxic to rat
pulmonary alveolar macrophages or to macrophagelike P338D-, cells. Similarly,
Gi GL
Saffil alumina and Saffil iirconia (diameter 2 to 6 ym) were found to be
minimally cytotoxic and nonfibrogenic to rat peritoneal macrophages.
Teratogenicity and reproductive effects studies were not found in the
available literature.
Based on the weight of evidence from animal toxicity data summarized in
Chapter 9 (see Table 9-5), the carcinogenicity classification for ceramic
fibers is C.
Human Health Effects
No information was found on the health effects of ceramic fibers. .
1.2 SYNTHETIC FIBERS
Similar to MMMF, the synthetic fibers discussed In this document are not
discrete entities definable by a fixed chemical composition. Their chemical
and physical properties depend upon their chemical composition.
1.2.1 Aramid Fibers
Aramid fibers are aromatic polyamids synthesized from aromatic diarr.ines
and diadic chlorides. Two categories of fibers are available: heat- anc!
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flame-resistant fibers (Nomex ) and ultra-high-strength, high-modulus fibers
(Kevlar ). Most aramid fibers are highly crystalline. They are found in a dry
pulp form, which consists of short fibers (0.5 to 8 mm) with fine fibrils
attached to the surface. They have excellent wear resistance, are nonabrasive,
and have multiple applications, including the following: Nomex* fibers are
used in industrial protective clothing, carpets, tents, and solution paper for
electrical motors and transformers; Kevlar fibers are used in tires, cables,
£
parachutes, and body armor. In 1975, the annual production capacity for Nomex
£
and Kevlar was reported to be 9,100 and 23,000 tons/year, respectively.
Environmental Release and Fate
• Estimates of environmental release of aramid fibers were not available.
Also unavailable were information on airborne concentrations in manufacturing
plants and ambient air, NOHS and NOES estimates of worker exposure, and esti-
mates of consumer exposure. Aramid fibers are susceptible to weathering and
aging. Their chemical composition and tensile strength are affected by photol-
ysis, temperature, and oxidation but not hydrolysis. Analytical methccs
similar to those described for fibrous glass are used to identify and quar.fi-
tate aramid fibers.
Metabolism
Information on the pulmonary deposition and clearance of aramid fibers in
laboratory animals is very limited. However, it appears that these are influ-
enced by the same mechanisms noted for other fibers.' Following inhalation
exposure or intratracheal administration to rats, fibers with a Dfle of <5 urn
were found in the alveolar region. Fiber-laden macrophages were not immedi-
ately observed after inhalation, whereas fragmented and markedly shorter fibers
were observed within 3 months.
Animal Toxicity
Mild to moderate foreign body reaction was found in the lungs of rats
exposed to aramid fibers for 2 weeks at concentrations of 3 and 18 mg./m but
not at <0.5 mg/m . Fibrosis was noted at the highest exposure level and was
still evident 6 months postexposure. Only one chronic inhalation toxicity
£
study was available for Kevlar fibers (diameter 90 percent <1.5 urn, length^
75 percent <20 urn). Moderate pulmonary toxicity characterized by hyperplasi^H
obi iterative bronchiolitis with collagen formation, emphysema, and a
-------
dose-dependent increase in squamous cell carcinoma was noted in rats exposed to
concentrations of 0.63 and 2.23 mg/m3. The NOAEL and LOAEL for systemic
effects were 0.08 and 0.32 mg/m3, respectively, and the RfD volume was
0.0008 mg/m . The estimated cancer risk was 9.4 x 10~2 (ug/m ).
The results from three studies with Wistar rats injected intraperitonesny
£
with Kevlar* fibers (diameter <1.0 pm) indicate a weak carcinogenic potential.
The incidences of nesotheliomas and sarcomas were low (6 to 13 percent) and
were not dose-dependent.
Genotoxicity studies were not found in the available literature. Aram id
fibers with mean diameters of 0.14 urn and mean lengths of <5 pm were found to
be as cytotoxic as asbestos when incubated with cultures of rat pulmonary
alveolar macrophages. The fibers induced a dose-dependent release of cytosomal
and lysosomal marker enzymes with a concomitant decrease in ATP cell content.
Teratogenicity and reproductive effects studies were not found in the
available literature.
Human Health Effects
No information was available on the health effects of aramid fibers.
Based on the weight of evidence from animal toxicity data summarized in
Chapter 9 and in the absence of human effects data (see Table 9-5), the
carcinogenicity classification for aramid fibers is B2.
1.2.2 Carbon Fibers
Carbon fibers are produced by controlled pyro'lysis of rayon,
polyacrylonitrile (PAN), or mesophase pitch. The fibers have diameters of 5 to
15 urn and are characterized by flexibility, electrical conductivity, chemical
inertness except oxidation, refractoriness, and high tensile strength.
Rayon-based carbon fibers are produced in a high-modulus or a low-modulus forrr.
and are used in tire cords and aerospace applications. The estimated consump-
tion was 100,000 to 250,000 kg/year for 1970 to 1976. Applications of PAN
fibers include use in structure fabrication for the aerospace industry, sport-
ing goods, prostheses and artificial joints, and reinforcement for plastics.
Production volumes were not available. Mesophase pitch-based carbon fibers
have a carbon (graphite) content over 99.5 percent. They are produced in three
forms, differing only in filament modulus.
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Environmental Release and Fate
Estimates of environmental release of carbon fibers are not available.
Airborne concentrations of carbon fibers vary with sampling location and
process within the same plant and from one plant to another. The ranges of
concentrations found in air samples from two plants were 0.024 to 1.2 and 0.9
to 659,000 total fibers/L, respectively. The range of respirable fibers in a
third plant was 0.03 to 0.16 mg/m3. No information was available on ambient
concentrations, NOHS and NOES estimates of worker exposure, or estimates of
consumer exposure. Information on the environmental fate of carbon fibers wes
unavailable. However, carbon fibers are chemically inert except for oxidation.
The analytical methods used to identify and quantitate carbon fibers are
similar to those used for fibrous glass. In addition, microwave absorption
and induced charge detectors can be used with larger fibers.
Metabolism
Phagocytosis of carbon fibers in exposed guinea pigs occurs within hours
after inhalation and continues for 2 or more years. The nonfibrous dust is
primarily cellular in macrophages, and the number of. particles in each macro-
phage increases with time after exposure. Human subjects exposed to a carbon
dust aerosol for 3 minutes at a concentration of 50 mg/mL (mass median diameter
11 urn) retained approximately half of the inhaled carbon dust. Additional
information was not found in the available literature.
•
Animal Toxicity
Short-term toxicity studies with carbon fibers are limited to tissue reac-
tions associated with implants in the peritoneal cavity or bones of rats and
rabbits. Fibrous tissue ingrowth and mild to acute foreign body response
was evident. The results from two subchronic inhalation toxicity studies
indicate no pulmonary damage, although macrophage accumulation was.evident. In
the first study, rats were exposed to submicron carbon dust for 7 to 100 hours
and observed for up to 2 years. In the second study, hamsters were exposed to
20 mg/m Celion, a PAN-based carbon fiber with a mean diameter of 7 urn and
length of 20 to 60 urn, for 16 weeks. Chronic inhalation toxicity studies were
not found in the available literature. Consequently, an RfD value was not
calculated. Similarly, intratracheal, intrapleural, and intraperitoneal
studies were not available. The results from a chronic dermal toxicity study
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with male mice treated three times & week for life with one of four carbon
fibers did not induce a compound-related increase in tumor incidences.
Genotoxicity studies were not found in the available literature. Carbon
fibers of various sizes (diameter 0.2 to 15 urn) were only minimally cytotoxic
to rat peritoneal and pulmonary macrophages.
Teratogenicity and reproductive effects studies were not found in the
available literature.
Human Health Effects
Results from one cross-sectional study provided no evidence of respiratory
manifestation in 88 workers employed in a carbon plant.
Based on the weight of evidence from human health effects and animal
toxicity data summarized in Chapter 9 (see Table 9-5), the carcinogenicity
classification of carbon fibers is 0.
1.2.3 Polvolefin Fibers
Pclyolefin fibers are long-chain synthetic polymers consisting of at least
85 percent by weight ethylene, propylene, or other olefin units. They are
fabricated commercially by a melt extrusion technique. This involves expulsion
of the polymer through a spinneret, solidification, and winding onto packages.
Polyolefin fibers are extremely hydrophobic and inert to acids and bases and
organic solvents at room temperature. Polyolefin fibers are primarily used in
home furnishings, such as carpet facing and backing for upholstery.. Industrial
uses include synthetic turf, cordage and twine, agricultural fabrics, and
sewing threads. Production and consumption values for 1963 were 603 and 767
million pounds, respectively. Production has increased steadily to correspond
with increased demand.
Environmental Release and Fate
Estimates of environmental release of polyolefin fibers were not avail-
able. Similarly, no information was available on airborne concentrations in
manufacturing plants and ambient air. NOHS estimated that 96,784 workers were
exposed to polyolefin fibers during 1972-74; NOES provided no estimates. No
information was available on the environmental fate of polyolefin fibers,
although they tend to be chemically inert at room temperatures. Analytical
procedures similar to those described for fibrous glass are used to identify
and quantitate polyolefin fibers.
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Hetabolism
No information was found on the retention and clearance of polyolefin
fibers.
Animal Toxicity
Short-term toxicity studies are limited to tissue reactions associated
with implants in the peritoneal cavity and femoral bone of rats. Fibrous
tissue ingrowth was noted in both tissues. Subchronic and chronic inhalation
toxicity studies were not found in the available literature. Consequently, an
RfD value could not be calculated. Male rats dosed intratracheally with
1.25 mg of polypropylene fibers or dust and observed for 21 months exhibited
lung granulomas with foci containing irregularly shaped birefringent particles.
No other effects or pulmonary tumors were noted. Intraperitoneal administra-
tion of polypropylene fibers (diameter <2.1 pm, length <23 urn) to female Wistar
rats elicited a weak carcinogenic response. Two of 51 rats developed mescthe-
liomas or sarcomas, but the incidence was not significantly different froir that
of control animals.
Genotoxicity studies were not found in the available literature. Polye*J
ylene (diameter 3 to 75 urn) and polypropylene (diameter 4 to 50 urn) exhibited
low cytotoxicity when incubated with rat peritoneal or pulmonary alveolar
macrophages at 0.5 mg. Less than 1 and 4 percent of the peritoneal and alveo-
lar macrophages, respectively, were killed following phagocytosis of the
fibers.
Teratogenicity and reproductive effects studied were not found in the
available literature.
Human Health Effects
No information was available on the health effects of polyolefin fibers.
Based on the weight of evidence from animal toxicity data in the absence
of human health effects data (summarized in Chapter 9 and Table 9-5), the
carcinogenicity classification for polyolefin fibers is D.
1.3 MINERALS
All minerals and their asbestiform varieties are defined by a crystal
structure and a chemical composition that is restricted to a limited range c|
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permissible substitution. Their physical and chemical properties are deter-
mined by their crystal structure, chemical composition, and crystallization
habit.
1.3.1 Attapulgite
Attapulgite (CAS ho. 12174-11-7) is a trade name for the common
asbestiform, short-fibered (length 0.8 pn>, diameter 0.06 pm.) variety of
palygorskite mined at Attapulgus, GA. Palygorskite is a layered silicate
structurally related to the clay minerals and has the composition of
Mg5(OH)2(H20)4Sig02Q'4H20. The mineralogic composition varies greatly with the
site of origin and the presence of other minerals. Approximately 2 million
short tons were produced or used in 1985. Attapulgite, a light cream-colored
powder, is chemically inert and its properties are unaffected by changes in pH.
Attapulgite finds a wide commercial application in both absorbent and jelling
or thickening agents due, in part, to its sorptive and colloidal properties.
Environmental Release and Fate
Emissions of minerals are associated with natural weathering, mining
operations, and the use of these materials in secondary products, but no
estimates are available for attapulgite. The range of concentrations of
attapulgite in air samples in mining and milling facilities was reported to be
0.09 to 23 mg/cm and 0.05 to 2.7 mg respirable fibers/cm . NOHS estimated
that 134,121 workers were exposed to attapulgite in 1972-74. NOES provided no
estimates. Estimates of consumer exposure were not available. Attapulgite is
inert and is not expected to undergo chemical transformation. Analytical
procedures used to identify and quantitate attapulgite are similar to those
reported for fibrous glass.
Metabolism
Limited information was available on the metabolism of attapulgite. The
results of two case reports suggest that inhaled attapulgite can reach the
alveoli and that ingested attapulgite is absorbed and eliminated in the urine
when consumed in large amounts. A total of 14 different mineral groups were
identified in the lungs of 11 men and 9 women with no history of occupational
exposure at the time of death. These included asbestos, apatite, gypsum, talc,
silica, and attapulgite. About 86 percent of all of these fibers were <5 ur in
length.
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Animal Toxicily
No information was available on the acute and subchronic toxicity of
attapulgite. Similarly, no information was available on chronic inhalation
toxicity. Consequently, an RfD value was not calculated. Intratracheal
instillation of 100 mg attapulgite (0.02 x 0.8 urn) in sheep resulted in bio-
chemical changes, accumulation of alveolar macrophages, and sparse areas of
peribronchiolar fibrosis. Intrapleural administration of attapulgite to two
strains of rats was not tumorigenic. Intraperitoneal administration of
attapulgite (0.07 x 1.3 urn) obtained from Caceres, Spain, was tumorigenic;
40 percent of the rats developed mesotheliomas or sarcomas. However, three
other samples from Spain, the United States, and France (0.04 x 0.8 urn), were
not tumorigenic following intraperitoneal administration in the same study.
The compositions of these samples were not defined.
Attapulgite does not induce unscheduled DNA synthesis in primary cultures
of rat hepatocytes at concentrations of 1 and 10 pg/mL. Limited information
also suggests that attapulgite does not increase the frequency of sister
chromatid exchange. No other genotoxicity studies were available. Attapulgite
(0.06 x 0.77 urn) generally appears to exhibit cytotoxic and hemolytic activity
when incubated with peritoneal and alveolar macrophages. Attapulgite was mere
cytotoxic and hemolytic than chrysotile asbestos. Cytotoxicity increased witn
increased fiber length and decreased diameter as shown by increased cytctox-
icity in mouse peritoneal macrophages, A549 type II alveolar human tumor cells,
and V79-4 Chinese hamster lung cells.
Teratogenicity and reproductive effects studies were not found in the
available literature.
Human Health Effects
Limited information was available on the health effects of attapulgite.
The results from a cross-sectional morbidity study indicated no consistent
relationship between worker exposure and respiratory symptoms. In attapulgite-
related occupations, pulmonary function was generally low and the prevalence of
pneumoconiosis was elevated in the older age categories; however, neither
effect was statistically significant for workers in occupations that generated
dusts other than attapulgite. Despite the low power, when compared with U.S.
rates, a threefold excess in lung cancer mortality was noted in a cohort
mortality study of 2300 miners and millers with >5 years exposure duration and
^20 years latency who were employed for at least 1 month frorr, 1940 to 1977.
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However, the evidence is inadequate for a causal relationship because the
excess was noted in only one study, the number of deaths was small, the power
was low, and mortality rates were comparable to national mortality rates.
Based on the weight of evidence from human health effects and animal
toxicity data summarized in Chapter 9 (see Table 9-5), the carcinogenicity
classification for attapulgite is C.
1.3.2 Erionite
Erionite (CAS No. 66733-21-9) is a fibrous 2eolite found in deposits in
the Western Intermountain Region of the United States. Erionite occurs as
either single needles or in clusters and ranges from 0.25 to 1.5 um in diameter
and up to 50 um in length. U.S. erionite is classified as "probably
asbestiform," whereas the erionite found in Turkey is a suspected "truly
asbestiform" material owing to exposure-associated adverse health effects. A
sample taken from the Cappadocia region of Turkey had the following chemical
composition: (Na^K-CaMg)^ ^AlgSi-yOy-^HpO.
Erionite has been used for nitrogen retention in fertilizers and concrete
aggregate and in road surfacing, but production and use volumes are unavail-
able. The annual production of natural zeolites in the United States was
estimated to be 2500 to 500D tons for 1982-84. However, erionite apparently is
not produced in the United States at the present time.
Environmental Release and Fate
Estimates of environmental release of erionite are not available. Simi-
larly, estimates of airborne concentrations in mining facilities and ambient
air, as well as worker and consumer exposure, were not reported. However, in
two Turkish villages with relatively high incidences of mesothelial tumors
among the villagers, airborne concentrations of respirable dust ranged from 0.2
to 2.8 mg/m , whereas fiber concentrations ranged from <0.01 to 1.38 fibers/cm .
No information was found on the environmental fate of erionite. The analytical
procedures used for fibrous glass are also used to quantitate and identify
erionite fibers.
Metabolism
Although the mechanisms governing lung deposition and clearance of
erionite fibers are similar to those governing lung deposition and clearance of
other fibers, very little information is available on the deposition and
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clearance of erionite. Erionite has been shown to penetrate the pleura! and
parenchyma! tissues in Turkish villagers exposed to low levels. Fibers recov-
ered from the lungs of these individuals were uncoated and had a mean diameter
of 0.3 urn and a maximum length of 9 urn. Ferruginous bodies containing erionite
fibers were noted in a few individuals.
Animal Toxicity
No information was found on the acute and subchronic toxicity of erionite.
Chronic toxicity data from several studies indicate that erionite samples fron
Oregon and Turkey are highly carcinogenic in rats via the inhalation, intratra-
cheal, intrapleural, and intraperitoneal routes of administration. The tumor
incidences in treated animals were 48 to 100 percent, with mesothelial tumors
being the most predominant. Erionite has also been shown to be carcinogenic in
mice following intraperitoneal injection. The carcinogenic unit risk basec! on
tumor incidences following inhalation exposure is 5.56 (mg/m ) . However,
nonfibrous, synthetic zeolites do not appear to be carcinogenic following
intrapleural or intraperitoneal administration.
Erionite has been shown to induce significant increases in aneuploidy .
polyploidy in Chinese hamster lung cells and to induce chromosomal aberrations,
cell transformations, and unscheduled DNA synthesis at concentrations ranging
from 10 to 100 ug/mL. Erionite is cytotoxic to rat pulmonary alveolar macro-
phages and human polymorphonuclear leukocytes, but it exhibits a weak hemolytic
activity in rat erythrocytes.
Teratogem'city and reproductive effects studi'es with erionite were not
found in the available literature. A teratogenicity study with a synthetic
zeolite administered orally to pregnant Sprague-Oawley rats and New Zealand
rabbits at 160C mg/mL on days 6 to 15 and 6 to 18 of gestation, respectively,
indicated no adverse effects on the dams, embryos, or fetuses in either
species.
Human Health Effects
Several cross-sectional morbidity and mortality studies indicate a strong
causal relationship between exposure to erionite and increased incidence of
malignant mesothelial tumors and other pathological changes in inhabitants of
three Turkish villages. Although causal relationships are not discerned bv_
cress-sectional studies, the consistency of these findings among severe
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studies and the presence of erionite rather than asbestos indicate an etiologi-
cal role for erionite. Quantification of cancer risk was not performed for
these cross-sectional studies.
Based on the weight of evidence from human health effects and animal
toxicity data summarized in Chapter 9 (see Table 9-5), the carcinogenicity
classification for erionite is Bl.
1.3.3 Talc
Talc (CAS No. 14807-96-6) is made up of pulverized, foliated hydrous mag-
nesium silicates from minerals with low crystalline silica content. Talc is
a layered silicate, and both talc crystals and fragments are commonly platey
and nonfibrous. Its color can be white, yellow, green, or gray depending on
the number of impurities present. The chemical composition of talc is
(^(Si^Oe^MgCOH)^. jt is insoluble in water and exhibits varying resistance
to acids, alkalies, and temperature. Approximately 1100 short tons of talc
were produced in the United States in 1984. The largest end uses of talc are
in ceramics and paint; only 5 percent are used in cosmetics.
Environmental Release and Fate
Estimates of environmental release of talc are not available. Airborne
concentrations in mining and milling facilities have been found to range
between 0.28 and 2.64 mg/cm for total particles. Estimates of airborne
concentrations in ambient air are not available. NOHS reports that
1,536,754 workers were potentially exposed to talc in'1972-74, whereas NOES
estimated that 18,872 workers, including 5,244 females, were potentially
exposed to talc in the workplace in 1980. Consumer exposure to talc and
talc-containing products is potentially high, but no estimates were available.
Certain talc deposits have been shown to contain various concentrations of
asbestos, but estimates of asbestos exposure from talc during production or use
were not available. Talc is not expected to undergo chemical transformation
when released into the environment. Analytical procedures used to identify and
quantitate talc are similar to those described for fibrous glass.
Metabolism
Following single inhalation exposures, talc is retained in the lungs of
exposed hamsters and is cleared slowly with a biological half-life of 7 to
10 days. The talc content decreased to the detection levels founi in centre!
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animals 4 months after exposure. Pulmonary deposition of talc following
repeated exposures is dose-dependent. Pulmonary clearance is facilitated by
mucociliary activity and eliminated in the feces via the gastrointestinal
tract. Little, if any, talc is absorbed from the gastrointestinal tract of
rats, guinea pigs, mice, and hamsters following oral intubation. Most of the
material was eliminated in the feces within 1 to 2 days after dosing. No
measurable transport of talc was reported following intravaginal instillation
into cynomolgus monkeys. In rats, however, intrauterine or intravaginal
instillation resulted in migration of talc particles into the ovaries.
Animal Toxicity
No information was available on the acute toxicity of talc, although
intratracheal instillation of talc in hamsters resulted in pulmonary toxicity
as shown by biochemical and cellular changes. Subchronic inhalation exposure
(3 to 12 months) in rats resulted in pulmonary fibrosis that increased in
severity as the exposure period increased. A LOAEL of 10.8 mg/m and an RfD
value of 0.011 mg/m was identified from this study. Intratracheal or
intraperitoneal administration of talc resulted in a typical granulomatous
lesion consisting of dust-laden multinucleated foreign body giant cells, as
well as some fibrosis with collagen formation in several animal species. In
addition to the development of granulomas, intratracheal instillation of talc
resulted in moderate tissue destruction in hamsters, and intraperitoneal
administration has been shown to cause abdominal adhesions in rats and swine.
Talc is not carcinogenic following inhalation exposure or intratracheal
instillation in rats and hamsters. Similarly, no evidence of carcinogenicity
was noted following intrapleural, intraperitoneal, or oral administration in
rats. The results of one study suggest that talc may act as a cocarcinogen
following intratracheal administration in combination with benzo(a)pyrene once
weekly for life, but the exact mechanism is not known.
Limited data suggest that talc does not induce gene mutations in Salmonella
or Saccharomyces at 200 mg/mL, chromosomal aberrations in rat bone marrow
cells, or dominant lethal mutations in the germinal cells of male rats.
However, no details of these studies were presented. Natural or acid-purified
talc (particle size 0.2 to 20 urn) exhibits weak cytotoxicity in rat peritoneal
and alveolar macrophages. Talc particles within the respirable range were net
cytctoxic to A549 alveolar human tumor cells or V79-4 Chinese hamster luic
cells.
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Teratogenicity and reproductive effects studies were not available.
Human Health Effects
Several cross-sectional morbidity studies of miners and millers indicate
increased respiratory symptoms, higher prevalence of pleura! thickening or
calcification and pneumoconiosis, and decreased pulmonary function in workers
exposed to talc containing various amounts of tremolite, anthophyllite, or
silica fibers. These effects increased with age of workers, intensity of
smoking, and duration of exposure. However, exposure to talc free of asbesti-
form fibers was associated with less pronounced effects. Increased incidences
of ovarian cancer are reported in a case-control study of 215 white females
regularly using talc as a dusting powder on the perineum or on sanitary napkins,
or both, when compared to controls. However, the purity of talc used was
unknown. Similar to the findings described above, several historical prospec-
tive mortality studies indicate an excess of respiratory cancer and NMRO among
mining and milling workers. However, the talc was contaminated with asbestos,
silicates, carbonates, or radon. Consequently, a causal relationship for ta'c
alone cannot be established.
Based on the weight of evidence from human health effects and ar.itr.a1
toxicity data summarized in Chapter 9 (see Table 9-5), the carcinogenicity
classification for talc is D.
1.3.4 Vermiculite
Vermiculite (CAS No. 1318-00-9) is a micaceous hydrate of magnesium-iron-
aluminum silicates. Vermiculite crystals are composed of two silicate layers
connected by a hydrous layer. The chemical composition of vermiculite is
(Mg,Fe,A1)3(Al,Si)4010(OH)2'4H20. It is unique among minerals in its ability
to exfoliate or expand up to 20 times its original size at high temperatures.
It has cation exchange capacity and a very low thermal conductivity. About
285,000 short tons were produced in the United States in 1985. Most of the
vermiculite mined and beneficiated is exfoliated and used in construction
aggregates, insulation, and agricultural applications.
Environmental Fate and Release
Approximately 802 x 10 kg of vermiculite were released into the air,
89,900 x 103 kg were released into water, and 2.490 x 10 kg were release:! es
solid waste in 1979 based on a production volume of 1 millio- tens. Consumer
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use results in the release of 36 x 10 kg into the terrestrial compartment.
Airborne concentrations in mining and milling facilities were reported to range
from <10 to 39 fibers/cm. No information was found on concentrations in
ambient air. A recent study indicates that airborne concentrations prior tc
1964 were high (<182 fibers/cm ). However, exposure estimates have decreased
significantly and have leveled off from 1976 to 1982 to >1.0 fiber/cm. NOHS
reports that 104,456 workers were potentially exposed to vermiculite from 1972
to 1974, whereas NOES estimated that 4,293 workers, including 365 females, were
exposed to vermiculite 1n 1980. Certain vermiculite deposits have been shown
to contain various concentrations of asbestos. Estimates of occupational
exposure levels for asbestos ranged from undetectable to 9.7 fibers/cm of air
in mills and exfoliation facilities. Ambient air concentration of asbestos
near mills and exfoliation facilities ranged from undetectable to 0.5 fibers/err5
-5 -2 3
and 5.0 xlO to 2.5 x 10 mg/m , respectively. Nonoccupational exposure to
vermiculite is high. In 1979, approximately 13 million persons were estimated
to have been exposed to vermiculite near exfoliation plants in the United
States. In addition, about 106 million persons were exposed to consumer
products containing vermiculite. Vermiculite is not expected to undergo
chemical transformation when released into the environment. Analytical proce-
dures used to identify vermiculite are similar to those described for fibrous
glass.
Metabolism
No information is available on the metabolism of vermiculite following
oral administration or inhalation exposure.
Animal Toxicity
No information was found on the acute, subchronic, or chronic toxicity cf
vermiculite. Consequently, an RfD value was not calculated. Female
Sprague-Dawley rats injected intrapleurally with 25 mg vermiculite (<2 x <5 urr,
amorphous particles) developed granulornas in the lungs and viscera. However no
tumors developed after 104 weeks. Genotoxicity and cytotoxicity studies were
not found in the available literature. Similarly, teratogenicity and reproduc-
tive effects studies were not found.
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Human Health Effects
An association between previous vertniculite exposure and parenchymal and
pleura! radiographic abnormalities has been found in two cross-sectional
studies of miners and millers. Although these changes did not correlate with
pulmonary function tests, they did correlate with age and fiber-years. Howev-
er, vermiculite from both facilities contained fibrous tremolite/ actinolite.
A historical prospective mortality study of one of the mining and milling
facilities indicated a significant twofold excess in mortality for lung cancer
and NMRD, especially in the highest exposure category and among those with
>20 year latency. However, the presence of tremolite-actinolite asbestos
precludes a causal relationship between exposure to vermiculite and lung cancer
or NMRD.
Based on the weight of evidence from human h&alth effects and aniir,= 1
toxicity data summarized in Chapter 9 (see Table 9-5), the carcinogenicity
classification for vermiculite is D.
1.4 REFERENCES
Bayliss, D. L. ; Dement, J. M. ; Wagoner, J. K.; Blejer, H. P. (1976) Mortality
patterns among fibrous glass production workers. Ann. N. Y. Acad. Sci.
271: 324-335.
Shannon, H. S.; Jamieson, E.; Julian, J. A.; Muir, D. C. F.; Walsh, C. (1986)
Mortality experience of glass fibre workers--extended follow-up. Presented
at: international symposium on man-made mineral fibres in the working
environment; October; Copenhagen, Denmark. Copenhagen, Denmark: World
Health Organization, Regional Office for Europe.
Shannon, H. S.; Jamieson, E.; Julian, J. A.; Muir, D. C. F.; Walsh, C. (19E7)
Mortality experience of glass fibre workers -• extended follow-up. Ann.
Occup. Hyg. 31: 657-662.
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2. BACKGROUND INFORMATION
Concern surrounding the possible health effects of asbestos upon the
general population has stimulated interest in the potential health effects of
other natural and manmade fibers. The health effects of asbestos have been
recently reviewed by the National Research Council (1984) and the U.S.. EPA
(Nicholson, 1986). The purpose of this Health Assessment document is to review
key toxicologic data on manmade fibers (e.g., fibrous glass, mineral wool, and
ceramic fibers), synthetic fibers (aramid, carbon, and polyolefin fibers), and
naturally occurring fibers other than asbestos (e.g., attapulgite and erionite)
to assess whether significant human health effects are associated with envircr-
mental exposure. Data on talc and vermiculite are also reviewed in this
document because of concerns associated with the possible presence of asbestos
as a contaminant in some deposits of these minerals. In addition, data or,
other fibers and/or minerals are discussed in various parts of this document
primarily for comparative purposes.
2.1 PHYSICAL AND CHEMICAL PROPERTIES
Minerals and their asbestiform varieties are defined by a crystal structure
and a chemical composition that is restricted to a limited range of permissible
substitutions. Their physical and chemical properties are determined first by
their crystal structure, second by their chemical composition, and third by
their crystallization habit (Zoltai, 1986).
Unlike these environmental substances, which are discrete entities defina-
ble by a fixed chemical structure, the products currently referred to as
manmade vitreous fibers or more commonly as manmade mineral fibers (MMMF)
comprise a group of materials that are less easily defined (Table 2-1). MMMF
are manufactured by various techniques from a molten mass of raw material
(Klingholz, 1977). Table 2-1 also lists minerals that have a fibrous morphol-
ogy. This list could easily contain several hundred minerals if it were
expaned to include rare fibrous occurrences of common minerals or fibrous
minerals found only in small amounts. The minerals selected for inclusion are
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TABLE..2-1. MINERAL AND VITREOUS FIBERS
Manmade Mineral Fibers
Fibrous glass
Mineral wool
Rock wool
Slag wool
Ceramic fibers
Other fibers
Synthetic Fibers
Aramid fibers
Carbon fibers
Polyolefin fibers
Naturally Occurring Mineral Fibers
Asbestos
Chrysotile
Crocidotite
Amosite
Actino1ite--Tremo1ite asbestos
Anthophyllite asbestos
Attapulgite (palygorskite)
Zeolites (erionite)
relatively common throughout the world, have commercial applications, and see"
likely to have, or are known to have, at least some of the properties of
asbestifonr. fibers (National Research Council, 1984).
Physical properties common to asbestiform fibers, as compared with non-
asbestiform crystals of the same substances, Include, fiberlike morphology
and dimensions, enhanced strength and flexibility, diameter-dependent strength,
increased physical and chemical durability, and improved surface structure
(i.e., relatively free of defects). A continuum of these properties is possi-
ble, so that "high-quality" fibers have these properties to a greater extent
when compared to other more brittle fibers that have these properties to a
lesser extent (National Research Council, 1984).
2.1.1 Manmade Mineral Fibers
2.1.1.1 Fibrous Glass. Fibrous glass (CAS No. not available) is compose:!
primarily of the oxides of Si, Al, and B (Wagner et al., 1980). Silica (SiO^),
soda ash, B20,, fluorspar, rutile, and clay provide the raw materials for its
manufacture (Weil! et al., 1983). The manufacturing process allows production
of relatively narrow ranges of fiber size depending upon methods employed
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during production and commercial need. The physical properties of glass fibers
depend upon their chemical composition. During production, the chemical
constituents can be manipulated, and specific properties of the glass fibers
can thereby be promoted. Glass fibers that include glass wools and filaments
have greater concentrations of Ba and the oxides of the alkali metals Na and K
and lesser amounts of Fe and the oxides of the alkaline earths Ca, Hg, Fe, and
Ti; consequently, their chemical resistance is decreased and they are more
soluble in water. Glass fibers never split longitudinally but, instead, split
across their axis and form fragments (Klingholz, 1977).
The three main classes of glass fibers are textile fibers, wool fibers,
and fine fibers, but many subclassifications also exist within these classes
(National Research Council, 1984). Textile fibers, which are the coarsest,
consist of continuous-filament glass fibers that have flame-resistant qualities
and are used as reinforcement for plastics and other materials. They typically
have fiber diameters between 10 and 15 urn, but the diameters can range from 6
to 20 urn. Wool fibers are used for insulation; the diameters are usually
between 3 and 10 urn but can range from 1 to 25 urn. Fine fibers are produced by-
flame attenuation and are used for specialized purposes. They have nominal
diameters of 1 urn or less (National Research Council, 1984; Wagner et a!.,
1980), account for less than 1 percent of consumption (Lockey, 1981) and
contain no trace elements of biological significance (Hill, 1977).
2.1.1.2 Mineral Wool. Two types of fibers fall under the general heading of
mineral wool. The term "rock wool" (CAS No. not available) refers to glass
fibers formed by melting natural igneous rocks, whereas slag wool (CAS No. not
available) is produced from material consisting of premelted slag from ironblast
furnaces or from other metal-slagging processes (National Research Council,
1984). Rock and slag wools also consist predominantly of SiO., Al.O^, and
BjO,, as is the case with glass fibers, but they differ in that they contain
greater amounts of Fe and the oxides of the alkaline earths (CaO, MgO, Fe-O^,
and TiOO and lesser amounts of Ba and the oxides of the alkali metals. They
are more chemical resistant than fibrous glass and less soluble in water
(Klingholz, 1977). Spurny (1983), using LAMMA analysis, determined that rock
wool fibers of unspecified diameter and composition leached certain elements
after long-term exposure in water, alkali, and acid. Only Si was detected when
fibers were placed in 2 N rLSO., whereas traces of Ti and Fe were also detected
when the mineral wool was placed in 2 N HC1. Fibers immersed in 2 N NaOH
contained Mg, Ti, and Fe and leached Ca, Si, S, Mn, Al, and Co es corrps^ed to
July 1988 2-3 DRAFT--DO NO" Q'JOTE OR CITE
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fibers placed in water. Rock wool fibers exposed to both 2 N HC1 and 2 N
H.SO^ leached Al, S, Ca, Ti, Co, Mg, and Fe as compared to fibers placed in
water. Fibers of rock and slag wools tend to cleave transversally. Slag and
rock wools generally are formed into fibers that have diameters of 1 to 6 urr,
which provide optimal thermal conductivity (Klingholz, 1977).
The chemical composition of rigid rock wool fibers, supplied by Rockwell
International A/S Denmark, were described by Morgan and Holmes (1984). The
major components were SiO. (45.5 percent), CaO (14.9 percent), AIJD^ (13.1
percent), MgO (10.8 percent), FeO (8.0 percent), Na20 (2.4 percent), Ti02
(1.7 percent), and K20 (1.0 percent). The fibers had a count median length cf
about 27 ± 2.2 pm (geometric standard deviation) and a count median diameter cf
about 1.1 ± 2.2 pm. These sizes of rock wool fibers are somewhat thinner (0.3
to 5 urn thickness) than those of commercial rock wool, which have length-
weighted nominal diameters of about 4 pm.
2.1.1.3 Ceramic Fibers. Ceramic fibers (CAS No. not available) are produced
by combining kaolin clay or a mixture of alumina (Al-CU) and SiD- to fonr.
alutr.inosilicate glasses. The melted compound is then blown to form fibers
used primarily for high-temperature insulation (National Research Council,
1984). For even higher temperature applications, fibers of AKO, and 2^ ere
used because they possess strong refractory qualities. These fibers are able
to retain their physical and chemical characteristics in the presence of high
temperatures. A1203 fibers exhibit good chemical stability, and they resist
oxidation, reduction, and attack from most corrosive agents. They are net
resistant to hydrofluoric and phosphoric acids and concentrated alkalies.
Chemical analysis of one commercially available ceramic fiber consisting
predominantly of Al.O, revealed the following composition (Carborundum Company,
n.d.):
Major elements (
A1203 51.
Si02 47.6
Na20 0.3
B203 0.15
Fe203 0.02
Trace inorganics 0.2
teachable chlorides <50 ppm
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ZrO- fibers are able to resist aqueous solutions of alkali metal hydroxides
and molten alkali metal chlorides and carbonates at elevated temperatures.
2r02 fibers provide the lowest thermal conductivity of any commercially availa-
ble refractory material (Zircar Products, Inc., 1978).
Fibers of SiCL are also used for insulative purposes, but they are
restricted to low-temperature applications. Fibers high in SiO. content
exhibit superior mechanical properties (SRI International, 1985).
Ceramic fibers have an amorphous structure when formed, but some conversion
to crystalline material can occur at high temperatures (International Agency
for Research on Cancer, 1983). The majority of fibers produced are encap-
sulated or incorporated into structures. The desired range of fiber diameters
produced for industrial applications is 2 to 3.5 pm, but diameters can range
from less than 1 to 12 urn. Fiber length varies greatly and can range from e
few micrometers to several centimeters (National Research Council, 1984).
2.1.2 Synthetic Fibers
2.1.2.1 Aramid Fibers. Aratnid fibers (CAS No. not available) are aromatic
polyamides synthesized by the reaction of aromatic diamines and aromatic diacid
chloride in an amide solvent via interfacial or solution polymerization. These
fibers are of exceptional heat and flame resistance and have good to quite
remarkable tensile strength and modulus. The endothermic peak in a differential
thermal analysis (DTA) thermogram ranges from >AOO to 550°C, and glass transi-
tions range from about 250 to >400°C. These fibers do not melt because
V
decomposition occurs simultaneously. Most aramid fibers are highly crystalline
or are crystallizable, and their densities range from 1.35 to 1.45 g/cm
(Preston, 1979). They are found in a dry pulp form consisting of short fibers
(0.5 to 8\mm) with fine fibrils attached to the surface. They have excellent
wear resistance and are nonabrasive (Lee et al., 1983; Dunnigan et a!., 1984).
Aramid fibers are divided into two categories: heat- and flame-resistant
fibers (Nomex) and ultra-high-strength, high-modulus fibers (Kevlar).
Heat- and flame-resistant aramid fibers contain a high portion of meta-
oriented phenylene rings. They can retain useful tensile properties for 1 to
2 weeks at 300°C. They have high limited oxygen index (LOI) values, volume
resistivities, and dielectric strengths, and they are hydrolytically stable.
They are resistant to acids, strong bases, and ionizing radiation, but they are
susceptible to degradation by ultraviolet (uv) light (Preston, 1979).
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Ultra-high-strength, high-modulus aramid fibers have very high (>5DO°C)
melting/decomposition points and are heat-resistant polymers. However, they
have low elongations and therefore become too brittle to be of importance in
heat and flame resistance. Their important features are (1) the fibers are of
fine diameter slightly less than 0.013 mm and (2) they are produced from
rodlike polymers exhibiting extremely high intrinsic and inherent viscosity
values. On a specific basis (i.e., lower specific gravity), these ararr.id
fibers are stronger and stiffer than glass or steel (DuPont, 1976; Preston,
1979).
2.1.2.2 Carbon Fibers. Carbon fibers are filamentary forms of carbon with
diameters of 5 to 15 jjm and are characterized by flexibility; electrical
conductivity; chemical inertness except to oxidation; refractoriness; high
performance varieties; high Young's modulus (coefficient of elasticity
measuring the softness or stiffness of the material); and high tensile strength
(Volk, 1S79). They are corrosion resistant, lightweight, have a high degree cf
stability to traction forces, high degree of elasticity, low thermal expansion,
low density, high thermal conductivity, and abrasion and wear resistance (Holt
and Home, 1978; Neugebauer et al., 1981; Owen et a!., 1986; Wolter, 19E3).
However, carbon fibers are highly vulnerable to shearing forces due to a
decrease in interlamellar shear strength with increasing fiber modulus. The
Young's modulus, electrical and thermal conductivity, and tensile strength
depend upon, and correspond with an increase in, the degree of preferred
orientation (Volk, 1979; Wolter, 1983). Three types of carbon fibers produced
are rayon-based fibers, polyacrylonitrile (PAN)-based fibers, and mesophase
pitch-based fibers.
Rayon-based carbon fibers (CAS No. not available) are used in cloth form,
are very stable at high temperatures, and contain over 99 percent carbon.
Low-modulus fibers have a density of 1.43 to 1.7 g/cm , filament tensile
strength of 345 to 690 MPa (Megapascal), and Young's moduli of 21 GPa
•i
(gigapascal); and high-modulus fibers have a density and modulus of 1.65 g/cm"
and 345 GPa, respectively, or 1.82 g/cm and 517 GPa, respectively.
PAN-based carbon fibers (CAS No. not available) have a ladder polymer
structure that is maintained throughout carbonization and a carbon content of
92 to 95 percent. PAN-based fibers have a density of 1.7 to 1.8 g/cir. , teisi'ie
strength of about 2.4 to 2.75 GPa, and a Young's modulus of 193 to 241 GPa.
Mesophase pitch-based carbon fibers (CAS No. not available) are t*e onu
true graphite fibers with a carbon content over 9S.5 percent, an ap:-c»irr.;te
Julv 19BS 2-6 DRA-7--DO N3T QUC'E C- CITE
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density of 2.0 g/cm , and a tensile strength of 2.0 GPa. They are produced in
three forms differing only in filament modulus. Young's moduli for these
three types are 138 GPa (mat product), 138 to 517 GPa (fabric), and 345 GPa
(filament yarn) (Volk, 1979).
2.1.2.3 Polyolefin Fibers. Polyolefin fibers are manufactured fibers in
which the fiber-forming substance is any long-chain synthetic polymer of at
least 85 percent by weight ethylene, propylene, or other olefin units. Two
important characteristics of polyolefin fibers and their nearly total lack of
water absorption and their low specific gravity, which ensure that wet prop-
erties are identical with properties at standard conditions and lead to a
higher covering power. Polyolefin fibers are extremely hydrophobic and are
inert to a wide variety of inorganic acids and bases and organic solvents at
roorr; temperature, and to polar solvents at any temperature. Thermal degradation
is oxygen-sensitive and results from high temperature formation of hydroper-
oxides, but occurs at a substantially lower temperature (290CC) than with nylon
(360°C) and polyester. Ultraviolet light, degradation is similar to thermal
degradation but occurs preferentially on surfaces, thereby degrading fibers and
films more rapidly than thick objects. Polyolefin fibers are more combustible
than other common polymers due to their low limiting oxygen index (LOI) values
and are inherently difficult to dye. They exhibit elastic recovery (70 to
100%) that is the fractional length of fibers recovered from an initial exten-
sion. The product of elastic recovery and work recovery corresponds to the
resiliency of the fiber. Polyolefin fibers also exhibit creep (time-dependent
deformation) and stress relaxation (spontaneous relief of internal stress) that
are dependent upon, and inversely related to increases in, fiber molecular
weight, molecular orientation, and heat crystallization (Buchanan, 1979).
Polyolefin fibers of commercial importance are polypropylene (CAS
No. 25085-53-4) and polyethylene (CAS No. 9002-88-4). Polypropylene fibers
have a significantly higher melting point, equal tenacity and abrasion
resistance, and substantially better resilience than polyethylene. Melting
points for polypropylene and polyethylene are 170 and 130°C, respectively, and
densities are 0.90 and 0.95 g/cm , respectively (Buchanan, 1979).
2.1.3 Minerals
2.1.3.1 Attapulgite. Attapulgite (CAS No. 12174-11-7) is a naturally occurring
nonplastic clay that belongs to a group of commercially defined clays known as
Fuller's earth. Attapulgite is composed of short asbestifonr fibers of the
July 19BE 2-7 DRAFT—DO NOT QUOTE OR CITE
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mineral palygorskite, which consists of SiCL, AI-O,, and MgO in the form of a
complex metallic aluminosilicate with a composition of Mgt(OH)2(H20)4Sig020'4H-0
(Zoltai, 1986; Zoltai and Stout, 1984; Huggins etal., 1962). Mineralogic
composition varies greatly with the site of origin, and the presence of minerals
associated with attapulgite formation, such as calcite, quartz, and smectite,
have a direct influence on determining its purity (Bignon et al., 1980).
Attapulgite is grayish-white in color end occurs as elongated, lath-shaped
crystals in bundles that comprise thin sheets of minute interlaced fibers
(International Agency for Research on Cancer, 1987). It is soft and easily
cleaned, chemically inert, and its properties are unaffected by changes in pH.
Bignon et al. (1980) determined the mean size characteristics of attapulgite
originating from Caceres, Spain, to be 0.8 urn in length and 0.06 urn in
diameter. Bulk chemical analysis performed on calcinated samples of the
Spanish attapulgite revealed the following chemical composition:
Major elements (%) Minor elements (mg/kg)
Si02 80.1 Mn 750
A1203 4.6 P 100
Fe203 4.6 Ti 2800
MgO 9.7 Zn 100
CaO 3 Sr 100
Na20 0.5 Zr 120
K20 0.9 Nb 100
Ba 730
La 730
Ni 11
Cr 90
2.1.3.2 Zeolites. Zeolites are a group of naturally occurring crystalline
sedimentary minerals consisting of over 40 hydrated aluminum silicates that
contain alkali or alkali earth elements. They are poorly consolidated soft
rocks formed by the alteration of large beds of volcanic ash, usually in
alkaline lakes (Leineweber, 1980). In the United States, over 300 deposits
are thought to exist in locations across 25 States. The basic component of
the crystal structures of zeolites is the SiO^ and AID. tetrahedral coordina-
tion. They have a three-dimens.ional open network that allows the addition of
cations such as Na, Ba, Ca, and K to balance the negative charge incurred whe--
Al is substituted for Si. The centra"1 Si or Al atom is surrounded by four
oxygen atoms, each of which is shared by the neighboring tetrahedron, creating
-------
a honeycombed crystalline structure that possesses unique features character-
istic to each zeolite (Rom et al., 1983).
2.1.3.2.1 Erlonite. Erionite (CAS No. 66733-21-9) is a fibrous zeolite that
has been found in deposits in Arizona, California, Nevada, Oregon, and Uta^ in
the form of thin, pure beds within sedimentary tuff sequences or as outcrops
in desert valleys of the intermountain region (Rom et al., 1983). Erionite
fibers occur as white prismatic crystals in radiating groups, as either single
needles or in clusters and are, on the average, shorter than asbestos fibers
(International Agency for Research on Cancer, 1987). They can attain a maximum
length of 50 urn, and widths generally range from 0.25 to 1.5 urn, although
fibers exhibiting widths of 0.01 to 5.0 pm have been recorded (Wright et al.,
19E3; Suzuki, 1982). Mineralogic investigation of erionite samples taken fro-
sites near the town of Karain in the Cappadocia region of Turkey yielded tne
following chemical composition: (Na.l^CaMg)^ 5A1qSi27°72**7 H2° ^purny,
19S3). Documented uses for erionite are: noble metal-impregnated catalyst in
a hydrocarbon cracking process in a U.S. plant; house building materials;
increase soil fertility and control odors in livestock production. Extent of
its use for house building is minor and unknown for the latter two purposes
(International Agency for Research on Cancer, 1987).
2.1.3.3 Talc. Talc (CAS No. 14807-96-6) is composed of pulverized, natural,
foliated hydrous magnesium silicates originating from nonasbestiform minerals
that are low in crystalline SiO« content. It consists of a layer of Mg(OH)2
that is held between two sheets of SiO-. Weak van der Waals' forces hold the
sheets together. Platey crystals of talc slide past one another to produce
the smoothness associated with talc (Davies eta!., 1983). The chemical
composition of talc is Mg2(Si205)2Mg(OH)2, with theoretical contents of Mg and
Si of 19.2 and 29.6 percent, respectively (Hanson et al., 1985). Its appearance
can be white, yellowish, greenish, or gray depending on the number of impurities
present. Impurities and/or minerals commonly found in commercial talc include
MgO, TiO., calcium silicate, iron oxide (a color determinant), carbonates, and
aluminates. Tremolite and/or anthophyllite asbestos are also found as contami-
nants of some talc deposits (National Research Council, 1984; Lockey, 1981).
The specific gravity of talc is 2.6 to 2.9. It has perfect cleavage, is
insoluble in water, and depending-on its purity, exhibits varying resistance to
acids, alkalies, and heat (General Electric, 1978; International Agency for
Research on Cancer, 1987).
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2.1.3.4 Verim'culite. Vermiculite (CAS No. 1318-00-9) is a micaceous hydrate
of magnesium-iron-aluminum silicates. The chemical composition of vermiculite
varies, but an acceptable general formula is (Mg.Fe.Al), (Al,Si)4010 (OH)2«4H20
(Bates and Jackson, 1980). Vermiculite crystals are composed of two silicate
layers connected by a hydrous layer. The thickness of the unit cell in fully
hydrated materials is about 14 angstroms (Gruner, 1934). All of the major
commercial deposits occur in ultramafic and mafic host rocks. The material
that is mined is mixed-layer vermiculite-biotite and vermiculite-phlogopite.
Other minerals commonly present in the deposits include quartz, feldspar,
apatite, corundum, chlorite, asbestos, talc, and clays. The main commercial
mining deposits of Vermiculite are located in Montana, Virginia, and South
Carolina as well as South Africa (Dixon et a!., 1985). Vermiculite is a soft
mineral and unique among minerals in its ability to exfoliate or expand up to
20 times its original size when heated between 300 and 2000°F (Meisinger, 1955;
Lockey, 1981). Exfoliation can also be achieved by chemical processes such as
soaking in hydrogen peroxide, weak acids, and other electrolytes.
Crude vermiculite has a loose bulk density of 640 to 1000 kg/m , whereas
exfoliated vermiculite expands to a bulk density of 56 to 192 kg/m . It also
has a very low thermal conductivity and a relatively narrow range of cation
exchange capacity, primarily associated with magnesium.
2.2 PRODUCTION AND INDUSTRIAL USES
2.2.1 Hanmade Mineral Fibers
2.2.1.1 Fibrous Glass. During production, glass fibers can be divided into
two basic types: staple and continuous. Staple fibers are produced by melting
glass feedstock in furnaces and pulling the liquid melt through small orifices,
forming a thin coat of fibers that are then collected on a spinning drum.
Continuous fibers are mechanically extruded and collected on drums as yarn
(International Agency for Research on Cancer, 1983). Textile glass fibers are
produced and sold as continuous strands (drawn fibers), staple yarns and
slivers (blown fibers), roving and cake packages, chopped and milled fibers,
and mats. The major U.S. producers of textile glass fibers are listed in
Table 2-2.
Glass fibers are used primarily in reinforced plastics including unsatu-
rated polyester resins and polyamide, polyacetyl, and polybutylene terepnthalate
resins. Other uses include paper and tape reinforcements, automotive tire
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TABLE 2-2. MAJOR U.S. PRODUCERS OF TEXTILE GLASS FIBERS
Company and location
Product types
Owens-Corning Fiberglass Corp.
Aiken, SC
Amarillo, TX "
Anderson, SC
Ashton, RI
Huntingdon, PA
Jackson, TN
PPG Industries, Inc.
Lexington, NC
Shelby, NC
Manville Corp. &
Denver, CO'
Elizabethton, TN
Waterville, OH
Reichhold Chemicals, Inc.
Bremen, OH
Irwindale, CA
Nashville; TN
Lundy Electronics and Systems, Inc.
Pompano Beach, FL
Certainteed Corp.
Wichita Falls, TX
F.G.I. Fibers,"Inc.
Amsterdam-, NY
Nicofibers, Inc.
Shawnee, OH
Ywrti, roving, spun roving, woven
roving, mat, chopped, milled,
staple yarn, and sliver
Yarn, roving and woven roving, mat,
and chopped strand
thopped strand, mat, and sliver
Mat, roving and chopped roving,
woven roving, mat chopped, and
milled
Metallized glass, roving, strand,
and mat
Roving, woven roving, mat, chopped
strand, and combination product
Roving and chopped
Mat
Source: SRI International (1985).
reinforcements, and home furnishings (Table 2-3) (SRI International, 1965).
The annual production capacity of textile-glass fibers in November 1983 was
1618 million poonds. Approximately 20 million pounds were imported and
37.5 million pounds were exported in 1983 (SRI International, 1985). The
predicted growth rate for glass fibers is 17.5 percent per year (PTS Prorr.t,
1988). Data on the uses of glass fibers in insulation were not available.
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TABLE 2-3. U.S. CONSUMPTION OF TEXTILE GLASS FIBERS, 1983
Industrial and consumer-type products Millions of pounds
Reinforced plastics 632.7
Paper and tape reinforcements 33.5
Electrical applications
Automotive tire reinforcements 24.2
Other 499.9
Home furnishings 13.7
(curtains, drapery and
upholstery, other)
Total
1204.0
Source: SRI International (1985).
2.2.1.2 Mineral Wool. The National Research Council (1984) estimated that
total mineral wool production in the United States was approximately 200,000
metric tons. Mineral wool, which has many of the same applications as fibrous
glass, is mainly used in insulation for industrial processes.
2.2.1.3 Ceramic Fibers. Ceramic fibers can be grouped into three general
categories of production: (1) fibers that are produced in the form of blanket,
board, or module as insulative and refractory materials (alumina- silica,
Al-0,, and Zr-O,); (2) fibers prepared in the form of cloth for radiation and
heat-protective purposes (SiO.); and (3) fibers used in miscellaneous applica-
tions (potassium titanate, boron nitride, yttria, tantulum, and aluminum-boron-
silicon fibers). These exotic fibers are in limited production and are used
only for highly specialized applications (SRI International, 1985).
Alumina-silica fibers are produced either by blowing or centrifugal melt
.spinning. Alumina-silica producers are listed in Table 2-4. The total produc-
tion volume of alumina-silica fibers is believed to have been approximately
100 million pounds in 1983, about 75 percent of industry capacity. With
exports of approximately 10 million pounds and negligible imports, 19E3
domestic consumption was approximately 90 million pounds (SRI International,
1985). Consumption of alumina-silica fibers by industry is shown in Table 2-5.
Fibers of Al.O, are produced from a solution of aluminum salts using a
proprietary process. They are manufactured by Imperial Chemical Industries
Limited (ICI), Mond Division, at Widnes, United Kingdom, with a capacity of
approximately 1.5 million pounds per year. Bulk fiber and mat forms are
imported into the United States through ICI Americas, Inc., Wilmington, DE.
U.S. consumption in 1983 was approximately 150,000 pounds (SR! International,
1985).
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TABLE 2-4. MAJOR U.S. ALUMINA-SILICA PRODUCERS
Estimated annual capacity
as of January 1, 1954
Company (millions of pounds)
The Carborundum Electro Minerals Co. 55
Niagara Falls, NY
New Carlisle, IN
Ne* Iberia, LA
Babcock and Wilcox 40
Augusta, GA
Ponce, PR
Johns-Manville Corp. 20
Waukegan, IL
Combustion Engineering, Inc. 10
Erwin, TN
Source: SRI International (1985).
TABLE 2-5. U.S. CONSUMPTION OF ALUMINA-SILICA FIBER
PRODUCTS BY INDUSTRY, 1983
Industry
Iron/steel
Nonferrous metals
Chemicals and petroleum
Ceramics
Automobile
Other8
Total
Consumption
(millions of pounds)
19
11
23
7
11
19
90
Percent of
total
21
12
25
8
13
21
100
alncludes aerospace (acoustical insulation), shipbuilding (fire protection
and insulation), laboratory OEM industrial furnaces.
Source: SRI International (1985).
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Fibers of Zr^O^ are manufactured using a precursor process that req-ires
impregnation of an organic fabric with zirconium salt solution. Subsequent
pyrolysis removes the organic substrate and transforms the salt residue to
Z^Oj. Zircar Products, Inc., located in Florida, NY, is the only manufacture*-
of these fibers in the United States; their facility is believed to. have an
annual capacity of 10,000 pounds for bulk fiber and 1,000-2,000 pounds for
Zr203 cloth (SRI International, 1985).
Fibers of SiO- are actually high-purity silicon dioxide materials that
are used for many insulative, heat-protective, and reinforcement applications.
Silica fibers are produced by two distinct processes. The first involves
leaching of all other oxide containments by immersing glass yarn in hydrochloric
acid. The second involves drawing the fibers from a heated quartz rod.
Leached glass products are produced at the Materials Division of H1TCO, c
subsidiary of Armco, in Gardena, CA, with an annual capacity of 1.1 millic-
pounds. They are also produced by the Haveg Division of AMETEK, Inc., in
V»i lrr,i ngton, DE, with an annual capacity of 1.0 million pounds (SRI Interns-
ficric", 19S5). Overall ceramic fiber production totaled 33 million pounds ir
1987 aid is predicted to grow at a rate of 26 percent per year (PTS Pror.t,
1986). These fibers have major commercial applications in a wide range cf
refractory and insulative products (Table 2-6).
A laser-based method that produces stronger and more flexible cerarric
fiber faster than conventional techniques has been developed by MRI Ventures
in Kansas City, MO. This technique involves the injection of silicon chloride
and methane gases into a proprietary reactor and exposing them to radiation
from an yttrium/aluminum laser. The reactor temperature and pressure can be
varied to design the fibers for specific applications. This technique is also
used to produce other fibers (PTS Promt, 1988).
2.2.2 Synthetic Fibers
2.2.2.1 Aramid Fibers. Aramid fibers are usually produced by solution polym-
erization polycondensation. A diacid chloride and a diamine are polymerized in
an inert amide solvent. The polymer is then spun from the solution and dried.
Both types of fibers -- heat-/flame-resistant (Nomex) and ultra-high-strencth,
high-modulus (Kevlar) -- are relatively expensive in comparison to other
synthetic fibers primarily because of low-volume production. In 1975, the £.I|
du Pont de Nemours and Company, Inc., in Richmond, VA, the only producer lisle:
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TABLE 2-6. REPRESENTATIVE APPLICATIONS FOR CERAKIC, ALUMINA
ZIRCONIA, AND SILICA FIBER PRODUCTS
Ceramic Fiber Products
Furnace, kiln, reformer, boiler linings
Flexible high-temperature pipe insulation
Pressure and cryogenic vessel fire protection
Thermal reactor insulation
High-temperature gasketing
High-temperature filtration
Nuclear insulation applications
Replacement for asbestos blankets
Fill or packing material in
Expansion joints
Tube seals
Furnace base seals
Manufacture of secondary forms
Thermal and electrical insulation
Combustion chamber liners
Ingot mold linings
High-temperature baffles and muffles
Molten metal trough and distribution linings
Heat shields
Hct-gas duct linings
Refractory backup for brick and castables
Patching of refractory cracks and fissures
Coating for metal liners
Substitute for wet asbestos fibers
Expansion joint packing
Pipe, hose, cable protection
Jet-engine, fuel-line insulation
Thermal battery liners
Burner blocks
Alumina Fiber Products
Furnace, kiln, reformer, boiler linings
Expansion joints
Tube seals
Furnace base seals
Manufacture of secondary product processes
Molten metal trough and distribution linings
Resin reinforcement
Filtration
Zircom'a Fiber Products
Thermal insulation in laboratory and industrial furnaces
Radiation shielding in vacuum furnaces
High-temperature chemical and gas filtration
Battery and fuel-cell separators
Reinforcement for ablative materials in nozzles, nose tips, and
heat shields
Insulation in hot pressing, crystal growing, and annealing furnaces
(continued on the following page)
wr.T rvi'"7F fi-,
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TABLE 2-6. REPRESfNTATIVE APPLICATION FOR CERAMIC, ALUMINA
ZIRCONIA. AND SILICA FIBER PRODUCTS (continued)
Silica Fiber Products
Reinforcement of resin molding compounds
Thermal-insulative packing
Wrapping for seals and gaskets
Resin prepregs for aerospace
High-temperature gasketing
Protection of workers and equipment during welding and burning
operations
Thermal protection of hoses and cables
Reinforcement and insulation in elastomeric ablative coatings
Source: SRI International (1985).
in available literature, announced an annual capacity for Nomex and Kevlan of
9,100 and 23,000 tons/year, respectively (Preston, 1979; SRI International,
1967). The predicted growth rate for aramid fibers is 14 percent per year. By
1992, they will represent the greatest production volume (PTS Promt, 1985).
Due to their resistance to heat and flame, Nomex fibers are used in
industrial protective clothing, carpets, tents, insulation paper for electrical
motors and transformers, ironing board covers, and cargo and boat covers. The
ultra-high-strength, high-modulus Kevlar fibers are used in tires, cables,
parachutes, body armor, fire hoses, V- and conveyor belts, and high-performance
boats and aircraft (Preston, 1979).
2.2.2.2 Carbon Fibers. Carbon fibers are produced by subjecting rayon,
polyacrylonitrile, or mesophase pitch to controlled pyrolysis (Owen
et a!., 1986). U.S. demands for all high-performance carbon fibers have
increased from about 1 million pounds in 1980 to about 5.2 million pounds
in 19B7, with 50 to 75 percent of the fibers used in the aircraft and
aerospace industry (Table 2-7). The predicted growth rate for carbon
fibers is 19.5 percent (PTS Promt, 1988). The U.S. producers and their
annual capacity for all carbon fibers are shown in Table 2-8. The process
chemistry and uses for rayon, polyacrylonitrile, and mesophase pitch-based
carbon fibers are discussed below.
Low-modulus, rayon-based carbon fibers are produced by heat-treating
rayon at 200 to 350°C in a reactive atmosphere. The fibers are then carbonized
at 1000 to 2000°C followed by an additional heat treatment at temperatures
approaching 3000°C. To produce high-modulus fibers, the yarn must be stretched
-------
TABLE 2-7. U.S. DEMAND FOR HIGH-PERFORMANCE CARBON FIBERS
Industry
Aircraft/aerospace
Sporting goods
Industrial
Total
1980
(thousands
of pounds)
550
300
150
Wo
1984
(thousands
of pounds)
2000
500
400
I5U5
19878
(thousands
of pounds)
3900
600
700
5200
a
Estimated demand.
Source: SRI International (1985).
TABLE 2-8. MAJOR U.S. PRODUCERS OF CARBON FIBERS
Annual capacity
(thousands
Company of pounds)
Arr.occ Corp.
Greenville, SC
Ashland Oil
Catlettsburg, KY
AVCO Corp.
Lowell, MA
BASF Corp.
Rock Hill, SC
The Dexter Corp.
Sacramento, CA
Great Lakes Carbon Corp.
Eli2abethton, TN
Hercules, Inc.
Bacchus, UT
Owens-Corning Fiberglass Corp.
Gardena, CA
Polycarbon, Inc.
800
500
200
100
600
750
1400
2700
100
100
Type/brand Name
Polyacrylonitrile
Mesophase pile!-:
Petroleum pitch
Polyacrylonitrile
Polyacrylonitrile
Polyacrylonitrile
Polyacrylpnitri le
(Fortafir)
Polyacrylopitrile
(Magnamite )
Polyacrylonitrile
(Hl-TEX*)
Pitch and rayon
North Hollywood, CA
Stackpole Corp.
Lowell, MA
Total
450
F700
Polyacrylonitrile
Source: SRI (1967).
July 198S
2-17 DRAFT--DO NOT QJC-TE OR CITE
-------
during the last heat treatment. The carbon content of these fibers is approxi-
mately 99 percent. Production volumes are not available; however, the estimated
consumption for 1970-76 was 100,000 to 250,000 kg/year (Volk, 1979).
Rayon-based carbon fibers are used in tire cords and aerospace applica-
tions, e.g., phenolic-impregnated heat shields and carbon-carbon composites for
missile parts and aircraft brakes (Owen et al., 1986; Volk, 1979).
Polyacrylonitrile-based carbon fibers are produced in a wanner very
similar to that used to produce of rayon-based fibers. PAN fibers are heat
treated, under tension, in an oxidizing atmosphere at 190 to 280°C. At this
stage, a well-oriented ladder polymer structure is developed and is essentially
maintained throughout the production process. 'The yarn is carbonized in an
inert atmosphere, usually between 1000 and 1300°C. The fiber is then heat
treated again at 2500 to 3000°C. The filaments are gathered into tow bu-.Cles
and wound. The carbon content of PAN fibers is approximately 92 to 95 percent.
Production and consumption statistics are not available (Holt and Horne, 197£;
Jones et al., 19£2; Volk, 1979).
PAN-based ca-bcr, fibers are used in structure fabrication for the ae-cspa:€
industry, sporting goods (e.g., golf clubs, fishing rods, tennis rackets, bow;
and arrows, skis, sailboat masts and spars), textile and computer machi-ne-y,
automotive and general transportation, musical instruments, reinforcement fcr
plastics, and prostheses and artificial joints (SRI International, 1985; Holt
and Horne, 1978; Neugebauer et al., 1981; Owen et al., 1986; Volk, 1979).
Mesophase pitch-based carbon fiber production starts with a commercial
coal tar or petroleum pitch which is converted through heat treatment into a
mesophase state. The pitch is spun into a highly oriented fiber and is ther-
moset in an oxidizing atmosphere. The yarn is carbonized and then graphitized
at 3000°C. The high orientation is maintained during thermosetting and
enhanced during carbonization and graphitization. The carbon content, is over
99.5 percent. Production and consumption statistics are not available (Volk,
1979).
Mesophase pitch-based carbon fibers are used for electrical conduction,
resistance to heat distortion, improved wear, and stiffness critical applica-
tions (Volk, 1979).
2.2.2.3 Polyolefin Fibers. Polyolefin fibers are fabricated commercially by
a melt-extrusion technique. The fundamental elements of this technique are
expulsion of the polymer through a spinneret, solidification, and winding onto
packages.
Julv 1988 2'^8 DRAFT--DO N:T QUC-TE OF, CI'E
-------
Polymer pellets are melted and metered through a filter system to the
spinneret where they are extruded under pressure. Fiber form depends upon the
size and number of holes in the spinneret. Extrusion occurs at 100 to 150°C
above the melting point of the polymer.
As heat is expelled, the fibers begin to solidify. Due to the crystalline
and glass transition properties of polyolefin fibers, solidification occurs by
crystallization between the melting and glass transition temperatures and can
continue after winding.
Takeup velocities for winding the fiber onto packages vary from 1 to
2 meters per second (m/s) to speeds as great as 117 m/s. Slow velocities allow
further refining steps to be incorporated. Such steps include drawing to
induce further crystallization, texturizing to impart bulk and/or elasticity,
and annealing for stability of fiber structure and properties (Buchanan, 1S7S).
Production of polyolefin fibers has increased steadily due to an increased
demand for continuous filament yarn and monofilaments. Production and consump-
tion values for 1983 were 803 and 767 million pounds, respectively (Buchanan,
1S79; Chemical Economics Handbook, 1983).
Over 40 producers of polyolefin fibers may be found in the United States,
but greater than 50 percent of the film and filament products are manufactured
by Amoco Corporation (Chemical Economics Handbook, 19S3). The U.S. producers
and their annual capacities are listed in Table 2-9.
Polyolefin fiber usage is concentrated in home furnishings and industrial
areas. Home furnishing uses include carpet facing and backing, upholstery,
woven bags, and wall-covering materials. Industrial uses include synthetic
turf, cordage and twine, webbing, agricultural fabrics, fishing line and nets,
sewing thread, and book binders (Buchanan, 1979; Chemical Economics Handbook,
19B3).
2.2.3 Minerals
2.2.3.1 Attapulgite. Attapulgite, which is produced from regions including
Attapulgus, GA, and Quincy, FL, is composed predominantly of lath-shaped,
amphibolelike palygorskite. Most of the Fuller's earth produced in other
areas of the United States contains varieties of montmorillonite. Attapulgite
has numerous commercial applications (Table 2-10) due in part to its sorptive
and colloidal properties. It finds wide application in both absorbent and
gelling or thickening areas. The thixctropic properties of attapulgite day
July 1988 2-19 DRAFT—DO JOT QUOTE OR CITE
-------
TABLE 2-9. MAJOR U.S. PRODUCERS OF POLYOLEFIN FIBERS
Company
Annual capacity
(thousands
of pounds)
Type
Amoco Corp.
Amoco Fabrics and Fibers Co.
Andalusia, AL
Bainbridge, GA
Hazlehurst, GA
Nashville, GA
Sunburst Yarns, Inc.
Roanoke, AL
Afton, VA
Avtex Fibers, Inc.
Front Royal, VA
Camac Corp.
Bristol, VA
Exxon Corp.
Hangman, KS
Sumn-.erville, SC
Fibres South, Inc.
Trussville, AL
Hercules, Inc.
Oxford, GA
Integrated Resources, Inc.
Fibron Corp. of Tennessee
Chattanooga, TN
Synthetic Industries, Inc.
Chickamauga, GA
Phillips Petroleum Co.
Rocky Mount, NC
Spartanburg, SC
Polyloom Corp. of America
Dayton, TN
Wayn-Tex, Inc.
Waynesboro, VA
>295
20
20
35
<20
20
200
15
30
30
70
22
26
Monofilament, film
filament yarn, and
staple
Filament yarn
Monofilament
Film
Film, monofilament,
and filament yar-
Filament yarn and
staple
Film
Film
Filament yarn
Filament yarn,
staple, and tow
Film
Monofi lament, film,
filament yarn, ana
staple
(continued on the following page)
July 1968
2-20
DRAFT--DO N:T QUOTE OF. CITE
-------
TABLE 2-9. MAJOR U.S. PRODUCERS OF POLYOLEFIN FIBERS (continued)
Company
Annual capacity
(thousands
of pounds)
Type
Polyloom Corp. of America 22
Dayton, TN
Wayn-Tex, Inc. 26
Waynesboro, VA
Wellington Technical Industries, Inc.
Wellington Leisure Products, Inc.
Pilot Mtn, NC 10
Wellington Synthetic Fibres, Inc.
Leesville, SC 10
Other 166
Tctai ~9£5
Film
Monofilament, film,
filament yarn, and
staple
Monofilament and film
Monofilament,
filament yarn, ar,d
staple
aNct available.
Source: SRI International (1987).
provide the important thickening and viscosity controls necessary for suspending
solids. Mineral thickeners are used in such diverse markets as paint, joint
compound cement, and polishes. The reported estimate of attapulgite produced
or used in the United States in 1985 was 2,059,281 short tons (PTS Promt,
1988).
2.2.3.2 Zeolites. Zeolite minerals have many actual and potential commercial
uses due to their reversible dehydration (Wright et al., 1983), ion-exchange
behavior, thermal and acid stability, and molecular absorbency. Erionite has
been used for nitrogen retention in fertilizers; in concrete aggregate; and in
road surfacings (National Research Council, 1984). Other uses of zeolites
include heat exchanging in solar energy, decontamination of radioactive wastes,
and stack scrubbing in air pollution control systems (Rom et al., 1983).
Annual U.S. production of natural zeolites was estimated to be 2500 to
5000 tons for the years 1982-1984 (International Agency for Research on Cancer,
1987).
2.2.3.3 Talc. The amount of crude talc and pyrophyllite produced in the
United States in 1984 is shown in Table 2-11. The end uses for ground talc
'•••••• •"•>«•• * ?-?i DRAFT—nr. N-T QUOTE OR CITE
-------
TABLE 2-10. FULLER'S EARTH SOLD OR USED BY U.S. PRODUCERS
IN 1984, BY USE (short tons)
Use
Domestic
Adnesi ves
Animal feed
Drilling mud
Fertilizers
Filtering, clarifying, decolorizing
mineral oils and greases
Medical pharmaceutical, cosmetic
Oil and grease absorbents
Paint
Pesticides and related products
Pet weite absorbents
Other0
Miscellaneous
Total
Exports:
^ * ^ ^ .' K _ ft
ur 1 i i i r/g JTiuC
Oil and grease absorbents
Pesticides and related products
Pet waste absorbents
Miscellaneous
Total
Grand total
Attapulgite
1,798
12,139
105,716
52,291
18,017
105
209,831
6,606
96,200
291,943
25,872
26,710
849,228
1,245
41,020
9,135
27,642
10,090
89,133
938,361
Montmorillonite
...
...
...
10,576
784
...
220,878
--
120,223
506,279
1S.841
30,911
909, 4S2
...
38,138
373
12,295
466
51,292
960,784
Quantity
1,796
12,139
105,716
62,867
18,801
105 .
430,705
6,606
216,423
798,222
5,713
59,621
l,71c,72C'
1.2-5
79,15£
9,53£
39,927
10,5/6
140,425
1,859,145
alncludes paper filling and roofing granules.
Includes common brick; catalyst oil refining; chemical manufacturing glazes,
glasses, and enamel; gypsum products; mortar and cement refractories;
plastics; pottery; and sanitary ware.
clncludes paint and uses not specified.
Source: U.S. Bureau of Mines (1986).
and pyrophyllite are shown in Table 2-12. The largest portion of ground talc
is used in ceramics (37 percent), followed by paint (19 percent), paper
(10 percent), roofing (9 percent), other (9 percent), plastics (7 percent),
cosmetics (5 percent), rubber (3 percent), and insecticides (1 percent) (U.S.
Bureau of Mines, 1986).
2.2.3.4 Vermiculite. The amount of vermiculite produced in the United States
™ — - — - • "- I
in 1985 was 285,000 metric tons (PTS Promt, 1988). The largest domestic
producer is W.R. Grace and Co., with mines in Libby, MT, and Encree, SC.
**» r. r T _ _ ^ r»
-------
TABLE 2-11. U.S. PRODUCTION OF CRUDE TALC AND PYROPHYLLITE
IN 1984 (thousand short tons)
State
California
Georgia (talc)
North Carolina
Oregon (talc)
Texash(ta1c)
Other0
Total
• Quantity
74
15
87
a
283
711
IITo
Less than one-half unit.
Includes Arkansas, Montana, New York, Vermont, Virginia, and Washington.
Source: U.S. Bureau of Mines (1986).
TABLE 2-12. END USES FOR GROUND TALC AND PYROPHYLLITE
(thousand short tons)
Use
Ceramics
Cosmetics
Insecticides
Paint
Paper
Plastics
Refractories
Roofing
Rubber-
Other0
Total
Talc
358
44
8
189
100
67
4
86
29
85
970
Pyrophyllite
2l
m ^ u
14
1
—
1
21
6
11
"83
Quantity
367
44
22
190
100
68
25
92
29
96
1053
'incomplete data; some cosmetic talc is known to be included with "other."
Includes art sculpture, asphalt filler and coatings, crayons, floor tile,
foundry facings, rice polishing, stucco, and uses not specified.
cNo data reported.
Source: U.S. Bureau of Mines (1986).
July 19S£ 2-23 DRAFT-DO N3T QuCTE OR CITE
-------
Exfoliated vermiculite is produced by W.R. Grace and Co. at 29 plants in 24
States (of a total of 43 plants in 29 States). Vermiculite is also mined and
processed by Patterson Vermiculite Co. near Enoree, SC, and by Virginia
Vermiculite, Ltd., Louisa County, VA (Meisinger, 1985).
The largest portion of exfoliated vermiculite is used in construction
aggregates (51 percent) followed by insulation (26 percent), agriculture
(22 percent), and other end uses (1 percent). Vermiculite is sold in five
grades.
2.3 REFERENCES
Bates, R. L. ; Jackson, J. A., eds. (1980) Glossary of geology. 2nd ed. Falls
Church, VA: American Geological Institute; pp. 210, 373, 685, 710.
Bignon, J. ; Sebastien, P.; Gaudichet, A.; Jaurand, M. C. (1980) Biologies!
effects of attapulgite. In: Wagner, J. C.; Davis, W., eds. Biologies!
effects of mineral fibres = Effects biologiques des fibres minerales:
proceedings of a symposium, v. 1; September 1979; Lyon, France. Lyon,
France: World Health Organization, International Agency for Research or.
Cancer; pp. 163-181. (IARC scientific publication no. 30; 1NSERN symposia
series: v. 92).
Buchanan, D. R. (1979) Olefin fibers. In: Grayson, M. ; Eckroth, D., eds.
Kirk-Othmer encyclopedia of chemical technology: v. 16. 3rd ed. New York,
NY: John Wiley & Sons, Inc.; pp. 357-385.
Davies, R. ; Skidmore, J. W.; Griffiths, D. M.; Moncrieff, C. B. (1983) Cytotox-
icity of talc for macrophages ui vitro. Food Chem. Toxicol. 21: 201-207.
Dixon, G. M.; Doria, J.; Freed, J. R.; Wood, P.; May, I.; Chambers, T.; Desai,
P. (1985) Exposure assessment for asbestos-contaminated vermiculite.
Washington, DC: U. S. Environmental Protection Agency, Office of Pesti-
cides and Toxic Substances; EPA report no. EPA-560/5-85-013. Available
from: NTIS, Springfield, VA; PB85-183080.
Dunnigan, J. ; Nadeau, D. ; Paradis, D. (1984) Cytotoxic effects of a'ram id fibers
on rat pulmonary macrophages: comparison with chrysotile asbestos.
Toxicol. Lett. 20: 277-282.
General Electric. (1978) Fibrous glass (silicate base). Schenectady, NY:
Materials Information Services; material safety data sheet no. 46.
Gruner, J. W. (1934) The structures of vermiculite and their collapse by
dehydration. Am. Mineral. 19: 557-575.
•i"iw IQPC ?-?4 DRAFT—DO NOT OUDTE OR CITE
-------
Hanson, R. L. ; Benson, J. M.; Henderson, T. R. ; Carpenter, R. L. ; Pickrell, J.
A.; Brown, S. C. (1985) Method for determining the lung burden of talc in
rats and mice after inhalation exposure to talc aerosols. J. Appl.
Toxicol. 5: 283-287.
Hill, J. W. (1977) Health aspects of man-made mineral fibres. A review. Ann.
Occup. Hyg. 20: 161-173.
Holt, P. F.; Home, M. (1978) Dust from carbon fibre. Environ. Res. 17: 276-262.
Huggins, C. W.; Denny, M. V.; Shell, H. R. (1962) Properties of palygorskite,
an asbestiform mineral. Washington, DC: U. S. Department of the Interior,
Bureau of Mines; report of investigations no. 6071.
International Agency for Research on Cancer. (1983) Biological effects of
man-made mineral fibres: proceedings of a WHO/IARC conference; April 1S£2;
Copenhagen, Denmark. Geneva, Switzerland: World Health Organization,
Regional Office for Europe; Euro reports and studies no. 81.
International Agency for Research on Cancer. (1987) IARC Monographs on the
evaluation of the carcinogenic risk of chemicals to humans: silica and
other silicates, v. 42. Lyon, France: World Health Organization.
Jones, H. D. ; Jones, T. R. ; Lyle, W. H. (1982) Carbon fiber: results of a
survey of process workers and their environments in a factory prod-cine
continuous filament. Ann. Occup. Hyg. 26: 861-867.
Klinghol:, R. (1977) Technology and production of man-made mineral fibres. Ann.
Occup. Hyg. 20: 153-159.
Lee, K. P.; Kelly, D. P.; Kennedy, G. L., Jr. (1983) Pulmonary response to
inhaled Kevlar aramid synthetic fibers in rats. Toxicol. Appl. Pharmacol.
71: 242-253.
Leineweber, J. P. (1980) Dust chemistry and physics: mineral and vitreous
fibres. In: Wagner, J. C.; Davis, W., eds. Biological effects of mineral
fibres = Effets tiologiques des fibres minerales: proceedings of a sympo-
sium, v. 2; September 1979; Lyon, France. Lyon, France: World Health
Organization, International Agency for Research on Cancer; pp. 8S1-900.
(IARC scientific publication no. 30.; INSERM symposia series: -v. 92).
Lockey, J. E. (1981) Nonasbestos fibrous minerals. Clin. Chest Med. 2: 203-216.
Meisinger, A. C. (1985) Vermiculite. In: Mineral facts and problems.
Washington, DC: U. S. Department of the Interior, Bureau of Mines;
bulletin no. 675.
Morgan, A.; Holmes, A. (1984) Solubility of rockwool fibres uj vivo and the
formation of pseudo-asbestos bodies. Ann. Occup. Hyg. 28: 307-314.
National Research Council. (1984) Asbestiform fibers: nonoccupational health
risks. Washington, DC: National Academy Press.
July 1955 2-25 DRArT--DC NC* QL::"E C'~ -•''-
-------
Neugebauer, R.; Helbing, G.; Wolter, D.; Mohr, W.; Gistinger, G. (1961) The
body reaction to carbon fiber particles implanted in the medullary space
of rabbits. Biomaterials 2: 182-184.
Nicholson, W. 0. (1986) Asbestos health effects update. Research Triangle Pa'k,
NC: U. S. Environmental Protection Agency, Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office; EPA
report no. EPA/600/8-84/003F. Available from: NTIS, Springfield, VA;
PB86-242864/AS.
Owen, P. E.; Glaister, J. R.; Ballantyne, B.; Clary, J. J. (1986) Subchronic
inhalation toxicology of carbon fibers. JOM J. Occup. Med. 28: 373-376.
Preston, J. (1979) Aramid fibers. In: Grayson, M.; Eckroth, D.. eds. Kirk-
Othmer encyclopedia of chemical technology: v. 3. 3rd ed. New York,
NY: John Wiley & Sons, Inc.; pp. 213-242.
PTS Promt. (1988) Chemical production and consumption database.
Rom, W. N. ; Casey, K. R. ; Parry, W. T.; Mjaatvedt, C. H.; Moatamed, F. (1SE3)
Health implications of natural fibrous zeolites for the intermountair,
West. Environ. Res. 30: 1-8.
Spumy, K. R. (1963) Measurement and analysis of chemically changed rr.ine-e"
fibers after experiments j_n vitro and jr\ vivo. EHP Environ. Health
Perspect. 51: 343-355.
SRI International. (1963) Chemical economics handbook. Menlo Park, CA: SRI
International.
SRI International. (1985) Chemical economics handbook. Menlo Park, CA: SRI
International; section 543.5811A.
SRI International. (1987) 1987 Directory of chemical producers. Menlo Park, CA:
Stanford Research Institute.
Suzuki, Y. (1982) Carcinogenic and fibrogenic effects of zeolites: preliminary
observations. Environ. Res. 27: 433-445.
The Carborundum Company, (n.d.) Fiberfrax ceramic fiber: product specifica-
tions. Niagara Falls, NY: Refractories and Electronics Division.
U. S. Bureau of Mines. (1986) Minerals yearbook 1984. Washington, DC: U. S.
Department of the Interior.
Volk, H. F. (1979) Carbon (carbon and artifical graphite). In: Grayson, M.;
Eckroth, D., eds. Kirk-Othmer encyclopedia of chemical technology: v. 4.
3rd ed. New York, NY: John Wiley & Sons, Inc.; pp. 622-628.
Wagner, J. C.; Berry, G.; Pooley, F. D. (1980) Carcinogenesis and miners!
fibres. Br. Med. Bull. 36: 53-56.
-------
Weill, H. ; Hughes, 0. M.; Hammad, Y. Y. ; Glindmeyer, H. W. , III; Sharon, G. ;
Jones, R. N. (1983) Respiratory health in workers exposed to man-made
vitreous fibers. Am. Rev. Respir. Dis. 128: 104-112.
Wolter, D. (1983) Biocompatability of carbon fibre and carbon fibre
macroparticles. Aktuel. Probl. Orthop. 26: 28-36.
Wright, W. E.; Rom, W. N.; Moatamed, F. (1983) Characterization of zeolite
fiber sizes using scanning electron microscopy. Arch. Environ. Health 36:
99-103.
Zircar Products, Inc. (1978) Zirconia bulk fibers type ZYBF2. Florida, NY:
Zircar Products, Inc.; technical data bulletin no. ZPI-210.
Zoltai, T. (1986) Review of summary health assessment document for mine-si
fibers other than asbestos [letter to Dr. Nicolas Hajjar]. Minneapolis,
MN: University of Minnesota, Department of Geology and Geophysics; May 24.
Zoltai, T. ; Stout, J. H. (1984) Mineralology: concepts and principles. Minneap-
olis, MN: Burgess Publishers.
July 198E 2-27 DRAFT--DC NCT Qu:TE
-------
3. SOURCES OF EMISSIONS, AMBIENT LEVELS, AND ENVIRONMENTAL FATE
3.1 SOURCES OF EMISSIONS
Mineral fibers are released into the atmosphere as a result of both human
and natural actions, but no estimates were available. Manmade mineral fibers
(MMMF) are used extensively in the production of a wide variety of industrial
and consumer products (Corn et al., 1976). Release of fibers into the environ-
ment can occur during the manufacture, handling, use, and disposal of fiber-
containing products (National Research Council, 1984). Dust from MMM? and
their products is generated in sawing, grinding, and cutting processes as
well as in the installation and removal of these materials (Hill, 1S77).
Trie release of synthetic fibers into ambient air occurs during tne-'r
manufacture, handling, incineration, or disposal. However, no estimates were
available.
Emissions of minerals are associated with natural weathering, mining
operations, and the use of these materials in secondary products. These
secondary products include road-surfacing materials, pesticides, fertilizers,
and cosmetics. Additionally, release of mineral fibers present as impurities
in other minerals used commercially may occur (National Research Council,
1984).
Concern has been focused on the quantity of airborne fibers released by
mineral fiber-containing materials. However, the specific quantity of fibers
generated from a given product depends upon the mechanical operations performed
(Hill, 1977).
Estimates of the amounts of vermiculUe released into the environment
during mining, processing, transport, and use have been reported by JR8 (as
cited in Oixon et al., 1985) (Table 3-1). Based on a production volume of
Q
1 million tons (1.2 x 10 kg) of vermiculUe ore mined and beneficiated in
1979 to produce 314 x 10 kg of crude vermiculite, approximately 802 x 10 kc
were released into the air, 89,900 x 10 kg were released into water, and
2,490 x 10 kg were released as solid waste. The water releases were dis
July 1S5£ 3-1 DRAFT—DO NOT QUD7E On C3"E
-------
TABLE 3-1. RELEASES OF VERMICULITE INTO THE ENVIRONMENT
Process
Production and beneficiation3
Exfoliation
Transportation0
Consumer use
Release (x 103 kg)
Air
802.0
3,029.0
64.7
282.5
Water
89,900.0
5,787.0
_.e
0.6
Solic
2,490.0
4,856.6
125.0
36,070.0
Production volume of 1.2 x 109 kg.
Exfoliation volume of 1.046 x 10€ kg, includes some from South Africa.
cTransportation volume of 360 x 106 kg and 206.5 x 106 kg of crude and
exfoliated vermiculite, respectively.
Includes exfoliated and unexfoliated vermiculite.
eNot reported.
Source: Dixon et al. (1985).
of in settling ponds, and the water was recycled. Releases into air resulted
from fugitive releases from dust control equipment,' whereas particulates
collected in the dust control system constituted the solid wastes that were
disposed of in landfills. For estimates of releases during exfoliation, JRB
(1982) assumed that dust control equipment was 98 percent efficient. Releases
during transport are negligible, whereas the largest release is during direct
application of vermiculite, as a component of agricultural products, to soil.
3.2 EXPOSURE
Three routes of exposure are commonly addressed in exposure assessments.
These are inhalation, ingestion, and dermal absorption. The available data
indicate that the principal route of exposure to fibers is inhalation. This
route of exposure is also of toxicologic concern. The objective of defining,
both qualitatively and quantitatively, levels of exposure to airborne concen-
trations of mineral fibers has centered around the physical characterization of
the fibers themselves. Several of these physical properties appear to play a
role in the assessment of the potential risk associated with exposure. One
such property is respirability, i.e., the capability of the fibers tc enter the
small airways of the respiratory tract. The general definition cf respirarle
- 19SE
3-2
DRA'T--DC NCI QL':TE C" CITE
-------
fibers includes those fibers having a diameter of less than approximately 3 prr,.
Additionally, the length and the aspect ratio (length/diameter) of the fibers
determine where they will be deposited in the respiratory tract (National
Research Council, 1984). The length of a respirable fiber is less than 200 ptr
(Hill, 1977), and the aspect ratio must be >3 (Johnson et al., 1969). Different
samples of the same generic mineral fiber may vary greatly in physical proper-
ties, thus presenting different risks upon exposure (National Research Council,
1984).
3.2.1 Manmade Mineral Fibers
Measurements of airborne concentrations of fibers have been conducted to
provide a predictive method for assessing mineral fiber exposure. Following a
.study of three fibrous glass manufacturing facilities, Corn and Sansone (19/4)
reported that fiber concentrations varied greatly with the sampling location
within the plant and that the physical characteristics of the fibers varied
oreatly even among samples collected in the same area. The average fiber
i'is~6ter, content of fine fibers, and production rates were cited as being the
most important factors expected to result in increased fiber concentration in
the working environment. In contrast, the effective use of dust-suppressing
agents is expected to cause the opposite effect (Ohberg, 1987). Ohberg (1S£7)
also reported that furnace operators or transport workers were potentially
exposed to much lower fiber concentrations than production workers. Esmen
et al. (1978) found a difference of fivefold or greater in the average fiber
concentration among plants performing similar mineral wool processing opera-
tions. Considerable variations within and among plants were also found in
ceramic fiber production facilities (Esmen et al., 1979a).
Attempts to correlate airborne fiber concentrations, expressed as fibers/
cm , with the weight of total suspended paniculate matter (TSPK) expressed as
mg/cm in individual air samples, have been unsuccessful (Corn et al., 1576;
Corn and Sansone, 1974). However, an excellent correlation was found when
average TSPM concentrations for similar work activities were compared to the
average fiber concentrations for these same activities (Esmen et al., 1979a).
Fowler et al. (1971) concluded that the mean fiber diameter of fibrous
glass was not a reliable predictor of the mean diameter of the fibers in the
aerosol generated by that material. In later studies, however, Esmen et al.
(1978, 1979b) determined that the size distribution of the airborne fibers was
July 19S5 3-3 DRA-T--DO NOT QUOTE OR CITE
-------
consistent. They concluded that approximately 50 percent or less of airborne
fibers released by the production of mineral fibers with nominal diameters of
6 urn or more would be <3 urn in diameter. Approximately 50 to 90 percent of
airborne fibers released by the production of fibers with nominal diameters
<3 ym would be respirable (Esmen et al., 1979b).
Selected occupational exposure data for MMMF, as indicated by the airborne
concentration measured in various manufacturing plants, are presented in
Table 3-2. Esmen et al. (1979b) determined airborne fiber concentrations
in 11 glass fiber and 5 mineral wool factories as part of an environmental
epidemiological investigation of worker exposure (Enterline et al., 1986; see
Chapter 8). The average concentrations within the breathing zones were 0.0024
to 0.78 fiber/cm for glass fibers and 0.024 to 0.34 fiber/cm for mineral wool.
The highest fiber concentrations were detected in production, manufacturing,
and maintenance operations. In general, the average concentrations of fibers
in the respirable range encountered in fiber production varied between about
0.03 and 0.2 fibers/cm (Hill, 1977). Variations in exposure depend on the
habits of the workers, the processes involved, and the availability of control
measures, as well as on the physical characteristics of the fibers (Esmen
et al., 1979a).
As part of several epidemiologic investigations (Saracci et al., 1954;
Simonato et al., 1986a,b; see Chapter 8), a study was conducted by Cherrie and
Dodgson (1986) to determine worker exposure in 13 European MMMF factories
(4 manufacturing glass, 7 mineral wool, and 2 continuous filaments). Exposure
was divided into three "technological phases." The early technological phase
represented the period of highest airborne levels of MMMF, where no dust-
suppressing agents were used. The intermediate technological phase represented
MMKF production with and without dust suppressors. During the late.phase, oil
and resin binders (dust suppressors) were used during production. The results
of an environmental survey conducted between 1977 and 1980 indicated that the
average combined occupational group concentrations in the rock and glass wool
plants were generally low (<0.1 fibers/cm ), whereas airborne fiber concentra-
tions in the glass continuous-filament factories were much lower (<0.01 fibers/
cm ). The average plant median for fiber length ranged from 10 to 20 urn, and
the corresponding median diameters ranged from 0.7 to 2 urn. In general, the
glass wool fibers were thinner than the rock wool fibers (Cherrie et al.,
1985).
Julv 19£5 3-4 DRAFT—DO NOT QUOTE Oh CIT:
-------
tAtiir
nl 1 ilipr
finliK nl
MIS Ifl.ISS
MIS <|l .ISS
MIS l| I.ISS
MIS I|I.1SS
' MIS l| 1 .ISS
' MIS IJ I.ISS
' MIS <| I.ISS
1- MIS l| I.ISS
IIMIS l| I.ISS
IIMIS i|lass
IIMIS l|laSS
i-oiis i|lass
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mills ii l.iss
I*.S Wllltl
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ISS Wlllll
.IS S WIMt I
.»ss wool
imral wool
iK-r.il Html
ni-ral wool
iii-r.il wnnl
ii d/slai| wool
II Ir/S la<| WIIOl
II d WIMI I
II V WIMI 1
M It WIMll
i-r.imii
ill IIIIM
.iilMin
.ilium
ILtpii li| HP
1 1 .I|IM li| t l.p
.ill
.ill
.tli
fi-i mil til ill*
MIIU.IMT nl s.impli'S
|T
ll.il .1 mil prP'.pnli*
ronci>nlrali«ins, no. <
1'iross
No of
pistils RaiH/l* nf Rain|p ol
sam|>lpil avrraqps cnncpnlr.il innr.
40* 0.41 <0 07-7.11
I -- . -
3 HAC Ml -4. SO
n -- --
11 0. 0074-0. /fl
j
\ 0.04-1?.;'
S NA <0 01-71.09
1 -- 10°
S -- 0.001- .1.0
4 0.3* 0 1-14 5
1 S0.?
I.O
1 l?-36
444-I33J
6
1 0 ?• --„
3 1.8-7B ^.B-13.1
3 0.049-?.fi O.OOI?-5f,.W
1
--. -- 74-l?OOh ,
i 11
17 -- mm-n.yi * to"
7 -- 0.09- 2?. 9fi*
i
3 -- 0.70-2 M
I j-
5-73
I inl
• I,
•I.
'Mil Ni.l ili-li-i Inl
'mil/m1
Mi 11 inns (Mil it li--./ll 1
'l.i-i,m.-li IT mi-.lii ilni ini| \'MI l.o I'lMII.
0.0117
NA
0.011
•O.I
O.OI-O. 12
II. I'l
II .7" !-?.(•
O 4H
»0 117-1.03
O.OIU-0.073
»0 7
0.01-0 1
0.001-0. 1
0.01-0.34
II .1)111-0.463
lt.Oi-0. I
0.0.3-0. 16*
0 OS- 7. /I
i.n
(19/f.)
Bprlalfi el al. (19Wi)
Corn and Sansone (19/4)
Inlerline and Marsh (I9B2)
tsuen el al. (!9/9b)
Gardner el al. (I9IW.)
Mill el al. (19/3)
.Inhnson el al. (I9f>9)
Maqqioni el al. (1900)
Weil I el al. (I9B3)
Bay I Iss el al. ( 19/f.)
Shannon el al. (19B2. 19B4.
19B6. 19B7)
tnlerttne el al. (!9Hft)
Heriattl el al. (I9H4)
Moulin el al. (I90(>)
Cherrle el al. (l9Bfi)
Moulin el al. (I9iir.)
Shannon el al. (1907)
Wriqht (19GB)
Saraccl el al. (1904)
Alsbirk el at. (1903)
ls«en el at. (I979b)
Olsen and Jensen (I9B4)
Well! el al. (19B3)
Wei 11 el al. (19113)
Carpenler and Spolyar (1945)
Oodqson el al. (1907)
Halmberq el at. (I9B4)
Skuric and SlMhuljak-Rerilic (19114)
Saraccl el al. (I'lHI)
ts«»n el al. (19/9b)
,lon*i el at. (1907)
Henry el at. (1907)
Gieseke el at. (1904)
(.aoble el al. (I90S)
Va.wHIer el al. (I9BS)
Gamble el al. (1907)
W><|man el al. (1907)
Kleinfeld el al. ( I'lf./)
lockey ol al. (19114)
-------
Dodgson et al. (1987) developed a mathematical model to estimate past
exposure during the early technological phase to respirable glass wool and
rock wool fibers in the European wool insulation industry. The model WES
derived from data on airborne fiber concentrations measured during 1977-60 a-.s
1984, from dust emission measurements, and from the technical history of ea:>-
plant. It was found that the mean respirable fiber concentrations for rock
wool plants ranged from 1 to 2 fibers/cm during the early technological phases
with levels of about 10 fibers/cm3 for those areas with the highest dust
•5
concentrations. The current exposure levels are about 0.03 to 0.12 fibers'cr--
(see Table 3-2). Higher concentrations were reported by Cherrie et al. (1557)
in an experimental simulation of a rock wool/slag wool production process tc
estimate exposure during the early phases. It was found that the time-weig-.ted
average concentration during the period of the experimental production wcrk *a =
approximately 1 to 5 fibers/cm when oil was added and approximately 5 fibers/
err, in the absence of oil. The corresponding model estimates for the glass
wcol plants during the early technological phase were similar to curre-.t .
reipira^le fiber concentrations of about 0.1 fibers/err; or less (Ecdcsc"
et al., 1987).
Esmen et al. (197Sa) have suggested that, under similar plant CO"- fens,
employee exposures to fibers during ceramic fiber production will be approxi-
mately four times the exposures during mineral wool production.
Exposure of workers to mineral fibers occurs in locations other than
fiber production facilities. Specifically, workers engaged in the fabrication,
application, finishing, and other operations involved in the manufacture and
installation of mineral fiber-containing products are also exposed to airborne
fibers (Fowler et al., 1971). Corn et al. (1976) reported an average fiber
concentration of 0.42 (range, 0.11 to 0.95) fibers/cm in a production area in
which ceramic fibers were used to form ceramic blocks. Fibers <3 urn in diarete-
constituted an average of 75.2 ± 7.7 percent of the total fiber concentration.
No simple method currently exists for estimating the amount of respiratle
fibers likely to be released when mineral fiber-containing products are used
in practical situations (Schneider, 1979). Measurements taken during the
removal and replacement of MMMF insulation in a loft showed an 8-hour time-
weighted average (TWA) for respirable fibers of 9 and 0.5 fibers/cir . respec-
tively. The high concentration during removal was attributed to the age and.
type of insulation involved. Marconi et al. (1987) performed personal ar.c
3-6 DRAFT--DO
-------
area measurements of airborne fiber concentrations during the installation of
rock wool insulation blankets on walls and-ceilings of deckhouses in ships of
a naval dockyard. Mean respirable fiber concentrations ranged from 0.02 to
0.19 fibers/cm3 with a peak level of 0.65 fibers/cm3.
The National Institute for Occupational Safety and Health (NIOSH) he;
.conducted two workplace exposure surveys. The National Occupational Hazard
Survey (NOHS), conducted from 1972 to 1974, estimated the number of workers
potentially exposed to chemical agents in the workplace in 1970 (NOHS, 1976).
These estimates were derived from observations of the actual use of the ager.t,
the use of trade name products known to contain the agent, and the use of
generic products suspected of containing the agent. The NOHS estimates of
exposure to the manmade mineral fibers are presented in Table 3-3.
TABLE 3-3. NOHS ESTIMATES OF EXPOSURE TO MINERAL FIBERS
Chemical
t _C - : .
Glass fioers
Glass wool
Fibercless
insulation
Mineral wool
Polyolefin fibers
Attapulgite
Talc
Vermicul ite
No. of
people exposed
62,611
57
80,629
5,079
96,784
134,121
1,536,754
104,456
Source of exposure estirristej__percer.t
Actual
..a
100
74
-•
--
--
14
4
Trade name
61
--
—
100
4
29
31
21
Gene Me
3s
--
26
--
95
71
56
74
8No data available.
Source: National Occupational Hazard Survey (1980).
The National Occupational Exposure Survey (NOES), conducted from 1980 to
1983, estimated the number of workers potentially exposed to chemical agents
in the workplace in 1980 (NOES, 1984). Unlike NOHS, the NOES estimates were
based only on observations by the surveyor of the actual use of the agent.
Fibrous glass, mineral wool, and ceramic fibers were not found in the NOES.
The American Conference of Governmental Industrial Hygienists (ACGIK) has
recommended an 8-hour TWA threshold limit value (TLV) of 10 mg/m for mine -a1
wool fibers (American Conference of Governmental Industrial Hygienists, 19£r).
In 1977, National Institute for Occupational Safety and Health (1977)
recommended that the standard for occupational exposure to fifcrojs gU-s
July 19 = 5 3-7 DRAFT — CD NO' QJCTE C
-------
should not exceed 3 fibers/cm for fibers with diameters <3.5 um and lengths
>10 urn, determined as a TWA concentration for up to a 10-hour work shift in a
40-hour workweek. However, airborne concentrations determined as total fitrous
glass should be limited to a TWA concentration of 5 mg/m of air (FR, 1988).
The available data suggest that consumer exposure to fibers is low. In
many instances, the manufacture of secondary products from mineral fibers
includes the addition of a binder to form a matrix, thereby resulting in little
subsequent fiber exposure. Many of the uses of MMMF are primarily industrial
rather than residential. Fibrous glass and mineral wool are used mainly for
thermal insulation. The highest exposures would probably occur shortly after
the installation or disturbance of insulation materials. Fibrous glass is else
used in filtration applications. .The escape of fibers during use would cor,r-c-
•ir.ise the effectiveness and use of the filters. The specialized applicatio-s c*
ceramic fibers limit their potential for consumer exposure.
3.2.2 Synthetic Fibers
Measurements of airborne concentrations of polyolefin and aratr.'d fise-s
in manufacturing plants were net available. In a study by Chang (19£2),
aerodynamic size analysis and scanning electron microscopy of aerosols ge^e-atec
during the manufacture of carbon fibers showed the presence of a significa-.t
quantity of respirafcle fiber-like particulates. The mass median aerodynamic
diameter (MMAD) was 4.0 urn compared to the geometric diameter (7 to 8 urn) of
unprocessed fibers. Similar to MMMF, fiber concentrations vary with tne
sampling location and manufacturing process involved.
Gieseke et al. (1984) studied carbon fiber emissions during the manufac-
ture and disposal of carbon fiber products. The average fiber lengths enc
diameters from 12 manufacturing operations were sampled; these ranged fror.
25 to 2000 urn and from 5.5 to 7.8 urn, respectively. Fiber concentrations
ranged from a low of 900 fibers/m in the handling operation to a high cf
6.59 x 10 fibers/m In the drilling operation. Of the manufacturing operations
_2
studied, drilling and weaving had the highest releases (1.44 x 10 percer.t
and 7.2 x 10 ng/cm , respectively). The authors concluded that release anc
distribution were highly dependent upon the particular operation. Selected
occupational exposure data for carbon fibers determined in manufacturing r'e-.ts
are presented in Table 3-2.
JVv 1S5S 3-5 DRAFT--D: N"T Qj"E C':.
-------
NOHS exposure estimates for polyolefin fibers are listed in Tatle 3-3.
No exposure estimates for aramid or carbon fibers were found in the available
literature. Similarly, NOES estimates for synthetic fibers were not found.
3.2.3 Minerals
Measurements of airborne concentrations of attapulgite, talc, and verrr.i-
culite in mining and milling activities conducted in environmental surveys as
part of epidemiological studies are listed in Table 3-2. No data were avail-
able for erionite. Vermiculite exposure at a mining and milling operation in
Libby, MT, was studied by Amandus et al. (1987).. The site was divided into
25 location-operations, and sampling information prior to 1950 through 19£2 was
collected and analyzed. Prior to 1964, the greatest exposure came fror cry
mill jobs, and estimates for working areas, sweepers, skipping, and the qusVit,.
control laboratory were 168, 182, 88, and 13 f/cm , respectively. During the
years 1964-77, exposure estimates decreased greatly. For the same operations,
they were 33, 36, 17, and 3 f/cm , respectively. Prior to 1971, expcsu-e
estimates for mining jobs including drilling and nondrilling operations were 9
to 23, and <2 f/cm , respectively. At the- river loading station,
estimates prior to 1971 for ore loading, the river office, the conveyor tur.ne"! ,
the river dock, and the river station bin area ranged from 5 to 82, 10 tc 11.
112 to 113, 5 to 117, and 20 to 21 f/cm , respectively. Exposure estimates for
all operations decreased annually from 1972 to 1976 and leveled off to 1952.
Exposure in most areas during 1977-82 were <1.0 f/cm and ranged from 0.6 to
1.0 f/cm in the mill. Estimates for an 8-hour TWA fiber exposure in 19E1-S2
ranged from 0.6 to 0.8 f/cm for mine and mill jobs. However, based on samples
taken by the company in 1984, the average TWA exposure was 0.1 f/cm . Due tc
the presence of asbestos as a contaminant In vermiculite, Dixon et al. (19=5)
conducted a study to determine airborne concentrations of asbestos in process-
ing plants. Sampling was conducted in 1980 at the W. R. Grace mine and milling
facility near Libby, MT, from October 21 through October 26, and at both the
Grace and Patterson mine and processing facilities near Enoree, SC, from
November 3 through November 6. Both air samples and bulk samples were
collected at each location. The sampling method employed attempted to capture
particles during various stages of production. The possibility existe: that,
during exfoliation, asbestos fibers trapped between vermiculite plates co-id be
released; therefore, samples were analyzed as they were received a".i s'te1-
July 15 = : 2-8 DSA"--D: K" Ql'C": C: II":
-------
laboratory exfoliation, a process that allowed the samples to retain the
asbestos, to determine if additional fibers were shed. Laboratory analysis
suggested that a higher quantity of asbestiform fibers existed in smaller size
grades of vermiculite as compared with larger grades. Multiple grades of bulk
samples, mined from the Grace facility at Libby and observed under trans-
mission electron microscopy (TEM), consisted of the amphibole group minerals
anthophyllite and actinolite-tremolite and contained a range of 1 to
1800 x 10 fibers/kg. Corresponding concentration ranges were from 1 to
41,000 ppm (Dixon et al., 1985).
Table 3-4 summarizes data obtained from a study that monitored amfie-t
concentrations of asbestos-containing vermiculite at two different processing
facilities. Personnel sampling was conducted at various sites of activity,
and the values are expressed as fibers per cubic centimeter. Dixcn et e".
(1985) also reported estimates of occupational exposure to vermiculite. Tne
data were compiled from various sources and are listed in Table 3-5. However,
these numbers may overestimate occupations! exposure because they may include
clerical personnel or because nonvermiculite products may also be manu*act-"-e_
at the plant.
The NOHS estimates of exposure to attapulgite, talc, and vermiculite ere
presented in Table 3-3; however, information on erionite was not founc! in the
NOHS. NOES estimated that 18,872 workers, including 5,244 females, were
potentially exposed to talc and 4,293 workers, including 365 females, we-e
potentially exposed to vermiculite in the workplace in 1980. Information for
attapulgite and erionite was not found in the NOES. The ACGIH has recommenced
an 8-hour threshold limit value (TLV-TWA) of 2 mg/m respirable dust for talc
containing no asbestos fibers. No workplace exposure limits have been recor-
mended for attapulgite or erionite (ACGIH, 1985).
Exposure to attapulgite, erionite, talc, and vermiculite may arise frorr,
the use of these materials in consumer products such as pet waste absorbents,
fertilizers, pesticides, drugs, and cosmetics (Dixon et al., 1985; National
Research Council, 1984). However, reports of consumer exposure levels were
found only for vermiculite.
Due to the various uses of vermiculite, consumer exposure is relatively
high (Table 3-5). Table 3-5 also lists the ranges of asbestos concentrations
to which consumers may be potentially exposed as a result of vermiculite use.
-------
TABLE 3-4. OCCUPATIONAL EXPOSURE TO AIRBORNE CONCENTRATIONS
OF ASBESTOS IN PROCESSING PLANTS
Population
Asbestos fiber
concentration,
fibers/cm3
Comments
Miners and millers of vermiculite
0 Grace mine and mill at Libby
0 Grace mine at Enoree
0 Grace mill at Enoree
Exfoliators of vermiculite
0 G"s:e facility at Enoree
0 Patterson facility
(benef iciation, exfoliation
at Enoree)
0.03a
<0.01
1.7
0.8
6.4
0.11
0.15
0.15
<0.01
0.03
0.14
0.08
o.oe
0.02
0.16
0.05
Front loader, mine
Pit haul driver, mine
Mine analyst, mine
Bottom operator, mill
No. 2 Operator, mill dozer-
Operator mine
Shuttle truck between plants
Truck driver
Dragline operator
Mill monitor
Mill lab technician
Bagger (Grade 4)
Bagger (Grade 3)
Payload operator
Plant foreman
Bagger/fork! ift
Concentrations are an average of values determined by two independent
laboratories, Ontario Research Foundation and IIT Research Institute.
Source: Dixon et at. (19S5).
3-11
ncz.-7-.rv-.
-------
TABLE 3-5. SUMMARY OF OCCUPATIONAL AND NONOCCUPATIONAL
INHALATION EXPOSURE TO ASBESTOS IN VERM1CULITE
Population
Occupational
Miners and millers
Exfol iators
Users of exfoliated
vermiculite
Aggregates and
insulation producers
Transportation
Truck
Rail
Warehouse
Consumers
Attic insulators
Garden fertilizers
Lawn .
Disposal
Food
Drinking water
Ambient air
Near mi 11s
Near exfoliation plants
Ambient water
Ambient land
Number
of persons
exposed
•^250
1,694-1,979
1,694-1,979
298
129
108
Unknown
18£,000
32,000,000
74,400,000
4,600
13,147,496
Exposure level
fibers/cm0 pg/m-51
NDa-9.7
ND-0.38
ND-0.38
K
-- 6,800
<0.01-0.3
Unknown
0
6,800
20
4.4
Unknown
Unknown
Unknown
ND-0.5
S.OxlC'-5
2.5x10-*
Unknown
Unknown
Duration
(hours)
42.0
41.5
41.5
3t 9
3- c
7C C
39. 9
c
1
^
16 =
15£
a
ND = None detected.
No data available.
Source: Dixon et al. (1985).
-------
3.3 AMBIENT LEVELS
The presence of mineral fibers appears to be ubiquitous; therefore,
exposure of the general population is expected to some extent. The sources c*
most fibers found in the ambient environment are not currently identifiable.
The nominal diameters of most MMMF exceed the respirable range (National
Research Council, 1984). The larger fibers tend to settle out of ambient sir
(Balzer, 1976).
Manmade mineral fiber concentrations in ambient air have been reported
for a limited number of indoor and outdoor environments. Balzer (1976)
collected 300 ambient air samples from sites around the State of California tc
determine glass fiber concentrations in the environment. In 36 samples
selected for detailed examination, the average concentration of glass fibers
was 2.57 i 2.98 fibers/L. The average diameter of the glass fibers was 4.3 pr,
with a range of 0.1 to 17.7 pm.
A majority of the U.S. population is probably exposed to mineral fibers
tc some extent by living or working in buildings with fibrous glass insulgfic"
(Na-.iv.-al Research Council, 1964). The airflow through fibrous-gless-1 irec
duct systems in public buildings at six locations was analyzed for fiber
concentration to evaluate the possible erosion of glass fibers frorr, the liners
(Cho.lak and Schafer, 1971). In each case, no glass fibers were found on the
filter of the particulate air sampler. Balzer (1976) examined 37 samples
taken from 13 fibrous-glass-lined ventilation systems in the San Francisco Bay-
area. Fiber concentrations ranged from none seen to 2.0 fibers/L, with ar.
average concentration of 0.87 ± 0.48 fibers/L. The average diameter of tne
glass fibers was 3.7 pm, with a range of 0.1 to 17.7 pm.
Schneider (1936) determined the airborne concentration of MMMF in two
groups of buildings. Group A consisted of 11 schools with mechanical ventila-
tion. Group B consisted of kindergartens, offices, and one school. MMMF
levels in group A ranged from 0 to 87 fibers/m for nine schools. Two schocls
were excluded fron the results because of high MMMF concentrations due tc
uncoated ventilation ducts (120 fibers/m ) and previous handling of MMMF
(950 fibers/m ). Nonrespirable fibers were found in only one school. MK'-'.F'
levels in group B ranged from 380 to 10,000 fibers/m . Nonrespirable fibers
were found in all buildings.
J_.1v< 19:£ 3-13 DRAFT—DD N:T Q':;-£ D: :'."-
-------
In Australia, 193 air samples collected in 22 asbestos-containing office
and plant buildings were analyzed for their mineral (nonasbestos) fiber concen-
trations. The samples were collected during working hours under dynamic
ambient airflow conditions. Fibers <3 urn in diameter, >5 ym in length, anc
having an aspect ratio >3:1 were counted. The fiber concentrations ranged
from 0 to 13 fibers/L, with 75 percent having 0 to 1 fibe.r/L (Altree-Williams
and Preston, 1985).
In a-pilot study (Van der Wai et al., 1987), the concentration levels of
MMMF in eight homes in the Netherlands were investigated during a thermal
insulation procedure in which glass or rock fibers were blown into the cavity
wall. The average concentration in the homes during the insulation procedure
varied between 5 and 25 light microscopically detectable fibers/L, with pecks
up to 65 fibers/L. The next day the concentration had decreased to 1 tc
10 fibers/L, which was equal to or less than the preinsulation concentrate cr.
found in the homes.
Ambient levels for synthetic fibers were not found in the available
literature.
Mining and natural weathering of minerals cou.ld lead to significa-t
localized airborne fiber concentrations. However, no reports of airborne
concentrations of the naturally occurring mineral fibers were found (Nations!
Research Council, 1984). Ban's et al. (1981) determined the airborne concen-
tration of gross and respirable eriom'te fibers in two villages (Karain and
Karlik) in Central Turkey. The concentrations of respirable dust from the
street were 0.2 to 2.8 mg/m in one village and 0.3 to 1.5 mg/m in the other
village. Total dust concentrations from street, work, and recreational and
indoor samples were <0.01 fibers/cm in all areas in one village, and <0.01,
<0.01 to 0.3, and <0.01 to 1.38 fibers/cm , respectively, in the other village.
Ambient air concentrations of asbestos near vermiculite manufacturing anc
processing plants have been reported (Dixon et al., 1985; see Table 3-5).
Exposure to mineral fibers could also occur from drinking water. Sources
of fiber concentrations in drinking water could include natural processes,
such as leaching or rainfall runoff, and industrial discharges (Nations!
Research Council, 1984). Attapulgite has been found in some water supplies
(Millette et al., 1979b, as cited in National Research Council, 1954). Arcie-t
air concentrations of asbestos near vermiculite manufacturing and
p!ar,ts have been reported by Dixon et al. (1985; see Table 3-6).
19:£ 3-K DRA-T—DC NOT QJOTE
-------
TABLE 3-6. ASBESTIFORK FIBER MEASUREMENT METHODS'
Measurement
Col lection
Quantification
Identification
Mass, gross Filter
Electrostatic
Impaction
Hi-vol/filter
Mass, Horizontal elutriator/
respiratle filter
Cvclone/filter
Count
Impingement
Impaction
Thermal precipitator
Membrane filter
Nucleopore filter
Nucleopore filter
Gravimetric
Gravimetric
precipitator
Beta-absorption
Microscopic
Gravimetric
Gravimetric
Light microscope
Light microscope
Light microscope
Light microscope/
phase contrast
TEM,b SEM,C
image recognition
Light scattering
Mineral identification
by x-ray; chrysotile
(asbestos) identifi-
cation by Mg analysis
Not applicable
(piezoelectric)
Not applicable
Mineral identification
by x-ray
Mineral identifies*.:^
by x-ray; chrysov'le
identification by Kg
analysis
Mineral ident'ificetic*.
by x-ray; chryscv 'e
identification ty M;
analysis
Identification by
morphology
Identification by
morphology
Identification by
morphology
Identification by
morphology; mineral
identification by-
dispersion staining
Mineral identification
by SAED; chemical
composition by EDXA
Identification of fibers
by magnetic alignre-t
aAdapted from Burdett et al. (1980, as cited in National Research Council, 19£-).
Transmission electron microscope.
cScanning electron microscope.
Selectee" area electron diffraction.
Energy-c^spersive x-ray analysis.
J-lv !5££ 3-15 DK-rf--:>: N:* Q-"": -'• ::~-
-------
3.4 ENVIRONMENTAL FATE
The fate of mineral fibers in the environment has been studied mainly in
comparison to that of asbestos fibers (Spurny, 1983; Spumy et al., 19£3).
These studies have focused mainly on glass fibers as representative of MMMF.
The results of these studies have shown that MMMF can undergo chemical and
physical changes, including changes in fiber size, chemistry, and crystalline
structure under different environmental conditions (Spurny, 1983).
Manmade mineral fibers are mechanically stable and insoluble in aqueous
solutions. They are not resistant to hydroxides; glass fibers dissolved in 2f«
NaOH by the end of a 1-year period (Spurny et al., 1983). Resistance tc acic
solutions is dependent upon fiber type. Glass fibers showed little evioen:e
of surface changes following exposure to acids, but MMMF other the-- glass
fibers were not acid-resistant. Analysis indicated that the fiber surface w=s
rm'croporous following acid exposure (Spurny et al., 1963). In addition tc
surface corrosion, acid exposure leached some elements (Na, K, Ca, Al, anc Zr.)
frorc the fibers (Spurny, 19£3). Exposure to stronger acids ca~ cause g'ess
and rock wool fibers to dissolve starting from the fiber ends, resulting ir,
the development of inverted cones (Wojnarovits-Hrapka, 1978, 1977, as cite: ir
Notional Research Council, 1984). These data suggest that the exte-nal fic-er
structure is more acid-resistant than the internal structure.
The chemical and physical changes that affect mineral fibers are not
homogeneous. Considerable variation exists in composition along the length of
a fiber as well as between fibers. Thus, the effects of environmental condi-
tions, such as acid leaching of elements, vary with location along a fiber and
affect individual fibers differently. Fine glass fibers (diameter <3 uir.) are
degraded much more rapidly than coarse fibers (Spurny et al., 1983). Unlike
asbestos fibers, which can split longitudinally to produce thinner fibers, MMMF
break transversely, creating shorter fibers (Weil! et al., 1983). However, for
brittle asbestos, especially noticeable in low fiber quality, the coherence
between the fibers may be extensive so that when their separation is attempted,
some fibers will break transversely before they separate longitudinally.
The rate at which fibers settle out from the air is determined mainly by
their diameters, with larger fibers settling out rapidly (Hill, 1977). As
with asbestos fibers, the major environmental fate of mineral fibers is Drcta-
bly the deposition and eventual burial of the fibers in soils and sediments
(National Research Council, 1984).
-------
Ultraviolet light and gamma radiation have been found to affect the
ultimate tensile strength and chemical composition of Kevlar 49 fibers (Morgan
et a!., 1983; Harper and McAlister, 1975; Toy, 1987). Aging by gamma irradia-
tion was enhanced in the presence of oxygen (compared to uj vacuo conditions)
and was more severe than ultraviolet light. Ultraviolet light (120 watts,
2537A) lowered the strength by >25 percent in 1 week, whereas soft white
fluorescent lighting had a lesser, but significant, effect (Harper and
McAlister, 1975). Toy (1987) subjected Kevlar® fibers to photodegradation in
18
an CL atmosphere, using a concentrated sulfuric solvent, at temperatures of
25 and 196°C. Rapid decarboxylation occurred *t 25°C at the terminal groups
of the fiber macromolecules. At 196°C, the fiber macromolecules broke dew.
completely. Kay and Ross (1972) reported that several physical characteristics
of Kevlar5" fibers such as fabric elogation, breaking strength, and tear strencf
were reduced by 29, 179, and 20 percent, respectively, following accelerated
weathering. The fibers were exposed for periods of up to 150 hours in ar,
accelerated weathering unit before property testing began.
The rates of hydrolytic degradation of Kevlar 4S fibers depend on the
relative humidity, time, temperature, and stress level. However, Morgan et a*.
(19£2) reported that hydrolytic degradation is not a significant aging mecha-
nism. Auerbach (1985) also studied the effects of temperature and humidity cf
Kevlar 29 yarns. Initial degradation rates were slow due to an inhibitor but
increased rapidly as the inhibitor was depleted. Kevlar 29 tolerated huridity
levels in the range of 90 percent or less.
Vermiculite and talc are not expected to undergo chemical transformation
when released into the environment. Their refractory nature precludes the
effects of melting/boiling point, solubility, vapor pressure, octanol/water
partition coefficient, etc., on their transport. This is also true for the
MMMF and mineral fibers. Terrestrial and fluvial transport processes affecting
these minerals are not well characterized.
3.5 ANALYTICAL METHODS
The principal measurement techniques that have been used to quantify a-c
identify asbestiforir fibers, including asbestos, MMMF, and synthetic anc
naturally occurring mineral fibers, are presented in Table 3-6. These analyti-
cal methods evolved as measurement technology progressed and as tie
for mere precise information grew.
3-i7 Dn-r>-DQ N:T c-.:r~£ o~
-------
The earliest methods measured mass, providing total airborne dust concen-
trations. The use of x-ray diffraction techniques provided identification of
the mineral phases present. Filtration techniques were often applied to rencve
the larger particles, thus permitting a measurement of respirable particle
concentrations. However, these methods were limited by the inability of the
x-ray diffraction technique to detect small particles (National Research
Council, 1984) and by the inability to derive reliable estimates of the fiber-
concentration from the total dust concentration (Corn and Sansone, 1974).
Counting methods, which are far more sensitive than mass determinations,
can usually be applied to samples that are too small to be weighed. They
permit the counting of fibers separately from other particles and emphasize
smaller particles, since they greatly outnumber large particles in the a*'r
(National Research Council, 1984).
The use of these analytical methods is dependent on the sampling te:r-
niques, sample preparation, and the resolution capabilities of the instrur.e-ta-
f':~. Sampling techniques must be selected for their efficacy untie" tre
specific conditions encountered and must be effective over the entire range c*
concentrations anticipated. Current methods generally use Nucleopore poly-
carbonate or membrane filters for sample collection (Altree-Williams e^c
Preston, 1985; Rendall and Schoeman, 1985). The great variability amc-.g
samples collected within and among plants (Esmen et a!., 1978; Corn and Sansone,
1974) indicates the need to define the number, location, and timing of samples
collected (National Research Council, 1984).
Sample preparation entails the proper handling and treatment of the
collected samples to facilitate analysis by the chosen method. These pro-
cedures include ensuring no (or insignificant) loss of sample. For counting
methods, the fibers must be evenly deposited with spacing between the fibers tc
permit counting (National Research Council, 1984).
Walton (1962, as cited in National Research Council, 1984) has stated
that the use of the membrane filter/phase contrast optical microscope is the
only practical method for routine occupational monitoring. Henry et al. (19£2)
used an open-face membrane filter (Millipore; 0.45-Mm pore) collection mode and
a light microscopy method to count carbon fibers and to measure fiber size and
total fiber mass concentration. Samples were obtained from various st=t:or,a-y
emission sources and from a pilot-scale inhouse incinerator facility. Pr-icr t
analysis by light microscopy, carbon fibers were separated fror: ct*er pe'ti:--
late matter vie acid treatment. The carbon fibers were tner> depcsite: cv.c
-------
5.0-um pore-size Milipore filters. Low magnifications (about 10X) were used
for length measurements; width and short lengths were measured using higher
magnifications (100 to 400X). Carbon fibers were easily recognized and counted;
airborne concentrations ranged from 24 to 1200 fibers/m , and fiber lengths
were between 48 and 750 ym. Liu et al. (1983) used a dichotomous sampler witn
a V-groove impactor surface and optical microscopy to detect fibers with
average diameters of 8 pm.
However, the light microscopy methods are limited in resolution (only
fibers greater than 0.5 pm in length are visible) and generally do not provide.
fiber identification. Greater sensitivity is required to analyze fiber concen-
trations at ambient levels and to provide identification of source fibers
(Nations! Research Council, 1984). Use of the electron microscope and associ-
ated analytical techniques allows morphologic and structural characterizefc-
and elemental analysis of the fibers at high resolution (Paoletti et al.,
19S4).
6ot> $£'•' and TEK can be used with x-ray analytical methods tc P-CV^'CT
mineralogic identification of fibers (National Research Council, I9S-).
Electron probe microanalysis is the term used when either SEM or TEM is per-
formed in conjunction with x-ray analysis. This procedure produces elect-or
optical images of surfaces and generates x rays that are characteristic of the
elements contained within the irradiated surface of the compound being tested
(Pooley, 1977). Chang (1983) also used SEM and aerodynamic size analysis to
measure ambient levels of carbon fibers. The major limitation of SEM, however,
is the resolution; fibers less than 0.05 urn in diameter are not resolved well
(Vallyathan and Green, 1985), and no structural data are provided (National
Research Council, 1984). TEM can be used with several identification methods
(Spumy, 1983), The high resolving power of TEM, equipped with energy-
dispersive x-ray analysis and selected area electron diffraction, can elucidate
the morphology, chemistry, and crystalline structure of the fibers (Vallyathc-
and Green, 1985). This method has been used successfully to analyze the
composition of submicroscopic particles of asbestos dust. One of the main
advantages of this technique is that it enables the user to conduct simulta-
neous analysis of all elements that possess atomic numbers higher than that of
sodium (i.e., 11) (Pooley, 1975). The resolution of TEM is high encug- tc
detect fiber dimensions as small as 0.2 nm (Chatfield and Lewis, 19BCO-
July 19SS 3-19 C-;A-T--DC fC~ QJ:~£
-------
Another current analytical method is the LAMMA procedure, a mass spectrc-
scopic analysis of single fibers (Spurny, 1983). The instrument combines a
high-energy laser beam with a mass spectroscope to provide a microchemical
analysis of individual fibers.
Loo et al. (1984) reviewed the various other methodologies that can be.
used in measuring ambient carbon fibers. None of these methods appears to be
as sensitive as those described above. Passive collectors, such as sticky
tape and the pridal veil, can be used in conjunction with automated image
analyzers or a high-voltage tape analyzer. Optical counters, such as a tre-ss-
mitometer or LADAR can detect only dense clouds of fibers; length distribution
may be determined by observing the light scattering or diffraction patterns
exhibited by the fibers using other photodetectors. Microwave absorption is
usec to irradiate the carbon fibers with microwaves and to sense the nested
fiber with an infrared detector. This method is very specific for carbon
fibers and can detect fibers 1 mm in size. Other analytical methods involve
using low-voltage or high-voltage (spark counter) grid detection and measuring
the induced charge acquired by a conducting fiber in an electric field. Lcc
et al. (1984) also developed a prototype-induced charge detector capable cf
measuring fiber length distribution between 0.08 and 9 mrc and fiber concer,t
-------
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-------
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Scandinavia. Ann. Occup. Hyg. 22: 153-162.
Schneider, T. (1986) Manmade mineral fibers and other fibers in the air a-.d in
settled dust. Environ. Int. 12: 61-65.
$r,3T,-,D-ri H. ; Hayes, M. ; Julian, J. ; Muir, D. (1982) Mortality experience c*
glass fibre workers. In: Biological effects of man-made miners", fibres:
proceedings of a WHO/IARC conference, v. 1; April; Copenhagen, Der,- = ^,.
Geneva, Switzerland: World Health Organization, Regional Office for
Europe; pp. 347-349.
Shannon, H. S. ; Hayes, M. ; Julian, J. A.; Muir, D. (1984) Mortality experience
of glass fibre workers. Br. J. Ind. Med. 41: 35-38.
Shannon, H. S. ; Jarr,ieson, E. ; Julian, J. A.; Muir, D. C. F. ; Walsh, C. (19S6)
Mortality experience of glass fibre workers--extended follow-up. Preser.tec
at: international symposium on man-made mineral fibres in the work-ing
environment; October; Copenhagen, Denmark. Copenhagen, Denmark: World
Health Organization, Regional Office for Europe.
Shannon, H. S.; Jameson, E.; Julian, J. A.; Muir, D. C. F.; Walsh, C. (1SE7)
Mortality experience of glass fibre workers -- extended follow-up. A".
Occup. Hyg. 31: 657-662.
Simonato, L. ; Fletcher, A. C.; Cherrie, J. ; Andersen, A.; Bertazzi, P. A.;
Charney, N. ; Claude, J.; Dodgson, J.; Esteve, J.; Frentzel-Beyme, R. ;
Gardner, M. J.; Jensen, 0.; Olsen, J.; Saracci, R.; Teppo, L.; Westerholir,,
P.; Winklemann, R.; Winter, P. 0.; Zocchetti, C. (1986a) The man-made
mineral fibers (MMMF) European historical cohort study: extension of tne
follow-up. Presented at: international symposium on man-made minere"
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Copenhagen, Denmark: World Health Organization, Regional Office for
Europe.
Julv 19:5 3-26 DRAFT—DC NC~ D-I": Cn C!
-------
Simonato, 1.; Fletcher, A. C.; Cherrie, J. ; Andersen, A.; Bertazzi, P. A.;
Charney, N.; Claude, J.; Dodgson, J.; Esteve, J.; Frentzel-Beyme, R. ;
Gardner, M. J. ; Jensen, 0.; Olsen, J.; Saracci, R.; Teppo, L. ; Westerned,
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July 1S££
3-27
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3-2£ DRi"--DC M:T
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4. RETENTION AND BIODISPOSITION
4.1 INTRODUCTION
The two primary factors that influence the deposition of fibers in the
respiratory tract are aerodynamic equivalent d-iameter and aspect ratio (i.e.,
length/actual diameter). In general, deposition and retention of fibers
decrease with increasing diameter and length; most fibers recovered froir, trie
lung are <3.5 urn in diameter and <5 urn in length. Mechanisms involved in tie
clearing of fibrous materials from the lung include removal by mucocilia-y
activity, transport by alveolar macrophages to regional lymph nodes, uptake
b> epithelial cells, and direct translocation of fibers between epitheVis1
cells to the interstitium and the pleura. Transport via the systemic circula-
tion has also been observed. Short (<10 urn) fibers are usually phagocytizei bj.
alveolar macrophages prior to clearance; longer fibers fragment easily aic
•often are found only partially phagocytired. Fiber types and composition
affect solubility and fragmentation. Natural fibers (e.g., asbestos, attap.'-
gite, erionite) essentially are in soluble and split longitudinally in to
thinner fibers, making clearance difficult. Manmade (glass, mineral wool, ar.c1
ceramic) and synthetic (aramid, carbon and polyolefin) fibers break crosswise,
increasing solubility and the rate of clearance.
4.1.1 Host Entry and Retention
Fibers enter the body by inhalation or by oral intake. Various factors
influence the deposition of inhaled particles in the respiratory tract. Whe~
nonfibrous compact dust particles are inhaled, the particles having a diameter
greater than about 5 urn are generally trapped in the nasal passages before
reaching the respiratory system (Walton, 1982, as cited in National Research
Council, 1984). However, the aerodynamic behavior of fibers deviates sigr-'fi-
cantly from that of nonfibrous particles. Fibers having a given diameter will
behave aerodynamically in the same manner as spherical particles of the same
density that have a significantly larger diameter (Gross, 19E1; Ti;r,rre" 1
4-1
-------
et al., 1970). The equivalent or aerodynamic diameter of a particle is defined
as "the diameter of a sphere with a density of 1 g/cm3 that has the same
falling speed as the particle."
Timbrel! (1965) found that the equivalent diameter of a fiber is determined
predominantly by the actual diameter with length being of secondary importance,
especially when the fiber has a high aspect ratio. The aerodynamic diameter of
glass and asbestos fibers was about three times the actual diameter of the
fibers. Since the largest compact particles normally found in the lungs ere
about 10 um in diameter, it was concluded that asbestos fibers with diameters
greater than about 3 um would be very unlikely to reach the alveoli.
Gross (1981) developed graphs representing aerodynamic behavior charac-
teristics of glass fibers to illustrate the relationship of fiber dimensions t:
the equivalent diameter of a unit-density-sphere having the same aerodyneT^c
behavior (Figure 4-1). The relationship of these dimensions to alveola--
deposition was also studied. It was found that the aerodynamic equivalent
dia«»te- of glass fibers in the respirable range was approximately three fiires
its actual diameter when the aspect ratio approximated 20. The aerod/narric
equivalent diameter increased to roughly three to four times the actual d'ar.eter
for aspect ratios greater than 40 and up to lengths of 150 urn. It was sug-
gested that a glass fiber with a unit-density-sphere larger than 3.5 um (i.e.,
diameter ^1.5 urn and length >10 urn) has little chance of alveolar deposition.
Using mathematical models, Gross (1981) also showed that alveolar deposition
increased as the diameters of the fibers decreased (Figure 4-2). Maximum
alveolar deposition was reported for inhaled fibers with 0.25 to 0.5 pm actual
diameter (about 17 to 18 percent by count). Deposition of fibers of various
diameters drops rapidly with increasing length, being about 16 percent by count
for a glass fiber with 0.5 um actual diameter and 10 urn in length to about
3 percent by count for 120-um-long fibers with the same diameter.
In a similar study, Asgharian and Yu (1988) developed a mathematical
model that indicated a maximum relative alveolar deposition of fibers (type
unspecified) with a length(£p) of 7 um and a diatneter(dp) of 0.75 um following
nose-only breathing by humans (Figure 4-3). The authors reported that although
total deposition is high (about 80 percent) with nose-only exposure, tracnec-
bronchial and alveolar deposition of fibers are lower for nose brectvnc
compared to mouth breathing due to a strong impact deposition in the ncse a->c
interference by nasal hairs.
-------
o:
ijj
Li
i
O
or
Ul
o
O
o
6 -
5 -
4 J
3 -
2 H
1 -
0
0
20
40
60
«
80
100
ODER LENGTH, urn
120
140
Figure 4-1. The relationship of glass fiber diameter and length
to aerodynamic equivalent diameter (Dae).
-------
O
V
O.
Z
O
-
ui
o
o
I
20
40
60 80
FIBER LENGTH, urn
100
120
140
Figure 4-2. The relationship of alveolar deposition to the
diameter and length of glas^jpers.
-------
100
Figure 4-3. Bivariotc distribution of fiber deposition in the
olveoli following nooc-only breathing by humans.
Source: Asghorian and Yu (1988).
-------
The significance of fiber dimensions on the deposition of a variety of
inhaled fibers following nose-only exposure of rats (sex and strain not spec-
ified) was also investigated by Morgan (1979). It was demonstrated that
alveolar deposition increased from about 10 percent at an aerodynamic equiva-
lent diameter (Dfle) of 1 pm to a maximum of about 15 percent at 2 urn.• Deposi-
tion declined steeply to a value of 3 percent at a D of 3.4 urn (for glass
fibers with a count median diameter (CMD) of 1.1 pm). Alveolar deposition in
humans was reported to follow a similar pattern in that the maximum deposition
occurred at a D._ of about 2 urn, but absolute values are greater than those
oe
observed in rats.
Both the configuration and dimensions of asbestiform fibers determine
whether these fibers will be deposited in the "lungs of rats after inhe1ef:c-
(Timbrell, 1965; Morgan, 197S; Evans etal., 1973). Morgan (157S) repo'te:
that for thin fibers (e.g., crocidolite, Da = 1.2 urn), most of the fibers
3e
inhaled by rats were exhaled without being deposited. However, of the ir,ste~ia'. s
tr.ct were deposited, more than half were found below the level of the t*e:-e=.
In contrast, thick glass fibers (D = 3.4 urn) were all deposited ir. t-e
respiratory tract when inhaled, but very few were found below the level c* the
trachea. Timbrel! (1955) reported that long fibers that escaped depositic- at
the nasal hairs were expected to deposit where respiratory bronchioles branch
to smaller sizes and diameters. The more symmetrical a fiber (e.g., glass
fibers), the greater the probability of its reaching the alveoli.
Similar results were reported by Evans et al. (1973), who studied the
deposition of inhaled crocidolite asbestos in the respiratory tract of rats
using radioactive tracer techniques. Examination of autoradiographs of thin
lung sections showed that the largest number of fibers were located at bifurca-
tions of the smaller bronchioles just downstream from the carina.
4.1.2 Translocation and Clearance
Several mechanisms are involved in clearing fibrous materials from the
lung. These include removal by mucociliary activity, transport by alveolar
rr.acrophages to regional lymph nodes and distal sites, uptake by epithelial
cells that line the airways and alveoli, and direct translocetion of fibers
between epithelial cells to the interstitium and the pleura (National Rese=-cn
Council, 1964).
-------
The physical properties (i.e., length and cross-sectional dimensions) of
fibers appear to determine the mechanisms of cellular interaction and transport.
Larger fibers deposited in the upper respiratory tract have a greater chance of
being removed from the lung by clearance mechanisms (Timbrel!, 1965). Elimina-
tion from the lung via the airways has been demonstrated, using radiotracer
techniques, by the presence of radioactive fibers in the feces of exposed
animals (Morgan, 1979; Evans et al., 1973). However, the rates of clearance
may be affected by infections or smoking (Sanchis et al., 1971). Fibers with
smaller diameters that penetrate deeply into the alveoli before being deposited
are engulfed by pulmonary macrophages. However, for macrophages to completely
engulf fibers, they should not exceed a critical length of approximately 5 p~
(Morgan, 1979, 1980).
Sebestien et al. (1979) reported that at least three mechanisms m5j te
involved in the translocation of small chrysotile fibers from the lung tc t*,e
pleura: transport in the lymphatic circulation, direct penetration of tr,:n
fibers, and transport via the blood circulation (especially when asbestcs
fibers are found in nonlymphoid organs).
4.2 MANMADE MINERAL FIBERS
4.2.1 Glass Fibers
4.2.1.1 Host Entry and Retention. The retention of glass fibers following
single, repeated, or chronic inhalation exposures is dependent on fiber dimen-
sions. Retention decreases with increased diameter and length and increases
with repeated dosing. Most of the retained fibers were found in the rig1--*.
upper lobe and left lobes of rats. Those fibers retained in the lung were less
than 5 urn long.
Morgan et al. (1980) and Morgan and Holmes (1984a) used radioactive
tracers to investigate the regional deposition of inhaled glass fibers (of
discrete size) in the respiratory tract of the rat. Groups of eight Alderly
Park (Strain 1) SPF rats (5 months old, approximately 350 g) were exposed
once, for 2 to 3 hours and by nose only, to one of six glass fiber aerosols.
Fibers with a nominal width of 1.5 urn and lengths of 5, 10, 30, or 6C urn were
administered at a rate of 119, 99, 108, and 77 ug/L/min, respectively: 3 *
10 um fibers were administered at 48 ug/L/min; and nonsized fibers were acrr.^r.-
istered at 236 mg/L/min. Prior to administration, about 20 mg of esc* fiber
24
sample were irradiated with Na. Following irradiation, fibers were Swsre~cec
V.i.. icic t-i r.r'CT._rv«i I<-,T r.
-------
in water containing 0.001 percent Dowfax. The amount of fiber in the lung, in
airways external to the lung, and in the gastrointestinal tract, skinned head
(nasal passages), head skin, gastrointestinal tract, feces, and remaining .
carcass were measured by x-ray spectrometry. (Data were then normalized to an
aerosol concentration of 100 pg/L/min.)
Immediately after exposure, the total mass of 1.5-pm diameter fibers
deposited in the animals' bodies ranged from about 16 \ig for the 5-pm long
fibers to approximately 22 to 25 pg for the 30- and 60-pm long fibers. The
mean total deposition of 3-ptn diameter fibers was 25 pg. Approximately 2 tc
3 pg of the sized glass fibers were found on the pelt; animals probably
ingested these fibers during preening. Most (95 to 99 percent) of the rac'c-
activity recovered initially was found in the gastrointestinal tract. Sr,£""
24
amounts of Na were found in the skinned head (1 to 4.5 percent) and- lures
(0.5 to 2.5 percent). At 2 days, radioactivity appeared almost exclusively ir
? '
the feces, accounting for S7 to 99 percent of the recovered Na. Trace tc
srcs'i amounts were found in the skinnec! head, gastrointestinal tract, and r-e"t.
Longe^ (10 to 60 urn) fibers tended to concentrate in the gastrointestinal
tract. By contrast, the majority of fibers deposited in the respiratory tract
were shc't (<1C prr long). Most fibers deposited in the lungs were found i~ l~e
left azyoous and right diaphragmatic lobes (30 and 27 percent of lung racic-
24
activity, respectively); about 20 percent of the Na in the lungs was in the
right apical lobe. The right cardiac and right azygous lobes each
approximately 11 percent.
The data suggest that sized glass fibers are readily taken up by the
lungs and pass through the gastrointestinal tract unabsorbed. The results
also indicate that deposition of glass fibers in the lower respiratory tract
anci alveolar region declines with increasing fiber length. When the authc-s
(Morgan et a!., 1980; Morgan and Holmes, 1984a) compared their data with
results from similar experiments, they found that alveolar deposition pesked
at a diameter of approximately 2 pm and dropped dramatically between 2 and
3 pm. The authors concluded that despite the apparent size limitations o^
respiration of glass fiber particles, fibers with a diameter of 3 to 6 prr. also
are respirable and may have a small but significant alveolar deposition.
Griff is et al. (1981) studied the lung burden of rats exposed to a gless
fiber aerosol by measuring the acid-insoluble sodium content of lungs. Male
rets (number, age, and weight not reported) were exposed tc "Tone1 f^be-s
-------
with a nominal diameter of 0.2 um for 6 hours/day for 2 or 5 days. Lunc
burdens of glass were determined 1, 2, 4, or 5 days after exposure. The
average mass concentrations for these exposures ranged from 35 to 50 mg/m ;
approximately two-thirds of this was "respirable." The lung burden after one
6-hour exposure to the aerosol was 53 ± 11 ug. Lung burdens determined 2, 4,
and 5 days after exposure indicated that about 41 to 48 percent was cleared
from the upper airways between exposures.
A study by Hammad et al. (1982) was designed to measure the retention of
inhaled glass fibers present primarily in the alveolar compartment of the
lungs of male albino rats (strain and number not specified). The rats were
exposed, by nose only, 6 hours/day for 6 consecutive days. They were sacrifice:
5 days after the last exposure. The airborne fibers had a count median le-c*.~
(CM..) of 13 i 2.6 (± geometric standard deviation, GSD) and a CKD of 1.2 =
1.8 urn. The lungs were ashed and the fibers sized and counted by optical phase
microscopy. The fiber content of lung tissue was compared with that of the
airborne djst cloud. The following relationship between fiber retention a-c
fiber length for three fiber diameter categories was noted: the retention of
fibers less than 0.5 urn in diameter was significantly higher then for large'
diameters, with a peak of about 7.6 percent at 21-um fi'ber length. In contrast.
less than 1 percent of the fibers having diameters of 0.5 to 0.7 and C.7 t;
1.0 urn were retained, with peak lengths of about 21 and 5 um, respective~\.
When the effect of fiber aerodynamic equivalent diameter on fiber retention was
examined, maximum retention of about 7 percent was observed at a diameter cf
1 urn. Retention decreased rapidly to about 0.5 percent at equivalent diameters
of 1.5 to 2.5 um and about 0.01 percent at a diameter of about 4 um. In
addition, retention of fibers in the lung decreased sharply as the length of
the fibers, irrespective of diameter, increased from 2 to 10 um; thereafter,
the decrease in retention was gradual.
The distribution and physical characteristics of inhaled resin-free glass
wool in the lung were examined by Le Bouffant et al. (1984, 1987). A group of
24 male and 24 female Wistar rats (8 to 9 weeks old) inhaled an aerosol of £ mg
glass wool fibers/ml, 5 hours/day, 5 days/week for 1 year. About 50 perce-.t
of the airborne fibers had lengths of 10 um or less. Approximately 65 percent
were less than 1 um wide; an additional 15 percent were between 1 and 2 urr.
wide. After 1 year, half of the animals were removed frorr, the dusting chafers
and exposed to fresh air only. The other half were exposed tc the fibers fcr
an additional year. Rets were killed either immediately e'ter •irne1s*^:r
19£5 4-9 DRAFT — DC- N" Q."£ CS CTE
-------
12 or 24 months) or at various times after exposure was terminated: 7, 12, anc
16 months for animals exposed for 1 year and 4 months for those exposed for
2 years. An unexposed group of 24 male and 24 female Wistar rats served as
controls.
At the end of 12 months' exposure, the right upper lobe and left lobe of
the lung contained the highest concentrations of glass wool (between 2.1 and
2.8 mg dust/g dry tissue). The trachea, tracheobronchial glands, and diaphragm
contained the lowest levels of dust (from below levels of detection to
0.7 mg/g). , Females tended to have slightly higher tissue levels than males.
The authors concluded that migration of glass fibers (e.g., to the diaphrag'")
was minimal. Approximately 83 to 94 percent of the fibers deposited in the
left lung lobe, airways, and diaphragm of exposed rats were less than 5 y
long. Within 7 months after the 12-month exposure period, between 65 &~:
75 percent of the inhaled fibers were cleared from the rats' lungs. There-
after, the rate of clearance declined more slowly (Le Bouffant et a!., 195-}.
At 24 and 28 months after the inhalation experiments began, moderate
sorts': "et^CL'1 in fibres is was observed in the lungs. No other organs we-e
affected. Fibers were found either free in the alveolus or engulfed in a"!ve:"='
or septal macrophages. One pulmonary and four digestive tract tumors were
observed (control animals had none and one of these turners, respectively); t~e
high number of visceral tumors suggests that some of the dust may have bee-
ingested with the food consumed by exposed rats. During the postexposure
periods, the glass wool fibers took on an eroded and coarse appearance. Sore
fibers also showed a loss of opacity, and most exhibited a reduction in soc'iur,
calcium, and barium content. Small accumulations of dust macrophages, prima-
rily at the bronchoalveolar junctions, were found after 12 and 24 months of
exposure.
Glass fibers were analyzed by Johnson et al. (1986) following recovery
from rats and hamsters after nose-only exposure durations of 6 hours/day,
5 days/week, for up to 24 months. The animals inhaled glass fibers with mea-
diameters of 0.45, 3.1, 5.4, and 6.1 urn in monodispersed aerosols ranging fror;
3 mg/m for the 0.45-um mean diameter glass fibers to 15 mg/m for the 6.1-ur
mean diameter glass fibers. Fibers were recovered from tissues by sodiur
hypochlorite digestion and examined by electron microscopy. Animal variation
was noted, but the finer the dust, the greater the amount of dust reccve-e:
from the lung. The number of fibers found in lungs of the coarse fiber-exrose"
4*10 DRAFT—D: N:T QU:~E c; ::~E
-------
groups were larger in comparison to finer dusts when the aerosol fiber concen-
trations were normalized, indicating differential dust retention.
4.2.1.2 Translocation and Clearance. Microfibers (diameter 0.15 urn, length
5.4 urn) are readily eliminated following single inhalation exposures. Glass
fibers (diameter <3 pm for 50 percent of the fibers) retained in the lung
following single or repeated inhalation exposure are cleared slowly with a
half-life of about 44 days. The half-life clearance value following chronic
exposure is about 600 days. The rates of clearance following intratrachesl
administration decrease with increased fiber length (>10 urn) and dose. Short
fibers are phagocytized by alveolar macrophages and cleared to the lymph nodes.
Long fibers are usually partially phagocytized. Fiber type and compos •if: on.
which affect solubility and fragmentation, also influence the rates of fiber
retention in the lung. Following intrapleural injection in rats, fibers we'e
found in various organs; translocation apparently occurred via the blood
capillaries.
Clearance of fiber-containing macrophages and particles on alver'ic-
surfaces from 8- to 10-week-old male CD(SD)8R rats was complete within £ ds/s
•3
after a single 5- or 10-hour inhalation to fiberglass particles (10 tc 2G mg-'rr";
dimensions not reported) (Warheit et a!., 1988). A companion j_n vitro study
indicated that complement activation may play a critical role in the ability of
pulmonary phagocytic cells to selectively detect inhaled particles on alveolar
surfaces soon after exposure to fibers (i.e., within 3 hours).
Friedberg and Ullmer (1984) also studied the elimination of glass fiber
dust from rat lungs. Approximately 75 percent of the inhaled airborne pa-ticles
had an aerodynamic diameter less than 5.0 pm, 50 percent had a diameter less
than 3.0 pm, and 32 and 21 percent had diameters of 2.0 and 1.5 pm, respec-
tively. Each of 88 male Sprague-Dawley rats (200 g, age not specified) was
placed in an individual cage and exposed to 86 mg/m "TEL" fibers (which
contain 64.4 percent Si05) for 10 hours. Another set of 40 rats inhaled 86 rr,=
3
fibers/in , 10 hours/day, for 3 consecutive days. Animals were killed at
various times (between 1 and 90 days) after the final exposure period. The
lungs of rats receiving a single dose initially contained approximately 150 to
200 pg dust; nonexposed control lungs contained 8 pg/lung. Glass fiber content
of exposed rat lungs dropped slowly but steadily, measuring about 100, 75, and
50 pg/lung, respectively, at 30, 60, and 90 days postinhalation. The lungs of
multiple-dose rats contained an average of 900 pg fibers at 1 daj poste>r:sj^e;
-------
within 30 days, the average glass fiber content had dropped to 500 ug/lung. At
90 days, the fiber concentration was approximately 250 yg/lung. Despite a much
higher glass fiber body burden, rats receiving multiple doses eliminated the
fibers at nearly the same rate as the single-dose rats, with respective elimi-
nation half-lives of 46 and 40 days. When data from all animals were combined,
a mean elimination half-time of 44.3 days was calculated. Thus, at 280 days
after exposure, it was estimated that the body would contain only 1 percent of
the glass fibers inhaled, and after 440 days, only 0.1 percent of the fibers
would remain in the alveoli.
Long, thin JM 104/475 glass fibers persisted for an extensive period cf
time in the lungs of female Wistar rats following inhalation exposures of
100 ppm fibers 5 hours/day, 5 days/week for 1 year (Muhle et a!., 19S7). A
clearance half-life of approximately 600 days was reported; most of the fire-s
retained by the lungs had a diameter between O.OS and 0.2 pm and were mere
than 1 pm long.
Griff is et al. (1983) examined the deposition and elimination of c'ass
fibers in docs. A group of two male and two female beagle dogs were expose:
by nose only for 60 minutes to neutron-activated fibers with a CMD and O'. cf
C.15 and 5.4 urn, respectively, and an activity median aerodynamic diamete" c*
2.5 urn. Female dogs were approximately 2 years old and weighed between 6.S
and 9.0 kg; the two 3-year-old male dogs weighed between 9.6 and 10.4 kg.
Following inhalation exposure (39 to 88 yg fibers/L), dogs were placed in
metabolism cages, and urine and feces were collected for 4 days, at which time
the animals were killed. Radioactivity was measured in excreta samples and in
the gastrointestinal tract, head, trachea, and individual lung lobes. The
dogs' bodies contained approximately 2 to 6 mg (40 to 67 percent, respectively)
of the 5 to 9 mg of inhaled glass fibers. About 5 to 17 percent -of this was
deposited in the deep lung. Most of the radioactive dose (77 percent) was
eliminated within 4 days after exposure, with 96 percent being recovered in the
feces; the clearance half-life for glass fibers was calculated to be 2 days.
Approximately 88 percent of the radioactivity that remained in the body at the
time of sacrifice was in the lungs, where fibers tended to concentrate in the
right apical lobe. The authors reported that the deposition patterns exhibited
by the dogs in this study were in good agreement with previous predictions mace
for humans. They added that the aerodynamic diameter of glass fibers appea-e:
to be a good predictor of respiratory tract deposition in dogs.
19££ 4-12
-------
Bellmann et al. (1987) reported that short fibers (<5 urn) generally were
cleared from rat lungs more rapidly than long fibers (>5 urn) following intra-
tracheal instillation. Fiber type and composition also seemed to influence
retention by the lungs. Long fibers with a low alkaline earth content (ceramic
wool and 104/475 glass nticrofibers) and crocidolite had comparable clearance
half-lives (780 to 3500 days); long glass microfibers with a high concentra-
tions of alkaline earth metals (104/E-glass) had a low half-life (55 days).
Glass and rock wools had intermediate half-lives (about 280 days).
The clearance and jn vivo solubility of glass fibers in rat lungs were
examined by Morgan et al. (1980, 1982) and Morgan and Holmes (1984a). Fibers
of different lengths, with a nominal diameter of 1.5 or 3 urn, were administered
by intratracheal instillation to 5-month-old HMT Alderly Park SPF rats (sex r.ct
specified). For the 1.5-ym-diameter samples, groups of 12 animals receiver
0.5 mg of 5-, 10-, or 30-pm-long fibers or 1 mg of 60-pm-long fibers in 0.5 ir._
saline. Additional groups of rats received 1 mg doses of 10- or 60-urr-lcnc,
3-ptr-wide fibers in 0.5 ml saline. Fibers with a 1.5-um diameter we-e
24
irradiated with Na prior to administration.
After 1 year, about 90 percent of the 5 x 1.5 urn and 80 percent of the
10-pm-long (both diameter types) fibers were cleared from the body, with s
clearance half-time of about 60 days. No significant clearance of the 30- and
60-)jm-long fibers was observed during the same period of time. All fibers
were leached significantly during the investigation. The median diameter of
the 5 x 1.5 urn fibers was reduced by about 11 percent over 18 months; for the
10 x 1.5 urn and the 30 and 60 x 1.5 urn fibers, diameters decreased by approxi-
mately 28 and 55 percent, respectively. Many of the longer fibers had
fragmented and dissolved over the course of the experiment. At 19.5 months,
only 1 percent of the recovered alveolar macrophages contained fibers. No
abnormal pathology or change in lung weight was observed. It was concludec
that fibers with a diameter equal to or less than 3 urn and a length less ths-
or equal to 10 pm are efficiently cleared from the lungs (via macrophage-
mediated processes), while long fibers (>30 pm) are not cleared to a significant
extent for at least 1 year after exposure. The rate of dissolution of glass
fibers also was dependent upon fiber length. Long fibers dissolved rapid'y &*c
nonuniformly, often resulting in fragmentation. Short fibers dissolved slo-ly
and evenly. The results suggest that glass fibers behave differently frcr
«-i3 DRA-V-D: N:~
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amphibole asbestos fibers, which essentially are insoluble JD v'tro and not
readily cleared from the lungs (see Section 7.2.7.2).
In an attempt to better characterize the health effects of glass fibers,
Bernstein et al. (1980) exposed male F344 rats to fibers of defined sizes by
intratracheal instillation. The neutron-activated fibers had a geometric mean
diameter of 1.5 pm and a length of either 5 or 60 u.m. The deposition, translc-
cation, and ultimate fate of these fibers were then determined by radioassay cf
Zn. Groups of four rats were instilled with 20 ug of 60-um fibers, 2 ug of
5-um fibers (equal number of fibers), or 20 ug of 5-um fibers (equal mass of
fibers) and sacrificed 18 to 20 weeks after administration. Additional groups
were instilled with similar doses of fibers, and four rats from each group were
sacrificed at various intervals between at 6 months and 2 years. The "lungs.
lymph nodes, and various other tissues were collected for histologic examina-
tion and autoradiography to determine the presence of fibers in these tissues.
The clearance half-times for each group (as estimated by a one-compa-t<-e-t
expc-£-.tia1 rrocel and the percent of the initial dose that remained at sa:"i-
fice) were 35 and 38.5 days, respectively, for rats receiving 20 me of e-:t-;e-
lono or short fibers and 22.5 days for rats receiving 2 mg of the short fibers
(Bernstein et al., 1980). The whole-rat clearance rates, however, were sir-ler
among the groups. Histopathologic examination showed differences in the
responses of rats exposed to the long and short fibers. The major response tc
the short fibers was the production of macrophage aggregations in the alveoli
and lymph nodes, indicating that short fibers were successfully phagocytizei ty
alveolar macrophages and were cleared to the lymph nodes. The response tc the
long fibers was notably different. No long fibers were totally phagocytizei by
macrophages, although a few were observed to be partially phagocytized.
Moreover, only a few smaller fibers (<60 urn in length) were observed in the
lymph nodes, suggesting limited breakage of long fibers. The long fibers
produced a granulomatous response with giant cells, a response characteristic
of many types of foreign bodies. In addition to the above findings, few, if
any, fibers were found by light microscopy outside the respiratory tissues.
In contrast, glass fibers were recovered from the liver and spleen'of
female F344 rats and rabbits (strain and sex not reported) 2 to 5 years e'ter
intratracheal instillation of 2 to 10 mg of the test material (Spumy et el.,
1983). Most fibers retained their original size, although it appeared that
leaching and some dissolution had occurred after fiber migration. IP raP-^ts.
-------
preferential leaching of elements was observed, but the leaching was net
homogeneous at different locations (Spumy et a!., 1983).
Wright and Kuschner (1977) examined the migration of short and long glass
fibers following intratracheal instillation Into guinea pigs. Each of 30
guinea pigs (strain, sex, age, and weight not specified) was administered 25 mg
of short glass fibers (i.e., 93 percent of the fibers were less than 10 pm
long). Thirty animals in a second group of guinea pigs each received 12 mg of
a sample in which 92 percent of the fibers were longer than 10 urn. Animals
were sacrificed 2 years after dosing. Fibrotic lesions developed at the
terminal bronchioles of animals in the second group, and long glass fibers we^e
found in the areas of fibrosis. Short fibers induced alveolar macrophage
aggregation but not fibrosis. In both the short- and long-fiber groups, hicK-
numbers of short-fiber-filled macrophages were observed in the lymph nodes, tut
fibrosis was absent. It was suggested that many of the long fibers probably
had fragmented, resulting in a short-fiber-like response. Fragmentation of
"0-5 fibers was confirmee! by electron micrographic studies of ashed lung and
lyrr;ph nodes of animals administered long fibers. The authors conclude: the*
short fibers and fragmented long fibers acted similarly in that both were
capable of migrating from the lung to the lymph nodes and that neither indeed
fibrosis.
The translocation of JK 104 glass fibers through the respiratory systerr
after injection into the pleura! cavity of rats was studied by Monchaux et el.
(19S2). Groups of 15 Sprague-Dawley SPF male rats (8 to 12 weeks old) were
injected with 20 mg of fibers suspended in 2 ml of saline. A total of 1.8 x
10 glass fibers with a mean diameter of 0.229 urn and mean length of 5.89 urr,
was administered. Two rats were killed at various intervals up to 380 days,
and the fiber content in several lymphoid and nonlymphoid organs was determined
by TEM. Ninety days after intrapleural injection, fibers were found in all
organs analyzed: mediastinal lymph nodes, lung parenchyma, spleen, liver,
kidneys, and brain. The number of all fibers/g tissue was approximately the
same in all organs (about 10 to 10 ), except in the thoracic lymph nodes where
concentrations were 10 to 100 times higher. The number and mass of JM 10-5
glass fibers recovered/g mediastinal lymph node tissue remained relatively
p
constant up to 380 days (about 5 x 10 fibers/g and 0.5 mg/g tissue, respec-
tively). Less than 1 percent of the fibers migrated from the pleura! cavity tc
the lung. In addition, the mean length of the fibers remaining ir tne lung
4-15
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parenchyma increased with time. It was suggested that the fibers leave the
pleura! cavity mostly through the stomata, reaching the lymphatics of the
parietal pleura and, by retrogression, the mediastinal lymph nodes. Alterna-
tively, the fibers may migrate across the visceral pleura by a persorption
mechanism and then be carried by the fluid flow within the lung tissue and the
pulmonary lymphatic channels. However, the route that seems to be the most
important is the blood capillaries in the'lung, since all fibers were recovered
from nonlymphoid organs 90 days after injection.
No information was found in the available literature on the translocatior.
and clearance of glass fibers following oral administration to animal species.
In humans, Cook and Olson (1979) found that amphibole mineral fibers ingested
with drinking water are eliminated in the urine. This finding strongly suggests
gastrointestinal absorption and passage of fibers through the kidney, although
the exact mechanisms and rates could not be clearly defined. In another study,
silica fibers were recovered from the lungs of 20 individuals with no history
of occupational dust exposure (Churg, 1983; Churg and Warnock, 195C1) (see
section 4.4.2 for details).
4.2.2 Mineral Wool
Factors affecting retention and clearance of mineral fibers are similar
to those discussed for fibrous glass with similar dimensions. Hammad (1954)
examined 49 male rats (age, weight, and strain not reported) that were exposed
by nose only to an aerosol of mineral wool fibers (300 fibers/cm ), 6 hours/cay
for 5 or 6 days (number of days' exposure unclear). The CML and CMD of the
fibers were 13 and 1.2 pm, respectively. The respective CML and CMD of mineral
wool fibers, recovered from lung tissue of all animals were 7.0 and 0.5 urn.
Most of the fibers recovered 5 days postexposure were between 0.5 anc
1.0 pm wide and 2 and 30 urn long. In tissue examined at 5 days, the lupg
relative percent deposition was highest for fibers with a length af 11 pm aic
diameter of 0.5 pm. Concentrations were much lower for fibers with large'
diameters or shorter lengths. Fiber clearance was dependent on length anc!
diameter. Fibers >1 pm in diameter and <5 pm in length were associated witr.
the highest retention and, at 270 days postexposure, accounted for app-cxi-
mstely 10 percent of the fibers initially retained. Retention times dec'-essec'
sequentially for the following fiber length categories: 5 to 7, 7 to 11. 21 to
30, 15 to 21, 11 to 15, and greater than 30 pm. Fibers with c'iar.ete-s "ess
July 1S££ 4-15 DRtFT--C: N-"~ C-": C- CI'E
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than 0.5 urn were cleared first, followed by fibers with diameters of 0.5 to
0.7, 0.7 to 1.0, and 1.0 to 1.3 ptn. Thus, fiber retention appeared to increase
as fiber diameter increased. Only 6 percent of the mineral wool fibers tr-.et
had been in the lungs at 5 days postdosing remained in that tissue at 270 days
after exposure. An overall clearance half-life (for fibers of all sizes) C*
175 days was reported. The authors suggested that fiber clearance results frorr.
two mechanisms: normal biological clearance and elimination by dissolution anc
subsequent breakage.
4.2.2.1 Rock Wool. The retention of rock wool in F344 rats (number, sex,
age, and weight not reported) exposed to a dust cloud of 10 mg rock wool
fibers/ml, 7 hours/day, 5 days/week for 1 year was determined by Johnson-et a1.
(19S4). Each microgram of dust contained approximately 9.2 x 10 fibrous a-;
54.3 x 10 nonfibrous respirable particles. Nearly 30 percent of the resrira:"£
fibers were between 10 and 20 yro long and had a diameter greater than 1 urr;
about 70 percent were narrower, 52 percent were shorter, and 17 percent were
longer. At the end of the 1-year exposure period, animals were either kil'e:
or placed in a nondusty environment for various time intervals. At 6 and
13 months after inhalation, lungs contained about 5 x 10 fibers/mg tissue.
Retention was closely related to fiber diameter: nearly all (93 percent) cf
the recovered rock wool fibers were less than 0.9 urn wide, whereas distribution
of fibers by length was comparable to that of the inhaled glass. Rock wool
fibers were seen throughout the parenchyma of the left lung, in the airspace of
alveolar lining cells, and in the interstitium. Although some free fibers were
recovered, the majority of fibers were found in alveolar and interstitial
macrophages. A 6-ray microanalysis showed no apparent change in the elemental
composition of rock wool fibers through 13 months after termination of expo-
sures.
Le Bouffant et al. (1984, 1987) examined the clearance rate of rock woo"
fibers in groups of 24 male and 24 female Wistar rats exposed to fibers cf
respirable mass concentrations (5 mg/m ) and size (<10 \tm long). After 12 and
20 months of exposure, most of the inhaled rock wool fibers were found in the
lungs and lymph nodes. After 24 months, relatively high fiber concentrations
were also reported for the trachea, possibly reflecting increased bronchial
clearance. The authors reported that clearance of rock wool fibers was fairly
rapid and noted that 76 percent of the fibers were removed from the lungs
within 7 months a*ter exposure was terminated. Nearly all the fibers t-et
pe-sistei were less than 5 urr. long; the shortest fibers were DC-serve: ir- *"£
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lymph nodes. Fibers that were retained had lost some opacity and appeared
eroded. In addition, many of the fragmented and partially dissolved fibers had
a reduced sodium, calcium, and magnesium content.
Morgan and Holmes (1984b) studied the solubility of sized rock wool fibers
in the lungs of rats and the formation of pseudoasbestos bodies in the lungs of
Syrian Golden hamsters following intratracheal instillation (see also Section
7.2.7). The rock wool used had a CML (± GSD) of about 27 ± 2.2 urn and a CMD of
about 1.1 ± 2.2 urn. The amounts of rock wool administered to rats and hamsters
were 0.5 and 0.4 mg, respectively. The rats were of the HKT strain, Alderly
Park, SPF derived, and the hamsters were of the outbred DB and DSNO strain.
Rats were killed at various intervals up to 18 months after dosing, and the
CKDs of rock wool fibers recovered from the lung were determined by a TEK a-ic a
light microscope. Although no significant change was observed in the OKI of
fibers during the 18-month period, the fibers were apparently becoming thinner
at tneir ends than in the middle, indicating slow dissolution of the fibers.
Nc effects on the body weight and relative lung weights of the rats were nciec
during the observation period, and no histopathologic changes were observe: in
stained sections of the lungs of rats killed 18 months after instillatior.
However, only a small fraction of the dose was accounted for by long fibers
with diameters less than 0.5 urn, which are believed to be the most likely tc
elicit a pathologic response. In hamsters, the first signs of formation of
pseudoasbestos bodies in the lungs were detected after about 2 months. 0"".y
fibers with less than 2-um diameters were coated, although the coating was
often discontinuous on the longer fibers, suggesting that formation of pseudc-
asbestos bodies does not present the ultimate dissolution of rock wool fibers
(Morgan and Holmes, 1984a). The longer a fiber, the greater the probability
that body formation will occur with time (Morgan, 1980; Morgan and Holmes,
1984a) (see also section 7.2.1).
4.2.3 Ceramic Fibers
There is limited information on the pulmonary deposition, translocstio-.
and clearance of ceramic fibers. Results of the few available studies indicate
that pulmonary retention and clearance of ceramic fibers is similar tc U.cse
observed for glass and mineral wool fibers. However, slight differences we-e
noted in the distribution of fibers deposited within the various p-'rc-c-.,
lobes. In addition, the clearance half-life values for ceraT.ic fiDe-s »e-e
loncer then for other fibers.
-------
Nineteen male rats (weight, age, and strain not specified) were exposed
by nose only to a dust cloud, which contained an average of 709 ceramic
fibers/ml, 6 hours/day for 5 days (Rowhani and Hammad, 1984). The CMD and CK.
of the airborne fibers were 0.53 and 3.7 pm, respectively. The animals were
sacrificed 5 days after final exposure to allow for clearance of about 95 per-
cent of the fibers deposited in ciliated airways. (During the same time
period, pulmonary clearance is less than 5 percent.) Lungs were removed, and
lobes were separated, weighed, and digested. Fibers deposited in the lungs
had a CML of approximately 2.0 ym and a CMD of 0.35 urn; size distribution o*
ceramic fibers was similar for all lobes. The lobar fiber burden was weight-
dependent, with the combined left lung lobes and the right diaphragmatic lobe
carrying the greatest relative percent of the total lung fiber content (apprc^--
mately 32 to 45 and 22 to 29 percent, respectively). The left lobes anc tr,e
right apical lobe appeared to concentrate more of the longer, wider fibers tna~.
did the other lobes. However, these differences were not statistically signif-
icant (p >0.05).
In a study conducted by Hammad (1984), a group of 49 male rats (strain,
age, and weight not reported) were exposed by nose only to ceramic fiber dust
clouds (with an average concentration of 300 fibers/ml) for 5 consecutive
days. The mean diameter and length of the airborne fibers were 0.7 and 9.C pr,
respectively. Animals were killed in groups of seven at 5, 30, 90, 180, and
270 days after the last day of exposure. Ceramic fibers were cleared slowly
from the lungs, with a clearance half-life of 196 days. Fibers with a diameter
between 0.5 and 0.7 urn and a length of <5 urn were retained the longest. At
270 days postexposure, approximately 25 percent of the inhaled ceramic fibers
were still present in the lungs.
The results of the Hammad (1984) study suggest that pulmonary clearance
of ceramic fibers is dependent on fiber length. Ceramic fibers of all diameters
were cleared at similar rates, but the clearance rate increased as fiber length
increased to approximately 11 to 15 pm. Short fibers (i.e., those less then
5 urn in length) showed the highest retention in the rat lung for all time
periods.
Similar results were reported by Davis et al. (1984). Very few lone
ceramic fibers were retained by lung tissue 2 years after Wistar rats (nj-^er.
sex, and age not reported) had inhaled 8.4 mg fibers/ir. , 7 hours/day.
5 days/week for 224 days, despite a high concentration of alurinur silicate.
-------
Pigott et al. (1981) and Pigott and Ishmael (1981) also investigated the
migration of ceramic fibers following inhalation or intraperitoneal injecticr,.
In the study conducted by Pigott et al. (1981), groups of 40 adult Aider!ey
Park, Wistar-derived rats (20/sex) inhaled ceramic fiber dust clouds for a
minimum of 6 hours/day, 5 days/week, for 86 weeks. The exact fiber concentra-
tion of the dust clouds was not noted, but an estimated average exposure of
2.18 mg/m and a total cumulative exposure of approximately 7000 mg/m were
reported. Two animals of each sex were killed at weeks 14 and 27, one of eac*--
sex was killed at week 53, and the remaining rats were allowed to survive u-t: >
"natural" death occurred or until 85 percent mortality was reached within a
group. Fragmented fibers were found in the lungs of most rats, and the majesty
of the ceramic fibers recovered from rat lung tissue were relatively s~crt
compared to those inhaled. No other details on the size of retained fibers
were given. At all times after inhalation, fibers were detected in alveolar
macrophages and in the mediastinal lymph nodes. The authors suggested that the
fibers may have been transported via macrophages. The second study (Picctt en:
Ishmael, 1951) showed that at 3, 6, and 12 months after groups of 12 male end
12 female Wistar rats (140 to 160 g) were given an intraperitoneal iniecfic- c*
20 mg (0.2 ml of a 10 percent suspension) of ceramic fibers, fibers co^lc be
recovered in the sternal and mesenteric lymph nodes as well as in the peritoneal
cavity. The data indicate that ceramic fibers can migrate from the peritoneum
to the lymph nodes.
4.3 SYNTHETIC FIBERS
4.3.1 Aramid Fibers
Information on the pulmonary deposition and clearance of aramid fibers is
very limited. In one study, rats (strain, number, sex, age, and weight not
given) were given a single intratracheal instillation of 25 mg Kevlar (aramid)
polymer dust in physiologic saline (Reinhardt, 1980). Animals were sacrificed
at 2, 7, and 49 days and 3, 6, 12, and 21 months after treatment. Particles
were detected in lung tissue at all sacrifice times. Large fibers (diameter
100 to 150 um) concentrated primarily in the terminal bronchioles, and small
particles (diameter 5 um) were recovered in alveolar ducts.
In another study, fiber deposition and macrophage response were cose-
related following inhalation by groups of five male Spragje-Dawle\ rats e>.;cse:
tc 0.1, 0.5, 3.0, or 16 me ultrafine Kevlar'1" fiDers/ir.l, 6 news'ca..
-------
of 10 days (Lee et al., 1983). Approximately 85, 87, 24, and 45 percent of
these fibers, respectively had an aerodynamic diameter <5 pm. In animals
inhaling 3.0 or 18 mg/mL, fiber-containing macrophages accumulated in the
respiratory bronchioles and alveolar region immediately after exposure anc
were still present at 2 weeks postinhalation. Fibers appeared to be fragmer.te:
and markedly shorter within 3 months' time. Some dust cells containing short
fibers (i.e., less than 2 \im long) had migrated to the peribronchial lymphoid
tissue or tracheobronchial lymph nodes by 6 months after exposure. The results
suggest that following phagocytosis, short aramid fibers are transported to the
lymph system. In addition, long Kevlar fibers appear to be easily and rea:v>y
dissolved in the lung, a process which may facilitate their clearance from tne
body.
4.3.2 Carbon Fibers
Phagocytosis occurs within hours after inhalation of carbon fibers ar.d
continues for 2 or more years. The nonfibrous dust is primarily cellule" •>-•
rr.a:rcpr,ages, and the number of particles in each macrophage increases wif;
time after exposure. Human subjects exposed to carbon fibers by inhalatic*
for about 3 minutes retained approximately half of the inhaled carbon dust.
Holt and Home (1978) and Holt (1982) examined the phagocytosis of carbon
fibers by macrophages at various periods following inhalation exposure. Groups
of guinea pigs (strain, sex, weight, and age not specified) were exposed to an
aerosol dust cloud containing 370 carbon fibers/mL, 2.9 black fibers/ml, and
1.6 transparent fibers/ml. The transparent fibers were believed to be glass
fibers. Carbon fibers had diameters ranging from submicron to several microns,
black fibers were approximately 1.0 to 2.5 pm wide and no longer than 15 pm,
and transparent fibers typically had a diameter of 1.5 pm and lengths up to
30 urn. The dust also contained fibers that were above respirable range (i.e.,
10 urn wide and greater than 100 urn long). Twelve guinea pigs inhaled the dust
for a total of 100 to 104 hours and were then sacrificed between 6 and 144 days
postexposure. Three more animals, exposed for 7, 23, or 62 hours, were killed
at 1, 2, and 12 days after inhalation, respectively.
Tissue sections from the guinea pig killed 1 day after a 7-hour expos-re
to the fiber aerosol contained dust-filled macrophages, suggesting that phago-
cytosis had occurred within hours after inhalation (Holt and Home, 1S7£). The
highest concentration of dust-containing cells generally was foun: ir. tissues
-------
obtained later in the study, with cell numbers peaking IDS and 144 days post-
inhalation. Phagocytosis therefore appeared to continue for several months
following exposure. In a similar study (Holt, 1982), the presence of fiber-
containing macrophages at 2 years after inhalation indicated that engulfme-t of
carbon dust particles may proceed for an extensive period of time. Nonfibrous
dust was primarily intracellular in macrophages; these cells were frequently
found attached to the alveolar wall or embedded in tissue (Holt and Home,
1978). All fibrous particles longer than about 5 or 6 urn were extracellular,
even at 140 days postinhalation. Lung tissue from all animals contained an
2
average of two to four short (4 to 10 urn) carbon fibers/cm section; long
fibers (those greater than 10 urn) were recovered only in four guinea pigs
exposed tc the dust cloud for 104 hours. However, the authors reported that
through tissue processing, extracellular particles were washed out of lur.c
sections of animals killed shortly after exposure. Thus, the degree of phag:-
cytosis, retention, and number of carbon fibers could not be accurately
estirsted.
No unccated transparent fibers were found in any of the guinea pig lun;s.
although one or two of these presumed glass fibers -were covered with a thick •
ferruginous coating (Hclt and Horn*, 1978). Carbon fibers did not appear
coated. In lung tissue sections obtained toward the end of the study, a slight
thickening of the interalveolar tissue was observed. However, at 27 weeks
postexposure, sections showed no abnormal reticulin or collagen, and there
appeared to be no fibrcsis.
In a followup study (Holt, 1982), 27 guinea pigs (age, sex, weight, and
strain not reported) were exposed to 370 carbon fibers/mL for 100 hours and
were sacrificed at various times between 1 and 270 days after termination of
exposure. Minor contaminants, comprising a total of 1.2 percent of cell
fibers, included black, and transparent fibers. Two guinea pigs inhaled the
carbon fibers for 7 and 12 hours, respectively, and were killed on the follow-
ing day. Three additional animals, exposed for 10 hours each, were killed
after 420, 440, and 470 days. Lungs were sectioned and stained, and macrophages
containing fibers and/or dust were counted. Very few extracellular fibers were
seen, and the macrophages that were recovered 1 day after inhalation contained
only a few dust particles. The number of particles in each macrophage increased
with time; after 1 year, macrophages containing high concentrations of canton
dust were common, even in animals exposed to the fiber aerosol cloud fc- cr-_.
J_V 195£ 4-22 DRA"7--DD N"" CJI": C?. CI'E
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2
10 hours. There were about 20 dust-filled macrophages/mm lung tissue at
440 days postinhalation; that number doubled and then dropped to less than
20/mm within an additional 120 days. Engulfment of erythrocytes was else
evident throughout the study. Dust-laden cells accumulated near bronchi and
blood vessels, and some cells that penetrated the bronchiolar walls were founc
in the sputum. Inhaled submicron-sized carbon dust also reached the alveoli.
No pathology or fibrosis attributable to carbon dust or fibers was observed at
any time.
The tracheobronchial clearance of carbon dust particles in eight hurr.a-'
subjects was investigated by Camner et al. (1973). The subjects inhaled a
test aerosol of 6-um Teflon particles (density 2 mg/mL, aerodynamic diameter
approximately 8 to 9 urn) tagged with technetium Tc 99m, and then a carbo-
dust aerosol (concentration 50 mg/mL; mass median diameter 11 urn). Sutje:ts
"inhaled each of the test materials for approximately 3 minutes; one g-oup cf
four inhaled the carbon dust immediately after inhalation of the test aeroscl,
and a second group waited 1 hour before inhaling the carbon fibers. Recic-
ac*.••vity was monitored for 2 hours after exposure to Teflon. Two cf the
individuals smoked 10 to 15 cigarettes/day; the others were nonsmokers. Slight
irritation in the airways was noted following exposure to carbon fibers cr,\v.
Subjects retained an average of 67.2 percent of the inhaled Teflon pa-tides
and an average of 52.0 percent of the inhaled carbon dust (p <0.05). The
authors concluded that since inhalation of carbon dust followed that of Teflon,
the faster clearance rate for carbon indicates a faster mucociliary transport.
4.3.3 Pol^olefin Fibers
There was no information in the available literature on the pharme:o-
kinetics and/or translocation of polyolefin fibers.
4.4 MINERALS
4.4.1 Erionite
Very little information is available on the deposition and clearance cf
erionite fibers, although data from several epidemiological studies indicate
that erionite penetrated the pleura! and parenchyma! tissues in TU-K-IST.
villagers exposed to low levels (Ban's et al., 1976; Sebastien et al., 15:1;
Rohl et al., 1982. Fibers recovered from the lungs of these indix:S duals *e-e
4-23
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uncoated and had a mean diameter of 0.3 pm and a maximum length of 9 pm.
Sebastien et al. (1981) also detected in these individuals some ferruginous
bodies that contained erionite fibers (zeolite bodies). In a study conducted
by Moatamed et al. (1981), erionite fibers were distributed throughout rat
lungs following intratracheal instillation. Macrophages, giant cell-granulo-
matous reactions, and ferruginous bodies were present within 1 week after
instillation. No other information on the pharmacokinetics or biodispositicn
of erionite fibers was found.
4.4.2 Attapulgite
Little information is available on the deposition, translocation, anc
clearance cf attapulgite. Churg (1983) determined the total nonasbestes
mineral content in the lungs of 20 subjects who had no history of occupational
dust exposure. All subjects (11 men and 9 women) were selected from a general
autopsy service. All were aged 40 years or older at the time of death. The
average number of nonasbestos fibers was 106 x 10 ± 87 x 10 fibers/g wet IL~C.
with nc significant differences noted between men (96 x 10 fibers/g) and wore-:
(115 x 10 fibers/g). Similarly, no significant differences were noted between
the 15 smokers (S3 x 10 fibers/g) and 5 nonsmokers (140 x 10' fibers/g). A
total of 13 different mineral groups other than asbestos were identified, of
which apatite, gypsum, talc, silica, and attapulgite accounted for more than
half the fibers (Table 4-1). Silica was found in the lungs of all 20 subjects
and talc in IS of 20. About 86 percent of all fibers were shorter than 5 prr,
and most had aspect ratios less than 15. In addition, the mean number cf
nonasbestos fibers was similar to the number of asbestos fibers (1C2 x 10 /g
wet lung) found in these subjects, with chrysotile accounting for more than
80 percent of the asbestos fibers (Churg, 1983; Churg and Warnock, 1980).
The results of two case studies suggest that inhaled attapulgite fibers
can penetrate into the alveolar spaces and that ingested attapulgite is trans-
ported to the kidney and eliminated in the urine. In the first case, a 41-year-
old miner with lung fibrosis had been exposed to attapulgite dusts for 3 years.
Approximately 42,000 fibers/ml were found in lung washing fluid recovered by.
bronchoalveolar lavage (Bignon et al., 1980). The average attapulgite fine*-
was 1.5 pm long and 0.11 urn wide. An average of 300,OOC fibers/ml were
recovered from the urine of a 60-year-old woman who had been treated creTU for
6 months with a drug containing attapulgite (Eignon et al., 19EI). Nc ctne-
details were given.
-------
TABLE 4-1. THE NUMBER AND SIZE OF NONASBESTOS FIBERS
IN THE LUNGS OF 20 SUBJECTS
Mineral
Apatite
Talc
Attapulgite
Gypsum
Silica
Ctherb
Not identified
Total fibers8
(x 10s)
19.0 t 47
17.0 1 25
8.4 ± 13
7.0. t 23
6.0 1 6.4
18.4
31.0 1 58
Percent
of total
18.0
16.0
7.9
6.6
5.7
17.0
29.0
Length,
1-4.9
89.0
71.0
100.0
54.0
78.0
88.6
87.0
um, expressed
5-9.9
4.9
23.0
0
33.0
14.0
10.1
7.1
as %
>10
6.1
6.0
0
13.0
e. o
1.3
5.9
Mean value ± standard deviation.
Includes rutile, kaolinite, mullite, illite, pyroxene, pyrophyllite,
feldspar, vermiculite.
Source: Churg (1953).
Preliminary results on the absorption of attapulgite from the gastroin-
testinal tract of rats (sex and strain not specified) were reported by Masse
et al. (1980). Absorption was determined by collecting the lymph fluid at
various times after oral administration of 10 or 100 mg attapulgite to croups
of 20 rats and counting the fibers by TEM. No fibers were found at the low
dose. Systemic absorption of attapulgite (100 mg) was much less than that cf
asbestos. No other data on the pharmacokinetics of attapulgite were availstle.
4.4.3 Talc
The pulmonary deposition of talc following repeated exposure is dose-
dependent. Following single inhalation exposures, -pulmonary clearance is
slow with a biological half-life of 7 to 10 days. Talc is cleared by mucoci1,-
iary action from the lungs and eliminated in the feces via the gastrointestinal
tract.
The pulmonary deposition, translocation, and clearance of inhaled tele in
Syrian Golden hamsters were studied by Wehner et al. (1977b). A group of L-.
10-week-old female hamsters were exposed by nose only to nejtrcr.-acf'vstec
-------
talc aerosols for 2 hours. The mean aerosol concentrations during the t*c
sampling periods (from 15 to 30 and 60 to 90 minutes during the 2-hpur exposure
period) were 40 and 75 pg/L. After exposure, the urine and feces were
collected. Groups of four animals were killed at various times, and the lungs,
liver, kidneys, ovaries, and skinned carcass were collected and radioassayed by
6-ray spectrometry. The counts were compared with those obtained from nine
unexposed control hamsters. Considerable variations in pulmonary deposition
among animals killed at the same period were attributable to variations in
aerosol concentration at the different tier levels for animal exposure and to
differences in individual breathing patterns. It was estimated that animals
placed on tier levels 2 to 4 of the exposure chamber inhaled an average of
360 pg talc, whereas those on tier 1 inhaled an average of 570 pg. Nonethe-
less, the data indicated high pulmonary talc levels during the first 4 d=.. s
after exposure, with mean total measurements (± SD) of 33.1 ± 31 pg and 21. C :
15.3 pg at 15 minutes and 4 days after exposure, respectively. Thereafte-.
t=": cc-'tent in the lungs dropped gradually with mean values (3.7 ± l.£ pc)
beinc similar to those found in controls (2.3 i 0.4 pg) after 4 mcr.ths. T^e
biologies1 half-life of the talc deposited in the lung was reported tc be 7 to
10 days, and pulmonary clearance was complete within approximately 4 mr^t-.s
after exposure.
No significant difference was observed among mean radioactivity levels
found in the liver, kidneys, and ovaries of exposed and control animals.
Radioactive residues in carcasses were highest 4 hours after exposure
(455 ± 338 ug) and decreased gradually to control levels (about 3.5 pg) by day
8. This was attributed to talc deposited on or about the nose and nares d'j-inc
exposure as well as to talc passing through the gastrointestinal tract after
mucociliary clearance. Fecal samples contained relatively high quantities of
talc. The mean talc equivalent 21 hours after exposure was 106 ± 53 pg; by day
4, this value had increased by 3.5-fold (350 ± 292 pg). The presence of talc
in the feces was attributed to mucociliary clearance from the lungs probably
together with a fraction from licking the nose, lips, etc. Low levels of
radioactivity found in the urine were attributed to leached Cc being absorbed
in the gastrointestinal tract.
Hanson et al. (1985) developed a method to determine the lung burden of
talc in rats and mice after repeated inhalation exposure to te'c eerescls.
This method was based on the analysis of acid-insoluble Kg cc-te-.t ip *h£
lungs by flame adsorption spectrometry. Me was selectee be:e_se 'it e::c--ts
-------
for 19.2 percent of the composition of talc, and most of the endogenous Mg
present in the lung can be removed by dilute acids. Whole-body exposures of
male and female F344 rats and BBCSF^ mice were performed 6 hours/day, 5 days a
week for a total of 20 exposures. The mean lung burdens in rats were 77, 1£7,
and 806 pg talc/g lung tissue at exposure levels of 2.3, 4.3, and 17 mg talc/rr ,
respectively. In mice, mean lung burdens were 114, 325, and 1150 ug talc/g
lung tissue at exposure levels of 2.2, 6.3, and 20.6 mg talc/m , respectively.
The higher contents of talc in mouse lungs as compared to rats were related to
a difference in initial deposition.
In two studies with humans (Churg, 1983; Churg and Warnock, 1980), tei:
comprised approximately 16.0 percent of the nonasbestos fibers recovered frcr
the lungs of 20 individuals with no history of occupational dust exposure (see
section 4.4.2 for more details).
Several studies have been conducted to determine the metabolism of te^c
powder following oral administration. Little, if any, is absorbed from the
gastrointestinal tract following oral intubation of rats, guinea pigs, mice.
enfi hemjte^s; most of the material is eliminated in the feces within 1 or
2 days after dosing.
Studies on the absorption and disposition of H-labeled talc folio*: re
single and repeated oral administration to rats, mice, and guinea pigs were
conducted by Phillips et al. (1978). [3H]Talc (specific activity 100 pCi/g)
was administered by oral intubation as a suspension in aqueous glycerol jelly
solution (10 mg/mL, 1 uCi/mL). Groups of three male Wistar rats and three
female Duncan Hartley guinea pigs were administered a single oral dose of
[ H]talc at levels of 50 and 25 mg/kg, respectively. Urine and feces were
collected at 24-hour intervals for 4 days and on day 10. The animals were
then killed, and liver, kidney, and gastrointestinal tract tissues were removed
for radioassay. A similar experiment was conducted with three male Wistar rets
given daily oral doses of 50 mg [ H]ta1cAg for 6 days; these animals also were
killed 10 days after the last dose. Approximately 95.8 and 94.4 percent of the
administered radioactivity was excreted in the feces of single-dose rats and
guinea pigs, respectively, within 96 hours after compound ingestion; less than
2 percent was found in the urine, and only 0.2 percent was found in the gastro-
intestinal tract. The presence of radiolabeled material in the urine was
attributed to labile H associated with tritium-labeled talc and to contar.-:na-
tion of the urine. No radioactivity was found in the liver or kidneys e*te'
4-27
-------
10 days. Similarly, no radioactivity was eliminated in the feces by day 10. No
H was found in the livers of rats given six daily doses of [ H]talc, although
less than 0.02 percent of the total dose was detected in the kidneys.
Phillips et al. (1978) also administered a single oral dose (40 mg/kc) of
radiolabeled talc to four female LACA mice; two animals were killed at 6 hours
and two at 24 hours postdosing. At both sacrifice times, all of the radioacti-
vity was recovered in the gastrointestinal tract and feces, and none was
detected in the carcass.
Similar results were reported on the absorption of talc by female Syria-
Golden hamsters (Wehner et. al., 1977a). The talc used was a neutron-activate:.
commercially available baby powder. The talc was suspended in physiologic
.saline, and 1-mL aliquots of the suspension were administered by gastric
intubation to six 10-week-old hamsters. An additional group of four hairs ters
received an identical suspension of nonirradiated talc to determine if the
ta"lc had a cathartic effect. The urine and feces were collected for 24 hou^s.
The hamsters were then killed, and the skinned carcass, gastrointestinal tract.
lungs, liver, and kidneys were collected and radioassayed for Co and '"r- "•••
- W k.
6-ray spectrometry. About 74.5 percent of the talc was -found in the feces,
23.5 percent in the gut, and 1.9 percent in the carcass. No radioactivity was
found in the lungs. Detectable amounts were found in the liver and kidneys,
but these were not statistically different from control values. Approximately
0.07 percent of the total talc was found in the urine, but that was attributed
to leaching of Co from talc.
Wehner and Weller (1986) examined in monkeys the migration of talc frorr,
the vagina. Six female exbreeder cynomolgus monkeys each received 30 intra-
vaginal talc applications, consisting of 125 mg neutron-activated powder per
application, over a 45-day period. Doses were equivalent to 29 to 52 rr.g
talc/kg/day, depending on weight. Six untreated females served as controls.
Animals were between 4 and 12 years old and weighed between 2.4 to 4.35 kg.
The radioisotopes Sc, Co, Fe, and Cr were used as tracers for the
administered talc. Two days after the final application, abdominal lavaoe
fluid, ovaries, oviducts, uterus, and vagina with cervix were collected for
y-ray analysis. Only the vagina with cervix samples from dosed animals
contained talc tracers. The authors concluded that despite repeated applica-
tions to the fornix of cynomolgus monkeys, no measurable quantities (i.e.,
greater than 0.5 ug) of talc translocated to the uterus or beycic1.
-------
In contrast, Henderson .et al. (1986) reported that talc particles intro-
duced into the uterus and vagina of the rat migrated to the ovaries. Eight
female exbreeder (7.5 months old) Sprague-Dawley rats each received an intra-
vaginal dose of 250 uL of a talc-saline suspension (100 mg talc/ml). Four cf
the rats received additional uterine instillations on days 6 and 15, and twc of
these rats were treated again on days 22 and 30. Ovaries were removed from all
animals at the time of sacrifice (days 50, 20, and 49, respectively). In a
separate experiment, six Sprague-Dawley exbreeders were given 250 uL of the
same talc suspension, and an additional six rats received the.saline vehicle
only. Two animals from each of these groups were sacrificed at 24, 49, and
96 hours after treatment; ovaries of were removed as before. Talc particles
were recovered from the ovaries of all animals given intrauterine doses cf t~e
test material and frorr; the two rats that were killed 96 hours after intre.a;m'-
nal instillation. No talc was found in the ovaries of the other treate: or
nontreated animals.
<.%.£ Venr.iculite
There was no available information on the metabolism of vermiculite
following oral administration or inhalation exposure. However, vermiculite is
not expected to be absorbed frorr; the gastrointestinal tract to any appreciable
extent.
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4-23 DP.APT—:: N" C>": ;: ::"E
-------
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-------
5. ACUTE, SUBCHRONIC, AND CHRONIC TOXICITY IN ANIMALS
In this chapter, the available short- and long-term animal toxicity data
on manmade mineral fibers, synthetic fibers, and minerals are presented, a—
the noncarcinogem'c and systemic endpoints of toxicity are discussed. The
noncarcinogenic effects detailed in this chapter are then summarized anc
quantified in Chapter 9.
5.1 ACUTE TOXICITY
Limited information was available on the acute toxicity of MMi-'r, synthetic
fioers, and minerals.
5.1.1 Kanmade Mineral Fibers
5.1.1.1 Fibrous Glass. The ocular, dermal, and pulmonary effects of glass
fibers have been studied in rabbits, guinea pigs, hamsters, and rats. Gross
et al. (1960) reported observing no ocular irritation in rabbits after exposure
tc finely milled glass flakes. The flakes, which consisted of some particles
measuring 400 urn in diameter (the majority being <50 gin), were "thoroughly
dusted" on the eyes of six albino rabbits. The lids were then either held shut
or open for 1 minute. No effect was noted on either the corneas or the con-
junctivae.
The results of a study cited by NIOSH (1977) Indicate that fibrous glass
causes dermal irritation in rabbits and guinea pigs. Two types of unspecified
fibrous glass, two types of unspecified competing material, and two cotton
controls were rubbed on the skin of 16 rabbits (strain and sex not specified)
for 2 minutes each, 5 days/week for 1 month. The treated areas consisted of
six depilated patches 4.5 cm in diameter. Twenty-six guinea pigs were rubcei
at eight similar sites with two fibrous glass textile materials. The skin cf
the rabbits exhibited a faint redness, scaling, and superficial yello* crusting
as a result of the mechanical rubbing of the fibers on the skin. In c^nes
-------
pigs, the dermal reaction was similar reacted similarly, but with more intense
erythema and crusting. In another study, blood histamine levels in guinea pigs
increased when the skin was rubbed with fibrous glass (N10SH, 1977).
The inhalation of fiberglass (diameter 1.2 urn, length <3 urn) was show:; to
result in a mild inflammatory reaction in male Sprague-Dawley rats, Syrian
hamsters, and albino guinea pigs after 20 days of exposure (Lee et a!., 197S,
1981). This reaction was characterized by "foamy" dust-laden macrophage and
neutrophil aggregation in the bronchiolar and alveolar regions of the lungs.
Also noted in the affected areas were proliferation of cuboidal granular
pneumocytes and the thickening of alveolar walls. Exposure was for 6 hours/o=.v.
5 days/week, at a concentration of 420 mg/m (see section 5.2.1.1.2).
No pulmonary response other.than minimal foreign body reaction was nctec
a'ter intratracheal administration of glass fibers (Gross et el., IScLj.
Twenty-five mg of fine (1.1 urn diameter) or coarse (<50 urn diameter) glass
fibers were suspended in corn oil and administered to groups of 15 rats (strg-'n
and sex not specified). Control animals received either kaolin, quartz c'jst,
or corn oil alone. There was no evidence of gross changes in the animals
injected intratracheally with the coarse glass dust. These particles appea-ecf
to behave like inert foreign material and were associated with minimal foreign
body reaction without significant collagen formation. Similarly, no gross
changes were seen in the animals that received the fine dust.
5.1.1.2 Mineral WooJ. No information on the acute toxicity of mineral wool
was found in the available literature.
5.1.1.3 Ceramic fibers. No information on the acute toxicity of ceramic
fibers was found in the available literature.
5.1.2 Synthetic Fibers
5.1.2.1 Aramid Fibers. The inhalation of aramid fibers has been shown to
result in a mild to moderate foreign body reaction in the lungs of rats after
short-term inhalation exposure. In a group of studies reported by Lee et a'.
(1983), groups of 20 or 25 male Cr1:CD rats were exposed via inhalation to
ultrafine KevlarS fibers at concentrations of 0.1, 0.5, 3.0, or 18 mg./V.
Control animals were exposed to air. Exposures were conducted for 6 hours/cay.
5 days/week for 2 weeks. Mass and fiber concentrations are presented ir,
Table 5-1. Groups of five rats exposed to 0.1, 0.5, or 3.0 mg'm were k-'He:
after 2-week exposures, and the remaining animals were observed for recede-}
periods cf 2 weeks, or 3 or 6 months postexposure. Groups of five rets e^se:
.JL-IV 1S£= 5-2 DRA'T — DD NC~
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TABLE 5-1. MASS AND CONCENTRATIONS OF KEVLAR^ FIBERS USED IN
AN INHALATION STUDY IN MALE RATS
Mean cone.
(mg/m3 ± SD)
0.10 4 0.06
0.52 i 0.14
3.00 ± 0.4
18.20 1 2.8K
17.60 ± 4.4b
Fiber count
(fibers/cm)
1.3
26
280
..a-
...a
% Respirable mass
(diameter <5 ur:,)
65
87
94 .
49
13
Not determined.
Commercial Kevlar fibers.
Source: Lee et al. (1983).
to IS mg/m were killed after 4 days or 2 weeks of exposure, and the
animals in the group were observed for recovery periods of 1, 3, or 6 montr;
postexposure. A separate group of rats was similarly exposed to 1£ mg'r.
co!T;merciaT Kevlar" fibers (2.5 mg/m of respirable fibers), and five rats we-e
killed after the 2-week exposure. The remaining rats were subsequently kr-lei
after 3 or 6 months. All rats were examined grossly; and individual luncs were
examined histologically.
No clinical signs of toxicity or changes in body weight were noted at any
exposure level during the study. Few effects were noted in the lungs after
exposure to 0.1 or 0.5 mg/m for 2 weeks. The architecture of the lungs
appeared normal after 2 weeks; however, sparse accumulation of "dust cells,"
described as alveolar macrophages containing phagocytized Kevlar fibers, was
observed. The amount of dust-laden macrophage aggregation appeared to be dose
related, but most of the dust cells disappeared by 3 months postexposure.
Pulmonary effects and dust cell accumulation were similar in rats expcsec
to 3.0 mg/m ultrafi'ne Kevlar or 18 mg/m commercial Kevlar fibers, probsrly
owing to comparable levels of resplrable fibers. Accumulation of dust-lacer.
macrophages occurred mainly at alveolar duct bifurcations and resulted in
enlargement of the ridges, proliferation of fibroblasts, and inflammatory cell
infiltration after a 2-week exposure. Some thickening of alveolar ducts, d--e
to proliferation of dust-laden foreign body giant cells and chronic inflammatory
cells, was also observed. Three months after exposure, the aggregation of
dust-laden macrophages in alveolar ducts was increased. At this point, the
dust-laden mscrophages appeared to be filled with shortened c- C!-s-.w-1a' f^te-s.
July !=££
5-3
DRA-T--DO fCT
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Increased cellularity of granulomatous lesions was also evident. Six me-ins
after exposure, slight proliferation of dust-laden macrophages and fibroblasts
was noted in alveolar ducts but there was no deposition of collagen fiber.
Pulmonary effects in rats exposed to IB mg/rn ultrafine Kevlar" fibrils
for 2 weeks were most severe. Accumulation of dust-laden macrophages in
terminal bronchioles and alveolar ducts of adjacent alveoli was observed.
Accumulation was particularly prominent in alveolar duct bifurcations, result-
ing in partial blockage of the alveolar ducts. Fibrotic thickening of alveolar
ducts and proliferation of chronic inflammatory cells were evident. The
dust-laden macrophages appeared to be incorporated into fibroblast cells.
The thickening of alveolar ducts decreased progressively 1 to 3 months'afie'
exposure. However, dense reticulin fiber networks remained, and slight collage".
fiber deposition was noted in the alveolar duct region. Dense accumulator- cf
dust-laden macrophages was still evident at alveolar duct bifurcations, and e
few adjacent alveoli were completely blocked. As noted in other exposure
groups, the Kevlar6 fibers found in dust cells appeared to be fragmented a-:
shortened. Lung architecture appeared almost normal at 6 months postexpcsu^e.
although fibrosis was still apparent in alveolar duct regions. Some dust-lade-.
macrcphages had migrated to adjacent lymphoid tissue, but no inflammetcry-
reaction was observed.
Henderson et al. (1987) found that aramid (Kevlar") is biocompatible witn
skeletal muscle tissue following implantation in female New Zealand White
rabbits. Cylindrical pieces of embedded (methylmethacrylate) or exposed aran-.id
(12 mm in diameter and 4 mm in length) were surgically implanted in the para-
vertebral muscle of six rabbits. Silicone was implanted as a control. After
14 or 28 days, the rabbits were killed, and the tissue reaction was evaluate:.
No adverse tissue response was elicited in rabbits implanted with aramid.
Formation of a thin, fibrous capsule surrounding the implanted material was
observed at both aramid and silicone implantation sites, but there was nc
evidence of inflammation or necrosis.
5.1.2.2 Carbon and Polyolefin Fibers. Since carbon fibers and polyolefin
fibers are used in prosthetic devices, several studies have been conductec to
evaluate tissue reaction to these fiber implants. In a study reportec b;.
Neugebauer et al. (1961), minimal fibrosis was evident 2 to 12 weeks e'te-
injection of carbon fiber fragments (diameter 7 urn; length, 20 to IOC J.T) iru
saline into the medullary canals of the femur bone of C4EP:CH rassits. Ca-bc
containing macrophages were present, and a small amount of ne* bone fc--=fe-
•'.-•>" 1=:: 5-4 DRAFT--DO N:T QjC" C-, CT:
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was evident around and including the carbon fibers. Carbon fiber particles
were found in the lungs, liver, spleen, and kidneys, but no foreign body
reaction was noted.
The consequences of release of carbon fiber debris within the synovia!
joint was reported by Parsons et al. (1985). One hundred milligrams of carbon
fibers (mean particle size was 5 ym) suspended in saline were injected into
the synovial joints of male New Zealand White rabbits. The animals were killed
4 days, and 2, 4, 8, and 16 weeks after injection. No cartilage damage was
apparent, and no debris were found in the synovial fluid. Most of the fiber
material was located either in the suprapatellal region or in the posterior
aspects of the knee. An acute foreign body response was evident after uptake
of carbon debris into the synovial lining. After 8 weeks, the carbon fice'S
migrated to the deep subsynovial fatty layers; the fibers remained there
16 weeks after treatment. There were no abscesses in animals injected with
ca-bon fibers when compared to positive control animals treated similarly with
talc. The authors reported a more severe foreign body response with syno»itis
and subsequent development of small abscesses in subsynovial tissue in talc-
injected rabbits. In addition, selective staining revealed loss of proteogly
can from the cartilage after 2 weeks in rabbits injected with talc. Cartilage
from carbon-injected rabbits retained normal staining patterns, suggesting that
no significant loss of proteoglycan occurred.
Makisato et al. (1984) compared tissue reaction after implantation of a
1.5- by 1.5-cm strip of carbon fiber paper or polypropylene into the peritoneal
cavity, under the skin, and in the medullary canal of the femoral bone of male
rats (strain not specified). Animals were killed and examined 1, 3, 6, and
12 weeks after insertion. The authors reported that carbon fibers induced more
fibrous tissue ingrowth in both the tissue and bone than polypropylene, but no
bone ingrowth was induced by either fiber.
5.1.3 Minerals
5.1.3.1 Attapulgite. No information on the acute toxicity of attapulgite wss
found in the available literature.
5.1.3.2 Erionite- No information on the acute toxicity of erionite was found
in the available literature.
5.1.3.3 Talc. Intratracheal instillaton of talc has been shown to result in
pulmonary toxicity in hamsters (Beck et al., 1987). Groups of six har.ste'S
(sex and strain not specified) were given single intratracheal injecfic-s of
July 19££ 5-5 DRAFT—DC N3T QlTE 0* CITE
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talc (mean diameter, 0.8 urn) suspended in 0.9 percent saline containing
13.3 (jg/mL rabbit surface active material (SAM) at concentrations of 0.15,
0.75, or 3.75 mg/100 g body weight. Controls received saline plus SAM. The
pulmonary responses were quantified by measuring biochemical and cellular
indicators of injury in the bronchoalveolar lavage (BAL) fluid. One day after
talc instillation, elevated enzyme levels, pulmonary edema, and increased cell
numbers in the BAL fluid (RBCs, macrophage, and polymorphonuclear neutrophil
cells) were noted. Persistent elevation of enzyme levels and inhibition of
phagocytosis were also noted in a group of four hamsters receiving 3.75 mg/lGT g
body weight that were killed 1, 4, 7, and 14 days after administration.
5.1.3.4 Vermiculite. No information on the acute toxicity of vermiculite »ss
found in the available literature.
5.2 SUSCHRONIC AND CHRONIC TOXICITY
5.2.1 Manrriade Mineral Fibers
5.2.1.1 Fibrous Glass
5.2.1.1.1 Oral. Only one study on the oral toxicity of fibrous glass was
found in the available literature. Gross et al. (1960) fed four groups cf
10 male white rats (strain not specified) a diet that contained either 1C cr
50 percent of finely milled glass flakes. Two groups of animals served as
pair-fed controls. The animals were maintained on their respective diets fcr
1 year. No significant differences were found in mortality, weight gain, orga">
weight, or histopathology among the groups.
5.2.1.1.2 Inhalation. Inhalation studies of up to 2 years duration with
glass fibers of varying diameters and lengths generally failed to show any
substantial pulmonary damage in several experimental species (e.g., Mitchell
et al., 1986; Smith et al., 1984; Pickrell et al., 1983; Lee et al., 19£1.
1979; Gross et al., 1970, 1960; Schepers and Delahant, 1955). Pulmonary
responses generally consisting of macrophage infiltration, alveolar dust-lacer.
macrophage aggregation, and alveolar proteinosis resulting in some alteration
of the lung architecture occurred in rats, guinea pigs, and hamsters (Lee
et al., 1981, 1979; Gross et al., 1970, 1960). The physical characteristics
(diameter and length) of the fibers appeared to have some effect on the degree
of tissue response. In general, exposure to long (>20 urr), thick (>5 ur.)
fibers resulted in a minimal reaction cnaracterized by slight dust-lace-
^rT--DD N- CJ": 0=.
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macrophage accumulation in the alveoli. By contrast exposure to long, thin
(<3 pm) fibers resulted in alveolar proteinosis, development of reticulin
fiber networks, and some fibrosis. Short (<5 pm), thin fibers caused a severe
inflammatory response resulting in dense dust-laden macrophage aggregation,
and in some cases, enlargement of adjacent lymph nodes due to macrophage
migration. However, very little alteration of the lung architecture was
observed. Chronic inhalation toxicity studies indicated mild cellular reactions
for glass microfibers at exposure levels of <3.0 mg/m . Higher concentrations
of microfibers or fibrous glass (diameter <3 pm) resulted in more pronounces
pulmonary manifestations. Unlike asbestos exposure, the inhalation of glass
fibers of similar dimensions did not result in collagen formation or develop-
ment of pulmonary tumors. Technical problems associated with the design of
inhalation studies using fibers probably contributed to the lack of a pulr.c-sry
response; only a small percentage of fibers in the dust cloud may have beer.
inhaled.
Pickrell et al. (1982) suggested that a possible explanation for the U:<
of response following inhalation exposure, as compared to intratracheal ir.sv":-
lation, was that inhalation introduced a burden that was only 3 to 5 percer*, c*
the lowest concentration of glass eliciting a response upon intratraches1
instillation. Several other investigators (Gross et al., 1970; Lee et al.,
1979, 1981) have shown that high concentrations of glass fibers in the lur.cs
could be achieved, and these high concentrations increased the severity of the
pulmonary response but did not result in the collagen development that was
observed after intratracheal instillation.
Lee et al. (1979, 1981) conducted two subchronic inhalation studies to
determine the effects of glass fibers, Fybex , and potassium titanate (PKT)
in rats, hamsters, and guinea pigs. In the first study (Lee et al., 197S),
groups of male Sprague-Oawley rats, albino guinea pigs, and Syrian hamste-s
were exposed to ball-milled glass fibers at a concentration of 420 mg/rr.'3
(0.42 mg/L) for 6 hours/day, 5 days/week for 90 days. Controls were expose:! to
air. The glass fibers had an average diameter of 1.2 pm and length of <3 pm.
Only 15 percent of the glass particles were considered to be fibrous (lenct--'
diameter ratio >3). Animals were killed and examined after 20, 50, and SO ceys
of exposure and 6, 12, and 24 months after the last exposure. Gross exar-'-.e-
tion revealed numerous grayish-yellow foci throughout the visceral ple-jre c*
glass-exposed animals killed during the exposure period. Tne majority, o*
foci disappeared within 6 mcr.ths postexposu^e. The tvila- lytr.p- r.ossi c'
.!:,•".• 19t: 5-7 D2A"--DC NC" Q'jCTE C:. CITE
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animals exposed to glass dust were enlarged and appeared mottled (grayisn-
yellow foci). The pulmonary response.was similar in the three species, although
the response in guinea pigs was generally milder. Macrophage aggregation was
noted in bronchioles and alveoli after 20 days of exposure. There was a
thickening of adjacent alveolar walls that were lined with proliferating
cuboidal granular pneumocytes. By day 50 of exposure, these responses were
more prominent and had extended to peripheral alveoli. At day 90 of exposure,
there was evidence of macrophage disintegration with release of granular
material that preceded alveolar proteinosis. The granular material consistec
of myelin figures, lamellar structures, dust particles, cellular debris,
degenerating macrophages, and polymorphonuclear leukocytes. By 6 months
postexposure, the hyperplastic granular pneumocytes were replaced by mercbra-ic-.s
pneumocytes. The normal architecture of the alveoli was restored after rerrcva]
of dust-laden macrophages. After 2 years, alveoli still containing dust-lase-
macrophages were lined by granular pneumocytes. However, there was nc signifi-
cant collagen formation.
Similar results were obtained in a second 90-day inhalation study re?c"te:
by Lee et al. (1981). In this study, the fibrogenic potential of ball-milled
glass fibers was compared to asbestos (positive control), Fybex'5, and PKT. The
results of Fybex and PKT exposure are reported in section 5.2.1.4. Grours of
46 male Sprague-Dawley rats, 34 hamsters (sex and strain not specified), anc
32 male albino guinea pigs were exposed to approximately 420 mg/m of glass
fibers (average diameter 1.2 urn and length <2 urn; only 7 percent of the dust
particles were considered to be fibrous) or to 300 mg/m amosite asbestos
(average dimensions of 5.0 by 0.4 urn). The pulmonary response observed in all
animals exposed to glass dust Included dust-laden macrophage aggregation with
hyperplastic granular pneumocytes and slight alveolar proteinosis that appeared
on day 90 of exposure but disappeared by 1 year postexposure. Ferruginous
bodies were observed in the lungs of hamsters and guinea pigs but not rats. By
18 to 24 months postexposure, 2 of 19 rats and 2 of 7 guinea pigs exposed to
glass dust developed bronchoalveolar adenomas. There were no incidences of
Tung tumors in control rats or guinea pigs, and no hamsters exposed to glass
fibers developed lung tumors. In animals exposed to asbestos, marked brcn-
chiolization and collagenous fibrosis were noted after 90 days of exposure. Cf
the 16 rats exposed to asbestos, two developed bronchoalveolar adenomas anc one
an epidermoid carcinoma. It is difficult, however, to assess the p^lmo-e-y
i9£= 5-e DKAFT-DD N:T QL-C-'E o- ci"
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effects obtained from the two studies reported by Lee et al. (1979, 19cl)
because the total respirable concentrations were not reported and only 7 to
15 percent of the particles tested were fibrous.
Wagner et al. (1984) reported the results of an inhalation study compering
the fibrogenic properties of glass fibers, mineral wool (see section 5.2.1.2),
and chrysotile asbestos fibers. Three-types of glass fibers were tested:
glass wool with and without a resin coating and glass microfibers (Johns
Manville Code 100). Fiber dimensions for all test clouds were approximately
equivalent with diameters <3.0 pm and lengths >5 um. However, fiber counts
varied considerably as follows: 240, 323, 1436, and 3832 fibers/cm for t-e
glass wool with resin, uncoated glass wool, glass microfibers, and asbestos.
respectively. Groups of 56 Fischer 344 rats (28 males and 2E females) were
exposed to 10 mg/m (respirable fiber concentration) of each fiber for 7 hcu-s/
day, 5 days/week for 12 months, and observed for life. A group of control
animals was included in the study, but no information on exposure was repo-tec.
Interim kills were performed at 3 and 12 months during the exposure pe'io:. a-;-
et 12 months postexposure (24 months on study), to assess the extent of tissje
reaction to the dusts.
No fibrosis was noted in animals inhaling the glass wool (unccete: cr
coated) using the grading system of McConnell et al. (1984) presentee in
Table 5-2. Mean scores at 3 months of exposure and 12 months after exposure
were very similar, ranging from 2.5 to 2,7. These results suggested that tnere
was little increase in the severity of the cellular reaction with increasing
length of exposure. Mean scores were slightly higher for the glass microfibers,
ranging from 2.8 to 3.3, but again there was no increase in the severity of
cellular reaction with increasing exposure length. Unlike glass fibers.
asbestos exposure resulted in increased severity of cellular reaction with tne
development of fibrosis as the length of exposure increased. Mean scores for
asbestos were 3.0 at 3 months of exposure and 4.0 at 12 months of exposure.
Animals dying during the study exhibited a slightly more severe cellule"
reaction, and a few rats exposed to the glass nricrofibers developed some
fibrosis. Mean scores for animals dying during the study from the glass ificrc-
fiber group ranged from 3.4 to 3.7. Incidenr.es of bronchoalveolar hyperplasia
were 3/4£, 3/48, 1/47, and 5/46 for animals exposed to the glass micrcfine-s.
glass wool with resin, uncoated glass wool, and asbestos, respectively. 3r>
addition, 1/4S animals each from the glass microfiber and coste: g'asi *-c'
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TABLE 5-2. THE H1STOLOGIC GRADING SYSTEM OF PULMONARY CHANGES
IN RATS RELATED TO THE INHALATION OF FIBERS
Histologic change
Score
Description
Cellular
Fibrcsis
Normal 1 No lesion observed.
Minimal 2 A few macrophages in the lumen of the
terminal bronchioles and alveoli.
Mild 3 Presence of cuboidal epithelium lining
the proximal -alveoli (bronchiolization).
No collagen, but reticulin fibers may be
present in interstitium at the junction
of the terminal bronchiole and alveolus.
Luminal macrophages are more conszncjc-s .
and mononudear cells may be fojr.c ir
the interstitium.
Minimal 4 Minimal rollagen deposition at level c*
terminal bronchiole and alveolus.
Increased bronchiolization with
associated mucoid debris suggesting
glandular pattern.
Kile 5 Interlobular linking of lesion des^'oe:
in grade 4 and increased severity cf
fibrosis.
Moderate 6 Early consolidation. Parenchyma!
decrease is apparent.
Severe 7 Marked fibrosis and consolidation.
8 Complete obstruction of most airways.
__
Nonfibrotic lesions.
Source: McConnell et al. (1984).
groups developed an adenocarcinoma, and 1/47 animals from the uncoated glass
wool group developed "a benign adenoma during the study. A total of 12/48
animals exposed to asbestos developed lung tumors (11 adenocarcinomas ar.c
1 adenoma). One control animal exhibited bronchoalveolar hyperplasia, but nc
tumors were observed.
Le Bouffant et al. (1986, 1967) also studied the pulmonary effects c*
glass wool, rock wool (see section 5.1.2.2), and glass microfibe's (J:">~s
Manville IOC) in Wistar rats. Grcuos of 24 males and 24 females we^e expose:
-------
to each fiber at a respirable concentration of 5 mg/m , 5 hours/day, 5 days/week
for 12 or 24 months. Control animals were exposed to air. Rats exposed for
12 months were observed for up to 16 months, and rats exposed for 24 months
were observed for up to 4 months after exposure was halted. Approximately
31.5 percent of the glass wool fibers were 10 to 20 urn in length, and
4E.4 percent of the microfibers were 5 to 10 urn in length. The diameters were
as follows: glass wool <1 urn (68.7 percent) and microfibers 0.2 to 0.5 urn
(51.3 percent). The quantity of dust deposited in the lungs varied greatly
according to the fiber type; the shorter fibers migrated to the lymph nodes.
Chronic inflammation with hypersecretion of mucus and epithelial desquamation
but no metaplasia were observed in the nasal fossae of rats exposed to both
glass fiber samples. The trachea, larynx, and other organs except lungs we~e
normal, however. In the lungs, small aggregations of macrophages were observe:
mainly at bronchoalveolar bifurcations. Mild, localized hyperplasia of type II
pneumocytes was noted in areas adjacent to macrophage aggregation after
12 months of exposure. After 24 months of exposure, the lungs exhibited sir.e1.1.
sparse foci of macrophagic reaction with a small amount of septa! reticclin
fibrcsis. One of 45 rats exposed to the glass wool developed a pulmonary
carcinoma. Progressive chronic nephrosis was observed in glass-exposed rais.
The lesions were also noted in controls but were less severe than in gless-
exposed rats. No pulmonary tumors were observed in microfiber-treated animals.
Mitchell et el. (1986) and Moorman et al. (1985) reported that chronic
inhalation of commercially available glass wool insulation induced pleursl,
plaque!ike lesions in rats, but not in monkeys. Groups of 50 male and
50 female F344 rats were exposed to 5 or 15 mg/m of four fiber samples of
varying lengths and diameters for 7 hours/day, 5 days/week for 86 weeks, The
specific fiber dimensions and concentrations tested are presented in Table 5-3.
The plaquelike lesions, described as multifocal, tan or gray, raised, firm
areas 1 to 6 mm or more in diameter, were located on the surface of the lungs.
These pleura! plaques were found in all glass-exposed animals except these
exposed to the long, thick fibers (4 to 6 uni in diameter). In addition, the
lesions were most severe in rats exposed to the long, thin fibers and we"e
relatively mild in rats exposed to the short, thin fibers. The authors
concluded that the plaques resulted from accumulation of granulomatous foci in
pleura! and subpleural areas of the lungs. The only other pulmonary response
noted was the aggregation of macrophages and the presence of granuloires
5-11 DRAFT--D: N:~ QJ
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TABLE 5-3. DIMENSIONS AND CONCENTRATIONS OF GLASS FIBERS USED
IN A CHRONIC INHALATION STUDY WITH F344 RATS AND CYNOMOLGUS MONKEYS
Fiber
description
Glass-red binder
Glass-yellow binder
Glass-uncoated
Glass-uncoated
Centre!
Fiber dimensions3
d = 4-6 urn
1 = >20 urn
d = 0.5-3.5 urn
1 = >10 pm
d = <3.5 pm
1 = >10 pm
d = <3.5 pm
1 = <10 pm
--
Target concentration
(mg/ms)
15
15
5
5
0
ad = diameter, 1 = length.
Source: Mitchell et al. (1986).
containing "fibrous" glass fibers. As noted earlier, the long, thick fibers
did net elicit any gross pulmonary lesion including macrophage aggregation. It
is interesting to note that macrophage aggregation and granulomatous inflar-.s-
tion were more severe in animals exposed to the short, thin fibers, whereas the
severity of the plaquelike lesions was greater in animals exposed to the long,
thin fibers. Macrophage aggregation and granulomatous inflammation were also
noted in the thymic and tracheobronchial lymph nodes of a few glass-exposed
rats. Glass fibers were not found in any other tissues. Besides pulmonary
effects, the only other significant finding noted was an increased (significant
at p <0.05) incidence of mononuclear cell leukemia in rats from all glass
fiber-exposed groups as compared to the control incidence. However, the
biological significance of this finding is unknown.
A similar 72 weeks exposure of groups containing 15 male cynomolgu's
monkeys did not induce the plaquelike lesions or an increased incidence of MCt
noted in rats (Mitchell et al., 1986; Moorman et al., 1985). Scattered macrc-
phage aggregation occurred throughout the lungs, and dust-laden macrophsoes
were found in tracheobronchial lymph nodes as well as in the pleura anc sut-
pleura in all glass-exposed animals. No evidence of translocation tc cf-er
organs was found. Increased numbers of lymphoid nodules or aggregates we-e
5-12 DR;"T--DC N:~
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observed in monkeys exposed to the long, thick fibers. However, the autho-s
theorized that this resulted from an immunological response to the binder. The
results of the monkey study may have been compromised because of an intercurrer.t
lung mite infection that resulted in pulmonary lesions in the majority of the
monkeys (59/60) on study.
Gross et al. (1970) and Gross (1976) classified glass fibers as a nonfi-
brogenic or nuisance-type dust based on the tissue reactions seen in rats
and hamsters after long-term inhalation exposure. Groups of 30 rats and
30 hamsters (strains and sex not specified) were exposed to uncoated glass
fibers or glass fibers coated with phenol formaldehyde or a starch binder
(diameter 0.5 urn, length 5 to 20 urn) at approximately 100 mg/m for 6 hoys/
day, 5 days/week for 2 years. The fiber samples were specially manufactured
tc simulate the glass fibers found in insulation and textiles by addition of
coating materials, but these fibers had diameters within the respirable ranee.
An additional group of 20 rats and 20 hamsters served as controls. Results
revealed no differences in the pulmonary tissue reaction for the coated versus
the uncoated glass fibers. Dust-laden macrophage aggregation occurred ir. the
alveolar region at the alveolar duct bifurcations. No atelectasis was present
anc1 generally, alveolar architecture was unchanged. A few rats exhibited focal
collagenous fibrosis typically seen after inhalation of large amounts of non-
fibrous dust. The migration of dust-laden macrophages to the lymph nodes was
observed, and the lymph nodes of a few animals were enlarged due to macrophage
accumulation. Consequently, fibrosis developed in the lymph nodes. The tissue
reaction in hamsters was similar to that in rats except that macrophage aggre-
gation was more dense, and numerous ferruginous bodies were observed in the
alveoli of hamsters. Diffuse, focal, bland, acellular, collagenous fibrosis
of the pleura was noted in a few glass-exposed animals. Calcified., laminated
microliths were also noted in the alveoli of a few hamsters. In addition, tne
authors stated that several hamsters died of pneumonia during the study (the
number of mortalities was not reported). This early mortality and the presence
of alveolar microliths were attributed to alveolar clearance failure, suggest-
ing that the fiber concentration in the lungs may have been excessive.
In a comprehensive chronic inhalation study by Smith et al. (1984, 15=6,
1967), the effects of several manmade vitreous fibers were studied in rets and
hamsters. The fibers tested included an uncoated glass microfiber (Jonns
Kanville code 100); glass wool with a silicone lubricant (Certainteec"\
Julv 15S£ 5-12 PRA?T--DC M' C-'-T = c^ CI~-
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Insulsafe II , "blowing wool" building insulation); two glass wool build-ing
insulations coated with phenol formaldehyde binders; a refractory ceramic fiber
(see section 5.2.1.3); slag wool (see section 5.2.1.2); and crocidolite asbestos
as a positive control. The dimensions, concentrations, and particle ratios
(nonfibrous-to-fibrous) of the glass fibers used are presented in Table 5-4.
The particle ratios indicated that the aerosol clouds contained more nonfibrous
than fibrous particles. Groups of female Osborne-Mendel rats and male Syrian
hamsters were exposed nose-only to the various fibers for 6 hours/day, 5 days/
week for 24 months, and then observed for life (see Table 5-5 for numbers of
animals used).
The lifespan of the hamsters was not adversely affected by the inhalaticr.
of glass fibers. In fact, hamsters from all the glass fiber groups exce;t
those exposed to the 3.1-um mean diameter (MD) glass wool had significantly
longer lifespans than both control groups (p value not reported). Microscopic
examination revealed fibers in every section of the lungs. The fibers were
generally phagocytized, and numerous ferruginous bodies were present. Tnere
was a dose-related increase in the degree of macrophage aggregation, but tie
macrophage foci did not progress to fibrosis. After exposure was halted, tr.e
macrophage aggregation either regressed or remained the same. Pulmonary
lesions were scored using the grading system of McConnell et al. (1954) anc
are presented in Table 5-5.
Similar findings were observed in rats and again, the major lesion noted
was macrophage aggregation. The ferruginous bodies observed in hamsters were
not found in rats, however. The grades obtained for lung lesions did net
exceed 4 in any of the glass-exposed animals, indicating that no collagen had
developed. The smaller diameter glass fibers appeared to cause a greater
degree of cellular change in the lungs, but there was no apparent dose relation-
ship. The highest scores were obtained in animals exposed to asbestos, but
even these scores were less than 4, suggesting that asbestos exposure did net
result in collagen formation although fibrosis was present. Slight increases
in the incidence of bronchoalveolar metaplasia were observed in hamsters
exposed to 3 mg/m of 0.45-um MD glass microfibers and 1.2 mg/m of the 5.4-pr
MD glass wool when compared to controls, but the differences were not statisti-
cally significant. The incidences of fibrosis were comparable between glass-
exposed and control animals; no tumors were found in any of the glass-exposed
animals. Hamsters exposed to asbestos had significantly higher incidences
Ju'y 19:; 5-14 DRArT--D: MT QJC'E
-------
TABLE 5-4. DIMENSIONS, AEROSOL CONCENTRATIONS, AND PARTICLE RATIOS
OF FIBERS USED IN 2-YEAR INHALATION STUDIES WITH OSBORNE-MENDEL
RATS AND SYRIAN HAMSTERS
Fiber dimension
Fiber
description
"Glass microfiber
(no binder)
High level
Low level
Glass wool
(silicone
lubricant)
•Glass wool
(binder coatee)
Hig". level
Lov. level
Glass wool
(binder coated)
Refractory
ceramic glass
Slag wool
UICC crocidolite
asbestos
Mean
diameter
(urn)
0.45
3.1
5.4
6.1
1.8
2.7
"d
Mean
length
(um)a
7.5 1 10
37 ± 48
31 ± 33
114 ± 94
35 ± 34
40 ± 63
"d
Fiber
concentration
(fibers/cm3)
3000
300
100
100
10
25
200
200
3000
Mass
concentration
(nig/m3)
3.0
0.3
10.0
12
1.2
s.o
12.0
10.0
7.0
Respirable
mass b
fraction Part'
(% w) rat
4:
61
_b
30 6:
3£:
13
-a
31:
19
35 33:
15 28:
_a
*Mean ± SD.
Characterized using cyclone sampling data. Represents the total aerosol mass, not just
fibrous mass.
cRatio represents nonfibrous*to-fibrous particles.
Not reported; length ranged from 0.2 to 25 urn.
Source: Smith et al. (1986, 1987).
Julv 1S=.£
-------
TABLE 5-5. INCIDENCES OF PULMONARY LESIONS NOTED IN OSBORNE-MENDEL
(OK) RATS AND SYRIAN HAMSTERS EXPOSED TO VARIOUS GLASS FIBERS
BY INHALATION FOR 24 MONTHS
Exposure
level
Exposure group (mg/m3)
Glass tnicrofiber (MD 0.45 urn)
Syrian hamsters 3
OM rats
Syrian hamsters 0.3
OM rats
Glass wool (MD 3.1 urn)
Syrian hamsters 10
OK rats
Glass wocl (M: 5.4 urr.)
Syriar, hamsters 12
OK rats
.Syrian harsters 1.2
OM rats
Glass wool (K~ 6. 1 urr.)
Syr-; s- f.s-i-.ers 9
1st group
2nc group
0'-', rats
Refractory ceraxic glass
Syrian ha.rsters 12
OK rats
Slag wool
Syrian hamsters 10
OK rats
UICC crocidolite asbestos
Syrian hamsters 7
OM rats
.Chamber controls (clean air)
Syrian hamsters
OK rats
Unmanipulated cage controls
Syrian hamsters
OK rats
One mesothel ioma.
Eronchcal veolar tumor.
'"Significantly different from controls (p
So^-ce: Sir.it h et el (!<<£- 1937).
Lesion
grade
2.3 ± 0.1
2.3 ± 0.1
2.1 ± 0.1
2.3 ± 0.1
2.1 ± 0.1
2.3 ± 0.1
1.6 ± 0.1
2.1 ± 0.1
1.8 ± 0.1
2.4 * 0.1
1.9 ± 0.1
1.3 ± 0.1
2.3 ± 0.1
2.1 ± 0.1
3.0 ± 0.1
2.4 ± 0.1
2.8 ± 0.1
2.8 ± 0.1
3-7 ±0.2
1.8 ± 0.1
2.2 ± 0.1
1.7 ± 0.1
2.4 ± 0.1
value not reporte
Incidence
Broncho-
alveolar
metaplasia
6/69
4/57
2/70
4/57
3/60
1/52
1/65
1/57
7/65
0/61
4/61
0/36
1/56
2/69
1/55
2/69
0/55
11/58*
4/57
3/57
5/59
4/112
3/125
o.
o* arirr.a":
Fibrosis
4/69
4/57
3/70
3/57
2/60
7/52
0'66
4/57
1/65
5/61
C/6I
0/3£
3/5£
1/70
12/55
1/69
9/55
14/58*
30/57*
4/58
6/59
3/112
17/125
s w't1-,:
Primar
tumor:
C/6:
c/5:
0/7(
0/5'
0/c1
r. 't
w / -•
C '£
C/5
0/6
0/c
1
C ~
1/7
0/5
C/6
0/5
0/5
3/5
1/5
L' / 5
C-'l
C'l
L'"..--
-------
(p value not reported) of bronchos! veolar metaplasia and fibrosis than controls,
but no tumors were Induced. Rats exposed to asbestos had a significant increase
in the incidence of fibrosis when compared to controls, and 3/57 developed
pulmonary tumors. No tumors were found in the unmanipulated control rats or
hamsters. One of 58 sham control hamsters developed a bronchoalveolar turner.
No sham control rats developed tumors.
Although bronchoalveolar metaplasia nay be a preneoplastic event in the
development of epithelial tumors, none of the groups exhibiting increasec
incidences of bronchoalveolar metaplasia developed pulmonary tumors. There
are several possible explanations. The asbestos sample used had a mean lengtr
of 5 urn, which may have been too short to induce lung tumors. Although the
authors stated that fiber particles were observed in the lungs, the conce~trs-
tion of respirable fibers actually inhaled may have been too small tc inc'jce
fibrosis or development of tumors. Also, the generated aerosol clouds prots:1y
did net contain enough fibrous particles to adequately assess possible biclcc/-
csl effects of fibers on pulmonary physiology.
Goldstein et al. (19£3) demonstrated that focal peribronchiolar fitros'5
can develop in baboons following the inhalation of a fibrous glass dust clt-jc.
A total of 10 male baboons (age not specified) were dusted 7 hours/day, 5 c=ys '
week for up to 35 months, with either fibrous glass (Johns Manville C102 er.c
C104 glass wool) or crocidolite asbestos (positive control). No negative
control group was included. The glass fibers measured 5 to 100 urn in length
and 0.1 to 4 urn in diameter (mean diameter was approximately 0.75 pm), anc tne
total respirable concentration was 5.8 mg/m . The asbestos fibers ranged from
0.1 to 1 urn in diameter and 0.4 to 25 pm in length; the total
concentration was 13.5 mg/m . Fiber counts were similar for both dusts.
Minimal macroscopic changes were seen at all stages of exposure, the earliest
microscopic changes observed (after 8 months of exposure) in lung biopsies of
the glass-exposed animals included bronchiolar thickening, the presence c*
scanty ferruginous bodies, and moderately compact reticulin formation. An
organizing desquamative alveolitis usually preceded the appearance of peri-
bronchiolar fibrosis. The fibrosis was slightly more marked after 18 ar.c
30 months of exposure and did not appear to regress up to 7 weeks after expo-
sure was halted, although the animals were to be observed for life anc tne
study was not yet complete. The fibrotic lesions were morphologically sirr-'ia"
to those produced by asbestos but were less extensive. The a-tno^s sucrsite:
-------
that the difference in severity of response between fibrous glass and
crocidolite may be due to differences in fiber concentrations within the lungs,
which were ultimately attributed to differences in fiber dimensions. The
authors attributed the appearance of peribronchiolar fibrosis in baboons but
not in other animals (see above studies) to differences in fiber dimensions.
and/or species used. However, an assessment of this finding is difficult in
the absence of other supporting evidence and untreated control animals.
5.2.1.1.3 Intratracheal. Glass fibers of varying lengths and diameters were
administered by intratracheal instillation to several animal species in a
number of studies. The results indicate that the physical characteristics of
the fibers, as well as dose, determine the nature and extent of tissue injuTj.
Very short (<5 urn), very thin (<0.3 urn) fibers apparently cause no pulmonary
responses. Short (<10 um), thin (<2 urn) fibers elicit simple macrophage
response. Longer (>10 urn) or thicker fibers (<3 urn) result in a more pronc-j-.ce:
response and fibrosis.
Tne relationship between the physical dimensions of the fiber and tissue
injury was demonstrated by Pickrell et al. (1963). Groups of 20 male Syria-
hamsters received two biweekly intratracheal instillations of uncoated glass
micro-fibers or household insulation fibers in saline suspensions. The die-eter
and total dose administered for each fiber sample is listed in Table 5-6. A
group of 30 controls was instilled with saline. Animals were killed and
examined 1, 3.5, and 11 months after the initial instillation. The smallest
diameter microfiber (0.1 urn) caused deaths from pulmonary edema 2 to 30 days
after the initial instillation. A slightly larger microfiber (0.2 urn diameter)
and one type of household insulation fiber (2.3 urn diameter) induced increases
in total collagen and mild pulmonary fibrosis at 11 months, with the microfiber
producing a greater effect than the insulation fiber.
Kuschner and Wright (1976) demonstrated that the physical characteristics
of the fiber determine the nature and extent of tissue damage. Groups o*
30 guinea pigs (strain and sex not specified) received 2 x 12.5 mg or 3 x 4 rr.c
of a short or long glass fiber, respectively. Animals were sacrificed after 6.
12, or 24 months. Short, thin fibers (0.05 to 1.99 urn in diameter, only 7 per-
cent >10 urn in length) induced a macrophage reaction but not fibrosis. Lone.
thin fibers (0.05 to 1.49 um in diameter, only 7 percent <10 urn in ler:*.-)
induced peribronchiolar interstitial fibrosis after 6 months. Very short.
very thin fibers (0.03 to 0.29 umm in diameter, <5 um in length) cause: ~:
-------
TABLE 5-6. TYPE, DIAMETER, AND DOSE OF GLASS FIBERS
INTRATRACHEALLY INJECTED IN SYRIAN HAMSTERS
Fiber Fiber count median Total
description diameter (pm) dose (mg)
Type 1 glass
Type 2 glass
Type A insulation
Type B insulation
Type C insulation
0.1
0.2
2.3
3.0
4.1
7
2
21
18
17
Source: Pickrell et al. (1983).
pulmonary alteration up to 2 years after injection. Long, very thin fibers
(0.03 to 0.59 pm in diameter, 50 percent >10 pm in length) cat-see1 coarser.ir.c
of the lung texture with peribronchiolar interstitial fibrosis involving the
proximal alveoli. Some interstitial fibrosis was seen 2 years after trie
injection of short, thick fibers (2 pm in diameter, 88 percent <10 pm in
length). Finally, animals that received the long, thick fibers exhibited
focal areas of interstitial fibrosis at 6 months postinjection, and a ccs'se--
ing of lung texture with ferruginous bodies was noted at 2 years.
Drew et al. (1986, 1987) conducted intratracheal instillation stucies
with sized glass fibers in male Fischer 344 rats. The fibers were either 1.5
by 5 pm or 1.5 by 60 pm (short fibers having a mean length of 5.1 pm and lone
fibers having a mean length of 54 pm). Animals were killed 6, 12, 18, and
24 months after administration. Instillation of both short and long fibers as
a single 20-mg dose produced a granulomatous foreign body response. In
contrast, low concentrations of both short and long fibers in multiple dcses
(0.5 mg once each week for 10 weeks for a total dose of 5 mg) elicited a sircle
macrophage response up to 11 months after the last instillation. No lung
tumors were seen.
The pulmonary effects of glass fibers with equivalent dimensions but
different surface properties were reported by Gross et al. (1970) and Gross
(1976). The tissue reaction of uncoated glass fibers was compared with that
of a phenol formaldehyde-coated glass wool and a textile glass fiber with a
starch binder (0.5 pm in diameter, 5 to 20 pm in length). Groups of 15 c<-
30 rats and 12 hamsters (strains and sex not specified) were given intra-
tracheal injections of 3.5 mg (in 1 ml water) of one of the three samples. The
glass fibers were injected once weekly for 1 to 10 weeks, and the ar,ir,= !s were
-------
then observed for life. No differences in tissue reaction were noted for the
uncoated versus coated glass fibers. Dust-laden macrophage aggregation was
observed in the alveolar and bronchiolar regions. Numerous ferruginous bodies
were found in the airways of hamsters. A diffuse, bland, acellular,
collagenous pleura1 fibrosis was present in both rats and hamsters. The
authors classified glass fibers as nonfibrogenic or nuisancelike dusts based on
the tissue reaction observed in this study.
Schepers and Delahant (1955) studied the effects of fiber diameter on tr,e
lungs of guinea pigs. Groups of five to eight guinea pigs (strain and sex not
specified) were injected intratracheally with three types of glass wool fibers
(mean diameters of 6, 3, and £3 pm and average lengths of 20 to 50 urn) c*.
'concentrations of 0.03 and 0.003 mg in a saline suspension once weekly for 52
to 76 weeks. The investigators found that the largest fibers were relatively-
inert , the medium-sized fibers caused foci of atelectasis early in the study
with major pulmonary damage seen after 75 weeks, and the smallest fibers
appeared to cause mainly focal atelectasis. No fibrcsis was seen in any g"0i.-r,
and the severity of the reaction appeared to be inversely related to the
caliber (i.e., diameter) of the fiber.
5.2.1.1.4 Intrapleural. The extent of the tissue response after intrapleui-al
administration has also been shown to depend on the physical characteristics
of glass fibers. Davis (1976) injected a single dose of 10 mg (in distilled
water) of four different samples of boron silicate glass into the pleura'
cavities of groups of 25 BALB/c mice (sex not specified). The glass sarr.ples
consisted of fibers with mean diameters of either 0.05 or 3.5 um and were
either long (over several hundred microns) or short (about 20 |jm). The long
fibers produced massive fibrosis, whereas the short fibers induced only smell,
discrete granulomas with minimal fibrosis.
5.2.1.2 Mineral Wool. Several investigators have studied the pulmona-y
effects of mineral wool in rats and hamsters after inhalation exposure.
Mineral wool having dimensions within the respirable range elicited mainly
dust-laden macrophage aggregation with only slight changes in lung architecture.
The results were comparable to those obtained for glass fibers having similar
dimensions. In the study by Wagner et al. (1984) and McConnell et al. (15S-)
described earlier, groups of 56 Fischer 344 rats were exposed via inhalation to
commence! grades of Swedish rock wool, as well as several glass fiber sables
and chrysotile asbestos as a positive control. The rock woe"1 sample r,e: a
-------
length of >5 pm, and 87 percent of the fibers had diameters ranging from <0.02
to 2.0 pm. The gravimetric concentration was 10 mg/m , and the exposure period
was 7 hours/day, 5 days/week for 12 months. The animals were then observed for
life. Results indicated that the pulmonary reaction to all tested MMMF was
mi Id compared to that for asbestos. There was no apparent progression of
severity as the exposure length increased in the MMMF-exposed rats. Lesion
grades ranged from 2.7 to 2.9 in rock wool-exposed rats that survived 2 years
(see Table 5-2). Animals that died during the study, including those that
survived longer than 24 months, had slightly higher scores ranging from 3.C to
3.3. The grades for asbestos-exposed animals ranged from 3.C to 4.0 in
animals surviving 24 months and from 4.3 to 4.7 for rats dying during the
study. Two of 48 'rats exposed to rock wool developed lung tumors (both
benign adenomas), and one animal exhibited bronchoalveolar hyperplasia. A
total of 12/48 rats'' exposed to asbestos developed lung tumors (11 adenocer-
cinomas and 1 adenoma). Bronchoalveolar hyperplasia was noted in 5 of
45 astestos-exposed rats.
•,
Le Bouffant et'al. (1986, 19S7) exposed groups of Wistar rats (2-* rr.s'es
and 24 females) to rock wool and two glass fiber samples at respirable cc.i:e~-
trations of 5 mg/m for 5 hours/day, 5 days/week for 12 or 24 months. Tne
glass fibers were discussed above (see section 5.2.1.1). The length of
95 percent of the rock wool fibers was <50 pm, and the diameter of
82.7 percent of the fibers ranged from <1 to 4 pm. Rock wool inhalation
elicited mild macrophage aggregation in the lungs after 12 or 24 months of
exposure. Chronic inflammation was observed in the nasal fossae, and kidney
lesions, described as progressive chronic nephrosis, were noted after 18 mcr.tns
of exposure to rock wool. Kidney lesions were also noted in controls but were
more extensive in rock wool-exposed animals. One of 47 rats exposed to rock
wool developed a peritoneal carcinoma, but no pulmonary tumors were found.
In a chronic inhalation study by Smith et al. (1986, 1987) describee
previously (see Section 5.2.1.1.2), groups of female Osborne-Mendel rats ar.c
male Syrian hamsters were exposed to several manmade vitreous fibers inducing
slag wool. The slag wool was described as having a CML of 40 pm and an KZ- of
2.7 pm. Approximately 75 percent of these fibers were >10 pm in length, a —
95 percent had diameters <2.5 pm. Animals were exposed nose-only to sis; *cc'
at a concentration of 10 mg/m for 6 hours/day, 5 days/week for 24 mor.tns. e-c
observed for life. Aerosol characterization is presented in Te -
-.
-------
Mean lifespans were significantly shorter (p value not reported) for rats
exposed to slag wool when compared to controls (677, 754, and 724 days for
rats exposed to slag wool, chamber controls, and unmanipulated controls,
respectively). No corresponding decrease in mean lifespan was noted in slac
wool-exposed hamsters. The mean lesion scores based on McConnell et al. (1S6-)
for rats and hamsters exposed to slag wool were 2.8 and 2.4, respectively (see
Table 5-2). Bronchoalveolar metaplasia was noted in 2 of 69 hamsters but in no
rats exposed to slag wool. There was a slight increase in fibrosis in slag
wool-exposed rats when compared to controls, but there was no corresponding
increase in hamsters. A summary of the pulmonary effects of slag wool as we""
as the other manmade vitreous fibers tested in this study is presented in Tei'e
5-5. Nc pulmonary tumors were induced in rats or hamsters exposed to sis;
wool.
5.2.1.3 Ceramic Fibers. As observed with other vitreous fibers, the inhe'a-
ficr. cf cerarric glass fibers by rats has been shown to result in little p_l-
mo-a-y response other than dust-laden macrophage aggregation. Intraperii:-
neal administration of ceramic fibers resulted in fibrosis in rats. Ho*e.-er,
the fibrosis contained little cr nc collagen and was, therefore, in nc w=_.
comparable to the fibrosis elicited by asbestos. Several other long-te-rr
studies using the intraperitoneal and intrapleural routes were conducted in
hamsters and two strains of rats. However, only carcinogenic endpoints were
discussed, and therefore, these studies are presented in Chapter 7 (see
section 7.3.1.3).
In a comprehensive study by Smith et al. (1986, 1987), female Osborne-
Mendel rats and male Syrian hamsters were treated with refractory ceramic
£
glass fibers (Fiberfrax ) in addition to several other MMMF via inhalation or
intratracheal and intraperi.toneal injection (see section 5.2.1.1). The cerarri:
fibers had a mean diameter of 1.8 ym and a mean length of 35 urn. In the
inhalation study, rats and hamsters were exposed to a concentration of 12 mg/rr"
(200 fibers/cm ) for 6 hours/day, 5 days/week for 24 months, and observed for
life. The aerosol cloud reportedly contained more nonfibrous than fibrous
particles; the particle ratio was 33:1 (see Table 5-4). A summary of pulmc-a-\
effects is presented in Table 5-5. Results .indicated that the incidence o*
fibrosis was slightly higher in rats exposed to ceramic fibers than in cc-.t-c's;
12/55 ceramic fiber-exposed rats developed fibrosis compared tc 6/5? a"
17/125 chamber and unmanipulated controls, respectively. Ho*eve~. tne i-:'e=se
-------
was not statistically significant, and fibrosis was not evident in hamsters
similarly dosed. The incidence of bronchoalveolar hyperplasia was comparable
between controls and both rats and hamsters exposed to ceramic fibers. No
tumors were observed in rats. In hamsters, however, one animal developed 3
pulmonary spindle cell mesothelioma.
In the intratracheal study, the lifespan of hamsters dosed with ceramic
fibers was slightly shorter than that of controls. However, the lifespan cf
rats was unaffected by the instillation of ceramic fibers. A significant
.increase (p value not reported) in the incidence of bronchoalveolar metaplasia
was observed in rats but not in hamsters dosed with ceramic fibers (6/22 rat;
dosed with ceramic fibers versus 0/25 and 3/125 saline and cage controls,
respectively). No primary tumors were observed, however. In this experiment.
rats and hamsters received 2 mg of ceramic fibers in 0.2 ml of saline once
weekly for 5 weeks and were then observed for life. Cage controls received
saline.
In the intraperitoneal study, 21/36 hamsters died within 30 days efte- £
single injection of 25 mg of ceramic fibers. Consequently, an additional
g-OL'p cf 36 was dosed, and within 30 days, 15 hamsters died. The cause cf
death was reportedly acute hemorrhagic peritonitis resulting from vascular
collapse and the accumulation of fluid in the abdominal cavity. Early deatr.s
were not observed in rats. The lifespans of rats and hamsters (surviving the
initial 30 days of the study) injected with ceramic fibers were significantly
reduced (p value not reported) when compared to controls. Eight of 25 rats
and 7 of 36 hamsters dosed with ceramic fibers developed mesotheliomas.
Davis et al. (1984) exposed 48 rats (Wistar AF Han) to a dust clous
containing ceramic aluminum silicate glass insulation for 7 hours/day, 5 days/
week for 12 months. The mean total respirable concentration was 10 m'g/rr,
(95 fibers/cm). The majority of the fibers within the dust cloud were <3 un.
in length with a diameter of 0.3 \tn. Alveolar proteinosis and ferruginous
bodies were found in the lungs of the animals exposed to ceramic insulation at
the end of the 12-month exposure period, but little or no fibrosis was present.
Thirty-two months after study initiation, slight proteinosis was still evident
but the majority of the particulate dust observed in the lungs at 12 months had
been phagocytized and cleared. It is interesting to note that ferruginous
bodies are generally observed in hamsters, guinea pigs, and monkeys exposed to
vitreous fibers or asbestos but are extremely unusual in rats.
-------
Pigott et aT. (1981) investigated the potential toxicity resulting from
the inhalation of Saffil alumina fibers in rats. These fibers are composed
of aluminum oxide and contain about 4 percent silica. Three different batches
of Saffil alumina fibers with mean diameters of 3.0 to 3.2 pm and mean lengths
of 35, 62, and 10.5 urn, respectively, were tested. Three batches of "aged"
jpi
Saffil alumina (i.e., fibers that had undergone periods of intense heat such
as occurs during actual use) were also studied. These fibers had mean diameters
of 3.0 to 3.3 pm and mean lengths of 53 to 57 urn. Groups of 40 Wistar rats
(sex not specified) were exposed to 2.18 mg/m (Saffil6) or 2.45 mg/m ("aged"
Saffil ) for 6 hours/day, 5 days/week for 86 weeks. The pulmonary response to
the Saffil15 fibers was generally minimal at week 27 of exposure, and no fibres-;s
was evident. At study termination, there appeared to be a slight increase ir
,j
alveolar epithelialization in the animals exposed to the "aged" Saffil'', a-d
this appeared to be more prevalent in females. The epithelializatior, was
generally confined to the appearance of small foci of pigmented macrophages and
was regarded as a typical response to a nuisance dust. The authors ccncluced
,7
that Saffil" alumina was biologically inert.
Styles and Wilson (1976) administered a single intraperitones"1 injection
of 0.2 ml of a 10 percent suspension of Saffil" alumina fibers to 20 male a~.d
20 female SPF Wistar rats. An additional group of rats received a single
injection of 0.2 ml of a 5 percent suspension of chrysotile asbestos (positive
ff
control). The Saffil fibers had mean diameters of 2 to 6 pm and mean lengths
of 6 to 100 pm. The animals were killed after 6 months. Saffil alur.ine
caused deposition of connective tissue containing some collagen but did not
provoke a fibrosis that was in any way comparable histologically to that
produced by chrysotile asbestos.
Similar results were obtained in a study by Pigott and Ishmael (1981) in
which groups of 12 male and 12 female Wistar rats were injected intraperitc-
g
neally with a single dose of 20 mg of one of two types of Saffil fibers in
2 ml saline. Animals were then observed for 3, 6, and 12 months. The type A
fibers had a mean,diameter of 2.75 urn and length of 15.5 ym; the type B fibers
had a mean diameter of 3.7 urn and length of 17 urn. Survival and growth we'-e
«
unaffected. Both types of Saffil fibers evoked a mild inflammatory reaction
resulting in the formation of nodules consisting of fibers, inflammatory cells,
and a small amount of collagen. No progressive fibrosis was evident 12 mont
after exposure. It was interesting to note that although the surface p'-o
c.
is,
I
-------
and porosity of the two types of Saffil fibers differed considerably, the
tissue reaction was identical, suggesting that surface chemistry of insoluble
fibers may not influence their reactivity.
Styles and Wilson (1976) also tested the fibrogenic potential of Saffil'
zirconia after administering a single intraperitoneal injection of 0.2 ml in a
10 percent suspension to male and female rats. They found that Saffil zirccnia
also caused deposition of connective tissue that contained some collagen, but
to a lesser extent than that seen with Saffil6 alumina fibers. The fibrosis
that developed was not comparable histologically to that produced by chrysotile
asbestos. The fibers had mean diameters ranging from 2 to 5 pm and mean
lengths of 5 to 200 urn.
5.2.1.4 Other Manmade Mineral Fibers. The toxicity of several other synthetic
irineral fibers has been studied. Titanium-containing fibers are structurally
similar to asbestos in that they are composed of bundles of submicronic neecle-
shaped fibers and may replace asbestos as reinforcing agents. Titanates have
beer, shown to cause fibrosis after inhalation exposure, intratrachesl instilla-
tion, and intraperitoneal injection, although the fibrosis observed was rrjcr
less extensive that observed for asbestos. Calcium silicate fibers and
wollastonite (a naturally occurring calcium silicate fiber) have also been
used as substitutes for asbestos in insulation materials and as reinforcing
agents in ceramics and other products. The pulmonary response was found to be
similar to other MMMF and consisted primarily of dust-laden macrophage aggrega-
tion with little evidence of fibrosis. Wollastonite did not appear to be
particularly durable in the body (Pott et al., 1987).
Lee et al. (1981) conducted an inhalation study to determine the toxic
effects in rats, hamsters, and guinea pigs of potassium octatitanate fibers
'(also known as Fybex , which is a registered trademark of Dupont, and consists
of inorganic titanate-reinforcing fibers). The test material consisted prima-
rily of fibers that measured <15 \im in length. The investigators exposed
46 male Sprague-Dawley rats, 35 male albino guinea pigs, and 34 hamsters
(strain and sex not specified) to an atmosphere containing either 2.9 x 10 ,
13.5 x 106, or 41.8 x 106 Fybex6' fibers/L for 6 hours/day, 5 days/week for
3 months. One group of each species exposed to air alone served as centre's.
Dose-related decreases were observed in body weight gain in rats,
and guinea pigs exposed to Fybex . Dose-related increases in fibroger.i:
activity were also observed in the Fybex'-exposed animals; howev-e-, the f^-
5-25
-------
resulting from Fybex exposure was much less extensive than that of asbestos at
similar exposure concentrations. The fibrosis was accompanied by dust-laden
macrophage aggregation, granular pneumocytic proliferation, bronchiolarization,
and ferruginous body production. Rats tended to exhibit a more severe fibro-
genic pulmonary reaction than either guinea pigs or hamsters.
Lee et al. (1981) also studied the potential toxicity of pigmentary
potassium^titanate (PKT) fibers by exposing 46 male Sprague-Dawley rats,
35 male guinea pigs, and 34 hamsters (strain and sex not specified) to an
atmosphere containing 2.0 x 10 PKT fibers/L for 6 hours/day, 5 days/week for
3 months. The test material consisted primarily of fibers that were <10 urr, in
length. PKT was less fibrogenic than asbestos or Fybex . Very minute
pulmonary fibrosis occurred in rats and hamsters exposed to PKT, but not in
guinea pigs. Other pulmonary changes were also very slight.
The effects of titanium phosphate fibers administered by intratrachesl
and intraperitoneal injection to rats and hamsters were investigated by Gross
et al. (1S77). These fibers measured 0.2 to 0.3 urn in diameter and 10 tc 20 ur.
in length, and we-e given in doses of 2, 10, or 50 mg of fibers suspended
in 5 mL of saline. A slight dose-related fibrogenic response to titaniur
phespnate was observed following intratracheal instillation in rats. In
contrast, no effects were noted in hamsters. Intraperitoneal injection did not
induce any treatment-related lesions.
The effects of the inhalation of commercial calcium silicate insulation
materials (mineral tobermorite) were studied in rats (Bolton et al., 1SE6).
Groups of 48 male Wistar rats were exposed 7 hours/day, 5 days/week for
12 months, and observed for life. Three samples of a mineral tobermorite
(Cat(OH),,$i' 0,,-hLO) were tested. Fiber diameters ranged from 1 to 10 prr,
5 & b ID t *
.although chamber concentrations were adjusted to 10 mg/m respirable fibers.
Control animals were exposed to filtered air.
Dust-laden macrophage accumulation, particularly adjacent to bronchioles
and in alveolar spaces, was noted in all animals exposed to calcium silicate
immediately after completion of exposure (12 months). Aggregation decreased
with time during the recovery period. Fibrosis was noted in both control anc
calcium silicate-exposed rats that survived more than 10 months after cessation
of exposure. Incidences of fibrosis were 11 percent (5/45) for control anc
9 percent (13/139) for calcium silicate-exposed rats. Small amounts of pe-ticu-
late matter were observed in mediastinal lymph nodes of all animals exposed tc
-------
calcium silicate. However, more extensive changes were noted in animals
exposed to one calcium silicate sample denoted "A." Rats exposed to sample "A"
also exhibited a lesion exclusive to this group. The lesion was characterized
by small granulomatous nodules consisting of oiacrophage and fibroblast cells
within a network of reticulin and located in the peribronchiolar region of the
lungs. This sample, however, was contaminated with quartz (1 percent), and the
lesion may have been quartz-induced. Significant increases (p <0.01) in
lymphocyte counts were noted in rats exposed to calcium silicate when compered
to controls.
Pulmonary neoplasms were found in 2/139 rats exposed to calcium silicate.
These were described as a focal squamous carcinoma of low-grade malignancy and
a benign, adenomatous lesion. One rat exposed to calcium silicate developec a
peritoneal mesotheliome, but this was considered to be spontaneous because cf
the negative response obtained in a concurrent intraperitoneal study in whicr.
neither fibrosis nor tumors were obtained after a single intraperitonecl
injection of 25 mg calcium silicate in rats (Bolton et a!., 1986).
The fibrogenic potential of intratracheal instillation of wollastonite (e
naturally occurring calcium silicate) was compared to asbestos in a stucy
reported by Wozniak et al. (1986). Groups of male Wistar rats receive: a
single intratracheal instillation of 50 mg of Finnish wollastonite, crocido'iite.
or chrysotile suspended in 0.6 ml saline. Control animals received saline.
Wollastonite fibers ranged from 10 to 20 urn in length (the diameter was net
reported). Rats receiving wollastonite were killed 3, 6, and 9 months post-
dose, and those receiving the asbestos samples were killed 3 and 6 months
postdose.
The wet lung weight of animals receiving wollastonite was increased
compared to control animals, accounting for approximately a 21 percent increase
after 6 months and a 19 percent increase after 9 months. Hydroxyproline
content was also increased over controls in animals receiving wollastonite.
However, lung weights and hydroxyproline content were much higher in aniir-sls
receiving asbestos, suggesting that fibrotic changes were not comparable
between wollastonite and asbestos. Histological changes in the lungs of rets
receiving wollastonite were characterized by granulomas consisting of agc'eje-
tion of dust-laden macrophages with a few fibroblast and lymphoid cells. Tnere
was some accumulation of dust-laden macrophages in mediastinal lymph nodes, but
wollastonite fibers were not found in other tissues. There was nc evidence c*
-------
cell necrosis or fibrosis in the lungs or lymph nodes of rats exposed to
wollastonite. Conversely, Instillation of asbestos resulted in the development
of fibrosis in the lungs characterized by significant increases in wet lung
weight and hydroxyproline content, as well as proliferation of connective
tissue.
5.2.2 Synthetic Fibers
5.2.2.1 Araitn'd Fibers. Only one chronic inhalation toxicity study was found
in the available literature for Kevlar , a commercially produced aramid fiber
(Stadler, 1986). Specially refined Kevlar® pulp fibers (90 percent <1.5 urr, in
diameter and 75 percent <20 urn in length) were used to determine the effects
of chronic exposure to respirable fibers in the deep portions of the lung.
The results indicated moderate pulmonary toxicity characterized by hyperplesie.
obliterative bronchiolitis with collagen formation, emphysema, and development
of neoplastic lesions in the exposed rats. The study was conducted with.groups
of ICC male and 100 female Crl:CD BR rats exposed to the refined fibers at
chamber concentrations of 0.0£, 0.32, 0.63, or 2.23 mg/m (equivalent to 2.4,
25.4, 111.2, or 435.5 fibrils/cm , respectively). Exposures were for 6 hours/
day, 5 days/week for 1 (2.23 mg/m ) or 2 years (O.DS, 0.32, and C.63 mg/r*).
After 1 year of exposure to 2.23 mg/m , animals were observed for a recove-y
period of 1 year. This was instituted after study initiation because of high
mortality at this exposure level. Interim sacrifices were conducted after 3,
6, or 12 months of exposure.
Mortality was significantly higher (p <0.05) at the 2.23-mg/m level than
in controls after 1 year of exposure. The majority of these deaths were
.attributed to obliterative bronchiolitis characterized by granulomas containing
collagen fibers that partially blocked airways in the alveolar duct region.
g
The mortality rate during the second year with no exposure to Kevlar fibers
was comparable to controls. Body weight gains were significantly lower
c
(p <0.05) than controls for all Kevlar -exposed groups after 1 year, but no
differences were noted after 2 years of exposure. Absolute and relative lung
weights were significantly higher (p <0.05) for animals exposed to 0.63 or
2.23 mg/m than for controls. Dust-laden macrophages were evident in the lungs
g
of all animals exposed to Kevlar fibrils,.although the lung architecture was
unaffected at the lowest exposure level after 2 years. After 3 months of
exposure, lungs from the 0.63- or 2.23-mg/m groups exhibited type II ce'l
19== 5-2- DRA-T--D: N:~ c.:~: •-•. ::
-------
hyperplasia in the alveolar region. This was also noted in rats exposed to the
0.32-mg/m level for 6 months. Other lung effects noted at 0.32 mg/m or
higher doses were nodular thickening of ridges at alveolar duct bifurcations
and formation of ciliated columnar cells in the upper regions of the alveolar
ducts. Rats exposed to 2.23 mg/m exhibited emphysema characterized by dila-
tion of alveolar ducts and adjoining alveolar spaces adjacent to blocked
airways. This was evident after 1 year of exposure and persisted after the
recovery period of 1 year. In addition, Kevlar® fibrils migrated to adjacent
tracheobronchiolar lymph nodes in rats exposed to 0.32 mg/m or higher, altnoug-
fibrils were not found in other tissues. Neoplastic lesions were seen in the
lungs of rats exposed to Kevlar fibrils at levels of 2.23 mg/m (1/36 male:
and 7/56 females) after 1 year or O.F3 «g/m (10/69 female?) after 2 yea-s c*
exposure. No tumors were observed in controls.
5.2.2.2 Carbon Fitters. Very little information on the subchronic and chro-ic
toxicity of carbon fibers was found in the available literature. Two subchronic
inna'aiion studies with rats and guinea pigs indicated no pulmonary damage.
although macrophage accumulation was evident. Implantation of ca^bor.' fibers
did not elicit any unusual reaction in bone and muscle tissue.
Holt (1982) reported that exposure to submicron carbon dust via inha iatio->
for 7 to 100 hours did net induce pulmonary fibrosis or other pathological
effects in guinea pigs. Dust-laden macrophage aggregation was noted up to 2
years after exposure, but Perls-positive macrophages (ferruginous bodies) *ere
not observed before 5 months postexposure. Similarly, no evidence of pulmonary
fibrosis was noted in rats following subchronic inhalation of Celion, a PAN-
based carbon fiber (Owen et al., 1986). The study was conducted with a group
of 60 male Sprague-Dawley rats exposed to 20 mg/m , 6 hours/day, 5 days/week
for 16 weeks. The fibers had a mean diameter of 7 pm and length of 20 to
60 pm. Rats were killed and examined after 4, 8, 12, or 16 weeks of exposure;
the remaining animals were observed for a recovery period of 32 weeks. -Controls
(60 male rats) were exposed to air. There Were no significant changes in
pulmonary function. Histologically, the only treatment-related observation was
the presence of carbon fiber-containing macrophages in the alveoli. No pul-
monary inflammation or fibrosis was evident. The authors did not report f:€
concentration of respirable fibers or quantitate fiber concentration in tne
lungs. However, most of the carbon fibers were beyond the respiratle range
since the mean diameter was 7 pm. Consequently, fiber concentrations ^f^
L.
-------
the lungs may not have been adequate to elicit any pulmonary response other
than macrophage accumulation.
To evaluate the chronic tissue reaction to carbon fiber implants, strand
and powdered forms of AS3000 nonbraided filament carbon fibers were inserted
or injected (2.5 mL in a saline suspension) intramuscularly into the glutee.l
muscle or wrapped around the femurs of Wistar rats (Tayton et a!., 1982). The
animals were killed and examined an average of 17 months after insertion or
injection of the carbon fibers. No inflammatory reaction was observed.
Generally, the implants or the powdered fibers were surrounded by a thin
fibrous capsule. A few phagocytic cells were present, and an occasional giant
cell was noted. In rats receiving an implant, considerable fiber debris we-e
found in the interstitial spaces, and smaller quantities were also present ir
adjacent lymphatic capillaries. The muscle tissue exhibited a slight tnicke--
ing of the endomysium, but no neoplastic changes were evident. The wrapping cf
carbor, fibers around bone resulted in development of a thick fibrous caps-jle
around the fibers but did not cause unusual reaction or neoplastic chance in
bone tissue. I
5.2.2.3 Pclyolefrn Fibers. Polyolefin fibers did not cause any tissue response
ether than macrcphage accumulation after intratracheal or intraperitcnea"
administration. Styles and Wilson (1973) conducted a study designed to investi-
gate the relationship between cytotoxicity to macrophages i_n vitro and tne
j_n vivo fibrogenesis of several natural and manmade fibers. It was found that
polyolefin fibers cause low i_n vitro cytotoxicity (see section 7.2.3.3) ano dc
not produce fibrosis after intraperitoneal injection into Wistar rats. For the
intraperitoneal study, groups of 12 male and 12 female rats were given single
injections of 50 mg/kg of either polyethylene ("Alkathene," 3 to. 75 urr. in
diameter) or polypropylene (4 to 50 urn in diameter) suspended in physiologica"
saline. The animals were observed for 1 or 3 months; no lesions were evident.
The chronic effects of polypropylene fibers on rats after a single intre-
tracheal instillation of 1.25 mg were investigated by Moreno and Moreno (1981).
Groups of 40 male Long Evans rats were dosed with 0.5-mL suspensions of poly-
propylene fibers ("spurted") or polypropylene dust (obtained from a splitting
operation) at concentrations of 0.25 percent in a 0.1 percent Tween 60/wate-
solution. Controls received 0.5 ml of the Tween 60/water vehicle. Anircls
were observed for 21 months. No clinical signs of toxicity or changes ir. bcc\
weight or organ weight were observed in the polypropylene-dosed c-.-'r:a's *ne~
t.-'3~ nc :,"--<
-------
compared to controls. Histologically, the only observation considered to be
treatment related was the presence of lung granulomas with foci containing
irregularly shaped birefringent particles. The authors considered these to De
residual components of the Instilled material. However, it should be noted
that 48 percent of the animals from the polypropylene group died during the
first week after instillation presumably because of dosing errors, thus effec-
tively reducing the group size to half that of controls.
5.2.3 Minerals
5.2.3.1. Attapulgite. No information on the subchronic or chronic toxiciu
of attapulgite following inhalation exposure or intrapleural and intra-
peritoneal administration was found in the available literature. Intratre:^6:'
instillation of 100 mg (in 100 ml saline) of attapulgite into the tracnesl Icte
cf the lungs of sheep demonstrated that this mineral is biologically active ir.
broncnoalveolar spaces and induces lung lesions that are comparable to these
produced by short chrysotile fibers (Begin et al., 1927). The attspjlgne
sarnie consisted of fibers having a mean diameter of C.02 urr< and a mean le-.cl-
of 0.6 um (0.25 to 4 urn), whereas the mean diameter and length of the chrysc-
tile fibers were 0.08 and 0.92 urn, respectively. Results of bronchos!vec'e'
lavages (BAl), collected on study days 0, 12, 24, 40, and 60, indicated that in
attapulgite-exposed sheep, total BAL cells/ml increased significantly (p
-------
Suzuki (1982) also investigated the effects of roordenite, a zeolite
mineral using a mixture of fibrous and granular fragments. Five male Swiss
albino mice were given single intraperitoneal injections of either 10 or 30 mg
of mordenite suspended in 1 ml of saline and observed for life. The granular
mordenite was 0.33 to 5.7 urn on the long axis and 0.27 to 1.67 urn on the short
axis. The fibrous mordenite was 0.4 to 6 urn in length and 0.05 to 0.67 urn in
width. Five untreated nice served as controls. Peritoneal fibrotic lesions
were observed in the mordenite-treated mice, but the effect was not as pro-
nounced as that observed in the erionite-treated animals.
5.2.3.3 Talc. Talc is considered to be a particle rather than a fiber and.
therefore, the tissue response resulting from talc exposure cannot be directl\
•compared to that of fibers. Talc exposure generally resulted in a typical
granulomatous lesion consisting of dust-laden multinucleated foreign body
giant cells, as well as some fibrosis with collagen formation in several animal
species. In addition to the development of granulomas, intratracheal instilla-
tion of talc resulted in moderate tissue destruction in hamsters, and int-e-
pe-itoneal administration has been shown to cause abdominal adhesions in rets
and swine.
Wagner et al. (1977) exposed a group of 24 male and 24 female Wistar rats
to a dust cloud containing 10.8 mg/m talc (mean respirable concentration). A
total of 24 animals inhaled the dust for 3 months; 12 were exposed for 6 months,
and the remaining 12 were exposed for 12 months. An equal number o'f rats
remained unexposed as cage controls, and a group of 48 rats serving as positive
control animals was exposed to 10 mg/m chrysotile asbestos. Exposure was for
7.5 hours/day, 5 days/week. The test material (Italian 00000 grade) contained
approximately 92 percent talc, 3 percent chlorite, 1 percent carbonate
minerals, and 0.5 to 1.0 percent quartz by weight. The remaining 3.0 to
3.5 percent was not defined. Particle size ranged up to 70 urn but averaged
25 urn. Groups of rats were sacrificed at 10 days and 1 year after the end of
each exposure period, and the remaining rats were observed for life.
The severity of fibrosis produced was similar for the talc- and asbestos-
exposed groups, ranging from minimal to slight. There was evidence of
progression in severity as the exposure length increased. One of 4£ rat;
exposed to talc developed a pulmonary adenoma, and 7 of 4£ asbestos-expcsea
rats developed pulmonary tumors.
-------
Trautwein and Helmboldt (1967) studied the pulmonary effects of talc
after intratracheal instillation into chinchillas. Groups of male and ferr.ale
chinchillas received intratracheal instillations of 2 ml of a 2 percent suspen-
sion of talcum powder (purified Mg^i^.'H^O; particle size not specified) in
saline. Controls were treated similarly to test animals, and received 2 mL of
saline per injection. The study consisted of three experiments. In the first,
14 chinchillas received injections on study days 1, 20, 50, 70, and 90, and
were killed 11 months after the last injection. A second group of 24 animals
received a single intratracheal injection, and two animals were killed 24, 4£.
72, and 120 hours, and 1, 2, 3, 4, 6, 17, and 28 weeks, postdose. The lest
group of 18 animals received 11 weekly intratracheal injections for 10 weeks,
and chinchillas were killed 1, 2, and 3.5 months after the last injection.
Several animals died during the study from the acute effects of taU
exposure. All of these animals exhibited some form of pneumonia caused by
talc accumulation in the lungs. Two animals from the first experiment died
3 tie\ i after the initial injection from acute suppurative pneumonia. Five
animals died from the third experiment: two from proliferative and exucatne
pneumonia after 12 and 21 days (these animals received two and three injections
respectively), and three from extensive granulomatous pneumonia between 41 a-:
46 days after the initial talc injection.
Results indicated that talc caused exudative pneumonia that developer
into pro!iferative, granulomatous pneumonia. The granulomas consisted cf
multinudeated foreign body giant cells that surrounded or engulfed the talc
particles. Several stages of transformation were noted in alveolar lining
cells located only in areas of talc deposition or in close proximity to
.granulomas. Initially, swelling of alveolar epithelial cells was .noted. IMS
was followed by hyperplasia and progressed to epithelialiiation. -Finally,
columnar cells appeared, lining the affected alveoli and imparting an "adenor.a-
tous appearance." No fibrosis was noted in talc-injected or control animals.
Furthermore, single or multiple injections resulted in the same tissue reac-
tions.
In a chronic study by Stenback et al. (1986), groups of 48 Syrian hamster*
received weekly intratracheal instillations of 3 mg talc alone or in co-iira-
tion with 3 mg benzo(a)pyrene (BaP) in saline for life. The talc sample cc--.-
sisted of 64 to 66 percent SiOp and 34 to 36 percent McD.. and 5- percent c^
the talc granules had a particle size of <10 urn. Dust-laden mscrcpr.eos
-------
aggregation and accumulation of interstitial cells and histiocytes were noted
in hamsters exposed to talc alone. There were also increases in fibrillary
material (elastic fibers) surrounding alveolar and interstitial spaces, and
some accumulation of proteinaceous exudate within the alveoli. However, no
fibrosis or granulomas were observed in talc-exposed hamsters. Talc alone
caused moderate tissue destruction, slight metaplasia, and no dysplasia in the
tracheobronchial 2one; woderate hyperplasia was seen in the alveolar zone.
Talc plus BaP resulted in moderate destruction, moderate metaplasia, and severe
dysplasia in the tracheobronchial zone, and severe hyperplasia and dysplasia ir.
the alveolar zone. Talc alone did not induce tumors in hamsters but, when
given in combination with BaP, was found to be an effective cocarcinogen,
inducing an increased incidence of tumors in both the upper and lower respira-
tory tract when compared to talc or BaP alone. There was a high incidence of
peripheral (alveolar) lung tumors, and adenocarcinomas were the predominant
turner type.
In a study by Styles and Wilson (1973) that was designed to compa-e tne
_i_n vitro cytotoxicity with i_n vivo fibrogenesis of several synthetic arc
mineral fibers, intraperitoneal injection of 50 mg talc/kg talc into Wistar
rats (sex not specified) resulted in the development of a granulomatous res:-
tion that consisted of the aggregation of foreign body giant cells containing
talc particles 1 month after administration. The lesions were still evident
3 months after injection, but no fibrosis was evident. In this study, talc
was found to have low j_n vitro cytotoxicity resulting in death of less than
2 percent of peritoneal macrophages following phagocytosis (see also
section 7.2.5).
Kaiser et al. (1982) reported the development of foreign body granulorr.as
with adhesions in male and female Wistar rats 12 weeks after intraperitonea1
injection of talcum (dose and composition not specified). The development of
foreign body granulomas has also been reported in swine (Migaki and Gardner.
1969). The lesions found in the inguinal canal of four castrated male swine
consisted of talc-containing epithelioid and giant cells, lymphocytes, and
fibrous tissue. The pigs were thought to have been exposed to talc during
castration, but the exposure period was not reported. The peritoneal tissue
response to talc was also studied in rats, by Pelling and Evans (1965). Tel:
(50 mg) was implanted surgically into the peritoneal cavity of 60 male Sp-acje
Dawley rats. Sham-operated rats served as controls. Animals were ki'lec 2, 4
JL'V 19=: 5-3- D^rT--D: Nl" QJ-'E C: C":
-------
8, 13, 26, and 52 weeks after implantation and examined. Talc produced exten-
sive granulomatous peritonitis within 2 weeks that persisted until week 13.
Numerous focal lesions described as discrete pale nodules were observed in all
animals receiving talc (100 percent incidence). These nodules were still
apparent 52 weeks after exposure. Both control and talc-exposed-animals
developed adhesions. The animals receiving talc, however, had a significantly
increased incidence (p <0.001) of adhesions when compared to control rats over
the entire time period. Histologically, the lesions consisted of granulorr.es
containing dust-laden macrophages and dust-laden multinucleated giant cells
with some collagen formation.
5.2.3.4. Vermiculite. No information on the subchronic or chronic toxicity o*
vermiculite was found in the available literature.
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inhaled Kevlar aramid synthetic fibers in rats. Toxicol. Appl. Pharmacc"1. .
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Makisato, S. ; Paavoleinen, P.; Holmstrom, T. ; Slatis, P. (1984) Tissue
after implantation of carbon fiber and polypropylene. An
in rats. Acta Orthop. Scand. 55: 675-676.
McDonnell, E. E.; Wagner, J. C. ; Skidmore, J. W. ; Moore, J. A. (1984) A ccns-
ative study of the fibrogenic and carcinogenic effects of U1CC Ca-ac-'c-
chrysctile E asbestos and glass microfibre (JM100). In: Biological Effects
of Ksn-made Mineral Fibres: proceedings of a WHO/IARC conference; v. 2:
April 1962. Copenhagen, Denmark: World Health Organization, Reric-e"
Office for Europe; pp. 234-250.
Mic-ski, G. ; Garner, F. M. (196S) Talc-induced granulomas in swine. J. Ar. vet.
Mec Assoc. 155: 1595-1596.
Mitchell, R. I.; Donafrio, D. J. ; Moorman, W. J. (1986) Chronic inhalation
toxicity of fibrous glass in rats and monkeys. J. Am. Coll. Toxicol.
5: 545-575.
Moorman, W. J. ; Mitchell, R. I.; Mosberg, A. J. ; Donafrio, D. J. (1SE5) Chrcr.ic
inhalation toxicology of fibrous glass in rats and monkeys. Presentee at:
6th International Symposium on inhaled particles; September; Morgantown,
VA. Cincinnati, OH: National Institute for Occupational Safety and HeaHn,
Division of Respiratory Disease Studies.
Moreno, 0. M. ; Moreno, M. T. (1980) Twenty-one month observation after single
intratracheal insufflation [unpublished study]. Spinnertown, PA: M.e.
Research Laboratories, Inc.; Project no. 78-2806.
National Institute for Occupational Safety and Health. (1977) Criteria for
a recommended standard ____ occupational exposure to fibrous glass.
Cincinnati, OH: U. S. Department of Health, Education, and Welfare, Public
Health Service, Center for Disease Control; DHEW (NIOSH) publication
no. 77-152. Available from: NTIS, Springfield, VA; PB-274195.
Neugebauer, R. ; Helbing, G. ; Wolter, D. ; Mohr, W. ; Gistinger, G. (IBS'.) 7r>e
body reaction to carbon fiber particles implanted in the med'jllarv s;c:e
of rabbits. Biomaterials 2: 182-184.
-------
Owen, P. E.; Glaister, J. R. ; Ballantyne, B. ; Clary, J. J. (1986) Subchronic
inhalation toxicology of carbon fibers. JOM J. Occup. Med. 28: 373-376.
Parsons, J. R. ; Bhayani, S. ; Alexander, H. ; Weiss, A. B. (1985) Carbon fiber
debris within the synovia! joint. Clin. Orthop. 196: 69-76.
Pelling, D.; Evans, J. G. (1986) Long-term peritoneal tissue response in rets
to mould-release agents and lubricant powder used on surgeons' gloves.
Food Chem. Toxicol. 24: 425-430.
Pickrell, -J. A.; Hill, J. 0.; Carpenter, R. L.; Hahn, F. F.; Rebar, A. H.
(1983) In vitro and in vivo response after exposure to man-made mineral
and asbestos insulation fibers. Am. Ind. Hyg. Assoc. J. 44: 557-561.
Pigctt, G. H. ; Ishmael, J. (1981) An assessment of the fibrogenic potential c*
two refractory fibers by intraperitoneal injection in rats. Toxicol. Lett.
8: 153-163.
Pigott, G. H. ; Gaskell, B. A.; Ishmael, J. (19£1) Effects of long term ir.-.ra-
tion of alumina fibres in rats. Br. J. Exp. Pathol. 62: 323-331.
Pott, F. ; Roller, M. ; Ziem, U. ; Reiffer, F. J.; Bellmann, B.; Rosenbruc*. V. ;
Huth, F. (1987) Carcinogenicity studies on natural and man-made fioe-s
w;th the intraperitoneal test in rats. Proceedings of a Synpcsiir c"
rrineral fibers in the non-occupational environment; Lyon, Frar.ce;
September 8-10.
Schepers, G. W. H. ; Delahant, A. B. (1955) An experimental study of the ejects
of glass wool on animal lungs. AMA Arch. Ind. Health 12: 276-27S.
Smith, D. M. ; Ortiz, L. W.; Archuleta, R. (1984) Long-term exposure of Syria-
hamsters and Osborne-Mendel rats to aerosolized 0.45 urn mean diameter
fibrous glass. In: Guthe, T. , ed. Biological effects of man-made mine re"
fibres: proceedings of a WHO/IARC conference in association with JEMRE ar.d
TIMA, v. 2; April 1982; Copenhagen, Denmark. Copenhagen, Denmark: World
Health Organization, Regional Office for Europe; pp. 253-272.
Smith, D. M. ; Ortiz, L. W. ; Archuleta, R. F.; Johnson, N. F. (1986) Long-terr
health effects in hamsters and rats exposed chronically to .man-made
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Copenhagen, Denmark: World Health Organization, Regional Office for Europe.
Smith, D. M. ; Ortiz, L. W.; Archuleta, R. F.; Johnson, N. F. (1967) Long-te--
health effects in hamsters and rats exposed chronically to man-made
vitreous fibers. Ann. Occup. Hyg. 31: 731-754.
Stadler, J. C. (1986) Two-year inhalation study in rats with Kevlar ficn'ls
[unpublished study]. Michigan: E.I. du Pont de Nemours and Company, Inc.;
Report no. 290-86; MR no. 4442-001.
Stenback, F. ; Wasenius, V.-M. ; Rowland, J. (1985) Alveolar anc1 interstitial
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Mono? 2: 195-213.
-------
Styles, J. A.; Wilson, J. (1973) Comparison between j_n vitro toxicity of
polymer and mineral dusts and their fibrogenicity. Ann. Occup. Hyg.
16: 241-250.
Styles, J. A.; Wilson, J. (1976) Comparison between in vitro toxicity of twc
novel fibrous mineral dusts and their tissue reactions i_n vivo. Ann.
Occup. Hyg. 19: 63-68.
Suzuki, Y. (1982) Carcinogenic and fibrogenic effects of zeolites: preliminary
observations. Environ. Res. 27: 433-445.
Tayton, K.; Phillips, G.; Ralis, 2. (1982) Long-term effects of carbon fiber on
soft tissue. J. Bone Joint Surg. 64: 112-114.
Trautwein, G. ; Helmboldt, C. F. (1967) Experimental pulmonary talcum granule's
and epithelial hyperplasia in the chinchi.Ha. Path. Vet. 4: 254-267.
Wagner, J. C. ; Berry, G. ; Cooke, T. J. ; Hill, R. J. ; Pooley, F. D. ; Skic-r^e.
J. W. (1S77) Animal experiments with talc. In: Walton, W. H., ed. Inre'e:
Particles IV: v. 2. Oxford, England: Pergamon Press; pp. 647-654.
Wagner, J. C.; Berry, G. B.; Hill, R. J.; Munday, D. E.; Skidmore, J. W. (19:-;
Animal experiments with MMM(V)F--effects of inhalation and intra^le^'a"
inoculation in rats. In: Guthe, T. , ed. Biological effects of n-.£--rr£ce
ir.inei-ai fibres: proceedings of a WHO/IARC conference in association *~'~
JEKnB and TINA, v. 2; April 1962; Copenhagen, Denmark. Copenr.ace-,
Denmark: World Health Organization, Regional Office for Europe;
pp. 209-233.
Woznisk, H. ; Wiecek, E. ; Tossavainen, A.; Lao, I.; Kolakowski, J. (1985;
Comparative studies of fibrogenic properties of wollastonite, chrysctile
and crocidolite. Med. Pracy 5: 288-296.
-
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6. DEVELOPMENTAL AND REPRODUCTIVE TOXICITY
A review of the literature revealed that very little research has bee-
conducted on the developmental and reproductive toxicity of manmade fibers,
synthetic fibers, and minerals.
6.1 MANMADE MINERAL FIBERS
The only available information on the teretogenicity of mineral fibers is
a letter by Nolen and Dierckman (1963) and a report by the Food anc! Drug
Research Laboratories, Inc. (1973). The report presented the results o' fc-"
te-strgevlcity studies conducted with a fine white powdered sodium silicc-
aluminate material. The composition and dimensions of the fibers used were net
reported (Food and Drug Research Laboratories, Inc., 1973). However, Ncler' a re
Dierckman (19S3) stated that the above studies were conducted with a food-c-ase
sodium aluminosilicate with an Na:Al:Si ratio of 1:1:13. The studies were
conducted with CD-I mice, Wistar rats, golden hamsters, and Dutch-belted
rabbits. Adequate numbers (23 to 32 mice, rats, and hamsters and 11 to
18 rabbits) of pregnant females were dosed, by oral intubation, daily beginning
with day 6 of gestation for 9 to 13 consecutive days. All animals received
oral doses of 16.0, 74.3, 345.0, or 1600 mg/kg body weight. Dams were weighed
at various intervals during gestatip.n and wne then subjected to cesarear.
section upon completion of pregnancy. The body wights of the live pups were
recorded, and the urogenital tract of each dam was examined. Fetuses were also
examined for external congenital abnormalities. One-third of the fetuses frorr
each litter underwent detailed visceral examinations, whereas the remaining
two-thirds were cleared, stained, and examined for skeletal defects. The
results indicated no clear compound-related effects on reproductive indexes.
No maternal or fetal toxicity was noted, and the number of variations anc
abnormalities seen in either soft or skeletal tissues of test fetuses were net
different frorr: those observed in sham controls.
July 19EE €-1 DRA-T —SO N:T C-1": ^ ::"E
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6.2 SYNTHETIC FIBERS
No information on the developmental or reproductive toxicity of synthetic
fibers was found in the available literature.
6.3 MINERALS
No information on the developmental or reproductive toxicity of attapul-
gites, talc, or vermiculite was found in the available literature. Nolen enc
Dierckman (1983) reported results of a teratogenicity study with synthetic
zeolite (Type A) tested in Sprague-Dawley rats and New Zealand rabbits. The
zeolite contained 15.8, 19.0, and 20.1 percent Na, Si, and Al, respectively.
It was adrinistered in distilled water by gavage to rats at doses of 74 or Ifl!
mg/kg body weight on days 6 to 15 and to rabbits at 74, 345, or 1600 mg/kg o~
days 6 to 18. Zeolite A produced no adverse effects on the dams, the errc-ycs,
or the fetuses in either species at any of the doses tested.
6.4 REFERENCES
Food .and Drug Research Laboratories, Inc. (1S73) Teratologic evaluation cr" rD-
71-45 (sodium silicoaluminate). Rockville, MD: U. S. Department of Hea":tn.
Education, and Welfare, Food and Drug Administration; contract nc. FDA
71-260. Available from-. NTIS, Springfield, VA; PB-223S10.
Nolen, G. A.; Dierckman, T. A. (1983) Test for aluminosilicate teratogenicity
in rats. Food Chem. Toxicol. 21: 697.
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7. MUTAGENICITY, CYTOTOXICITY, AND CARCINOGENICITY
7.1 MUTAGENICITY
7.1.1 Manmade Mineral Fibers
7.1.1.1 Fibrous Glass. Glass fibers (0.12 and 1.9 pm in diameter) sho* nc
evidence of mutagenicity in bacterial assays. Studies with eukaryotic ce^s
sho* that rm'crofibers with average diameters of 0.1 to 0.3 pm induce chrcmcsc-e
aberrations in two hamster cell lines, whereas thicker glass fibers wit1-.
average diameters of 0.8 pm are much less potent. Chamberlain and Tarmy (1977)
tested glass fibers in bacterial strains and found no evidence of mutagenic'ty.
Fibers were Johns Manville codes 100 and 110 with mean particle sizes (dianete-
x length) of 0.12 x 2.7 uir, and 1.9 x 26.0 urn, respectively. No reverts--..; *5~e
found in Escherichia col i W-2uvrA or Salmonella typhimurium strains TA152; cr
TA153E with or without S9 activation at levels of 0.1 or 1 mg/plate. However,
as noted by the authors, bacterial systems may not be appropriate for assaying
the mutagenicity of particulates, since the fibers do not enter the bacte'ia
as they do eukaryotic cells. Crocidolite, chrysotile, amosite, and
anthophyllite were inactive in the same systems at the same dose levels.
Brown et al. (1979a) tested glass fibers (codes 110 and 100) for
genotoxicity in Chinese hamster V79-4 cells. The respirable fraction of the
coarser material (110R) was more cytotoxic than the total fraction (HOT); a
50 percent reduction in cloning efficiency occurred at 20 pg/mL 110R when
compared to 50 g/mL HOT. This concentration also caused a significant
(p <0.01) increase in chromosomal fragments and breaks, and a nonsignificant
increase in gaps. The distribution of fibers with a diameter of 0.1 to 0.3 prr
and lengths of 2 to 5 pm or 5 to 10 pm was 33 and 19 percent for 110R, respec-
tively. Results on chromosomal aberration with code 100 fibers were not
presented. Sincock et al. (1982) exposed Chinese hamster ovary Kl cells for
48 hours to 0.01 mg/mL of code 100 and 110 glass fibers and found that code
100 induced chromosome aberrations (all chromosome breaks) in 14 percent cf
the scored metaphases as compared to a 2 percent aberrant all frequency ir. the
control group. The code 110 fibers produced negative results.
•>• •>•• lest 7-1 DRArT--DD N" C.'I'H t~- --"-
-------
Hesterberg and Barrett (1984) studied glass fiber codes 100 and 110 for
their ability to transform Syrian hamster embryo cells in culture. Code 100
glass fibers had an average diameter of 0.13 ± 0.11 urn, ar>d code HO had an
average diameter of 0.8 ± 0.06 urn. The average length of the thinner fibers
was 9.5 ± 0.7 urn. The thin code 100 glass fibers were about as active as
chrysotile, on a weight basis, in inducing morphological transformation. There
was a good linear correlation between dose and transformation frequency, and
cytotoxicity and cell transformation frequency were also correlated. Transfo'r-
2
mation frequency was about 1.2 percent at 0.5 g/cm of code 100 glass fibers
2
and 1.6 percent at 0.5 ug/cm chrysotile. Code 110 thick glass fibers we<-e
20 times less potent on a basis of weight in their cytotoxic effect and induc-
tion of transformation. Milling of code 100 glass beads (10 minutes in 5-
electric blender) reduced the average fiber length from 9-5 to 1.7 pm but hac
little effect on diameter (0.11 versus 0.13 urn); milled fibers had decreased
cytotoxicity and a 10-fold decrease in transformation ability. Mining of
chrysotile also destroyed transforming ability, but these fibers tended to
clump after size reduction.
7.1.1.2 Mineral Wool. No information on the mutagenicity of mineral woo" was
found in the available literature.
7.1.1.3 Ceramic Fibers. No information on the mutagenicity of ceramic fibers
,was found in the available literature.
7.1.2 Synthetic Fibers
No information on the mutagenicity of aramid, carbon, or polyolefin fibers
was found in the available literature.
7.1.3 Minerals
7.1.3.1 Erionite. In vitro cytogenetic studies conducted by Palekar et el.
(1987) indicated that erionite fibers, over a mass dose range of 10 to
100 ug/ml, induced significant but not clearly dose-related increases ir
aneuploidy and polyploidy in V79 Chinese hamster lung cells. Although the per
mass dose response was comparable to that elicited by the two asbestos fibe-s
included in the study (UICC chrysotile and U1CC crocidolite), the findings or a
per fiber basis suggested that erionite was more reactive than the otne-
mineral fibers. The same investigators found that 100 pg erionite/mL caused a
significant increase in chromosome aberrations (chromatid breaks and frac^e'ts)
-------
however, the erionite was less effective in inducing structural aberrations
than the asbestos fibers.
Poole et al. (1983) found that Oregon erionite of respirafcle size was
genotoxic in cell transformation and unscheduled DNA synthesis (UDS) tests.
The median length and diameter of fibers was 1.7 x 0.2 urn; all fibers were less
than 1.0 pm in diameter, and 80 percent were <4 \im in length. Type III trans-
formed foci of C3H10T 1/2 cells were -found in 4/20 flasks at 20 pg/mL*1
erionite; at this level 46 percent of the cells survived, and the calculatec
transformation frequency was 0.6 foci/flask as compared to 0/20 foci in the
control group. In a second experiment, levels of 15, 20, 25, and 30 pg/rrL
erionite were tested. There were Type III foci in 6/12 (50 percent) flasks
(0.83/flask) at 20 pg/mL, but increased cytotoxicity and decreased transfo-~a-
tion were noted at higher levels. Erionite was, therefore, considered positive
in this test system. Stimulation of UDS in C3H1DT 1/2 cells and in A54S hi.r=->
cell cultures by erionite was also found at levels between 100 and 200 ug/rcL
(Poole et al., 1983).
7.1.3.2 Attapulcjite. Dem'zeau et al. (1985a) reported the absence cf
genotoxic effects when samples of attapulgite, xonolite, and synthetic
sepiolite were tested for UDS in primary cultures of rat hepatocytes at le.e's
of 1 and 10 pg/mL. Xonolite, however, was found to reduce UDS stimulate:: by
2-acetylaminofluorene (0.05 and 0.25 g/mL) in the rat hepatocyte system.
7.1.4 Talc
Lord (1978) reported that Litton Bionetics, Inc., evaluated talc for
mutagenicity in 1973. There were no increases in gene mutation in Salmonella
or Saccharomyces at 200 mg/mL, and no increase was reported for chrome-seme"!
aberrations in rat bone marrow cells or for dominant lethal mutation in the
germinal cells of male rats exposed to 30, 300, or 3000 mg/kg. Study details
were not available.
7.1.5 Vermiculite
No information on the mutagenicity of vermiculite was found in the avail-
able literature.
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7.2 IN VITRO CYTOTOX1CITY
7.2.1 Introduction
In vitro cytotoxicity screening tests are rapid, cost-effective, reproc'jc-
ible, and sensitive methods of determining the potential of mineral fibers to
induce cellular damage in cultured mammalian cells. The available assays
employ a variety of cell systems (erythrocytes, V79-4 Chinese hamster lung
cells, A549 type II alveolar human tumor cells, and P388D1 macrophage-type
cells) to measure critical endpoints of cytotoxicity. The assays correlate
well with _in vivo studies, provide valuable information regarding the physics"
and/or chemical modes of cytotoxicity, and are considered sensitive predictors
of potential mineral-fiber-induced fibrogenicity and/or carcinogenicity
(Mossman et al., 1985).
7.2.1.1 Procedures Available To Measure Cytotoxicity. Much of the vn vitrs-
cytotoxicity research examines fiber-induced membrane disruption. Biologically
active fibers that lyse erythrocyte membranes, causing a release of hemcclcbi r,,
are said to be hemolytic. Biologically active fibers that disrupt meir.bra-es i-
other mammalian cells, such as fibroblasts and macrophages, are classifies' as
cytotoxic. For these cells, the effects of the test agent on intracellulc-
menbranes can be assessed. For example, lactic dehydrogenase release is
indicative of adverse effects on plasma membranes. Lysosomal membrane disrup-
tion is indicated by the release of B-glucurcnidase, acid phosphatase,
p-N-acetylglucosaminidase, or B-galactosidase. Lysis of plasma and nuclear
membranes or a breakdown of DNA polymer can be determined by the release of
tritiated thymidine-labeled DNA into the cell culture medium (Richards and
Hunt, 1983).
Compound effects on cell viability are measured by trypan blue exclusion
and fluorescein d'iacetate uptake. The inhibition of colonial growth assay
developed by Chamberlain and Brown (1978) measures the ability of cells treated
with fibers to form colonies (a colony is an aggregate of 50 or more cells
arising from a single progenitor). Cytotoxicity can also be measured by tne
ability of test substances to promote morphological alterations in membrane
structures (e.g., giant cells) or decrease macrophage phagocytic activit;-
(Warheit et al., 1984). Although these i_n vitro assays have many applications,
they are not without limitations.
-------
glass fibers incubated with trachea! mucosa cells from 6- to 8-week-old male
Syrian hamsters produced a significant (p <0.05) cytotoxic response (Woodworth
et al., 1983). Fifty percent of the fibers had diameters <0.2 urn, and
94 percent were no greater than 1.0 urn wide. The majority of the fibers were
long, with 54, 78, 87, 94, and 100 percent having lengths <10, 20, 30, 50, er.c
100 urn, respectively. Approximately 1 and 2 percent of the cultured cells
either died or were sloughed off following exposure to 4 or 16 mg fibers/ml,
respectively. A similar response was recorded for short crocidolite asbestos
fibers. A nonfibrous analog (glass particles) failed to produce any signifi-
cant changes in the cell cultures. The authors suggested that fiber geometry
is critical in evaluating the toxic potential of fibers.
Maroudas et al. (1973) incubated AAA glass fibers (average thickness
0.6 um; length, <10 to 320 um) with cultures of 3T3 or BHK21 fibroblasts for
6 days. A sigmoid relation was observed between length and the probability cf
inducing growth. Both cultures showed maximum growth on 200 urn and longer
fibers and no growth on fibers with lengths of 20 urn or less. These resets
correlated with u> vivo studies showing increased incidence of mesotheliorr.as in
rats treated intrapleurally with AAA glass fibers as the percentage of longer
fibers (20 to 320 urn) in the implants increased.
The authors postulated that fibers with lengths ^40 um stimulate fibrc-
blastic growth i_n vitro by inducing an anchorage-dependent response (normal
anchorage-dependent cells cannot grow in suspension unless the cells can attach
to solid substrates above a critical mass). The induction of this response
i_n vivo may then lead to the development of mesothelioma. Persistent hyper-
plasia in fibroblasts or in reticuloendothelial cells may therefore constitute
a preinitiation and is probably an essential stage in the promotion of solio
* implant-induced carcinogenesis (Maroudas et al., 1973).
Vincent et al. (1983, in abstract form) compared the cytotoxicity of glass
fibers (codes 100, 108, and 110) toward human fibroblasts with that of several
forms of asbestos (UICC amosite, anthophyllite, crocidolite, and chrysotile A
and B), and found that long, thin glass fibers were as toxic as asbestos fibers
of the same dimensions. Cytotoxicity was evaluated by measuring cell viability
and the release of labeled cellular DNA into the culture medium. The two
active materials were the similarly sized UICC chrysotile B and hand-milled
code 100 glass fiber. Results of the viability assays showed that 100 ys'ir.L
UKC chrysotile B or code 100 glass fibers induced death in 40 to 60 percent o*
-------
the original fibroblast population. The release of radioactivity observed in
cultures exposed to either substance was associated with the reduction of
numbers of attached cells but not with [H]decay-induced damage to the nucleus.
The authors concluded that tritium leakage was not due to DNA degradation in
viable cells or to artifact accumulation from radiolabeling; rather, fH]DN-.
leakage was attributed to the direct cytotoxic attack of the fibers on plasma
and nuclear membranes. Structural changes observed in exposed cells supported
this conclusion.
Tilkes and 8eck (1980, 1983a,t>) investigated the cytotoxicity of well-
defined mineral fibers on macroph»ges (1983a) and phagocytic epitheloid ascites
tumor cells (1980, 1983b). The size distributions of the glass and asbestos
fibers are presented in Table 7-1. For the macrophage assays, guinea pig a-;
rat lung macrophages were obtairiicJ py pulmonary lavage and allowed to attacr. tc
culture dishes prior to fiber tntsiment. Fiber doses were equivalent on e
gravimetric basis in most expe-Mise'-.ts and on a numerical basis in additional
experiments. The release of ?arta.t€ dehydrogenase and 6-glucuronitiase w = s
measured as an indicator of Eyu/Lwcity. Assays measuring carboftyarste
metabolism and phagocytic. abilfoj-**fe also conducted. The asbestos end c'ess
fibers caused lactate dehydrogenej* and p-glucuronidase release from the c.-ires
pig macrophages at a relatively Tow concentration (100 fibers per cell).
Similar responses were elicited fry crocidolite, amosite, and glass fiibers when
the doses were numerically equivalent (100 fibers per cell), but the responses
were dependent on fiber diametf- and length. For fibers of similar physical
dimensions, the extent of cytoiD*icity of all asbestos and glass samples
detailed in Table 7-1 were comparable when doses were graviwetrically equivalent
(100 mg dust per million cells), frelinrinary experiments further showed tnat
" asbestos and glass fibers reducs-d the phagocytic abiHty of the unacrophages.
The authors concluded that if geometr?r dimensions are similar, fibers with
different physicocherrncat compusntions induced comparable responses. Long,
thin fibers of glass, chrysolite,, crocidolite, and synthetic fluoroamphiboles
were all toxic in the test system. These results support previous findings
using established macrophage cell lines (Beck et a!., 1972).
Similar results were obtained when the fibers listed in Table "'-1 were
incubated with cultures of phagi»cytic epitheloid ascites tumor cells (Tilkes
and Beck, I960, 1983b). The authors also measured DNA, RNA, and prcteir.
synthesis in these cultures and noted that fibers from diverse sources showed
-------
Mammalian cells can adjust to fiber-induced damage through various mecha-
nisms that are related to cell type and the conditions of the culture medium
(Mossman et a!., 1983). Cytotoxicity elicited by certain fibers can be merr-
brane specific; therefore, disruption of the plasma membrane does not assure a
similar response on surface membranes or other intracellular membranes (Davies,
1980; Yano et a!., 1986).
7.2.1.2 Test Material Composition. The physical state of the test material is
a major consideration in the evaluation of cytotoxicity. The Stanton hypothe-
sis (Stanton, 1973) holds that the pleura! sarcoma-inducing behavior of fibers
is a function of fiber length and diameter. On a per weight basis, "thick"
fibers generally are less cytotoxic and tumorigenic in the pleura of rets and
harr.sters than "thin" fibers (Smith et a!., 1980; Harington, 1981). Althojg" e
close association between the cytotoxicity of various fiber types and their
ability to induce neoplasia exists, it is also recognized that fibers with a
minimuir, length of 8 urn and a diameter of 1.5 pm or less are cytotoxic rec-s-d-
lesi of chemical composition (Archer, 1579).
Reason dictates that short fibers with a small diameter are more cytctcxi:
than longer fibers because they are more readily engulfed by phagocytes.
However, Gormley et al. (1980) showed an association between increasing fiDe-
length of 12 naturally occurring mineral dusts and cytotoxicity. In P3653, snc;
A549 cells, the greatest cytotoxicity effect was induced by fibers >8 urn in
length, whereas in the V79-4 cell line, fibers that were >10 urn in length were
the most cytotoxic. In the same study, the association between fiber diameter
and cytotoxicity was assessed. For P388D, and A549 cells, a fiber diameter of
0.2 to 0.3 urn was significantly correlated with cytotoxicity. However, no
correlation between fiber diameter and cytotoxuity could be established for
the V79-4 cells.
The number of fibers that can be potentially phagocytized and elicit a
cytotoxic response should also be taken into account before a fibrous material
is considered biologically inactive (Hesterberg and Barrett, 1984). The point
is illustrated by the findings of Brown et al. (1979b), who calculated the
number of fibers in a given weight of code 100 and code 110 glass fibers a-.:
found that code 110 glass fibers, although much less cytotoxic than the
code 100 glass fibers on a per weight basis, were more cytotcxic on a pe-
fiber basis.
-------
Most studies correlate fiber geometry with cytotoxicity and deemphasize
fiber composition. However, the cytotoxicity of a fiber does appear to depend
somewhat on chemical composition, since several types of absorption phenomena
are known to develop between cellular membranes and fiber components. Accord-
ing to Mossman et al. (1983), the release of oxygen free radicals is a poten-
tial result of this type of interaction that can, in turn, lead to pronounced
membrane alterations (see Section 7.2.7). In other cases, membrane—fiber
interactions can lead to cell depolarization that may produce changes in
membrane permeability (Mossman et al., 1983).
7.2.2 Manrr.ade Mineral Fibers
7.2.2.1 Glass Fibers. Several studies have confirmed the cytotoxicity of
glass fibers. Equivalent masses and numbers of various glass and asbestos
fibers induced comparable cell responses, but the extent of toxicity was
primarily dependent on fiber size. Long, thin (diameter ^0.3 pm and length ID
to 40 pm for £3 and 74 percent of the fibers, respectively) and long, ve-y tMr.
fibers (diameter <0.2 pm and length 10 to 60 pm for 9B.1 and 50 percent.
respectively) glass fibers were as cytotoxic to epitheloid ascites tumor eel's,
mouse peritoneal macrophages, hamster embryo cells, and guinea pic, rat, enc1
dog lung macrophages as similar-sized chrysotile, crocidolite, amosite, ani
synthetic fluoramphiboles. Long, thin asbestos and glass fibers also reduced
the phagocytic ability of macrophages and inhibited DNA, RNA, and protein
synthesis in the above-mentioned cells. These glass fibers (mean diameters
between 0.12 and 1.9 pm) also slowed the growth of adult and fetal human
fibroblasts and human bronchial epithelial cells. The cytotoxic behavior of
the long, thin glass fibers corresponds to results of in vivo studies in which
rats and hamsters treated intrapleurally and rats treated intraperitoneally
showed an increased incidence of mesotheliomas.
Hesterberg and Barrett (1984) reported that glass fibers (0.5, 1.0, 2.5,
5.0, and 10 pg/cm ) were as potent in reducing survival of Syrian hamster
embryo cells as were the positive controls, UICC chrysotile and crocidolite
asbestos fibers. Consistent with the earlier introductory statements regardinc
fiber length, thin glass fibers (diameter 0.13 ± 0.005 pm) were more cytotcxic
than thick glsss fibers (diameter 0.8 ± 0.06 pm). A dose of 1 pg/cm of the
thin glass fibers resulted in 5 percent cell survival; the same dose of tnick
glass fibers resulted in 86 percent cell survival. In another study, cede 100
-------
TABLE 7-1. SIZE DISTRIBUTION OF SOME ASBEST1FQRM FIBERS
USED IN IN VITRO CYTOTOX1CITY STUDIES3
Fiber type
Johns Kanville
respirable glass
(code 100)
Johns Manville
respirable glass
(code 110)
Short, very thin
glass fibers
(4105-23-7)
Lc~:, ve-y thin
class fibers
(4105-24-2)
Short, thin
glass fibers
(4106-4-3)
Long, thin
glass fibers
(4106-19-2)
Short, thick
glass fibers
(4106-5-1)
Length
Length
(pm)
2-5
5-10
10-20
>20
2-5
5-10
10-20
20-30
30-40
>40-
<1
1.0-1.9
>1.9
1.0-2.9
3.0-4.9
5.0-9.9
10-19
20-29
30-59
1.0-1.9
2.0-2.9
3.0-4.9
5.0-9.9
10-22
<5
5.9-9
10-19
20-39
40-59
60-99
1.0-2.9
3.0-4.9
5.0-9.9
10-19
20-29
distribution
% of
fibers
60.6
34.8
2.5
2.1
18.6
28.1
30.6
12.8
3.6
6.3
83.6
11.5
4.8
9.2
15.8
25.0 '
30.0
9.2
10.8
14.1
35.2
35.2
8.5
7.0
0.7
7.0
37.5
36.0
14.8
4.0
22.4
33.5
31.5
10.5
2.1
Diameter di
Diameter
(pm)
<0.1
0.1-0.3
0.3-0.6
0.6-1.0
<0.1
0.1-0.3
0.3-0.6
0..6-1.0
1.0-1.6
>1.6
<0.1
0.1-0.14
0.15-0.19
0.2-0.29
<0.1
0.1-0.14
0.15-0.19
0.2-C.2S
0.3-0.59
(0.41)
0.15
0.15-0.29
0.3-0.59
0.6-0.99
1.0-1.99
<0.15
0.15-0.19
0.20-0.29
0.30-0.39
0.40-0.59
0.60-1.49
<0.4-0.59
0.6-0.99
1.00-1.49
1.50-1.99
3.00-3.95
Strifcutioi
% cf
fibers
17.6
53.7
24.3
4.4
0
2S.4
20.0
25.2
15.2
9.2
52.0
35.4
5.7
6.9
62. 7
25.6
£.£
i. c
0. 3
c Q
16.4
35.4
26.2
16.1
51.4
15.6
11.9
6.1
6.2
4.6
3.£
5.£
15.2
2£.6
17.6
(continued on the following page)
7-5
-------
TABLE 7-1. (continued)
Fiber type
Long, thick
glass fibers
(4106-19-la)
Jeffry fibrils
(4173-46-1)
Je'fry fibrils
(4173-46-2)
Sno't Mjnroe fibrils
(4173-60-1).
Long Munroe
chrysotile
(4173-60-2)
Short crocidolite
(S. African)
Length
Length
3.0-4.9
5.0-9.9
10-19
20-29
30-59
60-99
<1.0
1.0-1.9
2.0-4.9
5.0-9.9
10-19
0.10-0.99
1.0-1.9
2.0-4.9
5.0-9.9
10-19
20-39
0.40-C.95
1.0-1.49
1.5-1.99
2.0-2.99
3.0-4.99
5.0-9.99
3.0
3.0-4.9
5.0-9.9
10-19
20-60
6D-SO
0.40-0.99
1.0-1.9
2.0-4.9
5.0-9.9
10-19
20-29
distribution
% of
fibers
9.9
14.6
28.9
20.1
22.1
4.4
29.5
34.7
27.6
6.6
1.6
11.8
20.0
24.1
20.5
17.7
5.9
22.5
29.7
21.0
15.3
10.0
1.7
0.0
0.7
4.3
26.4
65.7
2.9
17.6
44.4
19.8
6.2
1.6
0.4
Diameter di
Diameter
(urn)
<0.2-0.59
0.6-0.99
1.0-1.49
1.5-1.99
2.0-2.95
3.0-5.95
<0. 03-0. 05
0.10
0.03-C.05
<0.1
o!l-0.29
0.3-0.59
0.6-0.99
1.0-1.99
2.0-2.5
0.03-0.04
0.05-0.09
0.10-0.19
0.20-0.39
0.40-0.59
0.60-0.99
stribution
/t of
fibers
4.1
16.0
35.2
22.7
14. e
5.2
99.9
9r. S
c: c
4C.2
20.2
e.6
13.6
4.2
13.3
1.2
7.5
43.3
32.4
4.4
1.2
(continued on the following page)
-------
TABLE 7-1. (continued)
Fiber type
Length distribution
LengthS~oT"
(urn) fibers
Diameter distribution
Diameter% of'
(urn) fibers
Short crocidolite
(4106-23-9)
Long crocidolite
(4106-22-4)
Short f luoroamphiboTe
(4106-31-3)
Respirable
f luoroamphibole
(4106-30-1)
0.1-0.69
0.7-0.99
1.0-2.9
3.0-4.9
5.0-9.9
10-19
3.0-4.9
5.0-9.9
10-19
20-29
30-59
60-129
<1
1.0-1.9
2.0-4.9
5.0-19.0
0.5-1.49
1.5-2.9
3.0-4.9
5.0-9.9
10-19
20-39
47.8
22.3
24.6
3.5
1.5
0.3
4.2
13.6
28.3
23.0
24.1
6.8
89.9
5.8
3.6
0.75
8.2
21.5
27.0
27.5
12.5
3.5
<0. 05-0. 09
0.10-0.14
0.15-0.19
0.20-0.29
0.30-0.39
0.10-0.14
0.15-0.19
0.20-0.29
0.30-0.39
0.4-1.49
0.03-0.09
0.10-0.19
0.20-0.39
0.40-0.99
1.0-2.95
0.03-0.04
0.05-0.14
0.15-0.39
0.40-0.99
1.0-2.0
25.3
40.0
19.4
13.3
2.0
27.8
15.0
3C.S
13.1
7.9
46.0
40.9
c ~
2.9
0.6
44.7
25.3
20.9
5.6
3.5
Dsta on the size distribution for Johns Manville glass codes 100 and 110
are from Brown et al. (1979); all other data are from Tilkes and Beck
(19833,b).
the same trend, i.e., toxicity increased with increasing fiber length and dose.
In general, DNA, RNA, and protein synthesis of the cultures were inhibited by
long, thin fibers of glass, asbestos, and fluoroamphibole (a synthetic amphi-
bole). Cytotoxicity also increased when long, thin fibers were used in this
test system. The authors concluded that the toxicities of fibers from differ-
ent sources but with similar fiber dimensions were generally comparable, anc
for long fibers (>20 urn) of equivalent weights, the thinner the fiber, the
greater the toxicity. Additionally, a glass fiber fraction with a conficL-a-
tion similar to a UICC fraction of chrysotile asbestos exhibited the sare nigh
toxicity (Tilkes and Beck, 1983b).
-------
The importance of fiber length and diameter has been demonstrated with
other glass fibers in different jin vitro cytotoxicity assays. After milling
and collecting respirable fractions of codes 100 and 110 Johns Manville fiber-
glass (see Table 7-1 for size distributions), both fiber types were found to be
cytotoxic to cultured V79-4 cells, mouse peritoneal macrophages, and A549 cells
(Brown et a!., 1979a,b). The thinner fibers (code 100) were more cytotoxic
than the thicker fibers (code 110) when fibers were applied at equivalent
gravimetric doses. The authors suggested, however, that the increased cytotox-
icity of the code 100 fibers may have been due to the larger number of fibers/c
10 Q
(78.2 x 10A ), as compared to code 110 (25.2 x 10 fibers/g); numerically
equivalent doses were not used in these experiments. Similar results were
obtained by Hesterberg and Barrett (1984) with codes 100 and 110 fiberglass ir
Syrian hamster embryo cells and by Pickrell et al. (1963) using glass fibers of
specified dimensions in pulmonary alveolar macropnage cells of beagle docs.
Longer, thinner glass fibers were more cytotoxic and induced a higher incidence
c: cell transformation than shorter, thicker fibers (the materials were cra\->
metrically equivalent; see Section 5.1 for details).
In contrast, Nakatani •(19E3) reported that glass fibers with a larger
diameter (code 110) were more cytotoxic than smaller diameter fibers (code 10C-)
when gravimetrically equivalent doses were applied to cultures of mouse perito-
neal macrophages. The size distributions of the glass fibers used by Nakatani
(1953) were similar to these used by Brown et al. (1979b) (see Table 7-1).
Fiber diameter appeared to play a role in inhibiting the growth of primary
adult and fetal human fibroblasts following exposure to 50 and 100 ug/mL code
100 glass fibers (Sincock et al., 1982). Human cells were incubated with
either code 100 or code 110 glass fibers for 4 days. Mean fiber lengths
measured between 2.7 and 26 urn; mean fiber diameters were between' 0.12 and
1.9 um. Significant inhibition of cell growth was apparent in both cell lines
within 2 days of exposure to code 100 fibers; inhibition persisted through the
fourth day of the experiment. Fetal fibroblasts appeared to be more resistant
to the cytotoxic effects of the fiber (code 100) than did mature cells. Code
110 glass fibers had no effect on the growth rate of fetal or adult fibre-
blasts. Although cell growth was severely blocked after exposure to the code
100 glass fibers, cell viability was not affected by either fiber. The authors
concluded that the differences were probably related to particle diarr.ete".
since the code 100 fibers were much thinner than the code 110 fibers.
-------
The growth rate of human bronchial epithelial cells exposed to glass
fibers (0.3, 1.0, 3.0, 10, 30, or 100 ug fibers/ml; fiber dimensions not
reported) was inhibited in a dose-related manner (Haugen et al., 1982). The
number of cell population doublings/day (approximately 0.75 to 0.80) declined
slowly but was comparable to the control values for cells exposed to <10 ing
glass fibers/ml. However, as fiber concentration increased from 30 to
100 ug/mL, the number of dividing cells dropped to 0.6 and 0.45 doublings/dsy,
respectively. Although cell numbers were reduced, glass fibers were considered
to be only mildly cytotoxic when compared to asbestos fibers, which were 100
times more cytotoxic. Under similar conditions, human bronchial fibroblastic
cells exposed to 100 ug glass fibers/ml showed no cytotoxic effects.
Jaurand and Bignon (1979) indicated that glass fibers of an unreported
source and physical dimension were weakly hemolytic; however, the degree of
hemolytic activity was similar to that of UICC crocidolite, but less intense
than that of UICC chrysotile.
Chang et al. (1963) incubated samples of glass fibers and chrysotile w-:t"
macromolecules (bovine serum albumin, DNA, and RNA) and human dermal fife-
blasts. Results indicated that the glass fibers were neither cytotoxic nor
able to bind to any appreciable degree to tissue macromolecules. In contrast
to the negative results with glass fibers, the asbestos sample was both adsc^-
bent and cytotoxic. The authors drew a correlation between tissue binding
capacity and cytotoxicity. The data, however, are insufficient to support this
conclusion because no information on fiber dimensions was reported.
1.2.2.2 Mineral Wool/Rock Wool/Slag Wool. Nadeau et al. (1963) reported that
"type 1 and 2" mineral wool fibers (diameter 3.3 urn and length 221.4 urr: for
type 2) were not cytotoxic to rat pulmonary alveolar macrophages or erythro-
cytes. However, other investigators have demonstrated that rock and slag wods
can induce slight to considerable cytotoxicity (as measured by the release of
lactate dehydrogenase and £-glucuronidase) in V79-4 Chinese hamster lung cells,
A549 human tumor cells (Brown et al., 1979b), and mouse peritoneal macropr-ages
(Davies, 1980).
Respirable rock and slag wool fibers (160 mg/ml) induced an 11 to 16 pe~
cent increase in the release of lactate dehydrogenase and a 26 to 36 percevt
increase in the release of 6* glucuronidase from mouse peritoneal mac replaces
after an 18-hour incubation period (Davies, 198D). The authc^ conclude: that
the fibers were weakly cytotoxic to the murine cells.
July 19£E 7-13
-------
Rock wool and slag wool also wrre cytotoxic to cultured V79-4 cells and
induced giant cell formation in A545 human tumor cells (Brown et a!., lS79b,
1980). Although the exact size distributions of the fibers were not given, the
authors indicated that a "significant portion" of the fibers were less than
1.5 urn in diameter and had lengths greater than 8 urn.
7.2.2.3 Ceramic Fibers. Several inv-esti gators (Gormley et a!., 1980; Wright
et a!., 1980; Nadeau ct al., 1987) -have reported that ceramic (aluminum sili-
cate) fibers are neither hemolytic toward erythrocytes nor cytotoxic in rat
pulmonary alveolar macrophages or marrophage-like P338D, cells. The ceramic
fibers used had median diameters raiding from 0.2 to 0.6 urn and approximate
lengths of 2 to 100 urn. In all cas*=., the data showed minimal cell damage aio
cell death.
Potts et al. (1976) reported th?t 100 g of Dow Chemical Company "ceraT-c
foam" with a mean diameter of 5 urn was not hemolytic in Sprague-Dawley rat
erythrocytes. Less than 1 percent irf the rat erythrocytes were hemclyzec1 by
ceramic foam; positive controls exhibited 94.7 percent hemolysis. The ai-thcrs
noted that the low rate of hemolysvi for ceramic foam was consistent wit".
j_n vivo data showing that ceramic fri^s are not fibrogenic.
Two other types of ceramic fibtts, Saffil alumina and Saffil* zircor.ia,
were found to be minimally cytotoxic and nonfibrogenic when incubated with rat
peritoneal macrophages in vitro (Styles and Wilson, 1976). However, the
diameters of both fibers (2 to 6 urn) were probably beyond the respirable range,
since Sebastien et al. (1979) found Irat 99 percent of the mineral fibers fojns
in lung tissue of necropsied animals' •had diameters less than 0.33 urn. There-
fore, the relevance of the in vitro aata reported by Styles and Wilson (1976)
is questionable.
7.2.3 Synthetic Fibers
7.2.3.1 Aramid Fibers. Little information is available on the i_n vitro
cytotoxicity of aranritJ fibers. One study, however, showed that short arax-id
fibers incubated with cultures of rai .pulmonary alveolar macrophages can induce
leakage of cytosol and lysosomal ma"-ker enzymes with a concomitant decrease
in ATP cell content (Dunnigan et al., 1984). Aqueous solutions (25, 50, ICC.
ff
and 250 ug fibers/ml) of commercial-grade Kevlar fibers were incubate: for
18 hours with macrophages obtained '•••-om adult male Long-Evans black-hocce:
-------
rats. Approximately 90 percent of the fibers were less than 5 um long and
0.25 pm wide; the average length and diameter were 2.72 and 0.138 pm, respec-
tively. Dose-related increases in lactate dehydrogenase and p-glucuronidase
release and a dose-dependent drop in cellular ATP were observed for the
aramid-treated cultures. The response of freshly harvested aramid-exposec
alveolar cells was comparable to that of freshly harvested chrysotile-exposed
cells. When the respective cultures were grown 24 hours prior to fiber expo-
sure, the cytotoxic response was highest with aramid. The authors concludes
that aramid fibers are biologically active and suggested that the cytotoxic
behavior of these fibers should be confirmed in animal studies.
7.2.3.2 Carbon Fibers. Carbon fibers of various sizes (diameter 0.2 to 15 ur.)
were only minimally cytotoxic to rat peritoneal and pulmonary macrophages an:
induced no signs of toxicity following ip injections to rats. Styles anc
Wilson (1976) exposed peritoneal and alveolar macrophages from male and female
Wistar rats to approximately 0.5 mg (3.75 x 10 particles) carbon fibers
(diameter 0.2 to 15 pm) for 2 hours. Several other fibers, polymers, ar.d
mineral dusts were investigated to determine their relative cytotoxic pcte.r.-
tial. The overall cell mortality was highest in cells incubated with asbestos
or polyurethane foam dust; at least 10 and 60 percent of peritoneal anc1 pulr.c-
nary macrophages, respectively, were killed following exposure to these
materials. Carbon fibers were only minimally toxic to cells: less than 2 and
5 percent of the peritoneal and pulmonary cell populations, respectively, were
killed after phagocytosis of the carbon dust particles.
In a separate experiment, six male and six female Wistar rats were
injected intraperitoneally with 50 mg carbon fibers/kg in a 10-mg/mL saline
suspension. No lesions, fibrosis, or granulomatous reactions were observed in
any of the dosed animals. The authors found a good correlation between the
jm vivo and jjj vitro activities of the materials tested and concluded that
carbon fibers exert minimal uj vivo and HJ vitro toxicity (Styles and Wilson,
1976).
7.2.3.3 Polypiefin Fibers. In a study conducted by Styles and Wilson (19/6),
polyethylene "AUathene" and polypropylene exhibited low cytotoxic activity and
produced no i_n vivo histopathological or clinical signs of toxicity in rats.
Peritoneal and pulmonary alveolar macrophages obtained from male ana fe-=ie
Wistar rats were incubated with 0.5 mg of either type of polyolefin fiber
(diameter 3 to 75 um for polyethylene and 4 to 50 urn for polypropylene). Tre
July ISEc 7-15 DRArT--D: NCT £'*'" C-~ --":
-------
cell response to both polymers was similar: less than 1 percent of the perito-
neal macrophages and 4 percent of the pulmonary macrophages were killed follow-
ing phagocytosis of the test materials. Male and female Wistar rats (six/sex),
administered a single ip dose of 50 ing polyethylene or polypropylene/kg,
exhibited no lesions, fibrosis, or granulomatous reactions; no adverse clinical
symptoms were noted during the 3-month postdosing period. In the same study,
other fibers, polymers, and mineral dusts were evaluated, and the two polyolefin
fibers were judged to be relatively inert.
7.2.4 Minerals
7.2.4.1 Attapulgite/Sepiolite. The naturally occurring fibrous clay miners1,s
attapulgite and sepiolite generally appear to exhibit cytotoxic and hemolyfic
activity when incubated with peritoneal and pulmonary alveolar macrophages or
erythrocytes. However, a cytotoxic response was not observed in trachea
cells. I_n vitro studies showing that long and long, thin clay mineral fibers
are mere active than short, short and wide, or wide fibers, suggesting that
fiber dimension plays a role in the cytotoxicity of attapulgite and sepiolite.
Chamberlain et al. (1982) investigated the cytotoxicity of several natural
asbestiforrr: fibers in three different cell lines: mouse peritoneal macropr.ac-ss,
A549 cells, and V79-4 cells. Short-fibered sepiolite (PU 7) and short-fibered
attapulgite (palygorskite) (PU 7) were nontoxic in all three test systems.
Meerschaum (PU 0, palygorskite), the short-fibered PU 44 attapulgite, a no
another short attapulgite fiber (mean diameter 0.06 urn and length 0.77 urn) were
cytotoxic toward both mouse peritoneal and rabbit alveolar macrophages but net
toward the A549, V79-4, or rat pleura! mesothelial cells (Chamberlain et al.,
1982; Jaurand et al., 1987). Long-fibered sepiolite (PU 00), long-fiberec
attapulgite (PU 33), and fibrous diatomaceous earth (PU 55) were cytotoxic in
all three cell lines. The authors concluded that ^n vitro cytotoxicity
increases as fiber length increases. Long fiber lengths generally exceeded
25 urn; other fiber dimensions were not reported. Chamberlain et al. (1962)
made the following predictions based on the correlation between fiber length
and the cytotoxic responses observed: (1) short-fibered sepiolite and attapul-
gite, which were nontoxic nj vitro, would be similarly nontoxic M} vivo; (2)
test material PU 0 and PU 44, which induced toxic effects in macrophages,
would be fibrogenic but not carcinogenic i_n vivo; and (3) PU OC, PU 33, a-.3
PU 55 dust, which were cytotoxic to all cell lines, would be fibrogenic arc
carcinogenic. Jaurand et al. (19S7) concluded that there wes net a strc-.c
-------
correlation between the JD vitro cytotoxicity and the i£> vivo carcinogenicity
of attapulgite fibers; these authors noted, however, that a lack of consis-
tently positive effects may have been related to the short length of the
fibers.
Jaurand et al. (1979) reported that attapulgite fibers were cytotoxic to
rabbit alveolar macrophages and caused lysis of human red blood cells.
Macrophages were incubated with 50, 100, or 300 ug fibers/ml (dimensions net
reported) for 2, 4, 6, 8, 20, and 23 hours. Lactate dehydrogenase and
3-galactosidase activities were measured at the end of incubation. Hemolytic
activity was determined 1 through 10 and 15, 30, 45, and 60 minutes after
exposure; at least two fiber concentrations (50 and 100 pg/mL) were evaluates.
Significant cellular enzyme leakage was observed 20 hours postexposure to
300 ug/mL; media concentrations of lactate dehydrogenase and p-galactesitiase
were increased by 45.5 and 31 percent, respectively. Approximately 11 perce-.t
of the human erythrocytes exposed to 50 ug/mL were lysed; 100 percent hemclysis
••ci observed at 100 ug/mL. The authors reported that acid-treated fibe-s
exhibited greater hemolytic activity, but supporting data were not prese~tec.
Bignon et al. (1980) found that attapulgite formulations (mean fiber
length 0.53 to 0.59 urn) in drugs used to treat gastrointestinal diseases were
more hemolytic and cytotoxic than UICC chrysotile asbestos. They concluded
that attapulgite may be carcinogenic. Supporting evidence of attapulgite-
induced (diameter 0.2 urn and length 11.4 pm) hemolytic activity comparable to
UICC chrysotile B fibers was furnished by Nadeau et al. (1963). Parallel
cytotoxicity studies further indicated that attapulgite fibers produced a
"selective" leakage of enzymes, reduced both cellular ATP and lactic acid
production, and stimulated oxidant production in macrophages.
In a similar study (Woodworth et al., 1983), attapulgite fibers (1, 4, or
16 mg/mL) were incubated for 96 hours with trachea! mucosa cells harvested from
6- to 6-week-old male Syrian hamsters. Approximately 94 percent of the fibers
were no more than 1 pm long; 25, 60, and 100 percent had diameters less than or
equal to 0.6, 0.8, or 1.0 |jm, respectively. Cytotoxic effects were observed at
the two highest doses of attapulgite, but the results were not significantly
(p <0.05) different from the negative control.
7.2.4.2 Eriom'te. Erionite is highly toxic to human polymorphonuclear leuko-
cytes and caused a dose-related increase in the amount of lysesonal
p-glucuronidase released from cells (fiber dimensions not reported) Os*:
et al., 1966). Release of the cytoplasir.ic enzyme lactate denyc-ooe"=se.
• - •"— 7-17 D^T—D: N:7 •*•:": -'• £—
-------
however, was not observed. Normal -human serum treated with 100 ug erionite/mL
generated chemotactic activity, but no activation of complement (i.e., no C3
breakdown products) was detected at levels up to 500 ug/mL. Similar results
were obtained from crocidolite-exposed leukocytes. No other details were
given.
The hemolytic and cytotoxic activities of erionite (fiber size unspeci-
fied) were investigated by Nadeau et al. (1983). Samples of the mineral were
incubated with either rat pulmonary alveolar macrophages or rat erythrocytes.
Erionite exhibited weak hemolytic activity. Cytotoxic behavior was evident,
however, in the release of lactate dehydrogenase and cr-galactosidase and in the
reduction in cellular ATP and lactic acid production. No other details we-e
provided.
7.2.5 Talc
I_n vitro cytotoxicity assays conducted with natural or acid-purified talc
(diarr.eter from 0.2 to 20 um) indicate low-level cytotoxic activity in pe--'-
toneal and alveolar Wistar rat macrophages (Styles and Wilson, 1973), whic*
corresponded to the minimal toxicity exhibited by talc JU vivo. It is note-
worthy that within 1 hour of exposure, approximately 50 percent of the treatec
macrophages contained talc particles. Other investigators have reported that
talc particles (50 ug/mL) within a respirable range were not cytotoxic to
V79-4 or A549 cells (Chamberlain and Brown, 1978).
In contrast, intratracheal instillations of asbestos- and quartz-free
Vermont talc (0.15, 0.75, or 3.75 mg/100 g bw; median aerodynamic diameter
7.5 urr) produced a dose-related cytotoxic effect in hamsters, as evidenced by
elevated lactate dehydrogenase, B-N- acetylglucosaminidase, and peroxidase
levels in bronchoalveolar lavage fluid (BAL) (Beck et al., 1987). Cellular
damage was also indicated at 1 day postexposure by significantly increased
BAL albumin levels in higtrdose animals when compared to controls. Althougr.
an acute response was observed, the large diameter of the talc particles
precludes extrapolation to inhalation data.
The biochemical response of rabbit cartilage tissue to talc-induced
synovitis was investigated by Gerstuni et al. (1981). In this study, app"cx-;-
mately 0.25 cm of a talc-saline suspension was injected into the right hip of
30 immature (1-month-olti) New Zealand White rabbits (sex and weight net speci-
fied). Left hips and saline-injerted animals served as controls. Groups CT"
rabbits were sacrificed 1, 2, 3, and 4 weeks after injecfic-. Sectic-= o:
-------
cartilage were removed, and levels of water, hexuronic acid, hexosamine, and
collagen were measured. Cartilage thickness was measured directly on corre-
sponding hemisections from left and right femoral heads. Significant (0.05 <
p <0.005) swelling of the medial joint space of the right hip was apparent in
treated animals at all sacrifice intervals. Water content was significantly
(p <0.05) increased at weeks 1 and 2; hexuronic acid and hexosamine content
were decreased (p <0.05) but only at the end of the first week. Collagen
content was not affected. The 15 percent increase in cartilage thickness
(compared to control cartilage thickness) could not be attributed solely to the
3 percent increase in hydration. The authors concluded that the talc-induce:!
synovia! inflammation caused a local increase in temperature, hyperemia, a^.c
venous congestion that, in turn, facilitated anabolic cellular activity ar.i
increased production of cartilage.
7.2.6 Venriculite
No information on the i_n vityp cytotoxicity of vermiculite was feu" *>
the available literature.
7.2.7 Mode of Action
7.2.7.1 Cellular Responses. Cells respond to mechanical or chemical stir.li
caused by the presence of the fiber; the response is primarily defensive in
nature. Nevertheless, the stimulation of protective mechanisms can eventually
lead to cell disintegration, necrosis, and disease. The response of cells to
the physical presence of fibers is somewhat analogous to cellular responses
elicited in the early stages of tuberculosis where hypercellular activity
occurs and ultimately facilitates tubercule formation and disease progression.
It would, therefore, appear that the factors influencing cellular 'response are
of great importance if the relationship between fiber-cell interaction and
pathogenesis is to be clearly understood.
Four of the major mechanisms by which cells respond to fibers and the
implications are discussed below.
7.2.7.1.1 Development of ferruginous bodies. Mineral fibers, including
asbestos, are often found encapsulated in a cellular gel coat. These cc-atec
fibers are referred to as ferruginous, asbestos, or pseudossfaestos bcc^ei.
Ferruginous bodies have been observed in guinea pigs and hamsters, but n:t ir.
rats, following 90-day inhalation exposures (6 hours/day, 5 csys/week) tc c'sss
-------
fibers with an average diameter of 1.2 um (Lee et al., 1973). Time frorr,
exposure to recovery of ferruginous bodies was 6 months in hamsters and
12 months in guinea pigs. Histology revealed that most of the gel-coated
fibers developed from fibrous particles; few contained dust particles. The
significance of the findings was not discussed.
Davis et al. (1970) reported that following single intrapleural injections
of glass or ceramic fibers (25 mg), ferruginous bodies were observed in giant
cells. Glass fibers with average diameters of 0.05 to 0.99 um and ceramic
fibers (median diameter, 2 um) were taken up by the giant cells, and both we<-e
coated with iron-containing material by 2 weeks postexposure. At 6 weeks, a
large number of ferruginous bodies, some of them beaded, were present in
excised gran^iomss. Encapsulated particles were generally reduced in size.
The authors estimated that about 1 percent of the injected fibers were iruc'vec
in the process.
KcL'se peritoneal macrophages stimulated with thioglycolate broth we^e
exarrinec! following ip injection of carbon fiber particles less than 40 \;r 1o~:
and approximately 7 .to 8 urn wide (Hinson et al., 1983). The strain, sex, and
age of mice and fiber concentration were not reported. Aliquots of stimulate::
macrophages were plated 24, 48, 120, and 144 hours posttreatment. Phagocytoses
progressed over the specified time period, and by 120 and 144 hours, most
fibers were completely covered and a mini-encapsulated cyst had formed. Tne
authors noted that the carbon fibers generated a phagocytic response similar to
that of abestos.
As suggested by the above studies, ferruginous body development occurs
frequently; however, most investigators have failed to find an association
between fiber-induced pathology and development of ferruginous (or others)
bodies (Davis et al., 1970).
7.2.7.1.2 Effects of mineral fibers on cell membranes. The classical method
used by cells to defend against foreign substances is phagocytosis. In
general, phagocytosis tends to clear the surrounding tissues, but the ability
of cells to engulf solid particles is largely dependent on particle dimension.
The presence of long, thin fibers can result in "frustrated" phagocytosis
whereby cells can only partially engulf the fibers. Incomplete phagocytes1!:
with subsequent leakage of tissue-damaging enzymes has been proposer as e
possible mechanism of fiber-induced disease.
Frustrated phagocytosis was exhibited in a study conojctei t} De"':e=-
et el. (19£5fc). Cultures of primary hepatocytes (animal species ret re::-tec)
-------
were exposed to attapulgite and sepiolite fibers (respective diameters ranged
from 0.01 to 0.1 urn; average lengths were 0.8 and 2.04 urn, respectively).
Phagocytosis was evident within 20 hours; both fibers were found in plasma
membrane invaginations and deeper in the cytoplasm.
The effects of silica and talc on cellular and artificial membranes we^e
examined using three test systems: wonolayer cultures of trachea! epithelial
cells, suspensions of sheep erythrocytes (sRBC), and preparations of
phospholipid-cholesterol vesicles (Woodworth et al., 1982). Each mineral
preparation was at least 99 percent pure,.and approximately 60 to 70 percent o*
the talc or silica fibers were 3.0 urn or smaller. Particles were suspended in
veronal-buffered 0.95 percent NaCl and added to the test systems at concentra-
tions ranging from 0.003 to 20.0 mg/mL. Activity was monitored via radioa:-
tively labeled sodium chromate (specific activity of Cr, 200 to 500 uCi/g).
At the end of a 24-hour incubation period, both minerals were cytotoxic to t^e
trachea! epithelial cells. Phagocytosis of talc and silica particles was
evident within 4 hours, and cells containing talc or silica demonstrate:
retraction of lamellipodal extensions, surface blebbing, and morphologies"
changes. Release of Cr by trachea! epithelial cells was higher for cells
exposed to 0.1 mg/mL silica (20 percent) and talc (35 percent) than fc>-
nonexposed cells. As talc and silica concentrations increased from 1 to
20 mg/mL, percent hemolysis of sRBC increased steadily from approximately 5 to
90 percent following a 60-minute incubation period. Membrane distortion anc
sRBC ghosts were observed. Percent spontaneous leakage of [ Crjchromate fror
liposomes and liposomes exposed to 10 mg silica particles/mL was approximately
4 to 6 percent; following a 1-hour exposure to 10 mg talc/rnL, chromate release
rose to about 20 percent, suggesting an increased permeability of the
liposomes.
For additional information on the cytotoxic and hemolytic activities cf
specific fibers, see Section 7.2.
7.2.7.1.3 Release of superoxide. The release of oxygen free radicals by cells
of the respiratory tract has been implicated 1n the pathology of inhaled
mineral fibers. Hansen and Mossman (1967) incubated erionite or glass f"ibe-s
(in unspecified "nontoxic" concentrations) with alveolar macrophages isolate:
from young adult male Syrian hamsters or F344 rats. All fibers were dete —''ner
to be of respirable quality (<4 urn in diameter). Mineral dusts and rat cells
were incubated for 1 hour. Hamster cells and minerals were inr'jtate: :' =
serurr.-containing medium for 2 hours; the medium was removed er,d ce:1f <-?'"£
- - • ' — 7-21 D^"--:: s:~ c-"^ ::' ::~:
-------
exposed to zymosan (25 rog/mL). In both cell systems, erionite and fiberglass
caused significant (p <0.05) increases in the production of oxygen free radi-
cals when compared to untreated controls or nonfibrous analogs (i.e., mordenite
and glass beads, respectively). Superoxide release by hamster cells was
directly related to zymosan concentration, but zymosan activation was not
required for superoxide generation.
7.2.7.1.4 Development of proteinosis. Alveolar proteinosis developed in rats,
hamsters, and guinea pigs exposed by inhalation to 0.42 mg/L glass fibers at a
rate of 6 hours/day, 5 days/week (Lee et a!., 1979; see Section 7.2). Proteir,-
osis developed in all animals 90 days postexposure and persisted for 6 months.
A massive macrophage reaction accompanied the alveolar proteinosis but disap-
peared within 12 months. The light and ultra structural alterations were
similar to these seen in other experimental and human alveolar proteinosis.
Pulmonary alveolar proteinosis (lipoproteinosis) was noted in 24 individu-
als exposed to fine particulate matter (Abraham and McEuen, 1985). In all but
twa cases, more than 40 percent of the particles were less than 1 urn wide. The
concentration of inorganic particulates in the areas of lipoproteinosis range:
793
from 1.3 x 10 to 1.02 x 10 /cm . The lungs of three infants contained most'y
talc; approximately 97 percent of the particles found in the lungs of 5 s = ~c-
blaster were silica. Because high concentrations of inorganic particles were
found within the pulmonary lesions, the authors suggested that the presence cf
talc or silica triggered the lipoproteinosis.
The pathogenesis of alveolar proteinosis is. unclear, but Lee et al. (1979)
suggest several possibilities: an overproduction of normal or abnormal
phospnolipids by granular pneumocytes; desquamation of granular pneumocytes;
primary failure of lung clearance; or passage of blood proteins into alveola"
spaces due to the damage of alveolar basement membrane.
7.2.7.2 Physical Properties of Fibers. As discussed in detail in
Sections 7.2.1 through 7.2.6, the physical properties of fibers govern the type
of cytopathic responses elicited in mammalian cells. An awareness of how the
solubility properties, geometry, flexibility, and size of fibers relates to
toxicity is, therefore, an important aspect of the modes of action. Asbestos
fibers are not readily degraded by interaction with biological syster.s. Tr.i;
ability to maintain structural integrity has been implicated in asbestcs-
induced cytotoxicity, genotoxicity, and carcinogenicity (see sections 7.1 er.:'I
7.2). By contrast, manmade mineral fibers are relatively soluble ip PV-^"'
locical solutions but appear to have low carcinogenic pcte-tiel.
-------
Klingholz and Steinkopf (1984) noted that the mechanical corrosion of
nonasbestos fibers, especially when accompanied by the formation of a gel coat,
shows a weakening and increased plasticity of the fibers. As fibers become
smaller, they are more compatible with and less harmful to cells. The glass-
like nature of manmade mineral fibers generally permits only transverse
fragmentation into shorter fibers unlike asbestos and other naturally occurring
fibers, which split lengthwise to produce large numbers of thinner fibers.
Forster (1984) reported that several factors, such as time, pH, anc!
temperature, influence the dissolution and corrosion of mineral fibers, lor,
exchange (e.g., leaching) was greatest in an acidic solution (pH <7), and
chemical reactions (e.g., etching and network dissolution) occurred under
alkaline conditions (pH >9). At pH between 7 and 9, the two processes over-
lapped. In all cases, fiber corrosion was time-dependent, and as exposure time
increased, a thick colloidal surface formed around the core particle. Corrc-
sion was evident in most fibers held at 37°C; few changes were observed et
20°C. In experiments conducted at 60°C, the rate of leaching was rapid.
Significant corrosion and leaching occurred in all fibers (except asbestcs) at
95°C.
The reactions of slag, glass, and rock wools (diameter, 0.2 to 14 prr.) with
physiologic model fluids and water were examined by Klingholz and Steinkcrf
(1S84). The model fluids contained various inorganic salts and nonelectrolytes
(e.g., glucose and amino acids). Leaching patterns and chemical and physical
changes were followed for 25 days for fibers in stationary fluids or for 2- and
60 days for fibers in continuously replenished solutions. Structural changes
were observed via election microscopy. Fibers with mass ratios of 1:40 or
1:100 were kept in the stationary fluid; up to 10 mg of fibers (with the same
mass ratios) were used in the continuous leaching experiments. . Fibers
suspended in distilled water served as controls.
All fibers showed distinct signs of attack. After 25 days in the station-
ary fluid, calcium Ions were leached from slag wool, alkali ions were leached
from glass wool, and both calcium and alkali ions were released from rock woe1.
A shell-like gel coat, generated from the fiber core, formed around slag woc-1
fibers held in the replenishable leaching solutions. At 24 days, the alkali
alumino-silicate gel was about 2 ym thick; after 60 days, the thickness nso
doubled. As calcium and magnesium ions were leached from slag wool fibers into
the surrounding model fluid, approximately 1 urn of the original fiber's d'ia~e-
ter was converted into the gel. Similar (bjt much weaker) reactions *e--e
July 19 = 5 7-23 DRA'T —DC N" CvC" C-=- CIT:
-------
observed with slag wool suspended in water. Initially only alkali ions were
leached from glass wool into the replenished model solution. At the end of
24 days, some calcium ions had also been released from the glass fibers.
However, leaching and gel formation were slow. After 24 and 60 days, fibers
were coated with gels having a thickness of 0.1 to 0.25 urn and 1.0 to 1.5 uir,,
respectively. The gel-forming process was much slower for aqueous glass fiber
suspensions. Leaching of ions was less intense for rock wool fibers than for
the other two mineral fibers. Gel layers formed around the rock wool, however.
The chemical composition of rock wool fibers was not significantly altered
following suspension in water. The authors concluded that through corrosion,
fibers lose structural integrity and become more likely to break into shorter
lengths and to be cleared from the body; in addition, the formation of gel
layers may render fibers more susceptible to removal (Klinghclz anc! Steink:::',
1964).
In a similar experiment, slag wool, four types of glass wool, two types of
ceramic fibers (Fiberfrax ), erionite, and crocidolite and chrysctile asbestos
were suspenaed in a simulated extracellular fluid under constant flow condi-
tions (Scholze and Conradt, 1987). The durability of the various fibers were
ranked. Kanmade mineral fibers did not hold up well in the model fluid. *it-
the fiber networks dissolving at rates of 0.2 to 3.5 nm/day. Natural fibers
(chrysotile, crocidolite, and erionite) were very resistant to attack by the
"biological fluid" and had network dissolution velocities of 0.01 nm/day or
less. It was estimated that a manmade fiber (diameter 1 urn) would dissolve
completely in approximately 0.5 to 6.5 years and that natural fibers (diameter
5 um) would require a minimum of 100 years before dissolution was completed.
Spurny et al. (1983) also investigated the rn vitro chemical -and physical
durability of glass fibers, slag wool, and rock wool held for prolonged periods
in acid solutions (2N HCL and 2N H2$04), a basic solution (2N NaOH), water, and
human blood serum. The results indicated that all fibers corroded in the acios
and the base, fibers with a diameter less than 1.5 urn were degraded rapidly,
and glass fibers were the roost resistant to corrosion. Minimal leaching of
ions from fibers suspended in water also was observed. After acidification, Ce
and Zn ions were leached from the particles but electron microscopy showed
little evidence of surface change. In a similar experiment, a significant orc?
in the Mg, Al, and Ca ion content of acid-treated (1.4 K HC1) 104-E g'ess
ir.icrofibers was reported (Bellmann et al., 1967). Fiber etching, a 32 percent
overall reduction in fiber weight, and fiber swelling accompanied tnese c"=ices
-------
in elemental composition. However, no alterations were observed in other types
of fibers (glass, glass microfibers, and ceramic wool) suspended in acid
(Bellmann et a!., 1987) or in human serum for 1 year (Spurny et a!., 19E3).
Several investigators have studied fiber morphology in whole animals
following intratracheal instillation of glass fibers into rabbits and/or rats
(Spurny et al., 1983; Bellmann et a!., 1987) and glass, rock, or ceramic wool
fibers into rats (Bellmann et al., 1987). Considerable ni vivo leaching of Al,
Ca, Ba, Na, Mg, and Si from most manmade mineral fibers occurred. A relative
increase'in Mg, Al, and Ca ion concentrations was reported for 104-E glass
fibers (Bellmann et al., 1987). The length of glass, rock, and ceramic wool
fibers recovered from animal tissues remained fairly constant throughout the 2-
to 5-year followup periods. A relative increase in the number of long (>5 pr)
glass microfibers was observed by Bellmann et al. (1987), who suggested that
short fibers were cleared from the lungs more efficiently than long fibers.
Diameters of glass and ceramic wool fibers remained almost unchanged over
2 years, but the proportion of thicker fibers increased in animals exposed tc
glass microfibers or rock wool. On the basis of _in vitro and ^n vivo stusies,
the authors concluded that none of the fibers was entirely resistant to attack
by biological fluids or inorganic solvents, although glass fibers appease; tc
be more resistant than, rock wool and slag wool. It was suggested tnst
durability and flexibility may be related to the replacement of leached ions by
hydroxyl groups, which could decrease fiber stiffness and increase fiber
deformability (Spurny et al., 1983).
7.3 CARCINOGEN1CITY
7.3.1 Manmade Mineral Fibers
7.3.1.1 Fibrous Glass
7.3.1.1.1 Inhalation. Several studies have been conducted to determine the
carcinogenic potential of glass fibers in five laboratory animal species. The
results of these studies indicate that glass fibers of varying lengths ar.d
diameters were not carcinogenic in any of the animal species tested.
Lee et al. (1981) exposed groups of 32 to 46 young adult male Sprague-
Dawley rats, hamsters (strain and sex not specified), or male albino guinea
pigs to aerosols of fiberglass insulation dust. The diameter was about 1.2 urn.
the length <2 pm, and only 15 percent of the particles had a fibrous shape.
15£= 7-25
-------
Animals were exposed at a concentration of 420 mg/m for 6 hours/day for
3 months, and groups of animals were sacrificed at 6-month intervals for up to
24.months. Only a few pulmonary tumors occurred in dosed animals; the number
was too small to derive any conclusions on carcinogenicity. The glass fiber
used was not fibrogenic.
Muhle et al. (1986, 1987) exposed 108 female Wistar rats nose-only to
glass wool JM 104 (Tempstran 475) at aerosol concentrations of 3 mg/m ,
5 hours/day, 4 days/week for 1 year. A control group of 55 rats was exposed
nose-only to clean air, and 50 remained unexposed. The diameter of the fibers
used was 90 percent <0.80 urn and 50 percent <0.42 pm, and the length was
90 percent <12.4 pm and 50 percent <4.8 pm. In exposed rats, 12 broncho-
alveolar hyperplasias, 1 squamous metaplasia, and 1 squamous cell tumor cf the
lung were observed. No tumors were observed in the sham-exposed controls, t-t
4/55 and 3/50 from the cage and unexposed control groups, respectively,
exhibited bronchoalveolar hyperplasia. The authors concluded that the lo*
carcinogenic potency, which may be associated with thin and durable MKK',F, is
difficult to demonstrate in an inhalation experiment.
Wagner et al. (1984) reported similar tumor incidences (2 percent) in
groups of Fischer 344 rats exposed to 10 mg/m of glass microfibers (JM IOC'},
glass wool with resin, or uncoated glass wool. The fiber dimensions ano' tuner
incidences are presented in Table 7-2. Exposure was for 6 hours/day,
5 days/week for 24 months; animals were followed for life thereafter. The
turners observed in the glass-exposed animals were all adenocarcinomas. but
tumor incidences were not significantly different from those among controls.
In rats similarly exposed to chrysotile asbestos, 12/48 developed pulmonary
tumors (11 were adenocarcinomas). Although the pattern of tumor development in
this study was similar, the carcinogenic potential of glass fibers was much
lower than that of asbestos.
Smith et al. (1984) exposed 100-day-old male Syrian hamsters or female
Osborne-Mendel rats to aerosols containing glass microfibers (diameter 0.45 urn)
at concentrations of 3 (3000 fibers/in ) or 0.3 mg/m (300 fibers/m ). Exposure
was via nose only, 6 hours/day, 5 days/week for 24 months; sham control groups
were exposed to clean air. No primary lung tumors or unusual pulmonary lesions
were found in exposed animals of either species. Three of 54 rats sitr.il arly
exposed to crocidolite developed primary lung tumors: one developed e mesc-
theliorr.a and two developed bronchoalveolar tumors.
i..v, TOCC 7-9P.
-------
TABLE 7-2. NEOPLASMS AND HYPERPLASIA IN THE LUNGS OF RATS AFTER
INHALATION EXPOSURE TO VARIOUS MMMF
Sample
Canadian chrysotile
Glass microfiber
Rock wool without resin
Glass wool with resin
Glass wool without resin
Control
Fibers/cm38
(d <3 \im,
I >5 pm)
3832
1432
227
240
320
Number of rats with:
Number of
animals^
examined
48
48
48
48
47
48
Broncho-
alveolar
hyperplasia
5
2
1
3
1
0
Neoplasm
12**
1
2
1
1
0
ad = diameter, 1 = length.
Eight animals/group were killed after 3 months of exposure and were not
included in the evaluation of carcinogenicity.
"'Significantly different from control incidence at p <0.01.
Source: Wagner et al. (1964).
Sir.ith et al. (1965, 1967) exposed (via nose only) 100-day-old male Svr-£-
harrste^s and female Osborne-Mendel rats' to fibrous glass with mean diameters
of 0.45, 3.1, 5.4, or 6.1 urn. Details of this study are presented in Secticr
5.2.1.1 (see Tables 5-4 and 5-5). Animals were exposed to aerosol concentra-
tions of the 0.45-um mean diameter (MD) fibers at 0.3 or 3 mg/m (300 or
3000 fibers/m3); the 3.1-um MD fibers at 10 mg/m3 (100 fibers/m3); 5.4-unr KD
fibers at 1.2 or 12 mg/m (10 or 100 fibers/m ); or 6.1-um MD fibers at ? mg/r,
(25 fibers/m ), 6 hours/day, 5 days/week for 24 months. Surviving animals were
observed for life. No primary lung tumors were observed in any of the animals.
No lung tumors were induced in F344 rats or cynomolgus monkeys afte-
chronic inhalation of short or long glass fibers (commercially available glass
wool insulation) with diameters ranging from 0.5 to 6 urn (Mitchell et al.,
1986). In this study, 50 male and 50 female rats and 15 male monkeys were
exposed for 7 hours/day, 5 days/week. Exposures were conducted for 18 months
in monkeys and 21 months in rats. In another study, exposure of 10 baboons to
fibrous glass dust at a concentration 5.8 mg/m for 7 hours/day, 5 days/week
for 34 months, resulted in fibrosis but no neoplasms in the lungs (Goldstein
et al., 1983).
However, significantly increased incidences (p<0.05) of mononu:"ie = '
cell leukemia (MCL) were observed in rats from all glass fibe"-expcsec CTJ:S
r compared to control incidences (Mitchell et al., 19Sc). Fiber c^rre^' cr-s.
-------
aerosol concentrations, and incidences of MCL are presented in Table 7-3.
Since MCL occurs spontaneously in aged F344 rats, the biological significance
of this finding is not presently known. However, this data suggests that the
presence of glass fibers in lymphatic or pulmonary tissue may later the
cellular immune response. Since no glass fibers were found in the spleen.
TABLE 7-3. INCIDENCE OF MONONUCLEAR CELL LEUKEMIA (MCL)
IN F344 RATS EXPOSED TO FIBROUS GLASS INSULATION
VIA INHALATION FOR 2 YEARS
Fiber
description
Glass-coetec
Glass-coated
Glass-uncoated
Glass-uncoated
Control
Fiber Aerosol
dimensions (urn) concentration (mg/m3
d: 4 - 6
1: >20
d: 0.5 - 3.5
1: >10
d: <3.5
1: >10
d: <3.5
1: <10
--
15
15
5
5
0
ye
MCL
) incidence
37.0*
37 . 0*
35.4*
42.4**
21.2
ad = diameter, 1 = length.
*
Significantly different from controls (p <0.05)..
""Significantly different from controls (p <0.01).
Source: Mitchell et al. (1986).
7.3.1.1.2 Intratracheal. The results from five studies with hamsters, rats,
and guinea pigs provide equivocal evidence on the carcinogenic potential of
glass fibers following intratracheal administration. The results from one
study with rats and hamsters indicate that microfibers cause an increased
incidence of respiratory tumors. However, other studies with all three species
provided negative results.
Preliminary results with guinea pigs dosed twice intratracheally witn
12.5 mg of long, thin glass fibers indicated fibrosis of the lung but no turrets
6 months after instillation (Kuschner and Wright, 1976). The fibers hei a (
diameter of <1 yrr, and 13 percent were >10 urn in length. Animals were k;1lei
-------
6, 12, and 24 months after the last injection. Feron et al. (1985) instilled 1
oig glass fibers 1n >0.2 ml of a 0.005 percent saline solution of gelatin into
the trachea of 34 male and 35 female Syrian hamsters once every 2 weeks for 52
weeks and followed the animals until week 85. The length of glass fibers
(Johns Manville code 104) used was 58 percent <12 pm and 25 percent <5 pm; the
diameter of the fibers used was 88 percent <2 pm with 35 percent <0.25 urn. No
tumors were induced. Feron et al. (1985) suggested that repeated acute reac-
tions due to continued treatment for 52 weeks did not allow fibers to settle
and have constant chronic contact with the target cells. In contrast, unpub-
lished results of Pott et al. (1984b) indicated that the same type of glass
fiber induced mesotheliomas in the same strain of hamster by 113 weeks after
administration of 1 mg once weekly for 8 weeks. However, very few tumors
appeared before week 85. The results of Pott et al. (1984b) were summarize: by
Mohr et al. (1984). Groups of Syrian hamsters received once weekly instilla-
tions of 1 mg fiber dust for 8 weeks. Fibrous glass of two different lengths,
UICC crocidolite (positive control), and a negative control group (TiCL) we~e
studied. Approximately 50 percent of the hamsters survived for 2 years, a-.a
the study was terminated at 130 weeks. Fiber sizes and tumor incidence are
summarized in Table 7-4. No tumors were found before 18 months. Morphologi-
cally, the tumors were epithelial. The microvilli on the surface were plec-
morphic under scanning electron microscopy, whereas these projections were
uniform in normal mesothelial cells.
A significant increase (p value not reported) in pulmonary tumors was also
observed in female Wistar rats following intratracheal instillation of the same
glass fiber (Johns Manville code 104/475) (Pott et al., 1987a). Fifty percent
of the fibers had a diameter of <0.18 urn and a length of <3.2 urn. A total dose
of 10 mg (20 x 0.5 mg) was injected into each of 34 rats. Forty animals
receiving saline (20 x 0.3 ml) served as controls. Five of 34 glass-treated
rats developed pulmonary tumors (1 adenoma, 2 adenocarcinomas, 2 squamous
cystic carcinomas) compared to 0/40 for the control group. In animals
similarly dosed with crocidolite asbestos (10 mg), 15/35 developed pulmona-y
tumors; however, no mesotheliomas were found in any of the animals tested.
Smith et al. (1986, 1987) administered, by intratracheal instillation,
2 mg of glass microfibers (mean diameter 0.45 urn and count mean length 7.5 pm)
suspended in 0.2 mL saline to male Syrian hamsters and female Osborne-Kenoel
rats. The animals were dosed once a week for 5 weeks (total dose 10 mg) and
observe:? for life. No primary lung tumors were observed in either species.
July 19££ 7-29 DRAFT — DO N" Q'JCTE 0* CITE
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TABLE 7-4. TUMORS IN SYRIAN HAMSTERS AFTER INTRATRACHEAL INSTILLATION
OF GLASS FIBERS OR CROCIDOLITE
50% of fiber
less than
Material
Glass 1
Glass 2
Crocidolite
Ti02
Length
(pm)
7.0
4.2
2.1
Diameter
(urn)
0.3
0.3
0.2
-granular-
Number of
hamsters
136
138
142
135
Lung
carcinoma
5*
6*
9**
0
Tumors
Meso-
thelioma
37**
26**
8**
0
Thora*/
sarcorr.a
6
6
1
2
*Significantly different from control incidence at p <0.05.
'"Significantly different from control incidence at p <0.01.
Source: Mohr et al. (1984).
7.3.1.1.3 Intrapleural. Unlike inhalation or intratracheal instillation into
the lungs, the direct administration of glass fibers, especially micrcfibers,
onto the pleura! surface in rats and hamsters has been shown to result in tk:e
development of mesotheliomas. Stanton and Wrench (1972) found that various
fibrous glass samples (coated and uncoated glass wool insulation) that we^e
reduced to a distribution of sizes approaching that of conventionally mil lee
asbestos were carcinogenic when implanted intrapleurally into Osborne-Menoe1,
rats. Partially pulverized glass fibers with mean lengths of about 5 urn anc1
diameters ranging from 0.06 to 3 urn caused a significant increase (p
-------
that fibers £1.5 pm in diameter and >8 pm in length produced the highest
Incidence of pleura! sarcoma »fter 25 months. Analysis by statistical regres-
sion technique of tumor probability in relation to fiber size, using the
logarithm of the number of fibers in discrete size groups as the variable,
Indicated good correlation coefficients (>0.85) for two size categories: (1)
diameters <0.25 urn and lengths >8 urn, and (2) diameters between 0.25 and 1.5 urn
and lengths >64 pm. When the percent of total weight of fibers in discrete
size groups was the variable, the best correlation coefficient was with diame-
ters between 0.25 and 1.5 pm and lengths of 64 urn. This reinforced the
authors' hypothesis that carcinogenicity depends on dimension and durability
rather than on physicochemical properties for all fibers including asbestos.
Fibers with a length <8 urn are inactivated by phagocytosis.
Wagner et al. (1976) also tested the carcinogenicity of glass fibers
(Johns Manville) of different diameters by intrapleural injection into rats.
For the microfibers (code 100), 99 percent had a diameter <0.5 pm (median,
0.12 (jm), and 2 percent had a length of >20 urn (median, 1.7 urn). For the
coarser fibers (code 110), 17 percent had diameters <1 pm (median, 1.8 prr,), a"
10 percent were >5 pm in length (median, 22 pm). Groups of male and fe-,a"e
Wistar rats were injected with 20 mg of fiber in 0.4 ml saline and observed fcr
life. Four of 32 rats receiving code 100 microfibers, but none of 32 controls
or 32 receiving code 110 glass fibers, developed mesotheliomas. However, tne
increased incidence was not significantly different from controls. Mean
survival in all groups was Btout 700 days. The authors reported that the
microfibers were less carcinogenic than various samples of asbestos similarly
tested.
In another long-term study conducted by Wagner et al. (1984), the
carcinogenicity of several MMMF Including glass microfibers (JM 100) and
'uncoated glass wool were evaluated In Sprague-Dawley rats. Groups of 56 rats
received a single intrapleural injection of 20 mg of each respirable fiber ana
were observed for life. Results indicated that the glass microfibers were
carcinogenic; 4/48 rats developed mesotheliomas. In rats dosed with glass
wool, 1/48 developed a mesothelioma. Six of 48 rats similarly dosed with
chrysotile asbestos developed mesotheliomas.
The carcinogenic potential of JM 104 glass microfibers in Sprague-Da»ley
rats was determined following intrapleural injection by Monchaux et al. (1531)
in studies designed primarily to test acid-leached chrysotile. The mear. length
Julv 19E: 7-31 DRAFT—DO NOT QuT'E 0
-------
I
of the glass microfibers (JM 104) was 5.89 pm, and the mean diameter was
0.229 urn. About 11 percent of the glass fibers conformed to a length >8 pm and
diameter <0.25 pm. The rats (3 months old) received injections of a single
20-mg sample (1.8 x 10 fibers) in 2 ml saline and then were followed for
life; 32 controls received saline. Thirteen percent (6/45) of the rats receiv-
ing the microfibers developed mesotheliomas compared to 0 percent of controls.
Furthermore, the increased incidence was significantly different from the
controls (p <0.05). Mean time-to-tumor was 513 days for glass-treated rats.
Smith et al. (1980) studied the effect of glass fiber size on induction o*
tumors in Syrian hamsters after intrapleural injection of 25 mg/animal. Turc'-s
occurred in 9/60 animals when the fibers had a mean diameter of 0.1 pir and
82 percent were 20 urn in length; the first tumor appeared at day 284. Fibers
with a mean diameter of 0.33 urn and 46 percent >20 urn in length induced turr.c1';
in 2/60 hamsters; the first tumor was found at day 408. Fibers with a mesn
diameter of 1.23 pm and 34 percent >20 urn in length induced tumors in 2/60
hamsters at 533 dsys. No tumors were found in groups treated with prepa'ef'c-
having mean diameters of O.D9, 0.41, and 0.49 pm but with only 0 to 2 perce'.
having lengths >10 prc. Smith and Hubert (1974) found no tumors in 60 harr.ste-s
injected with 25 mg of an insulation grade glass fiber with a mean diarnete'- of
5 pm.
Davis (1976) was unable to induce tumors in groups of 25 BALB/c mice after
intrapleural injection of 10 mg of glass insulation fibers with 0.05- or 3.5-prr
diameters having lengths less than or greater than 20 pm. Surviving mice were
killed at 18 months. The authors reported that only 2/150 mice treated simi-
larly with chrysotile or crocidolite asbestos developed mesotheliomas. Tney
theorized that the pleura! cavity of mice may be very resistant to tumor
induction by any mineral fiber. It is also possible that the length of the
study (18 months) was not sufficient to adequately assess the carcinogenic
potential of glass fibers or asbestos in mice.
7.3.1.1.4 Intrapen'toneal. Glass microfibers have also been shown to be
carcinogenic after intraperitoneal administration to female Wistar and O.sborne-
Mendel rats. The predominant tumor type was mesothelioma. The results o* c^e
study indicated that the intraperitoneal injection of glass microfibe-s w=s
not carcinogenic in hamsters.
A dose-related increase in the incidence of tumors was reported b\
and Friedrichs (1972) after intraperitoneel injection of fibroji c~e=s (S
105) into female WistS'- rets. At dcses of 2, 10, ar.d IOC- (- * 25) &;, - ~
-------
4/40, and 23/40 rats developed tumors. No tumors occurred in 80 control rats.
The appearance of the first tumor was at day 762, 350, and 197 at the low-,
mid-, and high-dose levels, respectively. Pott et al. (1974, 1976) else
conducted studies with fibrous glass MN 104 (50 percent of the fibers having a
diameter <0.2 \im and and 50 percent with lengths <11 M1") and fibrous glass MN
112 (50 percent of the fibers having a diameter <1 ym and 50 percent with
lengths <28 pm). In female Wistar rats-injected intraperitoneally with MN 104
at doses of 2, 10, and 50 (2 x 25) mg (in 2 ml saline), 7/80, 23/80, and 47/60,
respectively, developed mesotheliomas; 1, 3, and 6 rats also developed spindle
cell sarcomas, respectively. Time to first tumor was 576, 210, and 194 days at
the low-, mid-, and high-dose levels, respectively. Following a single 20-mg
injection of fibrous glass MN 112, 11/40 rats developed tumors (10 mesothelic-
mas), and the first tumor appeared at day 390. The authors stated that NMRI
mice developed tumors at comparable rates after injection of fibrous glass,
whereas treated hamsters and guinea pigs did not develop tumors; however, dcta
were not presented. The tumors found following fibrous glass or asbestos
injection were histomorphologically indistinguishable.
Results reported by Miihle et al. (1986, 1967) indicate a significant
(p £0.05) increase in the tumor rate (17 percent) of female Wistar. rats
injected with glass wool JM 104 (Tempstran 475) when compared to controls
(6 percent). Thirty rats received 0.5 mg of JM 104 glass wool suspended in
1 ml saline by intraperitoneal injection. A control group of 32 rats received
saline only. The fiber length was <8.2 pm (90 percent), and the diameter was
<0.42 MFT, (90 percent). Similar treatment with crocidolite yielded a 55 percent
tumor rate. Smith et al. (1986, 1987) administered 25 mg fibrous glass (mean
diameter 0.45 urn) suspended in 0.5 ml saline to male Syrian hamsters and ferr.ale
Osborne-Mendel rats by intraperitoneal injection and observed the animals for
life. The mean lifespan of the treated hamsters was similar to that of the
saline and unmanipulated cage controls. However, treated rats had a reduced
mean lifespan compared to the controls, due to the occurrence of a statisti-
cally significant increase (p <0.01) in abdominal tumors: 8/25 glass-treated
rats developed abdominal mesotheliomas compared to 0/25 saline and 0/125 c£?e
controls. No tumors were observed in hamsters.
In a series of experiments conducted by Pott et al. (19£7a). 50 ma^sse
and naturally occurring mineral fibers, metal compounds, and other dusts were
tested via the intraperitoneal route for carcinogenicity in Wists" cr
Sprague-Dawley rats. A total of five fibrous glass, Uc slag- nocl. f:-"
July 1928 ' 7-33 DRfc"--DO NCT C
-------
attapulgite, and two erionite samples were tested; in addition, 1 sample each
of granular glass, rock wool (one portion processed to produce finer fibers),
£
and aramid (Kevlar ) were used. Groups of 28 to 115 rats (the majority were
females 3 to 9 weeks of age) received doses of a given test material suspended
in saline. Fiber dimensions, total dose, tumor incidences, and lifespan are
presented in Table 7-5. (Rock and slag wool, Kevlar , attapulgite, and
erionite are discussed in Sections 7.3.1.2., 7.3.2.1., 7.3.3.1, and 7.3.3.2,
respectively.) All fibrous glass samples were found to be carcinogenic, and
administration of the longer fibers resulted in a slightly higher tumor inci-
dences. As expected, granular glass did not cause a significantly increased
tumor incidence when compared to tumor incidences of rats injected with saline.
In general, Sprague-Dawley rats were more sensitive to the carcinogenic effects
of glass fibers than Wistar rats.
The carcinogenic potential of 11 naturally occurring and manmade mineral
fibers including glass microfibers (104/475) was compared in another study in
fer-='e wistar rats by Pott et al. (1967b). The size distributions and nur.ser
of fibers intraperitoneally injected are presented in Table 7-6, and the life-
span and turner incidences observed are presented in Table 7-7. Preliminary
results indicated that the microfibers were carcinogenic; 34/53 rats dosed *-ith
5 mg (990 x 10 fibers) glass fibers and observed for life developed tumors
(mesotheliomas or sarcomas). The first tumor occurred at approximately day 258.
7.3.1.2 Mineral Wool. Inhalation studies with hamsters and two strains of
rats indicate little, if any, evidence of carcinogenicity for slag wool and
rock wool. Increased incidences of mesotheliomas and sarcomas were noted for
rock wool following intrapleural or intraperitoneal administration. However,
rock wool has a low carcinogenic potential when compared to asbestos. The
tumor incidences for slag wool following intrapleural or intraperitoneal
administration were low (0 to 6 percent), thus providing equivocal evidence for
carcinogenicity.
No primary lung tumors were observed in male Syrian hamsters or female
Osborne-Mendel rats following inhalation exposure to slag wool at a concentra-
tion of 10 mg/m (200 fibers/m ), 6 hours/day, 5 days/week for 24 months (see
Section 5.2.1.2 and Tables 5-4 and 5-5). The mean diameter of the fibe-s
2.7 urn, and the animals were observed for life (Smith et al., 1985, 19S7).
Wagner et al. (1984) performed carcinogenicity studies in rats exposed b\
inhalation or intrapleural injection to glass wool, rock wool, and slag wo:":
(intrapleural administration only). Glass microfiber (JK 100) ana Canada-:
-------
TABLE 7-5. SIZE DISTRIBUTION, TUMOR INCIDENCE, AND L1FESPAN FOLLOWING 1NTRAPER1TONEAL
ADMINISTRATION OF MANMADE AND NATURALLY OCCURRING FIBERS TO FEMALE WISTAR RATS
Lifespan
(weeks) after first treatment of
Dimension (urn)
Fiber
Glass
Glass-104/475
Glass-104/1974
Glass-lOO/Pen
Rock wool
Slag wool
Kevlar-
Attapulgite
(Georgia)
(Mormoiron)
(Lebrija)
(Caceres)
Erionite
(Oregon)
(Turkey) -
Diameter
50%<
Length
50%<
--granulai —
0.18
0.18
0.29
0.29
0.30
0.33
0.33
0.64
1.54
1.5
2.6
-c
0.04
0.07
0.07
0.07
0.21
0.21
0.38
0.38
0.38
0.38
3.2
3.2
4.8
4.8
3.5
2.4
2.4
4.1
23
14
26
..c
0.8
0.7
0.5
1.3
1.8
1.8
2.9
2.9
2.9
2.9
Total
dose (ing)
40(2x20)
0.5
2.0
5
5
10
2.0
10
10
75(3x25)
40(2x20)
40{2x2£)
10
60
60
£0
10
0.5
2.0
5.0
1.25
5.0
20
% Rats
with
tumors
4.4
16.7
25.8
81. 5b
44.4
50.0
38. 9b
45. 3b
13. 3b
71.4b
2.1.
6.1
12.9
3.6
3.5
3.5 .
40
48.4
90.3
70 8
71. 7*
81.1*
69. 8b
All rats
20*<
102
95
84
52
7
6
79
68
88
61
94
94
109
89
92
95
94
81
60
50
64
45
35
50*<
119
116
110
64
34
37
90
79
97
77
107
111
121
108
116
116
IDS
108
79
61
83
52
41
6Q%<
136
138
127
79
53
54
112
91
115
56
126
127
139
129
13S
134
132
129
93
76
97
68
51
Rats
with tump_r
First
121
EC
64
40
24
17
53
53
6:
39
67
£3
12:
75
47
9£
74
62
51
40
41
32
30
Me a
129
113
107
67
49
51
95
83
105
75
77
114
13E
IOC
92
114
116
9£
8C
6£
82
54
44
aAnimals having abdominal sarcomas, mesotheliomas, or sarcomas were included.
This experiment was conducted in Sprague-Dawley rats.
cNot reported.
Source: Pott et al. (1987a).
-------
TABLE 7-6. SIZE DISTRIBUTION AND NUMBER OF MANMADE AND
NATURALLY OCCURRING FIBERS ADMINISTERED
INTRAPERITONEALLY TO FEMALE WISTAR RATS
Fiber length
(urn)
Fiber
Glass -
Ceramic Fiberfrax
Ceramic MAN
Kevlar6
Polypropylene
Wollastonite
Chrysotile
10%<
1.4
2.6
2.1
1.5
2.9
2.4
0.25
50«<
3.2
8.3
6.9
3.9
7.4
5.2
0.61
90%<
8.4
34
47
11
23
13
1.9
Fiber diameter
(um)
10%<
0.09
0.44
0.56
0.28
0.58
0.62
0.03
50X<
0.18
0.91
1.1
0.47
1.1
1.1
0.06
90/t<
0.40
2.4
2.9
0.75
2.1
2.3
0.12
Number of
fibers
injected'
(x 10e)
990
173
105
1260
409
430
202
Source: Pott et al. (19£7b).
TABLE 7-7. LIFESPAN AND TUMOR INCIDENCES IN FEMALE WISTAR RATS AFTER
INTRAPERITONEAL ADMINISTRATION OF MANMADE AND NATURALLY OCCURRING FIBERS
Fiber
Glass (104/475)
Ceramic r
Fiberfrax
Ceramic MAN
Kevlar*
Polypropylene
Wollastonite
Chrysotile
Saline
Total
dose
(nig)
5
45
75
20
50
100
0.05
0.25
1.00
2 mL
Rats
with
tumors/
rats
tested
34/53**
33/47**
11/54**
3/53
2/51
0/54
11/36**
21/34**
30/36**
1/102
Lifespan
(weeks) after first treatment of:
rats
20%<
53
38
71
78
86
88
81
80
52
85
an
50!t<
67
51
91
106
108
107
105
90
63
111
rats
805U
185
63
106
126
130
126
128
115
72
127
with tumors
1005e<
126
95
128
130
130
130
130
130
130
130
first
37
30
.64
35
126
--
61
58
35
93
mean
65
65
S3
62
126
--
IOC
92
62
92
**Significantly different from control incidence at p <0.01.
Source: Pott et al. (19S7b).
-------
chrysotile samples were used for comparison. In the inhalation study, groups
of 56 Fischer 344 rats were exposed to a nominal concentration of 10 mg/m
respirable dust for 7 hours/day, 5 days/week for 12 months, and then exposed
to clean air for lifetime observation. Size distribution of the fibers wes
determined by scanning electron microscopy. With the exception of the
chrysotile and glass microfibers, sample counts of nonfibrous particles
exceeded fibrous particles.
Table- 7-2 summarizes the incidence of pulmonary neoplasms and broncho-
alveolar hyperplasia observed in this study. Tumors were induced in 2/48 rats
exposed to uncoated rock wool: one benign and one malignant adenoma. A total
of 11 rats exposed to chrysotile asbestos developed adenocarcinomas, and one
developed a pulmonary adenoma. Pulmonary adenocarcinomas occurred in one ret
exposed to the glass microfibers and in one exposed to the glass wool wit!--
resin. All neoplasms in the lung occurred between days 500 and 1000. The
difference in tumor incidence between rock wool and asbestos may have bee" due
to the differences in the numbers of respirable fibers within each dust cicuc.
In the intrapleural study, groups of 48 Sprague-Dawley rats we^e
inoculated with 20 mg of respirable dust in 0.5 ml of saline. Table 7-6 shows
the estimated numbers of particles and fibers injected and the tumor respo~.se.
Tumor incidences for the rock wool with and without resin coating were 6 sr.c
4 percent, respectively. The low tumor incidences may have been due to the
high percentage of nonfibrous particles administered. No tumors were induced
in rats injected with slag wool.
Pott et al. (1984a) studied the carcinogenic potential of rock wool, slac
wool, and basalt wool samples in rats. Groups of 45 female Wistar rats
received a single intraperitoneal injection of 5 mg of the basalt or slag
wool, or 10 mg of rock wool. An additional group of 63 Sprague-Dawley rats
received three 25-mg injections of rock wool. The rats were then observed for
life. The diameters of the basalt wool (50 percent of fibers <0.52 urn) and
rock wool samples (50 percent of fibers <0.64 or <1.90 urn) were greater tna~
those of the JM 104 glass microfibers (described previously) that caused
sarcomas or mesotheliomas. The diameter and length of 50 percent of the sis:
wool fibers were <0.18 and <2.7 pm, respectively. The tumors noted were
reported as sarcomas or mesotheliomas and occurred at low rates, accc-T.tirc
for 5 (2/41) and 16 (10/63) percent in rats receiving slag wool (5 mg) and
Ji.lv 198E'
7-37
DRA"--DC'N:
-------
TABLE 7-8. INCIDENCES OF LUNG MESOTHELIOMAS IN RATS AFTER 1NTRAPLEURAL
INSTILLATION OF VARIOUS MMMF
Fibers
or particles (x 108)
Sample
Canadian chrysotile
Glass microfiber
Rock wool with resin
Rock wool without resin
Glass wool
Slag wool
Control
Fibers
>5 urn
196
30
1.6
2.6
4.2
1.3
Particles
>1 urn
8.8
25.2
29.4
47.0
19.6
55
Number
of rats with
mesotheliomas
6
4
3
2
1
. Forty-eight animals/group.
Twenty-four control animals.
Source: Wagner et al. (1984).
rock wool (25 mg x 3), respectively. No tumors occurred in animals receiving
5 mg basalt or 10 mg rock wool. The authors indicated that the slag wod
fibers were not durable i_n viv o during the testing period.
In a series of studies conducted by Pott et al. (1987a) and describe:
earlier (see Section 7.3.1.1.4), female Wistar or Sprague-Dawley rats were
administered intraperitoneal injections of rock or slag wool and observed for
life. Fiber dimensions, total dose, tumor incidences, and lifespan are
presented in Table 7-5. As seen in the previously mentioned study (Pott
et al., 1984a), administration of slag wool did not result in a significantly
increased incidence of tumors in Wistar rats (2.1 to 6.1 percent incidence).
No tumors were found in saline controls. However, tumor incidences of 13 a-,d
71 percent were obtained in Sprague-Dawley rats administered rock wool samples
having diameters of 0.64 and 1.94 pm, respectively (see Table 7-5). An inci-
dence of 5.6 percent was noted in Sprague-Dawley rats injected with saline.
The tumor counts included abdominal sarcomas, mesotheliomas, and/or carcinomas.
7.3.1.3 Ceramic Fibers. The results of animal studies on the carcinogeni'city
of ceramic fibers suggest that the carcinogenic potential is similar to that
obtained for other vitreous fibers. Inhalation of aluminum silicate ana
refractory ceramic fibers (Fiberfrax ) have been shown to be noncarcinogeri: ii
rats and hamsters in chronic toxicity studies, and intratracheal
of Fiberfrax did not result in pulmonary tumors. In contrast. intreperito-e;"'
injection of refractory ceramic fibers (Fiberfrax*) has bee- sncv. t: res.": i"
-------
high incidences of mesotheliomas in rats and hamsters. The incidences of
mesotheliomas following intraperitoneal or intrapleural administration of
aluminum silicate microfibers were 3 and 10 percent, respectively. Considerably
lower tumor incidences were obtained after Intrapleural administration of large
diameter alumina and zirconium oxide fibers.
Pigott et al. (1981) found that refractory A1203 fibers (Saffil& fibers
I.C.I), as manufactured or thermally aged, were not carcinogenic by inhalation
In Wistar-derived rats after 86 weeks of exposure. The median diameter of
fibers prior to processing (ball milling) was about 3 urn, and the median length
varied between 10.5 and 62 urn; ball milling did not change the median diameter
(3 urn), but the length of 6.6 percent of the fibers was reduced to <13.3 prr.
Animals were exposed 6 hours/day, 5 days/week at concentrations of 2.16 c-
2.45 mg/m . The cumulative exposure was about 6000 mg-hour/m .
Davis et al. (1984) studied the carcinogenicity of fibrous ceramic
aluminum silicate glass after inhalation exposure and intraperitoneal injection
in rats. In the inhalation experiment, 48 Wistar AF HAN rats were exposes tc c
respirable dust cloud of the ceramic glass for 12 months at 8.4 mg/m (actua"
respirable concentration); the rats were observed for up to 20 additional
months. The dust cloud consisted of large numbers of short, thin fibers, sic"
only 95 fibers/mL were >5 urn in length and <0.3 urn in diameter (aspect ratio
>3:1). Approximately 90 percent of the fibers were <3 urn in length. Some
animals were sacrificed early to determine lung dust burden (see Section 4.2.3).
Eight pulmonary neoplasms were found in animals exposed to ceramic fibers; one
adenoma, three carcinomas, and four malignant histocytomas. No pulmonary tumors
occurred in 40 control rats. However, the biological significance of the
.reported pattern of tumor development was unclear since the finding of malig-
nant histocytomas in rats exposed to ceramic fibers was not consistent with the
expected pattern of tumor development resulting from asbestos exposure.
Peribronchiolar fibrosis did not occur in the treated rats, but alveolar
proteinosis was found. In contrast, the authors found that fibrous ceramic
glass was slightly carcinogenic in rats after intraperitoneal injection. The
rats received a single 25-mg dose of ceramic dust. Three of 32 rats developed
peritoneal tumors (one mesothelioma). The first tumor did not appear until
day 850. Similar doses of chrysotile asbestos reportedly produced mescthelio-ss
in 90 percent of the rats, with the first tumor appearing at 200 days. Hc»-
ever, no data were presented.
.L.IV tote 7.39 nRA-T--n: N:~ OJ:~E Cr '.'.'-.
-------
In one of a series of studies conducted by Smith et al. (1966, 1967),
male Syrian hamsters and female Osborne-Mendel rats were exposed to refractory
ceramic fibers (Fiberfrax ) via the inhalation, intratracheal , or intraperito-
neal routes (see sections 5.2.1.1, 5.2.1.3, and Tables 5-4 and 5-5). Nose-only
inhalation exposure was for 6 hours/day, 5 days/week for 24 months. The
diameter of the fibers was 1.8 urn, and the concentration was approximately
12 mg/m (200 fibers/cm ). Controls were exposed to air, and the animals were
observed for life. Only 1/70 hamsters developed a pulmonary mesothelioma, and
although spontaneous mesotheliomas in Syrian hamsters are rare, the possiblity
that this tumor was incidental cannot be ruled out. No pulmonary tumors were
observed in rats. No primary tumors were induced in groups of hamsters and
rats dosed intratracheally once weekly for 5 weeks with 2 nig of ceramic fipe-s
suspended in physiological saline. In contrast, intraperitoneal administref'c-
of 25 mg of ceramic fibers in 0.5 ml physiological saline resulted in signifi-
cant increases (p <0.. 05) in the incidences of abdominal mesotheliomas in both
rats and hamsters. Tumors were observed in 7/36 hamsters and 19/23 rats dcsec!
with ceramic fibers. No tumors occurred in control animals (0/25 rats and G/23
hamsters). In animals similarly treated with asbestos, 8/25 hamsters anc! 20/2:
rats developed mesotheliomas.
Comparison of the carcinogenic potential after intraperitoneal injection
of 11 naturally occurring and manmade mineral fibers was reported by Pott
et al. (19£7b). Groups of 8-week-old female Wistar rats received five weekly
intraperitoneal injections of 1 mg 104/475 glass microfibers, 9 mg ceramic
Fiberfrax15', 15 mg ceramic MAN, 4 mg Kevlar fibers, 10 mg polypropylene fibers,
or 20 mg wollastonite (India) suspended in 2 ml of sodium chloride solution.
The si2e distribution and number of fibers administered are presented in
Table 7-6. Surviving animals were killed 130 weeks after the last injection.
Preliminary results indicated that glass microfibers and ceramic Fiberfrax"
induced tumors in at least 64 and 70 percent of rats injected, respectively
(Table 7-7). The tumors reported were either abdominal mesotheliomas or
sarcomas. Ceramic Fiberfrax6, which is a relatively thick fiber (0.44 to
2.4 urn in diameter), induced a similar tumor incidence as compared to glass
microfibers although the number of fibers injected was substantially less
(Table 7-6). The second ceramic fiber sample (MAN) evoked moderate induction,
resulting in the development of tumors in 20 percent of the rats injectec.
Rats injected with 0.05, 0.25, or 1.0 mg chrysotile asbestos (postive controls)
July 1S = £ 7-40 DRAFT — DO N-~ C;.
-------
exhibited a dose-related Increase in tumor incidence: 11/36, 21/34, and
30/36 rats developed tumors in the low, mid-, and high-dose groups, respec-
tively. Only 1/102 rats in the saline control group developed a tumor.
Stanton et al. (1981) studied the carcinogenic potential of two ceramic
glasses after intrapleural injection into female Osborne-Mendel rats (see
section 7.3.4 for details). These large-diameter fibers were composed of
>80 percent microcrystalline Al^O, (glass 21) or 90 percent microcrystalline
2r02 (glass 22). A single 40-mg injection of each ceramic fiber was adminis-
tered, and animals were observed for life. Tumor incidences for both ceramic
glasses were low; 2/47 rats receiving glass 21 and 1/45 receiving glass
22 developed pleura! neoplasms compared to 0/115 controls.
Low tumor incidences were obtained after intrapleural inoculation of
ceramic (aluminum silicate) fibers into Wistar rats (Wagner et al., 1972).
Ceramic fibers with diameters of 0.5 to 1 urn (length was not reported) induced
mesotheliomas in 3/31 rats. The fibers were administered in a suspension o*
physiological saline at a concentration of 50 mg/mL, and the rats were observe:
fcr life. In rats treated similarly with ultrafine chrysotile (dimensions net
reported), 44/68 developed mesotheliomas.
7.3.2 Synthetic Fibers
7.3.2.1 Aramid and Pol^olefin Fibers. Aramid fibers are carcinogenic fclio*-
ing inhalation exposure and have a low carcinogenic potential after intra-
peritoneal administration. Stadler (1986) reported the results of a chronic
inhalation study in rats conducted at Haskell Laboratory. Groups of 10G male
and 100 female CrV.CD BR rats were exposed to 0, 0.08, 0.32, or 0.63 mg/m
Kevlar fibrils (ultrafine) for 6 hours/day, 5 days/week for 2 years. In
addition, 100 males and 100 females were exposed to 2.23 mg/m under similar
conditions for 1 year and observed for a recovery period of 1 year. This was
instituted after study initiation because of high mortality in the high-
exposure group; the majority of these early deaths occurred between 9 months
and 1 year into the study. The fibers had a diameter of 90 percent <1.5 um ar.s
length of 75 percent <20 pm. Exposure concentrations of 0.08, 0.32, 0.63, and
2.23 mg/m were approximately equivalent to 2.4, 25.4, 111.2, and 435.5 Kevlar5
fibrils/cm , respectively.
Cystic keratinizing squamous cell carcinomas were induced in 1/36 surviv-
ing males and 6/56 surviving females exposed to 2.23 mg/m for 1 year ar.c in
4/69 surviving females exposed to 0.63 mg/m for 2 years. In females, the
increased incidence was dose related, statistically sie*';fica-.t (:
-------
and showed a positive trend (p <0.01). In addition, 1/56 females exposed to
2.23 mg/m for 1 year and 6/69 females exposed to 0.63 mg/m for 2 years
developed squamous cell metaplasia, which was associated with alveolar bron-
chiolarization. No tumors were observed in control animals. The authors
suggested that the low incidence of metaplasia observed at the high-exposure
level as compared to the higher incidence at the 0.63-mg/m level may have
been due to the reversibility of this lesion after a 1-year recovery period.
Pott et al. (1987a) conducted a series of experiments to determine the
carcinogenic potential of 50 materials including aramid (Kevlar ) following
intraperitoneal administration to female Wistar rats (see section 7.3.1.1.4).
A total of 10 mg of Kevlar was administered; the sample was prepared using
ultrasonic treatment, but the authors stated that the test material was fle^y.
and its dimensions apparently were not measured. The tumor incidence obtained
s
in rats administered Kevlar was 13 percent (see Table 7-5) compared to an
incidence of 6 percent in rats injected with saline. The tumor types reported
included sarcomas, mesotheliomas, and/or carcinomas.
Kevlar" and polypropylene fibers were found to have a low carcinogenic
potential in female Wistar rats after fiv« weekly intraperitoneal injections
of 4 and 10 mg, respectively (Pott et al., 19£7b). Fiber dimensions £-c
details of the study are presented in section 7.3.1.1.4 and Tables 7-6 and 7-7.
Three of 53 and 2/51 rats developed tumors (mesotheliomas or sarcomas) efter
£
injection of Kevlar and polypropylene fibers, respectively. The increased
incidences were not statistically different from controls.
Similar results were obtained in a second intraperitoneal study in Wistar
rats by Davis (1987). Groups of 48, 32, and 32 rats were administered single
intraperitoneal injections of 0.25, 2.5, or 25 mg of Kevlar in saline, respec-
tively, and observed for life. An additional group of 48 untreated rats served
as controls. The diameter of 96 percent of the fibers was reportedly <1 urr,.
The fiber length was not reported, but the author stated that the test substance
was prepared from Kevlar pulp material and contained both fibers and aggre-
gates. Intraperitoneal injection resulted in the development of mesotheliomas
in 2/32 high-dose rats (not significantly different from controls). Peritoneal
sarcomas were found in 3/48, 2/32, and 1/32 rats receiving 0.25, 2.5, end 25 me
of Kevlar , respectively. However, 2 of 48 controls also developed se-cc^:;,
and since the incidences were neither statistically different frorr controls nor
dose-related, the author considered this tumor type to be spontaneous.
iqe.= 7-42 DKA-T--C: N:
-------
7.3.2.2 Carbon Fibers. Only one dermal carcinogenicity study on carbon fibers
was found in the available literature. In a study conducted at Bushy Run
Research Center, OePass (1982) evaluated the chronic dermal toxicity of four
carbon fibers in male C3H/HeJ mice. The four carbon fibers tested were
"Thornel" type P, high-modulus, pitch-based continuous fibers (CF); "Thome"!"
pitch-based fibers (MAT); "Thornel" polyacrylonitrile-based continuous fibers
(PAN); and oxidized polyacrylonitrile-based continuous fibers (PAN-oxidized).
Approximately 1.9, 2.0, 1.1, or 1.3 mg of CF, MAT, PAN, and PAN-oxidized carbon
fibers, respectively, in 25 uL of a 10 percent (w/v) benzene suspension were
applied dermally three times a week for life to groups of 40 animals.
Survival was not affected in any of the carbon-dosed groups compared tc
controls. Administration of CF fibers resulted a tumor incidence of 7.5 per-
cent (3/40 mice). The tumors were all located at the test site and were
described as a papilloma, a squamous cell carcinoma, and a hemangiosarcorr.c
(subcutaneous). Similarly, MAT carbon fibers induced tumors in 3/40 mice.
These tumors consisted of a squamous cell carcinoma, fibrosarcoma, and
re"2igiosarcoma; all were located on the skin in areas other than the test
site. One mouse from the PAN-oxidized carbon fiber group developed a skin
tumor. This was described as a leiomyosarcoma of the skin and subcutis of the
shoulder region. No tumors were induced in the mice dosed with PAN carbo-
fibers or in control animals receiving benzene alone. Although dermal turners
were found in this study, the incidences were not significantly different fro-
those of controls, and the tumors observed were types frequently seen in tierrcsl
studies. Therefore, the tumor incidences were not considered to be treatment
related. In addition, the incidences of hyperkeratinosis and dermatitis
observed in every group including vehicle controls were attributed to the
benzene vehicle.
7.3.3 Minerals
7.3.3.1 Attapulgite. No studies on the carcinogenic potential of attapulgite
following inhalation exposure were found in the available literature. Limited
evidence suggests that attapulgite is carcinogenic following intraperitonecl,
but not intrapleural, injection. Pott et al. (1974) found that in addition tc
glass fibers, palygorskite (attapulgite) was tumorigenic when injected intra-
peritoneally into female Wistar rats. Three 25-mg injections were ad~inisterec
over a 3-week period to a group of 40 rats. The lengths of 37.5 percent c' the
July 19ES 7-43 DRA-T--D:
-------
fibers were <2 pm, and 70.0 percent were <5 pm. The tumor rate was 65 percent,
and the first tumor appeared at day 275.
In a more recent, comprehensive study by Pott et al. (1967a), the carciro-
genicity of attapulgite obtained from four different geographical regions
(Caceres, Spain; Georgia, United States; Lebrija, Spain; Mormoiron, France) was
tested via the intraperitoneal route in female Wistar rats (see section
7.3.1.1.4). The fiber dimensions, dose levels, tumor incidences, and lifespans
are presented in Table 7-5. Results indicated that the attapulgite sample fror.
Caceres was carcinogenic; a tumor incidence of 40 percent was obtained, com-
pared to a 6 percent incidence for saline controls. Animals having abdominal
sarcomas, mesotheliomas, or carcinomas were included. The tumor incidence for
each of the three other samples, which were all <1 pm in length, was approxi-
mately 4 percent.
In contrast, Stanton et al. (1981) found that two preparations of attapul-
gite were not carcinogenic when implanted intrapleurally into Osborne-Mendel
rats; tumor incidences of 7 percent were obtained for each sample. Beth
preparations consisted of small-diameter, short fibers; the common log of
fibers of the dimensions ^0.25 x >8 um was 0. Similar results were obteinec by
Jaurand et al. (1987) following the intrapleural administration of 20 mg of
attapulgite into male Sprague-Dawley rats. The mean diameter and length of the
attapulgite fibers were 0.06 and 0.77 pm, respectively. No tumors were fcjnd
in 36 rats dosed with attapulgite, and survival was reportedly comparable to
controls.
7.3.3.2 Erionite and Other Zeolites. Natural fibrous zeolites, especially
erionite, are highly carcinogenic in rats via the inhalation, intratrachesl,
intrapleural, and intraperitoneal routes of administration. Evidence suggests
•
that erionite may be more carcinogenic following deposition in the lungs tha.-.
asbestos. Zeolites have also been shown to be carcinogenic after intraperito-
neal injection in mice, but no information was found in the available literature
for other animal species. Nonfibrous, synthetic zeolites do not appear to be
carcinogenic following intrapleural or intraperitoneal administration.
Palekar and Coffin (1986) reported in a recent abstract that fewer fibers
of erionite produced more mesotheliomas in F344 rats after intratrachecl
injection as compared to chrysotile or crocidolite asbestos fibers. Adcitic'-ici
details were not presented.
-------
Wagner et al. (1985) tested two samples of natural fibrous erionite, and
nonfibrous natural and synthetic erionite, for carcinogenicity in Fischer 344
rats using both inhalation exposure and intrapleural injection. Dusts of a
rock sample from Karain, Turkey, which was characterized as an incompletely
formed erionite, and a sample of Oregon erionite were prepared by disc milling.
Groups of 20 male and 20 female rats (57 days old) were exposed to mean respir-
able dust concentrations of 10 mg/m Oregon erionite, nonfibrous synthetic
erionite, or crocidolite asbestos for 7 hours/day, 5 days/week for 1 year, and
were observed until death. The size distribution of the Oregon erionite fibe-s
was as follows: a diameter of <0.2 urn for 56 percent and <0.4 urn for 92.6 per-
cent of the fibers, and a length of 3 to 5 urn for 40.2 percent and 3 to 10 v~
for 66.7 percent of the fibers. The particle size of the nonfibrous syr.thef'c
erionite was >0.5 utr.. Twelve rats/group were sacrificed prior to 1 yes- tc
determine dust retention. Mesotheliomas were found in 27/28 of the surviving
rats exposed to Oregon erionite. The average time-to-tumor was 580 days. N:
mesotheliomas occurred in the asbestos-exposed rats; 1/28 developed a squares
carcinoma (517 days). Unexposeti controls had no tumors (0/28), and 1/26 rats
exposed to nonfibrous synthetic erionite developed a. mesothelioma (784 days).
In the intrapleural study, 20 mg of Karain (Turkey) rock fiber (d.-icmete-
of 59 percent <0.2 urn, length of 4.9 percent >4 urn), Oregon erionite, c-
nonfibrous natural zeolite (Japan) were administered to rats in a saline
suspension. Chrysotile was used as a positive control. Mesotheliorr.ss were
found in 40/40 rats injected with Oregon erionite and mean time-to-tumsr WES
390 days. Karain rock fiber caused mesotheliomas in 38/40 animals with a mesr
time-tc-tumor of 435 days, and 2/40 rats receiving nonfibrous zeolite developed
mesotheliomas at a mean time of 715 days. Nineteen of 40 rats receiving
asbestos developed mesotheliomas (678 days), and one mesothelioma was fount? in
40 controls (720 days).
Johnson et al. (1984) examined seven pleura! tumors induced in rats b>
inhalation of erionite using Mstochemical, immunocytochemical, and electro-
microscopic techniques. The mesothelial nature of the tumors was confirmee by
a mucopolysaccharide and keratin staining pattern and was almost identical to
human mesotheliomas. All of the tumors had both epithelial and spindle ce-1
(sarcomatous) components; the proportions of each cell type varied wit*-
tumor. The pluripotential nature of the tumors was indicated by ver-ic
JuU lSc£ 7-45
-------
degrees of differentiation; two tumors had dense cord granules staining posi-
tively for neuron-specific enolase, an indicator of endocrine cells (epithelial
components). One tumor had osteoblastlike cells, and two were lipid rich; both
features were indicators of mesodermal expression. Spindle cells in most
tumors were indications of fibroblastoid differentiation, although the cells
were not true fibroblasts.
Maltoni et al. (1982a) tested the carcinogenicity of sedimentary erionite
in groups of 20 male and 20 female 8-week-old Sprague-Dawley rats after intra-
pleural or intraperitoneal injection. The animals received a single dose of
25 mg erionite in 1 ml water. By week 53, mesotheliomas developed in the
pleura of 9 of 10 animals (6 males and 3 females) that died. Survival was
13/20 for males and 17/20 for females. None of the vehicle controls and
0/40 rats receiving intraperitoneal doses of erionite developed tumors. IT,
contrast to these results, crocidolite caused mesotheliomas following i-ntra-
peritoneal but not intrapleural administration. In an update of this study,
Maltoni et al. (19825) reported that by week 67, 12 of 20 males and 9 of
20 females that died developed pleura! mesotheliomas after receiving irtra-
pleural injections of erionite. None of the 40 control animals (20 males a-.d
2u females) developed turners. The final report of this study has not bee"
published.
Pott et al. (1984a) tested fibers obtained from a piece of stone fror
Ankara, Turkey, in Sprague-Dawley rats. Fifty percent of the fibers had a
diameter <0.36 urn, and 90 percent were longer than 15.1 urn. Intraperitoneel
doses of 5 and 20 mg resulted in tumor rates of 65 and 72 percent, respec-
tively. The tumors were sarcomas or mesotheliomas. The first tumor appeared
at 288 and 222 days for the low and high dose, respectively. Mineralogic
testing of the sample, which was incomplete at the time of publication,
suggested that the sample was not a zeolite. A sample of zeolite from Nevaoe
was not carcinogenic following similar testing.
In a more recent, comprehensive study by Pott et al. (1967a), the carcino-
genicity of erionite samples from Karain (Turkey) and Oregon were tested in
female Wistar and Sprague-Dawley rats via the intraperitoneal route (see
section 7.3.1.1.4). The fiber dimensions, dose levels, tumor incidences.
and lifespans are presented in Table 7-5. No information on the composition
of the fiber samples was reported, however. Both samples were carcinogenic.
A dose-related increase in tumor incidence was noted in Wista" rets dose: *:t ,
-------
erionite from Oregon; incidences of 48 and 90 percent were obtained in the
low- and high-dose groups, respectively. The mean times-to-tumor were 98 and
80 weeks. Sprague-Dawley rats proved to be slightly more sensitive to the
carcinogenic effects of the Turkish erionite than Wistar rats (see Table 7-5).
Ozesmi et al. (1985) also tested a zeolite from the village of- Karain for
induction of tumors in Swiss mice using the intraperitoneal route. A rock
from Karain containing both fibrous and nonfibrous zeolite was ground to dust.
Characterization of fiber content and size were not reported. One milli'lite"
of a suspension containing 5, 10, 15, 20, 30, or 40 mg of the dust in physic-
logic saline was injected intraperitoneally into groups of 37 to 98 6-week-old
mice, which were followed until death (up to 32 months). Tumor incidences ere
presented in Table 7-9. The predominant tumor type was mesctheliome. The
incidence of tumors did not appear to be dose related. However, this may have
been due to a disparity in survival at the higher dose levels; survival after
6 months was not reported. The authors stated that no turners occurred before
9 months. Three mesctheliomas and one lymphoma occurred in 55 saline cor*re's.
Suzuki (19£2) studied the carcinogenic potential of two natural zeolites,
erionite and mordenite, after intraperitoneal injection into male Swiss mice.
The erionite sample consisted of fibers that were 0.4 to 24.urn in length
(mean length 1 urn) and 0.01 to 2.5 urn in diameter (mean diameter 0.1 urn).
The mordenite sample, which consisted of granular and fibrous particles.
was 0.33 to 5.7 um in length and 0.05 to 1.67 urn in diameter. A total of
45 mice received a single intraperitoneal injection of 10 or 30 mg zeolite
in 1 ml of saline solution. Six of 10 mice receiving 10 mg erionite
developed tumors (4 mesotheliomas). Fibrosis occurred in mice dosed witn
both zeolite samples.
Suzuki and Kohyama (1984) further studied the careinogenicity of
natural erionite and mordenite, and of a synthetic zeolite, after a single
intraperitoneal injection in male BALB/c mice. In two natural erionite
samples (from the western United States), 90 to 95 percent of the fibers
had a length <8 um, and 82 to 100 percent had a diameter <1 um. Erionite
II was purer than erionite I. Mordenite was a mixture of fibrous anc
granular forms; 94 percent of the fibers had lengths <3 um, and 89 percent
had diameters <1 um. Synthetic zeolite 4A was about 2.4 x 2.24 um.
I..TV. ictc 7-i7 DRArT--c:
-------
TABLE 7-9. PERITONEAL TUMOR INCIDENCES IN MICE AFTER
INTRAPERITONEAL INJECTION OF KARAIN DUST
Amount of
dust (mg)
Control
(saline)
5
10
15
20
30
40
Total
No. Of
mice
55
69
97
98
45
45
37
391
No.
surviving
6 months
46
55
81
73
43
39
30
321
No.
Meso-
thelioma
3
6
12
10
6
3
4
41
of tumors
Lymphoma
1
0
11
7
5
4
4
31
Both
0
4
4
0
0
1
2
11
Percent
with
tumors
8.7
18.1
33
22.3
2r
20.5
33
26.1
Source: Ozes-i et al. (19£5).
Groups of 20, 50, and 75 mice received 0.5, 2.0, and 10 mg erionite II,
respectively. Mortality was excessive at the high dose; consequently, a seccr.c
group of 50 mice was dosed with 10 mg erionite I. Between 7 and 23 months
after exposure, 6/18, 24/44, and 3/8 mice developed peritoneal tumors at acse;
of 0.5, 2.0, and 10 mg erionite II, respectively; in the second group.
21/42 mice developed tumors at a dose of 10 mg of erionite I. Six cf the
54 tumors were plasmocytomas, and 48 were mesotheliomas. The mesothelion-cs
resembled asbestos-induced tumors in their gross appearance, histology, and
close association with fibrosis. No tumors were observed in groups of 118 rr.-ice
receiving saline, 44 receiving 10 mg mordenite, or 46 receiving 10 mg synthetic
zeolite 4A.
7.3.3.3 Talc. Talc is not carcinogenic following inhalation exposure or
intraperitoneal and intrapleural administration to rats, hamsters, and mice.
Evidence from one study suggests that talc may be an effective cocarcinoge-.
when administered with benzo(a)pyrene (BaP). Ingestion of talc (100 ing/ret/is..)
for 101 days resulted in the development of leimyosarcome of the storr.*:* i-i
1/32 Wistar rats observed for life (Wagner et al., 1977). No centre's oeve'opec
tumors. Inhalation exposure to 10.8 mg/ir, talc for 7.5 hours/day. 5 dcys-»ee<
7-ic
-------
for 12 months, resulted in a pulmonary adenoma in 1/24 Wistar rats observed for
life (Wagner et al., 1977). No pulmonary tumors were noted in 48 control rats.
Wehner et al. (1977) exposed groups of 50 male and 50 female Syrian hamsters to
8 mg/m talc 2.5 hours/day, 5 days/week for up to 300 days. The animals were
then killed. No carcinogenic effects were found.
In a chronic study by Stenback et al. (1986), groups of 48 Syrian hamsters
received weekly intratracheal injections of either 3 mg talc alone or in
combination with 3 mg BaP in a saline vehicle. Talc alone did not induce
tumors. However, in combination with BaP, talc was found to be an effective
cocarcinogen, inducing increased incidences of alveolar tumors when compare:
to BaP or talc alone. Single intrapleural administration of 40 mg talc tc
Osborne-Mendel rats (Stanton et al., 1981) or 20 mg talc to Wistar rats (Warper
et al., 1977) did not result in tumor induction after lifetime observation.
Similarly, no tumors were found after four intraperitoneal injections of 25 rr.g
in 40 female Wistar rats (Pott et al., 1974) or after a single intraperitciea"
injection of 20 mg talc in 24 Swiss mice (Ozesmi et al., 19E5) observe:! *f
life. Hamilton et al. (1954) injected talc (10 mg) intrabursally on tne
surface of ovaries of rats; the animals were observed for 18 months. Nc turcr-s
were found.
7.3.3.4 Vermiculite. Results from one study indicate that vermiculite is net
carcinogenic following intrapleural administration. Hunter and Thomson (1873)
tested the carcinogenicity of vermiculite after intrapleural injection of 25 me
in 0.2 ml saline into a group of 21-day-old female Sprague-Dawley rats. The
vermiculite sample consisted of amorphous particles and had a particle sire
93 percent <5 um and 37 percent <2 urn. The animals receiving vermiculite
developed granulomas in the lung and viscera, but no tumors developed after
104 weeks. A comparable dose of chrysotile asbestos produced mesothelio^as
in 48 percent of the rats.
7.3.4 Other Fibers
Potassium titanate was carcinogenic after intrapleural administration,
£
and limited evidence suggests that Fybex , a commercially available potass^u-
octatitanate, may be carcinogenic after inhalation in hamsters. Calciun-
silicate fibers and wollastonite (a natural calcium silicate) have bee" s".cw.
to be noncarcinogenic following inhalation exposure and intraperitoneel e-=
intrapleural administration in rats. This may be due to the lack of d-re:-'"iity
•iv i9:S 1-^ Ds
-------
of these fibers In vivo. Several other manmade and natural mineral fibers
including dawsonite and aluminum oxide whiskers induced tumors after intra-
pleural administration, but studies by other routes of exposure were not
available. Ferroactinolite, another fibrous mineral, was found to be more
carcinogenic after intratracheal than intrapleural administration.
Lee et al. (1981) studied the pulmonary responses of potassium octatita-
nate (Fybe* ) after inhalation exposure in male Sprague-Dawley rats, male
albino guinea pigs, and male hamsters (strain not specified). Exposure was
for 6 hours/day, 5 days/week for 3 months, at concentrations ranging fror
2.9 x 106 to 41.8 x 106 fibers/L. Fybex® had an average size of 6.7 by
B
0.2 urn, and animals were examined at 18 and 24 months. Fybex produced
mesotheliomas in 1/12 hamsters exposed at 2.9 x 10 fibers/L, 1/13 exposed at
13.5 x 106 fibers/L, and 1/16 exposed at 41.8 x 106 fibers/L. No mescthe 1 iorr.ss
were found in control hamsters (0/34), and no tumors developed in any of the
Fybex^-exposed rats or guinea pigs. Although the development of mesothel iorr;=s
ir. hsrr-sters cannot be ignored, the short-term exposure, the small numbe- c*
animals tested, and the smell number of tumors produced in the lungs precluoed
any conclusions on the carcinogenic-potential of Fybex .
Stanton et al. (1981) reported tumor incidences of 69 and 72 percent in
Osborne-Mendel rats after single intrapleural injections of 40 mg of two
potassium octatitanate samples (Table 7-9).
The chronic inhalation toxicity of manmade calcium silicate (wollastonite)
insulation materials (Ca^OH^SigO^-H^O) in rats was reported by Bolton et al.
(1985). Groups of 48 male Wistar rats were exposed for 7 hours/day, 5 days/week
for 12 months, to 10 mg/m (respirable fibers only) of three different sar.ples
(A, B, and C) of calcium silicate. Fiber diameter ranged from approximately 1
to 10 urn. Control animals were exposed to filtered air. All animals were
observed for an additional 12 months postexposure. Pulmonary neoplasms occurred
in 2/139 rats exposed to calcium silicate (both rats were exposed to sample B)
and were described as a focal squamous carcinoma of low-grade malignancy and a
benign adenomatous lesion. No pulmonary tumors were found in control rats.
One rat from the calcium silicate-exposed group developed a peritoneal mesctne-
liorna, which the authors considered to be spontaneous.
No tumors were induced after intraperitoneal injection of a single 2r-rcc
dose of each of three calcium silicate samples in groups of 36 male Wists"
rats (Bclton et al. , 1986). Wcllastonite was also found to be
-------
in female Wistar rats after intraperitoneal injection of 20 mg weekly for
5 weeks (total dose 100 mg) in saline (Pott et al., 1987b). No tumors were
found. The authors hypothesized that wollastonite may not be durable in a
saline vehicle.
Pott et al. (1974) found that nemalite was tumorigenic after four intra-
peritoneal injections of 25 mg in Wistar rats. For the nemalite fibers used,
91.6 percent had diameters <2 urn and 96.4 percent had lengths <5 urn. The
tumor rate was 62.5 percent, and the first tumor appeared after 249 days.
Gypsuir, (4 x 25 mg) produced tumors in 5 percent of the rats. Granular dusts
(actinolite, biotite, hematite, pectolite, and sanidine) were inactive after
similar exposure.
The most comprehensive survey to date on fiber induction of tumors fo1"!ow-
ing intrapleural injection has been published by Stanton et al. (19E1).
Seventy-two experiments were conducted with different fibrous materials.
Dimensional ranges of fibers were tested for many groups: 13 samples cf
crocidclite asbestos, 22 samples of classes, 8 samples of aluminum oxiae.
(AI^CO whiskers, 7 samples of talc, 7 samples of-dawsonite, and 4 samples cf
wollastonite. Also studied were two samples of tremolite, attapulgite.
potassium octatitanate, and halloysite (a natural fibrous aluminum silicate),
anc! single samples of nickel titanate, silicon carbide, and amosite asbestos.
A standard dose of 40 mg dispensed in hardened gelatin was applied to the left
pleura! surface of groups of 30 to 50 female Osborne-Mendel rats (12 to
20 weeks old), and the rats were followed for 2 years. Control groups included
untreated rats, rats receiving thoracotomies but no pleura! implants, and rats
receiving pleura! implants of nonfibrous material. Size distribution of each
of the 72 preparations was presented, and fiber counts in discrete-size catego-
ries were reported as the common log; electron-microscopic photomontages with
magnification of about 5,000 to 100,000 were used for size measurements. The
actual incidence of tumors was counted, and life-table analysis was used to
calculate percent tumor probability. Table 7-10 presents selected data.
Fibers of potassium octatitanate, silicon carbide, synthetic and natural
dawsonite (expt. 21), fibrous glass, and Al.O, whiskers were a!! carcinogen:,
and the predominant fiber size was <0.25 x >8.0 urn. Representative date fc-
some asbestos fibers are also presented in Table 7-10. Nickel tita-ste.
halloysite, attapulgite, and talc samples (common log fibers/ug = 0) we'e all
negative; Al.O, (log = 2.60) was marginal (4/25 tumors). Glass fibers wif
-------
TABLE 7-10. SELECTED DATA ON CARC1NOGENICITY OF DIFFERENT
FIBROUS MATERIALS FOLLOWING JNTRAPLEURAL IMPLANTATION IN RATS
Compound
Nonasbestos
Potassium octatitanate
Potassium octatitanate
Silicon carbide
Dawsonite 5
Dawsonite 1
Dawsonite 7
Dawsonite 4
Dawsonite 3
Glass 1
Glass 2
Glass 3
Glass 4
Glass 5
Al-,03 1
AUO-: 2
AiJDs 3
Asbestos
Tremolite 1
Crocidolite 1
Crocidolite 3
Amosite
Control s
Glass 18
Untreated
Expt.
No.
1
2
3
4
7
20
21
22
13
15
16
17
19
18 .
27
28
5
e
10
11
67
* "
Actual
tumor
incidence
21/29
20/29
17/26
26/29
20/25
16/30
11/26
9/24
9/17
12/31
20/29
18/29
16/25
15/24
8/27
9/27
22/28
18/27
15/23
14/25
0/115
3/488
Percent tumgr
probability
(± SO)
95 * 4.7
100
100
100
95 ± 4.8
68 ± 9.8
66 ± 12.2
66 4 13.4
85 4 13.2
77 4 16.6
74 4 8.5
71 4 9.1
69 1 9.6
70 4 10.2
44 4 1.7
41 ± 10.5
100
94 i 6.0
93 4 6.9
93 4 7.1
0
••
Common log
fibers/ug
(<0.25 x >6 prr.)
4.94
4.70
5.15
4.94
4.66
4.71
4.01
5.73
5.16
4.29
3.59
4.02
3.00
3.63
2. 95
2.47
3.14
5.21
5.01
3.53
0
• •
Calculated by life-table analysis.
bDawsonite (NaAl(OH)2C03) samples 5, 1, 7, and 3 were synthetic, and
sample 4 was a natural fiber from Tanzania.
Source: Stanton et al. (1981).
-------
log - 0 to 1.30 were negative, as were samples of dawsonite, wollastonite,
attapulgite, and crocidolite with a log of 0. Two .ceramic glass samples, glass
21 (80 percent A1203) and glass 22 (90 percent Zr02), were also inactive. The
correlation coefficient of a graph of logit (In p/l-p) of tumor probability (p)
versus the log of the number of particles/mg with dimensions of £0.25 x >£ ur
was 0.80, but relatively high correlation coefficients (0.68 and 6.63) were
also observed in categories having dimensions of 1.5 x >8.0 pm and of <0.25 x
>4 to 8 pm.
Coffin et al. (1982, 1983) compared ferroactinolite and amosite asbestos
(cummingtonite-grunerite) for tumorigenic response after administration to
Fischer 344 rats via the intrapleural or intratracheal routes and conclude:!
that in this case, intrapleural administration failed to predict the carcino-
genic potential of ferroactinolite in the lungs. The fibrous classification c*
ferroactinolite is apparently debatable (Zoltai, 1986), but for the purpose cf
this document it is considered to be an asbestiform mineral. Single dcses cf
20 mg were administered via the intrapleural route; 12 doses of either C.E rr;
te or 0.2 mg amosite were administered via the intratraches"! rojte
for a total of 6.0 or 3.08 urn, where*s
only O.OS x 10 fibers/ing ferroactinolite were in the same size category.
However, the incidence of pleura! tumors was approximately equal (Table 7-11).
There was a significant increase in mesotheliomas in both the ferroactinolite
and amosite groups and a slight but significant (p = 0.05) increase in pooled
primary lung tumors for ferroactinolite in the intratracheally dosed group.
Ferroactinolite was more carcinogenic on the basis of total fiber dose or fiber
dose of the selective size category (^0.25 x >8 urn) following intratracheal
instillation. When the lungs of rats were examined at various times after
intratracheal injection, the ferroactinolite fibers present were split, and the
number of thinner fibers increased (Cook et al., 1982). The number of long,
thin fibers present after a year was similar for both amosite and ferroactinc-
lite groups (Table 7-12). The ferroactinolite sample had essentially no fibers
meeting Stanton's criteria at the time of intratracheal instillation, but fiber
splitting produced 24.6 x 10 of such fibers after 1 year whereas the ccr'-e-
sponding amosite dose had 18.6 x 10 fibers at 1 year.
A tabular summary of carcinogenicity data for each material is found in
Table 7-13.
Jjiy 1965 7-53 DRArT--:: rC" QL/1TE Z-". CITE
-------
TABLE 7-11. INCIDENCE OF PLEURAL TUMORS INDUCED IN F344
RATS BY FERROACTINOLITE AND AMOSITE
Route/fiber
Intrapleural
Ferroactinolite
Amosite
Sham control
Untreated control
Intratracheal
Ferroactinolite
Amosite
Sharr control
Untreated control
No. of
animals
135
137
134
219
561
139
212
219
Percent of
Meso-
theliomas
23
33.6
1.5
0
0.89
1.4 '
0
0
animals
Lung
tumors
1.5
0.73
0.75
0.4
3.9
0.71
0.6
0.43
with tumors
Metastatic
tumors
0
0
0
0.46
2.1
0
0.9-:
Source: Coffin et al. (1963).
TAS.E 7-12. SIZES OF MINERAL FIBERS RETAINED IN THE LUNGS OF RATS
AT VARIOUS INTERVALS AFTER INTRATRACHEAL INSTILLATION
Fiber/time
Ferroaciinolite
1 dayc
4 months
12 months'"
Amosite.
4 months
12 months0
Fibers/mo
(x 1C6)"
107
262
366
585
393
202
Mean length
2.86
2.00
1.77
2.60
3.02
3.62
Mean width
(MB!)
0.37
0.17
0.11
0.24
0.22
0.21
Asrecj
10.6
10.9
15.7
20.1
8A function of length and width.
Single instillation of 0.5 nig ferroactinolite or 0.25 mg amosite.
GTwelve weekly instillations for a total of 6 mg ferroactinolite or 3 mg
amosite.
Source: Cook et al. (1982).
~\ CiC.
7-54
DR-r7--:o N:T £J:~E --• -• • =
-------
1AIIII 7-1.1. SUMMARY 01 URClNOr.l Nlcl IV MIIIMIS C1N HHMI . SYMIMItM. I HUN',. AND HINIRnlS
i.il 1 ihi-r Rinile
i'ii'. ijl.r.s inhalation
Inhalal ion
Inh.ilation
Itihalat ion
Inhalation
Inhalation
Inhalation
Inhalation
Idlralracheal
Intratracheal
lot.ralr.icheal
Inl ralrarhral
Sp«r. les/slrain
H.tt/f. Os,horne-
Mpn.lel;
h,imsler/M, Syrian
flat/M. Spraque-
llawley;
nuinpa pig/M;
hamster
Rat/F. Osborne-
Mendel;
hamsler/H. Syrian
Rat/F. Wistar
Rat. Fischer 344
Rat. Fischer 344
Monkey /N, cynowolgus
Baboon/N
Hamster, Syrian
Hamster. Syrian
Ral/f , Oshorne-
li'imvter/M, Syrian
Rat/f. Wislar
n,,,.
0. .1 at- 1 mii/m1,
f> h/.l. S d/wk,
inn wk
470 mij/m1
h h/il. S ini o»t lustvp
mi'.iii il:0 4S. 3.1. No lung tumors - 70
V 4 , or f>. 1 |im
•IM P»4 IK/perplasI*. - 70
,1 'MH '0.11 |im I liimor
Mrt '11.47 (im
l:'Mit . 17.4 nm
'.lit • 1 n |im
.IM ion |/4fl developed tumor. - 10
il • .1 |im 7/4R developed hyper-
1: - S inn plasia
70 |i»
il •l.'j-C. |im No lung tumors - 73
1:. Ill ami -70 |im
d:ft.l-4 |im No lung tumors - 79
1 . S- 10(1 |im •
il: ISt '07'. |im terminated at Week - 6
l'>ialiX <7.fl |im developed respiratory
tumors, mostly
mpsutheliomas
W...HI
-------
(AMI I Ml (mill iim<-il)
iin-i.it 1 ilinr Rnulp Ippr IpS/stralll
tl.ii.u-, yl.i-.s lntr.ipleiir.il R.tt/F. ffsliorne-
<"»'l » Mendel
Inlraplpiiral Rat/F . Wistar
Inlraple.ural Ri«* » SP*«q«e-0.i««ley
lntr,ipletiral Rat. Spraque-Oawley
Intrapletiral Mouse. BAlB/c
Inl.rapleural Hamster, Syrian
Intr.tplpiiral Hamster, Syrian
Inl raperitoneal Rat/F, Wistar
litlraprrilnneal Ral/F , Wlslsr
1 ilii-i SI /i'/ll<'si ri|.l mil
Ilits.iilP (il ili.imi'lri . 1 lrn<|lli)
10 *M|. l» il O.I. /'. |in:
lll |i*i
7S *H|, IK mi-an il: b |im ( insul.il inn
l|l Mill')
0 ', IM| .IM 101
il •I0t-0. mil .w.ii l.ililc
7% mi|. 1«
Comwenls Carclnoqpn Roferrncp
Proh^liillly of I
plpnral sarcoma:
M-RSX »
M-77X •
«-nx
7
0/3? lunq tumors
4/J? developed •
mpsothel lomas
4/4R developed » III
mesotheliomas
6/4S developed • 1
mpsolheliomas
No tumors - .11
9/60 developed « 4
tumors. 1st at d 784
7/60 developed « 4
1 timers, 1st at d 4 OH
2/60 developed • 4
tumors, 1st at
ri i>11
No tumor* In - 4
Kin animals
No tumors In 60 - 5
animals
in tumor rate . • 71
evposed
compared to 6Y
in controls
1/40. - 1?
4/40, and •
7.1/40 ilpve loped •
IIIMI) tumors.
rrspiM. lively
(unit iniii-il
-------
IAHII /-It (mill i mini)
HiniM.il 1 ilirr Rmilp
1 ilimii', ijl.r.s Inlrapprilnnpal
(mill )
Inlraperitoneal
Inlraperitoneal
Inlraperitoneal
Inlraperitoneal
i.l.iss wool Inhalation
Inlrapletirat
Miin-i.il wiml
(fill I Wllll I
Inhalation
Inlraplpwal
Intraperiloneal
Species/tlr.iin
Ral/f , Wistar
Hamster/M, Syrian
Rat/F . Osbornp-
Mpndpl
Rat, Spraqiie-
Oawley
Rat/F, Wlslar
Rat/F. Wistar
Rat, Fischer 344
Rat. Spr ague -Daw ley
Rat. Fischer 344
Ral, Spraqiie-Oawlpy
Ral/t, Spraipie-
Pawley
1 iln-r '.i/i'/Di-M i ipt inn
nn'..it|i- (il ili.im-ti-i , 1 li-ni|lh)
7 mil. l« HM 1114
.1 MIT .0 7(1 |im
I iirr. • 1 1 |tm
10 lm|. l»
7'.» mil. ?«
70 «M|. Ic HN 1 1?
d I |im
I:, 'II |im
?b «M|, Ix mr.in il 0 4'i (in
1: / '• |.«
?S «M|. Ix nn-.iii il:O.4S \tm
\:l ', |im
7-10 «H|. l» il:-0.:H |im
1 '" " 1™
(1 ',-10 «i|. Ix •
S d/wk. 17 IMI 1: •'• |im
nh'.prve 74 «HI
70 M|. Ix il:« .1 l«"
10 «M|. Ix i! Vlt OT ,11 im
7*> M|. .Ix il MIT • 1 sothel iomas
or sarcomas
2/95 developed
limq neoplasms
4/9'j developed
hyperplasia
1/4R developed
Mfsothet iooa
7/4B developed
liMors; I/4B
tlpyp loped
hyperplasla
S/% developed
•psolhellonas
0/4S developed
Immirs
|(,X liinor inriilpncp
(inpsolhpl ltK«*s or
•..tr i >HI>.I\ ). I1. 1 limnr
al .1 7/4
Carcinmjen Rplerente
i 33
'
•
« 13
70
« 20
« 39
« 39
« 7?
i 10
J 10
10
• 10
II
• II
(i mil i mini im Mn> liillnwim) p*<|i>)
-------
I All! I Ml (l 1.1,1 ilHM.I)
.il 1 ilii-r Rnulp
• 1 1 Wllltl
1 wniil Inl r.ippri Inneal
i.nl (
Inl r.ippri loneal
"1 win.) lnli.il.it inn
Idl.raplpiiral
Inlrapleurat
1 nt raper i loneal
nil 1 iliprs
mi in um lnli.ll.il Ion
. t 1 ii .it P
Intraplpural
Intraperiloneat
, .11 In, v Inhalation
cr.imii
ih...-.
ii. i 1 r.ii""' )
Inl r.il r.trhpal
Inl r.i|n%r ilni.pal
Inl r..|ipr itnnpal
Species/strain
R.»l /F . Spraf|up-
ll.iwlpy
R.it /' . Spra<|up-
ll.iwlpy
Rat/I . Osborne-
Henile 1 ;
hamslpr/M, Syrian
»at/F. Wistar
Rat. Sprague-Dawley
Ral/F. Wislar
Ral. AF Han Wislar
Ral. Wislar
Ral. AF Han Wislar
llamsler/M. Syrian
Ral/F , Osborne-
Mpmle I
Hat/F. Osbornr-
Hrnile 1 ;
li.imslpr/M, Syrian
II.IBC. tpr/H. Syr i. in
H..I/I . nsln.rnp-
1.
10 «i|. Ix
7'. mi|. wprkly,
Ix
10 mil/Hi1, f, hAI,
', rl/wk. 104 wk
5 «|. Ix
70 Ml). Ix
70 m<|. wppkly.
?x
H 4 MCI/Hi1
(ar.lual rps-
litr^lilp conr. . )
/ hAI. 5 d/wk.
1? wo
70 m<|. Ix
7S mi|. Ix
C. h/.l. 5 d/wk.
1(14 wk
17 mil/in1
104 wk
7 m>t. wppkly, '•*
?', m,,
r, .,
1 ilic. '•i/c/llcsi cipl inn
(il ili.imi-lr, , 1 l«.i.i|lli) CoMRpnls Carclno«|pn
il n 1.1 |im ITX liMor incidence •
11 I |.m
•I I '14 |im /|X liMior incidence •
I / 1 |im
MP.IK d 7. / |im Mo lunq linnors
1 40 ,iin
il SOT . o in |im SX tunor rate. >
1 :M« • 7 / |im 1st Itmor at
d bZI
il • '. |im No tumors In 48 rals
d 1 '. -7 «• |im 7-6X liMMr Incidence 1
1 11 71. |im
.1:0 1 |im 1 adenoma. 3 carcinomas.
1 : 'HO; . .1 |im 4 hisliocylomas of
lungs in 40 rats
il:O.S 1 n pm 3/31 developed t
mesolheliomas
il 0 1 |im 1/37 developed t
1 '10% • 1 pm mesolhelloma.
7/37 developed
f il.rosarcomas
mc.nt .1: l.ll |m 1//0 developed t
1 . .IS |im mpsothelinma
mi-.in .1 l.ll pm No tumors
1: IS |i«
•M'.III il 1 . II |im No tumors
1 I'. |,m
mi-.m il l.ll pm //.If. developed •
1 C, ,,m mpsolliel iiMias
mi-.in il 1 II |im 11/7 1 il.wplopeil '
I |i, |,m liimni". (M mi-siillii'l
Rplpll'lli p
3'l
3'»
7(1
II
10
39
13
311
11
70
70
711
70
"'
iiim.r.)
i i,.,n..l mi I IIP InllnwiiKl l>.»i|r)
-------
1AIIII Ml (MIII! iniM-il)
Mififr.fl 1 iluT
1 ilii-rl r.l«M
MAN
•..ill ilw 1 ilii-rs
(Al-.ll,)
Milt Al .O ,
•Mil /«(!
I'nl .<-.-. mm
in t .it 1 1 .iii.il i*
1 yl.l-.M
Al .11,
wlif.li-l •.
Ai .imiil 1 HUM s
tl>vl.llW
*""'•*
lntr.i|iprltnneal
Inlr.ipprilnneal
Inhalation
Inlrapleurat
liilrapleiirat
Initiation
Inlrapleural
Inlrapleural
Inhalation
Spp» les/s train
Ral/l . Wistar
,
Rat/r. Wistar
Rat. Wislar
Ral/f , Osborne-
Mpnde 1
Rat/r. Osborne-
Mende 1
Rat/H, Sprague-
Oawley;
hamsler/H;
quinea pig/H
Rat/r . Osborne-
Hende 1
Ral/r, Oshorne-
Hendel
Rat. Crl:CD BR
1 ilift '.i /iVIIr'.c ript iiitt
I»«S.I,,|. (.1 di.nw-lr,. 1 l.-»H|lh)
4't mi. wrrkly. 1 Mill • 14 \im
'.« ll.'MIl -74 (in
t'j nil). wrrHy. 1 ••Wii: • M |im
SK d/wV. 1 III .S-1,7 |im
lid wk
40 «H|, IK l.ni|i> ili.imrlrr
40 *H|. l« l.in|p .ll.im.-trr
7 9-41 fl x III •••.in d II 7 |if"
tiltprs/l mi-.in II, ; |im
fi h/d. 'j d/wk.
3 mo
40 f*f|, Ix l'"| (it>P.rs/|ii|
• »l 7?i « •» |im:
4 /ll-4.')4
40 *N|, IX llH| 1 il>ITS/|l<|
• II . 7S x -R |im:
0 1 /«
« h/day. 'j d/wk 1: /'.Y -70 |M
1114 wk d: 'Hit • 1 ') |im
II. OR mi/m*
0. 17 HHi/di1
n 1,1 •!)/•'
ft li/.l.iy. S il/wfc
'.7 wit
7.71 M|/«I'>
Conwenl*
.11/47 developed
atidnninal nesothp-
liomas or sarcomas
11/54 developed
atidtwinal mesolnp-
lii>*MS or sarciMs
Ho, pulmonary tumors
7/47 developed
pleural sarcomas
1/45 developed
pleural sarcomas
Small numbers of
wsolhpl innias
in hamstprs
69-77X tumor
incidence
4-f.Jt tumor
incidence
No tumors
No tumors
4/69 females oVvet-
oped cystic keratin-
i/ini| squamoiis re 11
carcinomas and d/h'l
fpmales developed
siniamnus cell
7/V7 rats developed
cystic keratinl/imi
sifiMmnus cell tar-
tare Inoqen Rpfprpnrp
» 7?
« 77
- 14
f 17
1 17
i 'i
• \7
• 1?
74
74
« 74
« 74
t tin MM s and I /Mi
tpn.ilPS developed
Miu.inmus rpll
m,.|.,|.|.r. U
(lonl imird on MM- !«>ll»wiiw| |MI|P)
-------
I Milt / II (< mil in I)
1 ilwr Roul.p SpPC IPS/sl rain
il.i-is •
<•> Inl i.iprrilonpal Ral./l , Wistar
lul i .ipiT ilonpal Rat. Wislar
liilr.ipprtloneal Ral/l , Wislar
1 i n
tupvlpiip Intratrachpal Ral/M. Long-Evans
Inlrappr itoneal Rat/I, Wislar
Normal Hnuse/H, C3M/IIP.I
rirrm.il Mnuse/M. C3ll/llp.t
Oi'im.il Moiise/M, C3H/IIP.I
.i.i.li/nl llr.m.il MicP/N. C3M/HP.I
lijiti- lnlr.iplpur.il H.il/M. SpraqiH--'
|,M k ili-) D.iwlpy
Oos.,,1,
70 mi|.
wppk ly . 'IK
II 7'. m<|. IK
7.S m>|, IK
7S m|, IK
10 mi|, IK
1.7V m|. IK
(0.7'jt in O.f» ml
of .1 II It «.olulilp
III IwPI-ll Ml/W.ltl'l )
10 mi|. fm, wpi-k ly
1.9 m| (7% |il
ol a lilt (w/v)
susppnsion),
3x/wk lor 1 ilp
?. 0 HHJ. .Ix/wk
lor 1 ilp
II m.|. .Wwk
lor lilp
1.3 m|. IK/W.
lor lilp
70 m|. IK
1 iltrr '• i /p/lli«M.r i|il iim
( as ,I|>I>VP 1 sqiiamous cell car-
cinoma, 1 flhro-
sarcoma. 1 heman-
qiosarcom* on skin
at nontesl site
in 40 mice
•..imp a', alutvp No tumors
'..imp as almvp 1/40 leimyosarroma
on skin at nonlesl
si IP
tin nil |im No tumors developed
1 II // |im
Ri-lfrcn
77
on
3')
7'i
77
?n
7f.
7fi
7f.
I/
Inl i .iplpiiral H.I I/I, Oslmrnp- 111 mi|. l»
Hi-iiilp I
11,11 ,I|IPI iliiiip.il II,11/I. Wi'.l.u 7S m<|. IK
lin| I ilipr-./mi) • II. 7'i « -M |im:
II
I I/ '.•!. . 7 |im. /lit • '. |im
ft tumor im:ldpnti>
li'it ImiHir r.«|p,
l-.l .il 71'« il
(i mil initpil mi tin- lol liiwuii) |i.H|p)
-------
I Atll I M I. (niiillmii-il)
il I iln-1
I I.-
I.I Ml)
I'll)
ill. II. I)
il iir.i I )
Until P
Int r.iper i lonpa 1
InlrAppriloneal
Int.rappriloneal
1 nlraper i toneal
Int taper itoneal
Inh.italion
lnh.il all on
Int ralracheal
Int.r.iplpiiral
Inl r.iplpurat
In! r.ipprilnnpal
lin|i'-.l inn
•.per |p pm
7.S h/d. 5 d/wk.
1110 il
3 m|, wppkly p.irlir. IP si/p: '.in^im
for lilp
(nil 1 ilifi-s/mq' -0. 7Sx -M pm:
40 m|, IK II
70 mi|. Ix mp.ni p.irl ii IP sirr ?'• |im
?!> mi. 4» •.!/!• nut. i h.ir.n IPI i/nl
Mill mi|/r.il/il.iy mi-. in p. irtii.tr '.I/P: ;"> pm
I'll |ll| ll.ly.
Comments Carcinogen Hpfprpnce
31/371 lymphomas
11/171 lymfitiomas and
mpsnlhelionias
7 IX tumor Incidence » V)
77X tumor Incidence • .I'l
BIX tumor incidence • J'l
/OX tumor incidence * 3*1
4BX tumor Incidence • 3'l
91/X tumor Incidence • 31
6SX tumor Incidence. * II
1st at 7R8 d
77X tumor Incidence. • II
Isl al 77? d
6/18. * I/
74/44. and
71/4? most tumors
were mesotheliomas,
respectively
No tumors - 34
No tumors - 3fc
No tumors - Vj
No tumors - 17
No timmrs - 14
7.SX tumor Incldpnce - IS
I/I? dpveloppd - '4
stiim.uli Inmir
(i mil i illicit nil Utf Inllnwimi p.ii|p )
-------
Mill) 7-11. (timl imii-.l)
iii't.il 1 il>«-r Rniilr
Itilr.iperiloneal
"•I 1 ili« Intraperitoneal
I'.llv'l"' '«.k ill-)
W.Ofl i 1 l»
•.yiilhi-l it Int r.ipleural
n.iliit.il Inlrapleural
li um -,i 1 ii ,i|p
ii.tltu.il Inlrapleural
(Will I.V.I III! Ill-)
Intraperl loneal
•.ynllii-l ii. Inhalation
Inlraperl loneal
IMI ii.ii 1 iniilit<> Inlratracheal
Intrapleitral
i i if nt 1 1*
(niiM)nn) Inhalation
(K.i. mi) Intrapleiiral
Ilii .-1)1111) Inlrapleural
V,«e,/s,,,,,,
H.tl/f , Wislar
Ral/f. Wislar
Ral/f , Osbornp-
Mpnilel
Ral/f , Osborne-
Rat/F , Osbornp-
Mendel
Rat/r, Vlstar
Rat/M. Hlslar
Rat/M, Wislar
Rat. Fischer 344
Rat, Fischer 344
Rat, Fischer 344
Rat, M setter .144
Rat. fischer 144
„„,
II) «H|, 1"
40 m.|, |«
40 ni<|, 1*
40 imi. In
40 «H|
70 m<|, wrpkly.
bit
10 mM/m-1 rps-
pi rattle p.irti-
5 d/wk. 17 mo
75 *H|. In
o .; IHI, I?K
70 UNI. Ix
10 mq/m1. 7 I.AI.
5 d/wk. 17 mn.
ohservwl f:>n |im 77/Sfil developed
lunq tumors
%,imp ,is attnvf 7 IX developed
mesoOtellomas
7H
rm.ili-s itiwpln|ip.«|«-)
-------
1.11 I ilii-r Rntilr
i i. ii I ill*
1 nl r.i|.l rural
I AH! I /-M. (mill I i«ii-il|
type les /strain
Hal /I . S|>rai)in<-
Oawlpy
I il.fi- M/I-/HI-M i
(il ili.imi-lpi . I
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ts
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40. Davis (19fl/).
-------
7.3.5 Summary
The results of several chronic inhalation studies indicate that glass
fibers of varying lengths and diameters do not induce lung tumors in five
animal species tested (Table 7-13). Intratracheal instillation studies in
which animals were observed for 18 or more months provide conflicting evidence
on the carcinogenic potential of glass microfibers (diameter <0.45, length
<12 M"0. Pott et al. (1984b; Mohr et al., 1984; Pott et al., 1987a) found
increased incidences of lung carcinoma and mesothelioma in Syrian hamsters as
well as increased incidences of lung tumors (carcinoma but not mesotheliomO
in female Wistar rats following intratracheal instillation of microfibers. In
contrast, Smith et al. (1986, 1987) found no primary lung tumors in ei'ther
male Syrian hamsters or female Osborne-Mendel rats. The fiber dimensions and
total dose used with hamsters were approximately the same in both studies
(Pott et al., 1984b; Smith et al., 1987). The fibers used with Wistar rats
(Pott et al., 1984b) were significantly shorter and thinner (diameter 0.18 um,
ler.gth 3.2 urn) than those used with the Osborne-Mendel rats (diameter 0.45 urn
length 7.5 urn) (Smith et al., 1967), but the total dose was the same. Unlike
inhalation or intratracheal instillation studies, intrapleural or intraperitc
neal administration of glass fibers has been associated with increased lung and
peritoneal tumors in various strains of rats. All intraperitoneal studies we^e
conducted with microfibers (diameter 0.18 to 1 um, length 7.5 to 2.8 urn) at
total doses ranging from 0.5 mg to 25 mg, whereas intrapleural studies utilized
glass fibers of various lengths and diameters at total doses of 20 to 40 mg.
No tumors were noted in mice dosed intrapleurally (Davis, 1976).
Smith et al. (1980) reported tumors in hamsters dosed intrapleurally with
fibers having diameters of 0.1 to 1.23 urn and lengths >20 urn. No tumors were
noted with shorter (length <20 um) or with thicker fibers (diameter ^5 urn).
Carcinogenicity data for mineral wool administered by inhalation or
intrapleural injection were similar to those obtained for fibrous glass with
the same dimensions (see Table 7-13). Inhalation studies with hamsters and
two strains of rats indicate no evidence of Carcinogenicity for slag wool or
rock wool (diameter <3 um). Intrapleural administration of rock wool (diameter
<3 urn) or slag wool (diameter <0.18 um) to rats resulted in a low incidence cf
pulmonary tumors, whereas thicker fibers (diameter <5 um) did not. Intrase-i-
toneal studies conducted by Pott et al. (1984a, 1987a) in rats indicate that
slag wool (diameter 1.5 to 2.6 um) is not carcinogenic, whereas ro:^ wool
(aiar->eter 1.94 um) increased the incidences of pulmonary tumors.
JL.-I,- 19:: 7't'- DRAFT —D: N"~ 0*0': OF. CI'E
-------
The results of animal carcinogenicity studies with ceramic fibers suggest
similar carcinogenic potential to that obtained for fibrous glass and mineral
wool. Inhalation of refractory ceramic fibers and inhalation or intratracheal
administration of aluminum silicate fibers in rats and hamsters indicate nc
evidence of carcinogenicity. Intraperitoneal injection of various cerarr.ic
glass fibers results in high incidences of mesothelial tumors in rats and
hamsters. Considerably lower incidences of tumors were observed after intra-
pleural administration.
Carcinogenicity studies with synthetic fibers are limited (Table 7-13).
In an inhalation study with Kevlar® fibers in rats, increased incidences of
squamous cell carcinomas were noted at exposure levels of 0.63 and 2.23 mg'rr.
but not 0.32 mg/m . Increased incidences of mesothelial tumors and sa~co~.cs
were noted in rats following intraperitoneal injection of Kevlar" fibers
(diameter 0.75 to 1.0 urn). The increase, however, was relatively low (6 to
13 percent). Similarly, 2 of 51 rats developed tumors following intre-
peritoneal injection of polypropylene fibers. No tumors were observed ir re's
following intratracheal administration of polypropylene (unsized) fibers.
Results from a dermal carcinogenicity study with four carbon fibers in mice
were negative. Carcinogenicity studies by other routes of exposure were not
found. The carcinogenic potential of attapulgite was investigated following
intraperitoneal and intrapleural administration (see Table 7-13). Two samples
(of unspecified composition) were found to be carcinogenic in rats, whereas
three other samples from other regions were not. Attapulgite was net
carcinogenic following intrapleural administation to rats.
In contrast to the available data for manmade and synthetic fibers and
minerals discussed in this chapter, erionite has been shown to be highly
carcinogenic in various strains of rats and mice following inhalation or
intratracheal, intrapleural, and intraperitoneal administration at relatively
low doses (Table 7-13). All the fibers tested had diameters ranging from 0.2
to 1.0 um and lengths ranging from 1.8 to 15.0 um.
Talc powder is not carcinogenic following inhalation exposure or intra-
tracheal and intrapleural administration to rats, hamsters, and mice. Evidence
from one study suggests that talc may be an effective cocarcinogen wher. admin-
istered with benzo(a)pyrene. Carcinogenicity data for vermiculite were lirr.-itei
to one intrapleural study (Table 7-13). No tumors were observed following
administration of 25 mg; animals were observed for 2 years.
Julv 1SEE 7-65 DnA-T--D: tCT CJ:" C-r CI":
-------
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8. EFFECTS ON HUMANS
This chapter presents a critical review and analysis of the carcinogenic and
noncarcinogenic effects in humans following exposure to manmade mineral fibers
(mineral wool, glass wool, continuous glass filament, and ceramic fibers),
synthetic fibers (aramid, carbon, and polyolefin fibers), and minerals (attapul-
gite, sepiolite, erionite, talc, and vermiculite). An analysis of the data for
each fiber from cross-sectional studies, clinical evaluations, and case reports
is presented first, followed by reviews of the epidemiological studies.
8.1 MANMADE MINERAL FIBERS
8.1,1 Glass Fibers and Mineral Wool
8.1.1.1 Cross-Sectional Studies, Clinical Evaluations, and Case Reports
8.1.1.1.1 Eye and skin irritation. Skin and eye irritation have been associ-
ated with occupational exposure to fibrous glass and mineral wool fibers.
Mechanical irritation of the skin and eye is common, although immunologic
effects in a small number of exposed workers have also been observed.
In an early summary (Milby and Wolf, 1969), skin and eye irritation were
reported in 653 of 691 cases of occupational disease attributed to fibrous
glass exposure in California during a 30-month period between I960 and 1962.
.The nature of these effects was not described.
The prevalence of work-related dermatitis in approximately 4000 workers
employed at fibrous glass manufacturing plants in the United States was reported
by Fossick et al. (1970). Skin irritation, usually found on the arms, face,
and neck, occurred mostly in new workers. The workers' most common complaints
included burning, itching, or prickling sensations of the skin. Fibers of
large diameters were more likely to cause these irritations. Other workers
were found to have intermittent itching and dermatitis. The primary lesions
that developed in workers with dermatitis included papules and papulovesicles.
Secondary lesions were common and resulted from bacterial infection of the
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primary lesions. In addition, thickening of the skin was observed in a number
of exposed workers. The cause of the dermatitis was attributed to mechanical
Irritation and not to an allergic response.
Heise and Mattheus (1971) reported complaints of Uching skin and a number
of cutaneous eruptions in workers using insulation containing rock wool. Patch
tests performed on these individuals and a group of control subjects using
various types of rock wools revealed a higher frequency of $kin reaction in the
exposed workers. These effects were attributed to mechanical irritation of the
skin; no allergic reactions were noted.
Arbosti et al. (1980) performed dermatologic examinations and allergy
tests on 135 workers from an Italian glass fiber factory. Irritative dermato-
sis was found in workers from various areas of the plant. Skin disorders
appearing in 19 percent of the production workers had not only a primary
irritative etiopathogenesis but also an immune pathogenesis. It was concluded
that the risk of developing dermatologic disorders with immune pathogenesis
existed mainly in those workers involved in spinning and spooling of the glass
fibers, while the risk of irritative dermatosis existed at all production
steps.
An immunologically based topical eczema was also noted in 3 of 427 workers
from a plant that produced spun glass fibers (Maggioni et al., 1980). Skin
disease, mostly primary irritation dermatitis, was observed in 14 percent of
the workers. Total dust concentration in the plant averaged 1 mg/m , and the
percentage by weight of glass fibers in the total dust ranged from 1 to 7
percent.
In a recent review of glass fiber dermatitis, Bjbrnberg (1985) reported
that 65 percent of 700 workers in the Swedish building industry had.cutaneous
lesions from glass or mineral wool. Similar results were found among 62 glass
wool workers who were evaluated at the end of the working day for skin prob-
lems. Of these workers, 27 had both Uching and skin lesions, 10 had itching,
and 1 had lesions. Skin lesions were usually small, erythematous papules.
Other lesions, occurring less frequently, Included urticaria, petechiae,
erosions, and nummular eczema. Dermatitis was generally localized to the
forearms, hands, face, neck, and flexural folds. Covered areas were also
affected, since glass fibers can penetrate clothing. The severity and number
of the reactions varied directly with the size and coarseness of the fiber.
Twenty-five percent (79/135) of tested subjects exhibited positive skin
reactions when patch tested with mineral wool (rock wool) (Bjbrnberg and
i..i,, IQOO ft-? n.RAPT--nn NOT nnniF OR CITE
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Lowhagen, 1977). Coating the fibers with phenol-formaldehyde did not change
the skin reactions. It was postulated that the skin reactions were mechani-
cally induced since the fibrous, but not the powder, form of the mineral
produced the positive skin response. Clinically, the reactions are character-
ized by either an allergic macroscopic appearance or an erythematous dermal
infiltration. The findings for tiineral wool correspond to those in a subse-
quent study (Bjbrnberg, 1985), where approximately 25 percent of a nonexposed
population showed a positive response to patch tests with glass fibers.
Clinically, the lesions resembled allergic contact dermatitis. Workers in the
glass wool industry had the same level of patch test reactivity, and chronic
exposure to glass fibers did not change the original level of reactivity
(Bjornberg, 1985).
The ocular effects of MMMF were investigated by Stokholm et al. (1982) in
a cross-sectional study of 15 workers exposed to mineral wool. A matched
reference group consisted of 15 nonexposed persons. Ocular examinations were
performed on the exposed group just before beginning work after the weekend and
again 4 days later. A significantly (p <0.001) higher frequency of eye symp-
toms (running, red, and smarting eyes) related to work conditions was found
among exposed workers. The number of microepithelial defects on the medial
bulbar conjunctiva increased significantly (p * 0.009) after 4 days of exposure
in comparison to those in the reference group. A pathologic increase (p =
0.006) in the neutrophil count of the conjunctiva! fluid occurred in six
exposed workers after 4 days. This effect was observed 1n only one worker
before the exposure. An increased amount of mucus was found in 10 of 15
conjunctiva! fluid samples taken prior to exposure and in 8 of 12 samples taken
after exposure. In addition, there was a significant (p <0.01) .correlation
between the number of microepithelial defects on the medial bulbar conjunctiva
and the number of fibers accumulated in the opposite eye of the exposed work-
ers. There was also a significant (p <0.01) correlation between epithelial
defects and the total airborne dust. The authors suggested that the symptoms
and cellular changes observed 1n the exposed workers were a result of mechani-
cal irritation of the eye similar to that observed following skin exposure.
Alsbirk et al. (1983) examined 39 workers for ocular irritation. The
workers were exposed for an unspecified duration to mineral wool fibers
released from ceiling boards at their workplace. A nonexposed control group
consisted of 23 individuals of the same average age and sex, and with the same
smoking habits. Total airborne dust concentrations at the workplaces ranged
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from 0.14 to 0.27 mg/m for the exposed group, and from 0.10 to 0.45 mg/m3 for
the controls. Airborne mineral fiber concentrations were not reported. In the
exposed group, a significant increase was observed in the incidence of burning
eyes, watery eyes, swollen eyelids, disturbances of sight, and smarting of the
nose. In addition, conjunctiva! hyperemia was significantly increased and, in
five exposed workers, «ineral fibers were found 1n the conjunctiva! mucous
threads.
A study by Rindel et al. (1987) reported that symptoms of eye and skin
irritation among persons at 24 Danish kindergartens were more frequent in
institutions with ceilings covered by MMMF products produced with either
water-soluble or resin binder. The concentration levels in the indoor environ-
ment were more than 10,000 times less than the Threshold Limit Value (TLV) in
Denmark, and there was no significant difference between the mean concentra-
tions of respirable MMMF from control and study institutions. In addition,
measured levels of fibers/cm (both respirable and nonrespirable) were often
below the reported analyzed detection limit of 40 to 80 fibers/cm . The
authors concluded no association between MMMF and the reported symptoms and
diseases.
8.1.1.1.2 Respiratory effects. Several studies have been conducted to deter-
mine the possible respiratory effects of fibrous glass and mineral wool.
Respiratory manifestations including bronchitis, pharyngitis, rhinitis, asthma,
laryngitis, and sinusitis have been associated with exposure to MMMF. These
effects are apparently reversible when exposure to fibrous glass is discontin-
ued. No clear evidence of pulmonary abnormalities among exposed workers was
found in several studies. However, increased prevalence of small lung opaci-
ties and higher incidences of chronic and dysplastic pharyngolaryngitis have
been noted in a few workers exposed to fibrous glass for more than 5 years.
During a 30-month period from 1960 to 1962, 691 cases of occupational
disease attributed to fibrous glass exposure were reported in California (Milby
and Wolf, 1969). Of these cases, 38 involved respiratory tract irritation. An
additional 28 case reports describing adverse respiratory reactions to fibrous
glass were reported for a 13-month period from 1967 to 1968. Among the com-
bined 66 cases, 11 were females and 55 were males. The individuals ranged in
age from 17 to 68 years. Occupational designations revealed that most of the
complaints were made by individuals who were working directly with fibrous
glass or fibrous glass plastics, especially in dusty operations that involved
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cutting, sanding, or machining of the material. However, a number of case
'reports involved Individuals who worked in the general area where fibrous glass
dust was being generated. Chest x-ray evaluations were performed in 13 of the
28 cases that occurred during 1967-68, and none showed changes that were
attributable to fibrous glass exposure. Three case reports, resulting from the
same exposure, Involved maintenance employees who had removed fibrous glass
Insulation from steam pipes. Adverse effects developed by these workers
included sore throat, nasal congestion, laryngeal pain, and cough. A summary
of the respiratory manifestations in the 66 case reports attributed to fibrous
glass exposure included bronchitis in 64 percent, pharyngitis in 38 percent,
rhinitis in 30 percent, asthma in 9 percent, laryngitis in 6 percent, and
sinusitis in 5 percent of the cases. There were no reports of permanent
disability in any of the exposed individuals. However, the extent of the
followup period was not reported. Recently, Finnegan et al. (1985) reported
that work-related rhinitis, developed by 20 percent of the workers in a contin-
uous filament glass fiber plant, was due to an irritant reaction to airborne
glass fibers.
No unusual pavtems of radiologic densities were noted in chest x-rays of
1389 employees «ftga%fd in the **m;facture of glass wool for 10 or more years
(Wright, 1968). Tt>e workers were divided into four exposure categories ranging
from minimal to heavy exposure. Total dust concentrations varied from 0.93 to
13.3 mg/m . Particle concentration ranged from 0.09 to 0.32 million
particles/ft (3.3 to 11.9/cm ), and fibers made up less than 1 percent of the
total particles. The median diameter of the fibers was 6 urn, with 85 percent
being in the range of 2 to 10 urn. The average values from samples throughout
the plant indicated that 16 percent of the fibers were less than 40 urn in
.length and 6 percent were less than 20 urn.
Utidjian and de Treville (1970) examined a number of respiratory parame-
ters, including chest x-ray* and pulmonary function tests, in 2332 workers from
a fibrous glass manufacturing plant. The workers were categorized into age
groups (<30, 30 to 49, and >50 years) and further subdivided Into three catego-
ries based on exposure levels (least, medium, and highest exposure). The
environmental concentrations of fibrous glass and duration of exposure were not
reported. No relationship was observed between the degree of exposure and
respiratory history or radiologic findings. In addition, deviations froir.
predicted pulmonary function values did not correlate with exposure.
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In a followup of the above study, a more detailed evaluation was made of
30 of these workers who were over 50 years of age, 15 from the least exposed
group and 15 from the most exposed group (Hook tt al., 1970). After obtaining
medical histories from respiratory disease questionnaires, the investigators
conducted physical examinations, fluoroscopies of the chest, electrocardio-
grams, hematologic tests, pulmonary function tests, and tests for lung diffu-
sion capacity. No adverse effects were observed that could be attributed to
exposure to fibrous glass dusts. Moreover, the Incidence of ventilation or
diffusion abnormalities found in the highest exposed group was similar to the
incidence in the least exposed group.
No evidence of a respiratory hazard attributable to glass fiber exposure
was noted in a group of 70 workers who had a mean exposure of almost 20 (12 to
24) years in the manufacture of insulation-type fiberglass (Hill et a!., 1973).
Chest x-rays, pulmonary function tests, and a questionnaire regarding respira-
tory symptoms performed on the exposed workers were compared with those of a
control group living in the same geographic area and matched for age, sex,
height, and weight. Environmental investigations found that total dust in the
workers' breathing zone ranged from 0.4 to 12.7 mg/m . Respirable size fibers
ranged from 1.0 to 4.8 fibers/cm . Approximately 75 percent of fibers
collected at the site of emission were less than 4 urn in diameter, and 35
percent were less than 2 urn in diameter. Over 50 percent of these fibers were
less than 50 pm long.
Nasr et al. (1971) conducted a chest x-ray survey of 2028 male employees
of a factory manufacturing glass fibers. The employees (196 office workers and
1832 production workers) ranged in age from 20 to 59 years, and approximately
two-thirds of the workers were employed for 10 years or longer. The degree of
exposure of each worker to glass fibers was classified as low, average, or high
based on previously performed industrial hygiene surveys. No information on
airborne dust, particle, or fiber concentrations was provided. Approximately
16 percent of the workers were found to have radiographic abnormalities, the
most common being "increased lung markings," emphysema, and abnormal shadows of
aortas and hearts. Although there was a correlation between duration of
employment and age with the occurrence of abnormal chest radiographs, the
prevalence of all abnormalities was similar among office workers and production
workers.
A clinical evaluation of 427 workers with an average of 12 years' experi-
ence in a spun-glass fiber plant was performed by Maggioni et al. (1980).
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Results were compared to a group of 40 nonexposed workers of similar age and
smoking habits. Airborne dust concentrations in the plant averaged 1 mg/m .
The percent by weight of glass fibers In the total dust was about 1 percent in
the production units and 3 to 7 percent in the spinning department.
Respirable-size glass particles were detected following morphologic analysis of
glass fibers. No cases of pneumoconiosis end/or pulmonary fibrosis were found.
The incidence of chronic bronchitis in subjects exposed to higher concentra-
tions of glass fibers was similar to that of the controls. However, the
incidence did increase with years of service and smoking. It is worthwhile
to note that the comparison group of unexposed workers was extremely small. A
higher incidence of chronic and dysplastic pharyngolaryngitis was observed in
workers who had worked more than 5 years in departments where exposure to glass
fibers was high.
Hill et al. (1984) conducted a stratified cross-sectional morbidity survey
at a plant that manufactures fibrous glass wool insulation in the United
Kingdom. The study involved 340 men and women, including all current living
and former employees aged 55 to 74 years with over 10 years of employment,
workers of the same age with 1 to 10 years of employment, and two groups aged
45 to 54 with either I to 10 years or over 10 years of employment. There wes
no information on exposure concentrations. All subjects were given a respira-
tory questionnaire and a physical examination. In addition, lung function
tests and chest x-rays were performed. The prevalence of small lung opacities
on chest x-rays of category 1/0 or more (using International Labor Organization
(ILO) classifications) was 10.6 percent and was significantly related to age,
sex, previous employment in dusty occupations, and to never having lived in a
smoke-free zone. There was a greater prevalence of small opacities >1/0 in men
with more than 15 years of prior dust exposure in comparison to those who had
worked less than 15 years (38.7 percent versus 9.6 percent). A residual
prevalence of small opacities was observed among 9.3 percent of the men with no
previous dust exposure. However, no relationship was found between small
opacities in men with less than 15 years or no previous dust exposure and
duration or intensity of exposure to MMMF. There was also no significant
relationship with duration of exposure for any lung function index. Respira-
tory symptoms were not significantly associated with employment in the MMMF
industry.
Weil! et al. (1983) conducted a cross-sectional investigation of the
respiratory health of 1028 male workers at seven plants (five glass fiber and
i..i., IODO fi-7 DRAFT--nn NOT niJCTE OR CITE
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two mineral wool) in the United States. The average age of the workers was 46
years, and the median length of employment was 18 years. Employees were
classified, based on smoking habits, as smokers, ex-smokers, and nonsmokers.
Health assessment was performed through respiratory questionnaires, ILO classi-
fication of chest x-rays, and pulmonary function tests. Concentration of
airborne fibers in the plants ranged from 0.001 to >1.0 fiber/cm , and the
sizes of the fibers were classified as ordinary (>3 urn in diameter), fine (1 to
3 pm), very fine (<1 pm), and mineral wool fibers (>3 urn). The prevalence of
respiratory symptoms, Including dyspnea, chronic bronchitis, and shortness of
breath, was not related to KMMF exposure but was significantly (p <0.05)
related to cigarette smoking. Although lung function tests did not indicate
any adverse effects of exposure, measurements were related to age, height,
race, and cigarette smoking. Of 941 chest x-rays examined, the prevalence of
small opacities in categories 0/1, 1/0, and 1/1 was, respectively, 7, 3, and 1
percent with no opacities >1/1 being observed. The prevalence of small opaci-
ties increased as both age and smoking increased. Among the smokers, the
probability of small opacities was positively associated with exposure dura-
tion. However, among ex-smokers and nonsmokers, there was no association with
exposure measures. In addition, exposure to a mixture of ordinary and fine
fibers significantly increased the probability of low-level small opacities
among current smokers. Among ex-smokers and nonsmokers, this effect was
observed only in a plant having higher airborne concentrations of fibers less
than 1 urn in diameter.
Carpenter and Spolyar (1945) evaluated chest x-rays of 84 workers in the
rock and slag wool industry with 7 to 26 years of exposure. The workers were
exposed during the major portion of their industrial employment to airborne
dust concentrations ranging from 12 to 36 million particles/ft (444 to
1333/cm3). No evidence of silicosis or fibrosis was found in the exposed group
when compared to a control group of nonexposed workers from the same plant and
living in the same community.
Skuric and Stahuljak-Beritic (1984) reported results of ventilatory
function tests performed on 106 male and 56 female workers exposed to airborne
rock wool fibers at three production plants. Airborne dust mass had a mean
range of 1.8 to 28 mg/m with an average mass concentration varying from 2.8 to
13.1 mg/m3. The range of mean respirable fiber concentrations was 0.003 to
0.463 fiber/cm3. The results of the pulmonary function tests were signifi-
cantly (p <0.05) lower than the expected reference values in both men and
1..1,, TOOO *»-fi noftCT._nr\ UHT AMHTC no PTTF
-------
women. No relationship, however, was found between the magnitude of changes in
ventilatory function and the cumulative exposure of workers to total dust or
fibers. Since the workers 1n this survey had previous exposure to other
occupational dusts before starting employment at the rock wool plant, a followup
survey was performed 5 years later. Ventilatory function tests were.performed
on 102 workers (63 men and 39 women) from the original survey population
exposed only to MMMF. The authors concluded that the observed changes in
ventilatory function occurring during the 5-year period could not be attributed
to MMMF exposure. Moreover, indices of lung function deficit and indices of
exposure (duration, fiber years, and total particle years) were not signifi-
cantly related.
Respiratory abnormalities in 21 male workers involved in the production of
rock wool were investigated by Ma1mberg et al. (1984) using lung function tests
and chest x-rays. Mean duration of employment was 17.6 years. There was no
history of previous exposure to asbestos or other potentially harmful dusts,
and no history of lung disease. The results were compared to a control group
of 43 male individuals, matched for age and smoking habits, from the same
county as the workers. Fiber levels in the plant averaged 0.21 fibers/cm , and
about 92 percent of these fibers were respirable. There were no significant
differences between the workers and the controls in any of the lung function
tests. In addition, all men had normal chest x-rays.
Newball and Brahim (1976) reported that severe respiratory symptoms
developed in a family of four during a 3-year exposure to fibrous glass fibers
liberated from the fibrous glass lining of the central air-conditioning system
in their home. Analysis of dust samples in the home revealed glass fibers with
diameters ranging from 1 to 15 urn. Respiratory symptoms included sinusitis
with obstructed nasal passages, nosebleed, shortness of breath, and cough. In
one family member, an 11-year-old boy, a chest x-ray revealed an edematous,
erythematous, tracheobronchial mucosa with marked tracheobronchitis.
In addition, bronchial washings contained fibrous glass with diameters ranging
from 0.5 to 0.7 urn. Three months after the exposure, the family showed no
objective signs that could be attributed to fibrous glass exposure. Chest
x-rays were normal, and pulmonary function tests indicated only mild obstruc-
tions in two individuals.
8.1.1.2 Epidemiological Studies. Prompted by evidence from animal studies
indicating that MMMF induce both carcinogenic and fibrotic responses in the
respiratory system, numerous epidemiological studies have been conducted to
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identify potential relationships between exposure to MMMF and malignant and
nonmalignant respiratory disease (NMRD). Three major studies, each consisting
of a series of historical prospective mortality studies with cohorts of occupa-
tional ly exposed workers from the United States, Canada, and Western Europe,
have been conducted. Subsequent studies In each series reported findings after
allowing additional years of followup of the cohort under study. Enterline
and March (1982) and Enterline and colleagues (1982, 1983, 1986, 1987) examined
the mortality experience of U.S. workers, Shannon and colleagues (1982, 1984,
1986, 1987) examined the mortality experience of Canadian workers, and Saracci
and colleagues (1984) and subsequently Simonato and colleagues (1986a, 1986b,
1986c, 1987) examined the mortality experience of workers from several European
countries. Recently, Doll (1987) examined the mortality experience of the
combined U.S., Canadian, and European cohorts.
8.1.1.2.1 Epidemiological studies in U.S. workers. Enterline and March (1982)
and Enterline and colleagues (1983, 1986, 1987) conducted a series of studies
on the mortality experience of production and maintenance workers in 17 U.S.
plants that produced MMMF at some time between 1940 and 1963. Special emphasis
was placed upon workers exposed to small-diameter MMMF, i.e., less than 1.5 urn,
because they are most similar to asbestos fibers. The maximum followup period
for the cohort was 37 years. It was found that the greatest risk of respiratory
cancer occurred among workers exposed to mineral wool. Fibrous glass workers
had much lower rates of respiratory cancer. No excess carcinogenic or noncar-
cinogenic risk was found among workers exposed to small-diameter fibers.
Enterline and Marsh (1982) conducted a historical prospective mortality
study of 7049 male production and maintenance employees who had worked for 1 or
•more years in any one of eight fibrous glass (FG) or mineral wool (MW) plants
between January 1, 1945, and December 31, 1963. For employees in one plant
producing small-diameter fibers, the cohort included those with 6 or more
months of exposure. After the cohort from all eight plants was assembled from
company employment records, vital status was determined through U.S. Social
Security Administration (SSA) records and other unspecified files. After using
a modified life-table technique to obtain person-years at risk of dying to
compute the standardized mortality ratio (SMR), the expected numbers of
cause-specific deaths were calculated from U.S. age-, race-, and sex-specific
rates for the years 1945 to 1973, presumably for appropriate 5-year time
intervals. The investigators did not state whether nonwhite males were exclud-
ed from analysis. By the end of the followup period, December 31, 1973, 14
• • •- o-in noACT—nn wnr nuniF nR CITE
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percent of the cohort had died. Vital status was determined for all but 31
(0.4 percent) of the 7049 cohort members. Of the 1006 deaths, death certifi-
cates were obtained for all but 39 (3.9 percent), Indicating a high degree of
followup and a high trace rate. The 7th Revision of the International List of.
Diseases and Causes of Death (ICO) was used to code causes of death.
Workers were exposed to MMMF 1n either FG or MW plants. To test the
hypothesis that exposure to respirable WMF results in malignant respiratory
disease, including mesothelioma, and NHRD, excluding influenza and pneumonia,
the investigators developed an exposure index for each worker. As of the end
of 1972, concentrations of respirable fibers to which FG workers were exposed
were very low; the estimated mean exposure level was 0.023 fibers/cm .
Exposure data for MW workers were unavailable because of the confounding
presence of asbestos in mineral wool plants.
Overall, investigators found no significant excess in mortality, a mani-
festation of the healthy worker effect in this group of factory workers (1006
observed, 1081.7 expected, SMR = 93). When investigators analyzed the data for
workers from all eight plants by time since first exposure (surrogate for
latency period), they found no significantly increased SMRs for any
cause-specific deaths among those with less than 20 years since first exposure
or among those with 20 or more years since first exposure. However, there was
insufficient power to detect digestive cancer, respiratory system cancer, and
all other cancers among those with 20 or more years since first exposure, and
there was insufficient power to detect NMRD in those with either less than 20
or 20 or more years since first exposure.
When the data were analyzed by plant, type of fiber, and time since first
exposure for malignant and nonmalignant respiratory disease, significant
excesses were limited to malignant respiratory disease among MW workers in
Plant 7 with less than 20 years since first exposure (2 observed, 0.794
expected, SMR = 251.6, p <0.05) and those with 20 or more years since first
exposure (2 observed, 0.22 expected, SMR « 905.7, p <0.05), even though the
power to detect a 50 percent increased incidence of respiratory cancer was low
(12 and 4 percent, respectively). However, the small numbers of deaths and low
power (except for those workers from all FG plants combined with less than 20
years since first exposure who died from respiratory cancer) precluded drawing
any conclusions from these data. Of the 7049 cohort members, 4120 (58.4
percent) had 20 or more years of observation. It was not possible, however, to
-------
determine the percent of the cohort with 20 or more years of exposure and 30 or
more years of observation following Initial exposure to MMMF.
To further determine whether exposure to respirable FG fibers (<3 urn in
diameter) resulted in malignant and nonmalignant respiratory disease, the
investigators analyzed the data by cumulative exposure to respirable FG fibers.
To avoid overlapping exposure and follovup periods, the investigators calcu-
lated each worker's cumulative exposure as of December 31, 1962, thereby giving
11 years of observation without overlapping exposure years. No relationship
was found because the power was low. Generally, such a technique alleviates
underestimation of cause-specific risks in the study group. However, the low
power to detect malignant and nonmalignant respiratory disease might account
for the failure to find a relationship between exposure to respirable FG fibers
and either malignant or nonmalignant respiratory disease.
Enterline and Marsh (1982) concluded that (1) the presence of asbestos in
one MW plant where significantly increased deaths occurred from malignant
respiratory disease confounds the interpretation of data on workers employed in
MW plants; (2) no direct relationship exists between exposure to respirable FG
fibers and the incidence of either aalignant or nonmalignant respiratory
disease; (3) there is no clear evidence that exposure to MMMF produced malig-
nant or nonmalignant respiratory disease; and (4) studies of workers exposed to
such low levels may be inappropriate for testing hypotheses regarding MMMF and
disease.
The conclusion of the investigators that there is no causal relationship
between MMMF, particularly respirable FG fibers, and disease is weakened by
several limitations. First, there was insufficient power to detect a 50
percent increased incidence of either malignant or nonmalignant respiratory
disease. Second, although no cases of mesothelioma were reported, because no
cause-specific expected values were reported, it was not possible to determine
whether the group of exposed subjects was large enough to detect an increase in
mesothelioma incidence of 50 percent above that of U.S. white males. Third,
the small number of deaths and low power preclude drawing the conclusion that
exposure to MMMF is not causally related to adverse health effects. In addi-
tion, the exposure levels might have been too low to detect a weak carcinogenic
effect if, in fact, it existed. Furthermore, under these conditions, 6 months
of MMMF exposure might have been too short a period to consider. Usually,
workers with less than 1 year of exposure are excluded because the briefer the
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period of exposure to a carcinogen, the longer the latent period and the more
likely the association will go unrecognized, Finally, besides asbestos expo-
sure, smoking is another variable that night confound interpretation of the
data because of Us influence on cancer «t several sites.
When data from additional MMMF production facilities became available,
Enter!ine et al. (1983) conducted a historical prospective mortality study of
16,730 male production and maintenance employees who had worked for 1 or more
years in any one of 17 FG (14,884 workers) or MW plants (1,846 workers) between
January 1, 1945, and December 31, 1963. For employees in two plants producing
small-diameter fibers (<1.5 urn), the cohort included those with 6 or more
months of exposure. The date of initiation of the study varied: (1) 1945 was
selected for 16 plants because of problems in tracing terminees prior to 1945;
and (2) 1940 was selected for 1 plant to permit comparison with a previously
conducted study at that plant. After the Thermal Insulation Manufacturers
Association (TIMA) and its member companies abstracted employment records to
assemble the cohort, vital status was identified through a search of company,
SSA, state drivers' license, and Veterans Administration (VA) files, as well as
personal contacts. A modified life-table technique was used to obtain
person-years at risk of dying. The U.S. white male average annual age-specific
death rates for 5-year time periods from 1940 to 1974 were applied to
person-years to obtain expected deaths for computing SMRs. The 1975 death
rates were applied to person-years accrued from 1975 to 1977. Because non-
whites constituted less than 2 percent of the cohort, investigators believed
that the use of U.S. white male death rates did not bias results. To determine
whether geographical variations in expected mortality rates existed, investi-
gators compared age and calendar-time adjusted state and national mortality
'rates and found similar results (results not reported). The years of followjp
were from January 1, 1941, for 1 plant and from January 1, 1946, for the
remaining 16 plants to December 31, 1977, allowing a maximum followup of 37 and
32 years, respectively. By the end of the followup period, 12,633 of the
16,730 (75.5 percent) cohort members were alive; 3,761 (22.5 percent) had died;
and 336 (2 percent) were lost to followup. Death certificates were obtained
for all but 108 (3 percent). Deaths were coded by a nosologist according to
the 7th Revision of the ICD.
Exposures to MMMF less than 3 urn in diameter for each worker were estimat-
ed by combining environmental survey results and individual job histories.
Exposure occurred from either January 1, 1940 (1 plant), or January 1, 1945
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(16 plants), to December 31, 1963. Each worker's occupational history was
characterized by an estimate of cumulative exposure and average intensity of
exposure to MMMF. For all FG plant workers, mean cumulative exposure was 4.47
fibers <3 urn/cm -months, and average Intensity of exposure was 0.039 fibers
<3 Mm/cm -months; for all MW plant workers, mean cumulative exposure was
53.26 fibers <3 urn/cm -months, and average Intensity of exposure was
0.353 fibers <3 urn/cm -months. A survey of certain MMMF plants conducted by
the University of Pittsburgh served as a basis for reconstructing historical
exposures of workers to respirable fibers. Personal samples were collected
from within the breathing zones of employees and analyzed by phase contrast and
transmission electron microscopy. The results of this survey were published in
Esmen et al. (1979b). Enterline et al. (1983) stated that the results of this
survey indicated that past exposure levels did not differ from present exposure
levels and thus were equivalent. However, because Esmen et al. (1979) made no
attempt to estimate past exposure levels, it is unclear how Enterline and Marsh
(1982) reached the conclusion that past and present exposure levels were
equivalent.
Neither observed nor expected numbers of deaths were reported for several
causes. Consequently, the overall mortality experience of the cohort, the risk
of bronchial, trachea!, and lung cancers combined, and the risk of laryngeal
cancer cannot be determined. No deaths from mesothelioma were reported.
Overall, investigators found significantly elevated mortality from NMRD (150
observed, 113.5 expected, SMR - 132.1, p <0.01). When the data were analyzed
by plant and time since first exposure, there were significant excesses from
respiratory cancer among those ever employed in MW plants (45 observed, 28.1
expected, SMR = 160.1, p <0.01), especially among those with 20 or more years
since first employment (30 observed, 19.0 expected, SMR = 157.2, p <0.05), even
though the power to detect a 50 percent increase In respiratory cancer was 64
percent or less. The greatest excess of respiratory cancer in MW workers
occurred among those ever employed 1n Plant 7 (6 observed, 1.32 expected,
SMR = 451.3, p <0.01, Power * 14 percent), especially among those with 20 or
more years since first employment (4 observed, 0.46 expected, SMR = 868.5,
p <0.01, Power = 3 percent). There was also an excess emong those ever employed
in Plant 12 (16 observed, 2.04 expected, SMR = 293.6, p <0.05, Power = 8
percent). The investigators stated that the excesses in Plant 7 were probably
not attributable to employment in the MW plant because the workers were hired
late in life and had short exposure. However, the power to detect a 50 percent
"-if nparr—nn NOT nuniF OR CITE
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increased incidence of respiratory cancer was only 4 percent among those with
less than 20 years since first employment, 3 percent among those with 20 or
more years since first employment, and 14 percent overall. Nevertheless,
significant Increases were observed. Because of an absence of quantitative
data on exposure to HW and because of possible asbestos exposure, these data
provide limited evidence of a causal association between respiratory cancer and
MW exposure.
Similarly, when the cohort was analyzed for NMRO by plant and time since
first exposure, there were significant excesses of death from NMRD among those
workers ever employed in FG plants (129 observed, 99.53 expected, SMR = 129.6,
p <0.01), particularly among FG workers with 20 or more years since first
employment (85 observed, 62.73 expected, SMR = 135.5, p <0.01). The signifi-
cant excesses of death from NMRD among all MMMF workers (150 observed, 113.55
expected, SMR = 132.1, p <0.01) were concentrated among those with 20 or more
years since first employment (100 observed, 72.93 expected, SMR « 137.1,
p
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To determine whether workers exposed to small-diameter FG were at
increased risk of respiratory cancer or NMRD, the investigators examined plants
where workers were most likely to have been exposed to fine-diameter fibers.
In Plant 9, a significant excess of NMRD occurred among workers never exposed
to fine fibers (71 observed, 52.07 expected, SMR « 136.4, p <0.05). Small
numbers of deaths and low power precluded meaningful analysis of fiber exposure
and respiratory cancer.
Next, the Investigators reanalyzed the data from Bayliss et al. (1976),
who studied the mortality experience of workers In Plant 9. Neither Bayliss
et al. (1976) nor interline et al. (1983) found a significant relationship
between exposure to fine-diameter FG particles and either NMRD or respiratory
cancer. However, the lack of statistical significance may be related to the
insufficient power to detect either respiratory cancer or NMRD in Plant 9 among
those ever exposed to fine fibers.
When the data on respiratory cancer were analyzed by cumulative exposure
to various lengths of MW, the investigators did not find a clear relationship
between exposure to respirable fibers and respiratory cancer excesses among MW
workers. A significant excess of respiratory cancer deaths was found among
workers with a cumulative exposure to 21.88 to 99.99 fibers/cm -months (17
observed, 9.54 expected, SMR = 178.2, p <0.05), even though the power to detect
a 50 percent increase in respiratory cancer was low. Small numbers of deaths
and low power preclude meaningful analysis and do not support the conclusion
that no relationship exists between respiratory cancer and cumulative exposure
to KW fibers. When the data on NMRD were analyzed by cumulative exposures to
various MW fiber lengths, no significant excess deaths were found in any of the
four fiber categories. However, there was insufficient power to detect a 50
percent increased incidence of NMRD in each category.
Finally, no significant excess of respiratory cancer deaths was found
among MW workers with 20 or more years of exposure and 3D or more years of
observation following initial exposure. However, only two of the seven MW
plants had deaths in this category, and there were too few workers and insuffi-
cient power to detect a 50 percent increase in respiratory cancer in either
plant or even in all MW plants.
The investigators concluded that no consistent evidence of a respiratory
hazard exists among MMMF workers, but there is some evidence, although weak, of
excess NMRD among both FG and MW workers. The authors correctly concluded that
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more followup, smoking habit histories, and information on the presence of
asbestos and other possibly confounding substances, e.g., silica, asphalt,
phenol, formaldehyde, ammonia, carbon monoxide, solvent vapors, and heavy metal
fumes, are needed.
However, as 1n the previous study, this study 1s limited by small numbers
of deaths and low power to detect respiratory cancer and NHRO when the data
were subdivided into many categories. Although data were analyzed by latency
and length of exposure, 1t was not possible to determine the percent of the
cohort with 20 or more years of exposure and 30 or more years of observation
following initial exposure to HMMF. In fact, only two MW plants had deaths 30
years after initial exposure among workers with 20 or more years of exposure.
The average duration of exposure was 11.67 years for all FG plants and 11.08
years for all MW plants. In addition, the selection of 1945 rather than 1940
for initiation of the study because of problems in tracing terminees in 16 of
17 plants may have underestimated the true risk of respiratory cancer and NMRD.
Based on these data, one cannot conclude that exposure to respirable MMMF is
not associated with respiratory cancer and NMRD.
Prompted by the need for more conclusive epidemiological evidence,
Enter!ine et al. (1986) extended the followup period of their 1983 study for an
additional 5 years and conducted a nested case-control study to control for the
effects of cigarette smoking. Because the start of the followup period for one
plant was delayed from 1941 to 1946, the cohort was reduced from 16,730 workers
in the 1963 study to 16,661 in this study. Therefore, this cohort consisted of
16,661 white male production and maintenance employees who had worked for 1 or
more years in any 1 of 17 FG or MW plants between January 1, 1945, and December
31, 1963. For employees in two plants producing small-diameter fibers
(<1.5 urn), the cohort included those with 6 or more months of exposure. A
modified life-table technique was used to obtain person-years at risk of dying.
The U.S. white male mortality experience adjusted for age and time was applied
to person-years to obtain the expected number of deaths. Because the previous
study (Enterline et al., 1983) showed no significant differences between SMRs
based on state versus national mortality rates, U.S. national rates had been
selected as the reference population. However, subsequent investigations found
that local death rates from the areas in which the plants were located were
more appropriate for calculating expected mortality from respiratory cancer
(Enterline et al., 1987). The investigators estimated that for FG plants, mean
exposure levels were 0.03 fiber/cm . For MW plants, mean exposure levels were
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1.5 fiber/cm before 1945, Q.3 between 1945 and 1960, and 0.03 after 1960.
Besides exposure to MMMF, workers had potentially confounding exposures to
silica, asphalt, asbestos, phenol, formaldehyde, ammonia, carbon monoxide,
solvent vapors, and heavy metal fumes.
The years of observation for workers from all 17 plants were from January
1, 1946, to December 31, 1982, allowing a naximum followup of 37 years, as well
as 19 years of observation without overlapping exposure years. By the end of
the followup period, December 31, 1982, 11,328 of the 16,661 workers (68.0
percent) were alive; 4,986 (29.9 percent) had died; and 347 (2.1 percent) were
lost to followup. Death certificates were obtained for all but 145 (2.9
percent). The investigators were successful in determining vital status and
obtaining death certificates for some workers who had been lost to followup in
the 1983 study. All deaths were coded to revisions in effect at the time of
death so that U.S. death rates for corresponding time periods were used to
generate expected numbers of deaths. For ease of presentation, investigators
used the codes listed in the 8th Revision.
Significantly increased causes of death for 1978 through 1982 and for the
entire period of 1946 through 1982 are listed in Tables 8-1 and 8-2, respec-
tively. Significant deficits during 1946 through 1982 are listed in Table 8-2.
When the cohort was analyzed by time sine* initial employment, investiga-
tors found among those with less than 20 years since first employment a signif-
icant excess from all other heart disease (56 observed, 30.48 expected,
SMR = 183.7, p <0.01). However, among those with 20 or more years since
initial employment, there were significant excesses from all causes' of death
(3263 observed, 2974 expected, SMR = 109.7, p <0.01); all malignant neoplasms
(735 observed, 658.01 expected, SMR = 111.7, p <0.05); respiratory system
cancer (301 observed, 242.15 expected, SMR = 124.3, p <0.01); lung cancer (26£
observed, 229.66 expected, SMR = 125.4, p <0.01); all other heart disease (139
observed, 120.24 expected, SMR = 151.6, p <0.01); NMRD including influenza and
pneumonia (236 observed, 197.15 expected, SMR ~ 119.7, p <0.01); NMRD excluding
influenza and pneumonia (172 observed, 127.50 expected, SMR « 134.9, p <0.01);
and nephritis and nephrosis (24 observed, 14.77 expected, SMR = 162.4, p <0.05);
and a significant deficit from accidents (94 observed, 116.04 expected,
SMR ~ 81.0, p <0.05). These findings indicate that 20 or more years of latency
are needed to develop NMRD. Except for laryngeal cancer, there was sufficient
power to detect a 50 percent increase in cause-specific deaths among the
exposed workers.
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TABLE 8-1. SIGNIFICANTLY ELEVATED SMRs BY CAUSE FOR ALL MMMF
WORKERS BETWEEN 1978 and 1982
Cause of death
All causes
All cancers
Respiratory system cancer
Lung cancer
NMRD
Observed deaths
1,251
320
135
130
69
SMR
114.7*
118.7*
129.7"
130.8*
128.5*
•Significantly different from national mortality rates: p <0.05.
Source: Enterline et al. (1986).
TABLE 8-2. SIGNIFICANTLY ELEVATED SMRs BY CAUSE FOR ALL MMMF
WORKERS BETWEEN 1946 and 1982
Cause of death
Respiratory system cancer
Lung cancer
Neoplasms of other lymphopoietic
tissue (residual)
Other heart disease (residual)
NMRD
Nephritis and nephrosis
Observed deaths
391
370
36
195
230
47
. SMR
115.6**
116.0**
144.2*
159.6"
132. 3«*
144.2*
"Significantly different from national mortality rates: p <0.05.
"•Significantly different from national mortality rates: p <0.01.
Source: Enterline et al. (1986).
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TABLE 8-3. SIGNIFICANTLY DECREASED SMRs BY CAUSE FOR ALL MMMF
WORKERS BETWEEN 1946 and 1982
Cause of death
Ischemic heart disease
Influenza and pneumonia
Cirrhosis of the liver
External causes of death
Accidents
All other causes (residual)
Observed deaths
1,686
64
99
405
279
437
SMR
94.9*
76. 5*
77. 6»
85.1"*
85.9"
91.0*
•Significantly different from national mortality rates: p <0.05.
"Significantly different from national mortality rates: p <0.01.
Source: Enterline et al. (1986).
In an update of their 1986 unpublished study, Enterline et al. (19E7)
found that after 20 or more years of latency, the observed excess from respira-
tory cancer among MMMF workers was significant compared to national mortality
rates (SMR = 124.3, p <0.01), but not compared to local mortality rates
(SMR = 112.3). The observed excess from lung cancer among MMMF workers after
20 or more years of latency, on the other hand, was significant compared to
national (SMR = 125.4, p <0.01) and local rates (SMR = 112.7, p <0.05). This
shows the strength of the lung cancer hazard, which appears to be responsible
for the respiratory cancer excess among MMMF workers (288 lung cancers out of
301 respiratory cancer deaths).
To explore a potential relationship between respiratory cancer, latency,
and type of fiber produced, the investigators next subdivided the respiratory
cancers among the cohort by type of process ((1) fibrous glass filament,
(2) fibrous glass wool, (3) fibrous glass filament and fibrous glass wool, and
{4) mineral wool) and time since initial employment. Among those with 20 or
more years since first employment, significant excesses from respiratory cancer
occurred among workers exposed in plants that produced both fibrous glass
filament and fibrous glass wool (155 observed, 119.73 expected, SMR = 129.5,
p <0.01) and mineral wool (45 observed, 30.80 expected, SMR = 146.1, p <0.05).
Neither excess remained significantly elevated when compared to local rates
(Enterline et al., 1987). Only one plant had sufficient power to detect a 50
percent increased risk of death from respiratory cancer. Despite low power,
statistically significant excesses from respiratory cancer were found in three
plants.
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When latency was further subdivided into four time periods since first
employment, there was a clear trend of increasing SMRs with increasing time
since first employment in plants that produced both fibrous glass filament and
fibrous glass wool. Among workers with 30 or more years of latency, signifi-
cant excesses were found in fibrous glass plants producing continuous filaments
and glass wool (90 observed, 65.29 expected, SNR = 137.8. p <0.01) and in
mineral wool plants (25 observed, 16.48 expected, SMR * 151.7, p <0.05).
Neither excess remained significantly elevated when compared to local rates
(Enterline et al., 1987). Enterline et al. (1987) found that the greatest
excess of respiratory cancer occurred among MW workers compared to either
national (SMR = 148.4, p <0.01) or local rates (SMR = 133.6, p <0.05). This
shows that respiratory cancer among MMMF workers is truly elevated in the MW
subcohort. Although the investigators claimed that no trends existed between
latency and fibrous glass filament and mineral wool plants, there was insuffi-
cient power to detect a 50 percent increased incidence in respiratory cancer,
if it did exist in these types of plants.
When the cohort was analyzed by process and by duration of employment
group (surrogate for length of exposure), no positive relationship between
respiratory cancer and duration of exposure by process was observed. However,
except for workers in the less than 10 years' exposure category, there was
insufficient power to detect a 50 percent increase in respiratory cancer in
workers with either 10 to 19 years, 20 to 29 years, or 30 or more years of
exposure to MMMr.
When respiratory cancer deaths were analyzed by latency and length of
exposure, among workers with 20 to 29 years of exposure and 30 or more years of
latency, there was a significant excess among FG workers (26 observed, 16.24
expected, SMR = 160.1, p <0.05), but not among MW workers. However, the power
to detect a 50 percent increase of respiratory cancer among workers was only 14
percent. Among FG and among MW workers exposed for less than 10 years, there
were increasing SMRs with increasing latency.
To determine whether exposure to small-diameter fibers produced in four
different plants was related to an excess in mortality from respiratory cancer,
the investigators examined respiratory cancer by plant among those ever and
never exposed. The only significant increase in respiratory cancer occurred
among workers in one plant who were never exposed to small-diameter fibers (169
observed, 140.58 expected, SMR = 120.2, p <0.05). The small number of deaths
(22) among those ever exposed contributed to the low power and lack of excess
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deaths in this group. When those 22 respiratory cancer deaths were further
categorized in workers ever exposed to fine-diameter fibers by both latency and
length of exposure, the investigators stated that the data supported the
hypothesis that exposure to small-diameter fibers is associated with respira-
tory cancer. However, there were too few deaths and insufficient power to .
permit meaningful analysis of the data.
To explore a potential relationship between NMRD (excluding influenza and
pneumonia), latency, and type of fiber produced, the investigators subdivided
the data for NMRD by type of process and time since first employment. Among
those with 20 or more years since first employment, there was a significant
excess from NMRD in plants that produced fibrous glass filament and fibrous
glass wool (93 observed, 65.60 expected, SMR ~ 141.8, p <0.01), which was
attributable to a significant excess among those with 20 or more years of
latency in one plant producing fibrous glass filament and fibrous glass wool
(87 observed, 63.26 expected, SMR = 137.5, p <0.01). This was the only plant
with sufficient power to detect a 50 percent increase in NMRD. Despite only 15
percent power, in one continuous glass filament plant a significant excess from
NMRD was found among those with less than 20 years since first exposure (8
observed, 2.37 expected, SMR = 338.1, p <0.01). The low power to detect NMRD
in individual plants may have precluded obtaining excess deaths.
When further subdividing latency into four time periods since initial
employment, significant excesses were found in FG plants producing both contin-
uous filaments and glass wool among those with 10 to 19 (24 observed, 13.97
expected, SMR = 171.8, p <0.05) and 20 to 29 years since first exposure (46
observed, 28.14 expected, SMR =163.5, p <0.01). Although there does not
appear to be an overall pattern of response for NMRD with increasing latency
"period, with the exception of workers in plants producing both types of FG
fibers with 30 or more years since first exposure, there was insufficient power
to detect a 50 percent increase 1n NMRD.
When the cohort was analyzed by process and by duration of employment
group, the investigators concluded that a positive relationship between NMRD
and duration of exposure appeared 1n none of the five processes. Except for
workers in the less than 10 years' exposure category exposed to both types of
FG (69 observed, 44.73 expected, SMR ~ 154.3, p <0.01), there was insufficient
power to detect a 50 percent increase in NMRD among workers with either 10 to
19, 20 to 29, or 30 or more years of exposure to MMMF.
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When NMRD deaths were analyzed by both latency and length of exposure,
among workers with 20 to 29 years of exposure and 30 or more years of latency,
there was a significant excess among FG workers (19 observed, 10.91 expected,
SMR = 174.1, p <0.05), but not among MW workers. However, the power to detect
a 50 percent Increase in NMRD among MW workers with 20 to 29 years of exposure
and 30 or more years of latency was only 17 percent.
The investigators also examined NMRD In four plants to determine whether
exposure to small-diameter fibers produced in four was related to an excess
mortality among those exposed and never exposed. The only significant increase
in NMRD occurred among workers in one plant who were never exposed to
small-diameter fibers (the same plant where there was a significant excess of
respiratory cancer: 107 observed, 77.19 expected, SMR » 138.6, p <0.01). This
excess also resulted in a significant excess of NMRD for all four plants among
those never exposed (115 observed, 66.15 expected, SMR = 133.5, p <0.01).
The small number of deaths (11) among those ever exposed contributed to the low
power to detect NMRD in that group. The small number of deaths and low power
precluded meaningful analysis of these data by further categorizing the 11 NMRD
deaths among workers ever exposed to fine-diameter fibers by both latency and
length of exposure.
When investigators examined cumulative exposure to respirable fibers and
respiratory cancer or NMRD, the small number of deaths precluded meaningful
analysis of these data. In addition, except for FG fibers less than
2.14 fibers/cm -months, however, there was insufficient power to detect a 50
percent increase in respiratory cancer or NMRD. Similarly, the low power in FG
and/or MW plants precluded meaningful analysis of the data. Therefore, it is
difficult to conclude with certainty that no direct relationship exists between
respiratory cancer or NMRD and exposure to MMMF.
The investigators further explored the relationship between fiber exposure
and respiratory disease by examining average intensity of exposure. They
stated that a nonsignificant dose-response relationship existed between fiber
exposure and respiratory cancer for plants producing continuous glass fila-
ments. Once again, larger numbers of deaths would have made the analysis more
meaningful.
To control for smoking, investigators conducted a case-control study
nested within the historical prospective mortality study. All MMMF workers who
died of respiratory cancer or NMRD between January 1, 1950, and December 1,
1982, were cases. Controls for both causes of death were a 5 percent randomly
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selected sample of all workers stratified by plant and year of birth. Excluded
from controls were members of the cohort (1) who died of respiratory cancer or
NMRD; (2) who died of any cause prior to January 1, 1950; (3) who had an
unknown date of death; (4) who died before age 45; (5) who were less than 45
years of age at termination of study (December 31, 1982); (6) who terminated
prior to January 1, 1956; (7) whose termination minus year of birth was less
than 45; (B) whose date of termination was unknown; and (9) whose date of birth
was unknown. Through telephone interviews, smoking histories were obtained
from the worker himself, 1f still alive, or a knowledgeable informant, ideally
a member of the worker's immediate family, for 287 out of 386 (74.4 percent)
respiratory cancer cases, for 150 out of 205 (73.2 percent) NMRD cases, and for
426 out of 596 (71.5 percent) controls. Of those 426 controls for whom smoking
histories were available, the percentage who had ever smoked was similar to the
1976 U.S. white male population.
The investigators performed a backward stepwise logistic regression
analysis in which ages at termination of study or at death and date of birth
were used as control or matching variables and smoking as the possible con-
founding variable. For respiratory cancer cases among FG and MW workers,
smoking rather than time-weighted cumulative exposure to respirable glass
fibers was an important factor in respiratory cancer. For NMRD among FG or MW
workers, smoking appeared to be responsible for NMRD. However, the goodness of
fit value of <0.0001 indicates that the logistic model may be inappropriate for
this data set.
The authors concluded that conflicting evidence exists regarding the
relationship between exposure to MMMF and respiratory disease. In support of
this relationship, increasing SMRs were associated with time since first
exposure, with duration group, and among those ever exposed to smaTl fibers.
Against this relationship, neither duration of exposure, a time-weighted
measure of fiber exposure, nor measure of intensity was related to SMRs for
respiratory cancer. This lack of a dose-response persisted when smoking habits
were taken into account. In support of a relationship between exposure to MMMF
and NMRD, SMRs for NMRD are slightly higher than for respiratory cancer and
there is some evidence of a dose-response relationship among smokers exposed to
FG and MW combined when smoking habits are taken into account. Against this
relationship, the low exposure levels to MMMF relative to asbestos raises tfH
question of whether a dose-response relationship is attributable to MMMF or tc
low levels of asbestos.
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This study was strengthened by the addition of new members of the cohort
lost to followup in the previous studies. However, many of the limitations
that existed in the previous studies, such as low power in many subcategories
and length of employment used as a surrogate for duration of exposure, are
pertinent here as well. In this particular study, because historical exposure
data were unavailable, a conclusion that there
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Because of small numbers, women were excluded from analysis. After using a
modified life-table technique to obtain person-years at risk of dying, for
computing the SMRs, expected deaths were calculated from U.S. age, race, and
sex-specific rates for the years 1945 to 1972 for appropriate 5-year intervals.
By the end of the followup period, December 31, 1972, 111 (26.6 percent) of the
416 retirees had died and death certificates were located for 103 (92.7 per-
cent). Deaths were coded by a nosologist according to the 7th Revision of the
ICO. The mean followup was approximately 30 years. Overall mortality was low
and there was no excess from respiratory cancer mortality, a manifestation of
the healthy worker effect. When the cause of disability was examined among 127
workers who had retired early on a disability during the same period from the
same six plants, the cause was clearly stated for 115 (90.5 percent) of the 127
disabled workers. Causes of disability were compared with those expected based
on the percent of disability retirements by age and by cause among U.S. males
in all occupations as reported by SSA. This comparison showed no evidence of
any unusual health hazards among FG workers. The study was limited by the
small numbers of deaths, the low power to detect lung cancer and NMRD, the low
trace rate, and the restriction of mortality observations to those aged 65 and
above.
Bayliss et al. (1976) conducted a historical prospective mortality study
of 1448 white males first employed between January 1, 1940, and December 31,
1949, and who subsequently achieved 5 or more years of employment in FG produc-
tion, packing, or maintenance of an FG manufacturing facility. The cohort was
assembled from company employment files. A modified life-table technique was
used to obtain person-years at risk of dying by 5-year calendar-time periods
and 5-year age groups based on U.S. white male age, calendar-time, and
cause-specific mortality. Vital status was determined through records main-
tained by Federal, State, and local government agencies, including those from
SSA, city and county health departments, and area funeral homes. Deaths were
coded by a qualified nosologist according to the Revision of the ICD in effect
at time of death. Total airborne dust in the plant averaged 0.3 mg/m with a
mean concentration of 0.08 respirable fibers/cm . The collected glass fibers
had a median diameter of 1.6 urn and a length of 28 urn. Smoking histories were
not provided.
By the end of the followup period, June 1, 1972, 1072 (74 percent) employ-
ees in the cohort were alive; 376 (26 percent) had died. No workers were lost
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to follow-up, and death certificates were obtained for all 376 decedents.
Therefore, there was 100 percent followup and 100 percent trace rate.
Whereas overall mortality was 1«ss than expected, Investigators found a
significant excess from NMRD (19 observed, 10.04 expected, SMR « 189, p <0.05,
Power * 34 percent) and significant deficits from tuberculosis (0 observed,
4.69 expected, SMR « 0, p <0.05) «nd cirrhosis of the liver (2 observed, 8.93
expected, SMR = 22, p <0.05). When mortality from NMRD was examined by time
since first employment, a significant excess was observed among those with 10
or more years since first employment (19 observed, 9.51 expected, SMR = 200,
p <0.01). Despite the low power, the observation of any excess probably
reflects the investigators' excellent followup and trace rates.
To evaluate the pathogenicity of smaller diameter glass fibers, the
investigators performed a nested case-control study of malignant and nonmalig-
nant respiratory disease. They found no association between cases of malignant
and nonmalignant respiratory disease and work in operations involving exposure
to SfTiol 1-diameter fibers.
Morgan et al. (1984) conducted e historical prospective mortality study of
4399 males who had worked at least 10 years in FG production and who were
employed at some time between January 1, 1968, and December 31, 1977. The
cohort was assembled from company lists of active employees and from lists of
former employees with 10 or more years of service. Since the company could net
identify all former employees and retirees who had died prior to January 1,
1968, person-years for the cohort accrued from this date. These sources of
data were augmented by employment applications, job histories, and death
certificates. Employees' work histories were reviewed to exclude those with
less than 10 years of employment in FG production, those who left employment
prior to 1968, and those not exposed to FG. Job descriptions of interest were
classified into nine exposure categories. A modified life-table technique was
used to calculate SMRs based on U.S. white male mortality. Vital status was
determined through SSA records. Deaths were coded according to the 8th Revi-
sion of the 1CD. Actual exposure levels and smoking histories were not
provided.
By the end of the followup period, December 31, 1977, 294 (6.7 percent) of
the 4399 cohort members had died; 84 (1.9 percent) were lost to followup.
Death certificates were obtained for all but six (2.1 percent) of the
decedents.
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For the entire cohort, Investigators observed significant deficits from
all causes of death (SMR « 85, 95 percent CI = 76, 96, p <0.05, Power = 100
percent) and all external causes of death, particularly all accidents (includ-
ing motor vehicle accidents) and suicide. No significantly increased SMRs were
found for any category of mortality. Even when the mortality experience of
those with at least 30 years of observation and 20 years of exposure was
examined, no significantly elevated causes of death were identified.
This study was limited by concurrent exposure and observation periods, the
small numbers of deaths, and the low power to detect cause-specific deaths from
lung cancer, buccal cavity and pharyngeal cancer, laryngeal cancer, and NMRD,
excluding pneumonia. Although subdividing the cohort into those with at least
30 years of latency and 20 years of exposure is most likely to result in
detecting the effect of a deleterious exposure followed by a long latency
period, the small number of deaths and low power preclude meaningful analysis
of these data.
Robinson et al. (1982) conducted an industrial hygiene survey and a
historical prospective mortality study of 596 male production workers employed
for at least 1 year between January 1, 1940, and December 31, 1948, in a MW
production facility. The cohort was assembled from company lists of individu-
als who had ever worked at the plant. Detailed work histories, job titles, and
dates of specific jobs held by each employee were coded. A modified life-table
technique was used to calculate SMRs based on U.S. white male mortality. Vital
status was determined through records maintained by various government agen-
cies, directories, and other sources. Death certificates were coded by a
diagnostician according to the Revision of the ICD in effect at time of death
and subsequently converted into corresponding 7th Revision codes.
By the end of the followup period, December 31, 1974, 188 (31.5 percent)
of the 596 cohort members had died; less than 2 percent were lost to followup.
Four war casualties were excluded from the cohort. Death certificates were
obtained for all but one (0.5 percent) of the decedents.
Exposure was assessed by job description and location, from personal
samples taken at the time of study, and from historical exposure data. These
data suggested that the average historical airborne fiber concentrations did
not exceed 2.5 fibers/cm3 before 1935 and 1.0 fiber/cm3 after 1935. All jobs
in the plant were assigned to one of eight potential exposure categories to
assess the extent and severity of MW' exposure on employee mortality.
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Overall mortality was less than expected but was not statistically
significant. Although no cause-specific excesses or deficits were observed,
except for deaths from overall mortality and heart disease, there was insuffi-
cient power to detect any excess mortality for the remaining causes of death.
When the cohort was analyzed by latency for digestive cancer, lung cancer, and
NMRD, small numbers of deaths and low power precluded meaningful analysis.
When the cohort was analyzed by duration of employment, however, a significant
excess of digestive cancer was found among those in the highest duration group,
i.e., more than 20 years (5 observed, 1.5 expected, SMR * 333, p <0.05). The
investigators concluded that the results were not consistent with those of
other studies. While this study was strengthened by the 27 years without
overlapping exposure and observation periods, the small number of deaths and
the low power to detect cause-specific deaths hampered more meaningful
analysis.
8.1.1.2.2 Epidemiological studies in Canadian workers. Shannon and colleagues
(19S2, 1984, 1986, 1987) conducted a series of studies on the mortality
experience of current and former employees of an Ontario FG wool plant who had
worked for more than 3 months between 1955 and 1977. The maximum followup
period for the cohort was 30 years. Jt was found that an excess of lung cancer
was concentrated in production workers with the highest exposure, the longest
duration of exposure, and the longest time since first exposure. No excess
noncarcinogenic risk was detected.
Shannon et al. (1982, 1984) conducted a historical prospective mortality
study of 2576 current and former male employees who had worked for more than 3
months in a Canadian plant manufacturing FG wool between January 1, 1955, and
December 31, 1977. After the cohort was assembled from company employment
records, vital status was determined through income tax records for those
employed between 1960 and 1969, union records, group insurance records, senior-
ity lists, driver's license bureaus, Canadian Vital Statistics and Disease
Registry, U.S. Department of Immigration and Naturalization records, and
personal contacts. A modified life-table technique was applied to person-years
to calculate expected age, sex, and calendar-specific deaths using the Ontario
male population. By the end of the followup period, December 31, 1977, 2414 of
the 2576 cohort members were alive (93.7 percent); 88 (3.4 percent) had died;
74 (2.9 percent) were lost to followup. Death certificates were obtained for
all but one (1 percent), who was classified and used in the analysis as a death
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from ischemic heart disease (IHD). The Investigators did not state who coded
the death certificates.
Historical exposure data were unavailable for the period -of the study.
Samples taken in 1978 and 1979 suggest that optical microscopy counts rarely
exceeded 0.2 fibers/cm. Mean levels in most areas were reported to have been
3
less than 0.1 fiber/cm . Based on employment histories, workers were
classified into one of three exposure categories: plant exposure only (2239);
office exposure only (234); and mixed plant and office exposure (103).
No statistically significant excesses in mortality were Identified. As
might be expected from a group of factory workers, there was a significant
deficit from all causes of death (88 observed, 113.3 expected, SMR = 77.6, p =
0.02, Power = 99 percent). The authors stated that the deficit persisted when
the subcohort of those with 10 years since first employment was analyzed (56
observed, 75.54 expected, SMR = 75.1, p <0.05). When the cohort was analyzed
by job classification among plant-only workers, investigators found significant
deficits from circulatory diseases (30 observed, 40.74 expected, SMR = 73.6,
p <0.05, Power - 89 percent) and from accidents and violent deaths (13
observed, 22.57 expected, SMR = 57.5, p - 0.04, Power = 64 percent). According
to the investigators, deaths from NMRD and gastrointestinal (GI) tract cancers
were limited to plant-only workers and were equal to expected values. However,
there was only 22 percent power to detect a 50 percent increased incidence of
NMRD and 15 percent power to detect a 50 percent increased incidence of GI
tract cancers among plant-only workers. A significant deficit of IHD was found
among plant-only workers (20 observed, 29.92 expected, SMR = 66.8, p <0.05,
Power = 79 percent), but a significant excess among mixed exposure workers (7
observed, 2.94 expected, SMR = 238, p <0.05, Power = 16 percent). The investi-
gators concluded that three suspicious cancer deaths, upon pathological review,
were not attributable to mesothelioma.
When lung cancer mortality among plant-only workers was analyzed by
duration of exposure (<5 years or >5 years) and time since first exposure (<10
years or >10 years), too few deaths and low power precluded meaningful analy-
sis. Only 502 men (19 percent) had accrued 20 or more years since first
employment.
While the overall mortality of these workers appears to be low, this study
is limited by the following: (1) the small number of deaths in the cohort
(88); (2) the lack of direct exposure and the unavailability of quantitative
exposure measurements to FG wool fibers (exposure to FG was only inferred);
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(3) among workers classified as in-plant, the power to detect lung and Gl tract
cancer were only 19 and 29 percent, respectively; (4) the exclusion of 363
workers employed between 1948 and 1955 for whom records were incomplete,
potentially underestimating risk; and (5) observation and exposure years
overlapped, thereby underestimating risk.
Shannon et al. (1986, 1987) extended the followup of their previous study
for 7 years by conducting a historical prospective mortality study of 2557 men
who had worked at least 3 months in an Ontario FG wool plant between 1955 and
1977. The cohort was reduced from 2576 in the previous study to 2557 by
excluding women and some men who were counted twice. No deaths were observed
among the 19 excluded individuals. Since historical data on exposure levels
were unavailable, exposure was inferred by categorizing workers as plant
exposure only, office exposure only, or mixed plant and office exposure.
According to the investigators, hygiene measurements taken since 1978 have
shown fiber levels rarely greater than 0.2 fiber/cm (<3.5 diameter) using
optical microscopy counts. Mean fiber levels in most areas were below
0.1 fiber/cm , but anecdotal evidence suggests that dust concentrations were
previously higher (Shannon et al., 1987).
The Ontario male cause-specific mortality rates adjusted for age and
calendar period were applied to person-years to calculate expected deaths. The
investigators stated that both county and provincial age-adjusted mortality
rates for lung cancer were similar to the Canadian national rates for the
period 1966 to 1976. Therefore, the use of Ontario cause-specific mortality
rates would not underestimate the risk of lung cancer in the plant- only
workers.
Vital status was determined through the Canadian Vital Statistics and
Disease Registry and by linkage to the Ontario driver's license records. Years
of observation accrued from January 1, 1955, to December 31, 1984, allowing a
maximum followup of 30 years, only 7 of which did not overlap exposure years.
By the end of the followup period, December 31, 1984, 2312 of the 2557 (90.4
percent) cohort members were alive; 157 (6.1 percent) had died; 88 (3.4 per-
cent) were lost to followup. Death certificates were obtained for ell but one
(1.1 percent), which was categorized as death from IHD.
Although a significant deficit in overall mortality was observed, a
manifestation of the healthy worker effect in this group of factory workers
(157 observed, 187.54 expected, SMR = 84, p <0.05), there was a significant
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excess of lung cancer (21 observed, 11.90 expected, SMR = 176, p <0.05). Nc
cases of mesothelioma were reported. However, because no cause-specific
expected values were reported for mesothelioma, it was not possible to deter-
mine whether there were enough exposed workers to detect an increase in meso-
thelioma incidence of 50 percent above that of Ontario males.
When the data were analyzed by job classification, plant-only workers,
presumably those with the highest exposure, appeared to account for the signif-
icant excess of lung cancer, representing all but 2 of the overall lung cancer
cases (19 observed, 9.53 expected, SMR = 199, 95 percent Cl = 128, 311,
p = 0.002, Power = 36 percent). Except for all cancers, accidental or violent
death, and circulatory disease, especially IHD, among plant-only workers, the
power was too low to detect site-specific causes of death of interest. When
the lung cancer deaths were analyzed by duration of exposure (<5 years or >$
years) and time since first employment (<10 years or >10 years), too few deaths
and low power precluded meaningful analysis in the 1986 unpublished study.
However, in the 1987 published version, there was an additional death from lung
cancer, raising the SMR above the 0.05 level of significance. Thus, contrary
to the claims by Shannon et al. (1986, 1987), a significant excess of lung
cancer was found in workers with the longest duration of exposure and longest
time since first exposure (13 observed, 7.12 expected, SMR = 182, p <0.05,
Power s 28 percent). When the lung cancer deaths were analyzed by length of
employment in 5-year increments or by time since first employment in 5-year
increments, the numbers of death again were too small to analyze. It was not
possible to determine the percent of the cohort with 20 or more years of
exposure and 30 or more years of observation following initial exposure to FG
wool.
The investigators concluded the following: (1) although a significant
excess of lung cancer was observed, SMRs by length of exposure and time since
first employment were not consistent with exposure to FG wool; and (2) deaths
from NMRD were less than expected. These conclusions are weakened by several
limitations that also existed in the previous study, I.e., low power to detect
site-specific cancers and NMRD (30 percent for lung cancer, 33 percent for
digestive system cancer, and 11 percent for NMRD), small cohort size, and small
percentage of the cohort that died (6 percent).
8.1.1.2.3 Epidemiolooical studies in European workers. Saracci and colleagues
(1984) and subsequently Simonato and colleagues (1986a,b,c,1987) conducted a :
series of studies on the morbidity and mortality experience of 21,967 male and
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female production workers from 13 European plants that produced MW, FG wool, or
continuous FG filament at some time between 1933 and 1961. Maximum followup
varied among the plants. MW workers had excesses of lung cancer, particularly
if first employed during the early technological phase. This same group had an
elevated Incidence of buccal cavity/pharyngeal cancer. FG wool workers had an
excess of lung cancer limited to those first employed during the intermediate
technological phase, but only when compared to national nortality rates. FG
wool workers also had an excess of laryngeal cancer, but this was limited to
male production workers in an Italian FG wool plant. An excess of NMRD was
limited to short-term MMMF workers.
The following section begins with critical reviews of each European study
and culminates in critical reviews of the collated results presented by Saracci
and colleagues (1984) and Simonato and colleagues (1986a, 1986b, 1986c, 1987).
Andersen and Langmark (1986) conducted a historical prospective mortality
and morbidity study of 2361 men who had worked at any time between January 1,
1935, and December 31, 1977, in one of four Norwegian plants that manufacture
either mineral rock wool (MW; Plants 1, 2, and 3) or fibrous glass wool (FG;
Plant 4) and who were alive on January 1, 1953. The investigators excluded 20£
women, 25 men for whom essential information (date of birth and/or date of
first employment) was missing, as well as those ever employed in polystyrene
production. The cohort was assembled from employment records from each of the
four plants containing names, dates of birth, all periods of employment, and
months per worksite within each plant. Vital status end cancer morbidity were
determined through a countrywide automated vital statistics system and the
Norwegian Cancer Registry. A modified life-table procedure was used to calcu-
late person-years at risk, expected numbers of deaths, and expected numbers of
cancer cases. The Norwegian national age-specific mortality and incidence
rates for 5-year time periods from 1953 to 1983 were applied to person-years to
obtain the expected number of deaths or cancer cases. The years of followup
were from January 1, 1953, to December 31, 1983, allowing a maximum followup of
31 years. Since exposure occurred between 1935 and 1977, there were 6 years
without overlapping exposure and observation periods. Neither the degree of
completeness of ascertainment of cause of death or morbidity nor the percent of
workers lost to followup was reported. Because all death certificates are
coded by the Norwegian Central Bureau of Statistics and because reporting from
hospitals and histopathological labs is compulsory, presumably the potential
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bias from lack of disease ascertainment among workers lost to followup is
minimal. Actual exposure levels were not reported.
One of three MW plants employed 1815 workers (77 percent), and the FG
plant employed 546 workers (23 percent). Only 49 percent of the cohort was
employed for 1 or more years. Overall, • significant excess of death occurred
from accidents, poisoning, and violence (37 observed, 24.58 expected, SMR =
151, p <0.05), which was also found among those with less than 1 year of
employment (23 observed, 10.04 expected, SMR = 299, p <0.01). Although no
excess NMRD deaths occurred, the power to detect NMRD among those employed less
than 1 year, 1 or more years, or ever employed was low.
When cancer incidence data were analyzed, a significantly increased
incidence of buccal cavity and pharyngeal cancer was found among employees from
all factories combined with 1 or more years of employment (7 observed, 3.00
expected, Standardized Incidence Ratio (SIR) = 233, p <0.05, Power = 17 per-
cent). While the power to detect all cases of cancer was sufficient among
those with 1 or more years of employment (99 percent) and for the total cohort
(100 percent), there was insufficient power to detect *11 cases of cancer among
those employed less than 1 year (78 percent) and lung cancer among those in any
category.
When cancer incidence data among those with 1 or more years of employment
were analyzed by years since first employment and period of first employment
(either before 1960 or I960 to 1977), a significantly increased incidence of
intestinal cancer was found when both periods of MW production were combined
(14 observed, 7.14 expected, SIR = 196, p <0.05). When the 20 lung cancer
cases were analyzed by length of employment (less than 1 year or 1 or more
^years) and by plant, in Plant 2 (rock wool) a significantly increased incidence
of lung cancer was found among those ever employed (8 observed, 2.68 expected,
SIR = 299, p <0.05, Power = 11 percent), which was more pronounced among those
with 1 or more years of employment (8 observed, 2.07 expected, SIR * 385,
p <0.01, Power = 10 percent). Comparing lung cancer incidence among MW produc-
tion and nonproduction employees, a significantly elevated incidence of lung
cancer occurred among production and nonproduction employees combined who had
20 or more years since first exposure (11 observed, 5.52 expected, SIR = 199,
p <0.05, Power = 21 percent), which was concentrated among those employed for
1 or more years (9 observed, 4.36 expected, SIR = 206, p <0.05, Power = 21
percent). According to the authors, the use of county rather than national
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rates increased the expected lung cancer incidence, thereby decreasing the
SIRs. Nevertheless, the trends 1n SIRs persisted, but the data were not
reported.
The Investigators concluded the following: (1) no consistency occurred
across the four plants in cancer morbidity or nortality; the only excess
mortality was from violent deaths among those with less than 1 year of employ-
ment; (2) because the significantly elevated incidence of buccal cavity and
pharyngeal cancer was limited to one plant and because neither human nor animal
evidence suggests involvement of this site and MMMF, it appears that factors
other than MMMF are responsible; (3) the increased incidence of intestinal
cancer is attributable to random variation; (4) because the increased lung
cancer incidence was limited to one plant, agents other than MMMF might be
responsible; (5) no association exists between lung cancer incidence and
duration of employment or type of work; and (6) the risk of lung cancer proba-
bly is related to more hazardous environmental conditions present before 1960.
However, these conclusions are tempered by the low power to detect NMRD
mortality and lung cancer mortality and morbidity for the entire cohort, the
small cohort, the small number of deaths, and the short exposure period (over
half of the cohort was employed for less than 1 year). Although the investi-
gators stated that no positive association existed between the incidence of
lung cancer and duration of employment, they did find a significant excess of
lung cancer morbidity among those with 20 or more years since first exposure,
even though the power to detect lung cancer for the entire cohort was only 21
percent. It was not possible to determine the percent of the cohort with 20 or
more years of exposure and 30 or more years of observation following initial
exposure to MMMF. In view of these deficiencies, demonstration of a dose-
response relationship between MMMF and lung cancer or NMRD would be difficult.
The authors' suggestion that agents other than MMMF might have been
responsible for the increased lung cancer incidence in one plant is not sub-
stantiated in this study. The investigators made no mention of the presence of
other chemicals associated with lung cancer, and the increased lung cancer
observed in this plant could have resulted from higher exposures to MMMF
compared to the other three plants. Concerning the investigators' claim that
there is an absence of human evidence to suggest involvement of buccal cavity
and pharyngeal cancer and MMMF, aside from this study, significant excesses of
buccal cavity and pharyngeal cancer were reported by Moulin et al. (1986),
1,,1,, 1OOO
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Olsen et al. (1986), and Simonato et al. (1986b,c, 1987). Therefore, the
authors' conclusion is weakened by the finding of statistically significant
excesses from this site in three other epidemiological studies.
Westerholm and Bolander (1986) conducted a historical prospective mortal-
ity and morbidity study of 3600 male and female (20 percent) employees who had
worked for at least 1 year In one of two MW plants or one FG wool plant. From
personnel records available from the start of production for each of the three
plants, 1933, 1938, or 1943, working groups consisting of employer representa-
tives, unions, and former employees extracted the names, Swedish identification
numbers, and work histories of the cohort. Past or present exposure levels
were not discussed. Expected numbers of death were based on mortality statis-
tics for all Sweden by age, sex, and cause of death for each calendar year.
Expected numbers of cancer incidence were based on rates for all Sweden by age
sex, cancer diagnosis, and calendar year.
Vital status was determined through record linkage of the computerized
data bases from which dates and causes of death were coded according to the 1CD
in effect at the time of death were extracted. Cancer morbidity was determined
through the Swedish Cancer Registry, whose compulsory notification system
requires Swedish identification number, name, diagnosis, site and histopath-
ology according to the 7th Revision of the ICD. The years of exposure and
observation were concurrent.
By the end of the followup period, December 31, 1982, 3014 of the 3600 (84
percent) of the cohort members were alive; 524 (15 percent) had died; 62 (1.7
percent) were lost to followup. Of the 230 (6.4 percent) who had emigrated,
147 (64 percent) were successfully traced through the vital statistics regis-
tries of other Nordic countries. It is unclear, however, whether the remaining
83 emigrants accrued person-years until their dates of termination or whether-
they were totally excluded from the analysis. Adding the 83 emigrants to the
62 other persons lost to followup, it appears that 145 (4 percent) were lost to
followup.
Overall, a significant excess of accidents, poisoning, and violence
occurred among MW workers (35 observed, 25.7 expected, SMR = 136, p <0.05).
Since the cohort was too small to detect a 50 percent increase in lung cancer
(Power = 61 percent) or NMRD (Power = 76 percent), subdivision of the 18 lung
cancer deaths and 20 NMRD deaths failed to yield useful information. Neverthe-
less, when lung cancer mortality data were analyzed by length of employment and
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years since first exposure, an excess of lung cancers occurred among those with
1 to A years of employment and 30 or wore years since first exposure in MW
production (4 observed, 0.5 expected, SMR * 888, p <0.005, Power = 4 percent)
or in FG production (4 observed, 1.2 «xpected, SMR = 345, p <0.05, Power = 11
percent). It was not possible to determine the percent of the cohort with 20
or nore years of exposure and 30 or more years of observation following Initial
exposure to MMMF.
The investigators concluded that CD both FG and MW workers who developed
lung cancer were exposed for short periods of time, i.e., during the first 4
years of employment; (2) the observed excess cancer deaths nay be attributable
to agents other than MMMF; and (3) insufficient evidence exists to conclude
that exposure to MMMF contributed to the lung cancers observed in this cohort.
This study is limited by the low power to detect lung cancer and NMRD and the
small number of lung cancer and NMRD deaths, precluding meaningful analysis.
Although a high degree of followup was accomplished among Swedish nationals,
failure to determine the vital status of 36 percent of the emigrants could
result in an underestimation of. the risk of lung cancer and NMRD. Although the
investigators speculated that agents other than MMMF might have been responsi-
ble for the increased lung cancer deaths, the investigators made no mention of
the presence of other chemicals associated with lung cancer; furthermore,
historical exposure data were not available. Therefore, the increased lung
cancer mortality might have resulted from MMMF exposure.
Olsen and Jensen (1984) conducted a historical prospective morbidity study
of 53ES male and female employees (8 percent) who had worked in a Danish MW
plant at any time between the start of production in 1937 and December 31,
1977, allowing a maximum exposure to MW of up to 40 years. After using a
»
jnodified life-table technique to obtain person-years at risk, the expected
numbers of cancer cases were derived from Danish national age, sex, and calen-
dar time-specific cancer incidence rates for 5-year time intervals. Through
computerized record linkage with national and municipal files of the Danish
Cancer Registry, persons 1n the cohort were followed from date of first employ-
ment to date of death, emigration, or the end of the foTlowup period (December
31, 1977). Because the Danish Cancer Registry began reporting incidence data
in 1943, the years of observation were from 1943 to 1977. Although maximum
followup was 35 years, exposure and observation periods were concurrent. Of
the 5369 cohort members, 174 (3.2 percent) were lost to followup. Since many
.I'.iw IQRR 8-37 DRAFT--DO NOT QUOTE OR CITE
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of these workers were not Danish nationals, their vital status could not be
determined and, therefore, they were excluded from analysis.
The concentration of respirable fibers in the plant at the time of the
study was between 0.1 and 0.001 fibers/cm3. Although previous measurements
were unavailable, 1t was estimated that the concentration of respirable fibers
at the production lines 1n the past was between 9.8 and 26.5 fibers/cm3.
Overall, no statistically significant excess cancer cases (144 observed,
136 expected, SIR - 108) were reported. However, when cancer cases among
production employees were analyzed by site and time since first employment,
cancer of the digestive organs and peritoneum was significantly elevated during
the first 10 years after initial employment (21 observed, 13.8 expected,
SIR = 152, p <0.05). Among those with 20 or more years since first employment,
there was significantly increased incidence of lung cancer (9 observed, 4.3
expected, SIR = 209, p = 0.02, Power = 20 percent). When lung cancer and all
cancer cases among those with 20 or more years since first employment were
analyzed by category of employment (male, female, production, and nonproductior
workers), a significantly increased incidence of lung cancer was found among
male production workers (8 observed, 4.1 expected, SIR = 195, p = 0.05, Power =
17 percent) and among all employees (10 observed, 4.8 expected, SIR = 208, p =
0.02, Power = 19 percent). When cancer cases among those with 20 or more year;
since first employment were analyzed by duration of employment, no relationship
was found between cancer incidence and duration of employment. However, this
finding is not surprising because (1) there was only 38 percent power to detect
a 50 percent increased incidence of lung cancer among workers with 20 or more
years of latency; (2) only 25 percent of the cohort was employed before 1960,
i.e., had 18 or more years of latency; and (3) only 25 percent of the cohort
had been employed for more than 2 years. These observations indicate a high
turnover rate among employees and a short duration of exposure to MW, suggest-
ing that there might have been insufficient exposure or followup to detect an
excess risk of lung cancer. One case of mesothelioma was observed in a person
13 years after first employment. Because expected values for mesothelioma
cases were not reported, it was not possible to ascertain the power to detect
the risk of mesothelioma in this cohort.
To control for confounding variables, the investigators found that the us«
of local lung cancer incidence rates increased SIRs by 8.3 percent. They also
determined that SMR for respiratory system cancer among unskilled workers
-------
compared to Danish males was less than the SIR for respiratory system cancer
for male workers in this analysis. Finally, in the absence of smoking histo-
ries, the investigators surveyed smoking habits at the time of the study and
found 10 percent more smokers but 7 percent less heavy smokers compared to the
general population of eastern Denmark.
The investigators concluded that (1) a twofold increase In lung cancer
Incidence among MW workers with 20 years since first employment supports the
hypothesis that an association exists between lung cancer and mineral wool
production when the data are analyzed'by latency period; (2) It is unlikely
that this association could be ascribed to either disease ascertainment bias
because of the adequate degree of followup or to smoking; and (3) the lack of
a dose-response relationship requires additional followup to increase the evi-
dence of causality.
To further study the relationship between occupational exposure to MW and
lung cancer, 01 sen et al. (1986) extended the followup of their 1984 study for
an additional 5 years (December 31, 1982). The cohort of 5317 male and female
(8 percent) employees was assembled from manual files at the plant containing
information on dates of initiation and termination of employment and type of
position. The 52 individuals included in the 1984 study who were on file but
had never worked were deleted from the current cohort. In addition, three
alternative methods for calculating expected lung cancer cases among male MW
workers were used: (1) age-specific local rates; (2) weighted rates based on
place of residence (urban/rural) at time of first employment; and (3) age-
specific smoking-induced lung cancer risks for men aged 30 to 59 to account
for tobacco consumption. Through computerized record linkage with national and
municipal files of the Danish Cancer Registry, analysis of cancer morbidity was
for the period 1943 to 1982, allowing a maximum of 40 years of observation, but
only 5 years without overlapping exposure and observation periods. Of the 5317
cohort members, 173 (3.3 percent) individuals who were non-Danish nationals
were lost to followup.
As in the previous study, no statistically significant excess cancer
Incidence was observed among the total cohort (240 observed, 211.0 expected,
SIR = 114, 95 percent CI ~ 100, 129). When the cohort was analyzed by sex and
job classification (production or office staff), however, a significant
increase in total cancer incidence was found among production workers (222
observed, 191.9, SIR = 116, p <0.05, Power = 100 percent), which appears as a
result of the increase among male production workers (213 observed, 182.0
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expected, SIR = 117, 95 percent CI = 102, 134, p <0.05, Power = 100 percent).
When investigators analyzed site-specific cancer incidence among male workers
by time since first employment, they found a significantly increased incidence
of buccal cavity and pharyngeal cancers (13 observed, 6.3 expected, SIR = 210,
95 percent Cl = 110, 340, p <0.05, Power * 24 percent) and of digestive organ
cancers (64 observed, 43.9 expected, SIR * 150, 95 percent CI * 110, 190,
p <0.05, Power s 90 percent), but no trends of Increasing SIRs occurred with
increasing time since first employment. Although no significant elevations of
lung cancer incidence were found among males with 20 or more years since first
employment, the power to detect lung cancer In this group was only 53 percent.
In addition, the power to detect mesothelioma cases could not be calculated
since cause-specific expected incidence was not reported for this site.
Finally, even when adjustments to expected lung cancer incidence rates were
made to account for geographical differences in local and national rates, in
urban and rural places of residence, and in regional tobacco consumption, no
significant elevations in lung cancer SIRs were identified.
The investigators concluded the following: (1) the overall risk of lung
cancer appears restricted to the largest subgroup, male production workers;
(2) there was an increasing trend with time since first employment for cancers
of the buccal cavity and pharynx and respiratory organs, but a decreasing trend
for cancer of the digestive organs; (3) there is a moderately elevated risk of
cancer of the respiratory tract, especially lung cancer and buccal cavity and
pharyngeal cancer in workers with 20 or more years since first employment;
(4) adjustments for local lung cancer incidence, place of residence, or smoking
habits did not result in significantly elevated lung cancer incidence among
male production workers; and (5) although it is unlikely that the lung cancer
excess is attributable to disease ascertainment bias, life style, or occupa-
tional exposures unrelated to the plant, the number of cases was too small to
exclude the effects of chance.
Although this study indicates an overall risk of lung cancer in male
production workers, contrary to the conclusion of Olsen et al. (1986), when the
data are analyzed by latency period neither significantly increasing nor
decreasing trends in lung cancer incidence are identified. Furthermore,
although the excess lung cancer incidence among those with 20 or more years
since first employment was significantly elevated in the previous study, the
lung cancer incidence was reduced in this study. It was not possible to
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determine the percent of the cohort with 20 or more years of exposure because
the data were not analyzed by duration group. Despite the limitations of this
study, such as the short exposure period, the small number of cases, and the
small percentage of the cohort with 30 or wore years of latency, an excess of
lung cancer was found in KMMF workers.
Teppo and Kojonen (1986) conducted • historical prospective mortality and
morbidity study of 941 male (85 percent) and female (35 percent) workers who
were employed at least 3 months in a Finnish FG plant between 1941 and 1951 and
were alive on January 1, 1953, as well as all those employed at least 3 months
between January 1, 1953, and December 31, 1977. A list of workers assembled
from company employment records was compared and supplemented with a membership
list from a local trade union. Job histories were then extracted from employ-
ment records. If exposure periods were discontinuous, then the duration of
exposure was defined as the sum of an individual's exposure periods. In
addition to the presence of FG wool, asbestos had been used in both insulation
and personal protective equipment as well as in production from 1946 through
1948. Actual exposure measurements were unavailable.
The Finnish national age, sex, and calendar-time specific mortality rates
from the Central Statistical Office and the national age, sex, and
calendar-time specific cancer incidence rates from the Cancer Registry were
applied to person-years to obtain the expected numbers of deaths or cancer
cases. The years of followup were from January 1, 1953, to December 31, 1981,
allowing a maximum followup of 29 years, only 4 of which did not overlap the
exposure period. Of the 941 cohort members, 13 (1.4 percent) were lost to
followup, mainly because they emigrated to Sweden.
Although no significant excesses from specific causes of death were
observed, only 133 of the 941 (14 percent) cohort members had died. Further-
more, among male workers, the power to detect all malignant neoplasms and NMRD
was only 47 percent and 26 percent, respectively. There were no trends in the
SHRs with either length of exposure or time since first exposure. When the
data were analyzed by length of employment, among males and females with 20 or
more years of exposure, the power to detect all cancer deaths was only 2
percent and to detect all cancer incidence was only 6 percent. When the data
were analyzed by years since first exposure, among males and females with 30 or
more years since first exposure, the power to detect all cancer deaths was only
62 percent and to detect all cancer incidence was 28 percent. No excess
cause-specific cancer morbidity was identified. No mesotheliomas were reported.
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Since local lung cancer incidence approximated national rates and the urban/
rural distribution of the cohort corresponded with the distribution of the
Finnish population, neither affected the SIRs.
The investigators concluded that the results argue against an etiological
role between lung cancer and MMMF exposure for several reasons: (1) mortality
analysis did not reveal any statistically significant risks; (2) no excess risk
of lung cancer was identified (three of the four observed cases occurred among
those who worked less than 1 year); and (3) no dose-response relationship or
Increasing relative risk with increasing years of followup was found. The
investigators correctly noted that the lack of positive evidence was attribut-
able to the small cohort and small number of deaths. In fact, only 1.8 percent
of the person-years at risk had accrued among those with 30 or more years of
followup; mean followup was 12 years. When a cohort is small, they pointed
out, mortality and cancer morbidity will be too small to draw conclusions about
the presence or absence of an excess risk.
Claude and Frentzel-Beyme (1984) conducted a historical prospective
mortality study of 2096 male production and maintenance employees who had ever
worked in a West German MW plant between January 1, 1942, and December 31,
1977. After the cohort was assembled from company payroll records, a modified
life-table technique was used to obtain person-years at risk of dying, begin-
ning with date of first employment or January 1, 1942, whichever occurred
later. Individuals with unknown vital status contributed to person-years at
risk until the date of last information. Those for whom death certificates
were unavailable were assumed to have died from unknown causes. For an exter-
nal comparison group, the West German national age, sex, and calendar-time
specific mortality rates for 5-year age groups and 5-year calendar-time periods
were applied to person-years to obtain the expected numbers of cause-specific
deaths. For an internal comparison group, the number of deaths stratified by
10-year age groups among 1,77 male cork and styropor panel production workers
of the same plant were compared with deaths among the study group.
Although a steam-blown rock wool manufacturing process was in operation at
the plant since 1942, measurements of respirable fibers in production areas
were unavailable. In addition, because this operation was discontinued in
1977, no current exposure data were available. Consequently, the cohort was
classified by main job category as a surrogate for degree of exposure to MW.
Workers were possibly exposed to asbestos during the manufacture of other
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products within the plant, as well as the presence of other potentially con-
founding substances, including silica, formaldehyde, oil binders, and coal tar.
Exposure occurred between 1942 and 1977, allowing a maximum exposure period of
36 years. Since the observation period was from January 1, 1942, to December
31, 1979, allowing a maximum followup of 38 years, there were only 2 years
without overlapping exposure and observation periods.
Vital status was determined through personal contacts and through inqui-
ries made at registrar's offices regarding a worker's last residence or birth-
place. Death certificates were obtained from local government health offices,
but ascertainment of cause of death was impeded by recordkeeping laws requiring
the maintenance of death certificates for only 5 to 10 years. By the end of
the followup period, December 31, 1979, 1655 (79 percent) of the 2096 study
group members were alive; 242 (11.5 percent) had died; 199 (9.5 percent) were
lost to followup. Among the 1778 internal controls, 1372 (77.2 percent) were
alive; 219 (12.3 percent) had died; 187 (10.5 percent) were lost to followup.
According to the investigators, missing information on 7 percent of the deaths,
62 percent of which occurred in migrant workers, may have underestimated
cause-specific cancer mortality.
Although no significantly increased overall or cause-specific mortality
was found in the study group when compared to West German males, 43 percent of
the cohort were exposed for less than 1 year; only 3 percent were exposed for
30 or more years. There was insufficient power to detect either lung cancer
(46 percent) or NMRD (52 percent). When the exposed production and maintenance
workers were analyzed by time since first employment, a significant excess of
malignant neoplasms was found among those with 20 to 29 years since first
employment (27 observed, 17.5 expected, SMR = 154, 95 percent CI = 104, 221,
p <0.05). When the same analysis was restricted to production workers, a
significant excess of stomach cancer was observed among those with 20 to 29
years since first employment (5 observed, 1.8 expected, SMR * 273, 95 percent
CI * 102, 616, p <0.05). When restricted to maintenance workers, n significant
excess from all causes of death was found among those with 20 to 29 years since
first employment (37 observed, 25.3 expected, SMR « 146, 95 percent CI = 106,
200, p <0.05). When internal controls were used as the reference population,
investigators found a significantly elevated relative risk (RR) of neoplasms of
unspecified nature (RR = 7.03, 95 percent CI = 1.17, 42.29, p <0.05) and
pancreatic cancer (5 cases, 0 controls, p <0.05). No mesotheliomas were
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observed In the study groups; however, one mesothelioma occurred in the inter-
nal control group. Using one as an expected value, the power to detect meso-
theliomas was only 7 percent.
The investigators concluded that (1) no significantly increased risk
exists for any cause of death among persons engaged in rock wool production,
packaging, and maintenance activities compared to the general population;
(2) using job classification as a surrogate for Intensity of exposure, a
significant excess of stomach cancer existed among production workers; and
(3) interpretation of positive findings is complicated by the presence of other
substances, such as asbestos, silica, formaldehyde, oil binders, and coal tar,
the short exposure period, and the potential disease ascertainment bias. Thus,
the adverse effects identified in this study may not be causally related to
exposure to MMMF.
This study has several limitations. While the power to detect deaths.from
all causes was sufficient (100 percent), the cohort was too small to have
sufficient power to detect either lung cancer or NMRD. More important, incom-
plete enumeration of the causes of death in the study group, especially among
migrants, may have underestimated the cancer mortality risk in this cohort,
especially for rare tumors. Coupled witti the laro/e percentage of workers lost
to followup (10 percent), the potential disease ascertainment bias may have
greatly underestimated the risk of lung cancer and NMRD in this study. In
addition, because the majority of workers were exposed for less than 1 year
(median duration = 1.6 years), there .nay have beeri too short an exposure period
for this small a cohort to demonstrate a dose-response relationship between
MMMF and either lung cancer or NMRD.
To increase the size of the cohort with 30 or more years of observation,
Claude and Frentzel-Beyme (1986) conducted a historical prospective.mortality
study of 2092 male production and maintenance employees who had ever worked in
a West German MW plant between January 10, 1941, and December 31, 1977. An
investigation into past exposure by the Edinburgh Institute of Occupational
Medicine between 1983 and 1984 revealed that production began in 1941. There-
fore, the exposure period and person-years at risk were calculated from date of
first employment or January 10, 1941, whichever occurred later, rather than
January 1, 1942, as in the previous study. Except for extending the followup
by 3 years from December 31, 1979, to December 31, 1982, both the study group
and the reference group of 1775 cork and styropor panel production workers used
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as internal controls were identified through the same procedures used in the
1984 study. However, the study group was reduced from 2096 to 2092 and the
reference group from 1778 to 1775 because of earlier errors in coding sex.
Since local mortality rates did not differ significantly from West German
national rates, national rates were used to calculate expected deaths for an
external comparison group. After using a modified life-table analysis to
obtain person-years at risk, age, sex, and calendar-time specific national
mortality rates for the years 1952 to 1982 were applied to person-years to
determine expected deaths. The 1952 rates were applied to person-years accumu-
lated prior to the availability of the rates. For an internal comparison
group, relative risks were estimated for causes of five or more deaths. Where
cause-specific mortality was large, deaths were stratified in 10-year age
groups; where cause-specific mortality was small, in 25-year age groups.
Because Claude and Frentzel-Beyme (1986) stated that occupational exposure of
the reference group to low levels of MMMF cannot be excluded, the suitability
of this group as an internal control is questionable.
Although exposure data were unavailable, mineral oil was used as a binder
from 1941 until 1954 when resin binders were added, indicating a potential
change in exposure conditions. As in the previous study, coal tar, silica,
urethane formaldehyde foam, and polystyrene were used during production pro-
cesses. Exposure occurred between 1941 and 1977, allowing a maximum exposure
period of 37 years. Since the observation period was from January 10, 1941, to
December 31, 1982, allowing a maximum followup of 42 years, there were only 5
years without overlapping exposure and observation periods.
By the end of the followup period, December 31, 1982, 1564 (74.8 percent)
of the study group members were alive, 315 (15.1 percent) had died; 213 (10.1
percent) were lost to followup. Among the 1775 internal controls, 1300 (73.2
percent) were alive; 290 (16.3 percent) had died; 185 (10.4 percent) were lost
to followup. The proportion of persons lost to followup and through emigration
was large; 62 percent were migrant workers.
Compared to West German males, significantly increased mortality occurred
from all malignant neoplasms (80 observed, 63.1 expected, SMR = 127, 95 percent
CI = 101, 157, p <0.05, Power « 97 percent), benign and neoplasms of unspeci-
fied nature (10 observed, 3.0 expected, SMR « 336, 95 percent CI * 171,600,
p <0.05), mental disorders (7 observed, 3.1 expected, SMR = 228, 95 percent
CI = 100, 452, p <0.05) and symptoms and ill-defined conditions (23 observed,
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8.6 expected, SMR = 268, 95 percent CI = 174, 397, p <0.05). Although investi-
gators found no overall excesses from either lung cancer or NMRD, there was
insufficient power to detect both lung cancer (53 percent) and NMRD (53 per-
cent). To reduce the high number of deaths from 111-defined conditions for
which death certificates were unavailable, the investigators contacted last.
attending physicians and family to obtain Information on causes of death. When
additional cases identified in this Manner were included in the number of
observed deaths, deaths from accidents, poisoning, and violence became signifi-
cantly elevated (56 observed, 39.8 expected, SMR = 143, 95 percent CI = 110,
184, p <0.05).
Since those employed for less than 1 year contributed one-third of the
total person-years at risk, the mortality of the entire cohort was influenced
by this group. The mortality experience of those employed less than 1 year was
significantly increased overall (SMR = 140, 95 percent CI = 113, 173), but this
excess was not attributable to any particular cause of death. When short-term
workers were excluded, investigators found no significantly elevated causes of
death, but 19 of the 21 lung cancer deaths occurred *(nong those with 1 or more
years of employment.
When the cohort was analyzed by time since first exposure, investigators
found significant excesses of death from all malignant neoplasms among those
with 20 to 29 years since first exposure (39 observed, 24.3 expected, SMR =
161, 95 percent CI = 116, 217, p <0.05) and from benign and unspecified neo-
plasms among those with 9 or less years since first exposure (4 observed, 0.7
expected, SMR = 576, 95 percent CI = 184, 1388, p <0.05). Although it appeared
that the excess mortality from malignant neoplasms was unrelated to latency
.period or length of exposure, the power to detect site-specific cancers was
low, perhaps because only 1.4 percent person-years had accrued in the category
of 20 or more years of exposure and 30 or more years of observation since first
exposure.
To determine whether the introduction of resin binders in 1953 altered the
mortality experience of the cohort, analyses were performed by date of entry,
i.e., before and after 1953, and years since first exposure. Among those first
employed before 1953, investigators found significant excesses from all malig-
nant neoplasms (24 observed, 14.5 expected, SMR - 165, p <0.05) as well as
stomach cancer (6 observed, 2.3 expected, SMR = 261, p <0.05) among those with
20 to 29 years since first exposure; lung cancer among those with 10 to 19
years since first exposure (6 observed, 2.2 expected, SMR = 272, p <0.05, Power
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= 12 percent); benign and unspecified neoplasms among those with less than 9
years since first exposure (2 observed, 0.2 expected, SMR » 888, p <0.05); and
unspecified neoplasms overall (6 observed, 1.5 expected, SMR & 406, p <0.05).
Among those first employed after 1953, a significant excess was observed from
all causes of death (163 observed, 137.7 expected, SMR = 118, p <0.05).
When the cohort was analyzed by job classification as a surrogate for
degree of exposure, production workers demonstrated a significant excess of
deaths from benign and unspecified neoplasms (6 observed, 1.9 expected, SMR =
313, p <0.05), especially among those with 9 or less years since first exposure
(3 observed, 0.5 expected, SMR = 666, p <0.05). Maintenance workers exhibited
significant excesses from all malignant neoplasms among those with 20 to 29
years since first exposure (16 observed, 8.1 expected, SMR = 197, p <0.05),
lung cancer among those with 20 to 29 years since first exposure (6 observed,
2.4 expected, SMR « 249, p <0.05, Power = 16 percent), and benign and unspeci-
fied neoplasms (4 observed, 1.1 expected, SMR = 379, p <0.05), especially among
those with 20 to 29 years since first exposure (2 observed, 0.3 expected,
SMR = 618, p <0.05). Therefore, both production and maintenance workers had
significantly elevated deaths from benign and unspecified neoplasms, especially
among those with 20 to 29 years since first exposure. Lung cancer mortality
appeared to be higher in maintenance workers, especially among those with 20 to
29 years since first exposure.
When the data were analyzed using internal controls as the reference
population, there were significantly increased relative risks from pancreatic
cancer (RR = 6.76, 95 percent C! = 1.01, 42.50, p <0.05) and neoplasms of
unspecified nature (RR * 2.89, 95 percent CI = 1.14, 7.32, p <0.05). All seven
pancreatic cancers ard all! twat one of the unspecified neoplasms occurred in the
exposed group. The investigators stated that no cases of mesothelioma were
found. It Is unclear whether the mesothelioma found in the control group from
the 1984 study was not listed here because 1t occurred among one of the cases
excluded due to errors 1n coding sex.
The investigators concluded that (1) no significantly elevated mortality
from lung cancer was observed in the cohort; (2) most of the excesses from
other cause-specific deaths appear unrelated to MW production because they
occurred among those employed for short periods or as frequently among internal
controls; (3) there was 95 percent power to detect a twofold lung cancer risk,
but an increased risk of lung cancer was not significant and related neither to
time since first exposure nor to duration of employment; (4) as stated in the
Julv IPPft
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1984 study, -Interpretation of positive findings nay be complicated by the
possibility of multiple exposures and lack of information on previous occupa-
tional exposures, especially among short-term workers; and (5) the unavailabil-
ity of death certificates for 7 percent of the decedents resulted in an
underestimate of cause-specific risks.
This study suffers from the same limitations as its predecessor. In
addition, although the investigators correctly concluded that there was 95
percent power to detect a twofold risk of lung cancer, the cohort was too small
to have sufficient power to detect a 1.5-fold risk of either lung cancer or
NMRD. For example, when the data were analyzed by latency, duration of expo-
sure, and period of employment, only 1.4 percent of the person-years were
accrued by individuals with 20 or more years of exposure and 30 or more years
of latency. Nevertheless, with only 12 percent power to detect a 1.5-fold risk
of lung cancer, compared to West German males, there was a threefold excess
among production and maintenance workers employed before 1953 with 10 to 19
years of latency. Furthermore, without extensive exposure and latency for a
large percentage of the cohort, it is especially important to adequately follow
exposed individuals, whether terminated or retired, to determine whether they
develop cancer. Thus, the large percentage of the cohort lost to followup may
also explain why no significantly elevated lung cancer mortality was detected.
Bertazzi et al. (1984) conducted a historical prospective mortality study
of 1158 male production workers who were employed at least 1 year in an Italian
FG plant between 1944 and 1973. The cohort was assembled from company person-
nel records containing names, sex, place and date of birth, residence and/or
last address, chronological work history, and dates of employment. A total of
2434 workers -(2100 males and 344 females) were employed between 1944 and 1973.
Analysis was restricted to 1158 male production workers with at least.1 year of
employment. After using a computer program to obtain person-years at risk of
dying, the expected numbers of deaths were calculated by cause, sex, and 5-year
calendar-time and age groups based on three different sets of mortality rates:
(1) Italian national rates for the years 1942 to 1977; (2) Lombardy regional
rates for the years 1969 to 1978; and (3) rates from a nearby city with a
population of about 100,000 for the years 1954 to 1978.
Exposure was classified according to 20 different jobs, each implying a
different level of exposure to FG as estimated in 1980 by the Edinburgh Insti-
tute of Occupational Medicine. Personal samples from a random sample of 166
workers reported concentrations ranging from 0.007 to 0.023 fiber/cm for the
July 1988 8-48 DRAFT-DO NOT QUOTE OR CITE
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respirable fiber fraction and 0.002 to 0.10 fiber/cm for the nonrespirable
fraction. From scanning electron microscopy, median fiber length ranged from
3.7 to 7.5 pin and median diameter ranged from 0.3 to 0.7 pm. There was a
maximum exposure period of 30 years from 1944 to 1973. For each worker, two
exposure indices were calculated: a cumulative Index obtained by summing up
fibers/cm-months and a weighted cumulative Index. Since the observation
period was 1944 to 1980, «1lowing a maximum followup of 37 years, there were
7 years without overlapping exposure and observation periods.
Vital status was ascertained through the Population Statistics Office
nearest a worker's residence or place of birth. By the end of the followup
period, December 31, 1980, 1027 (88.7 percent) of the 1158 male production
workers were alive; 106 (9.2 percent) had died; 25 (2.1 percent) were lost to
followup. It was not possible to determine the percent of the death certifi-
cates obtained for decedents. Deaths were coded according to the 8th Revision
of the ICD.
There appeared to be a gradient of SMRs based on choice of reference
population: SMRs were highest compared to national rates, intermediate coir-
pared to local rates, and lowest compared to regional rates. The significantly
increased mortality from all cancers (34 observed, 22.90 expected, SMR = 14£,
95 percent CI = 105, 205, p <0.05) and laryngeal cancer (4 observed, 0.9£
expected, SMR = 408, 95 percent CI = 130, 985, p <0.05) compared to nations!
rates were no longer significant when local or regional rates were used.
Deaths from cardiovascular disease were significantly decreased compared to
national rates (20 observed, 31.39 expected, SMR « 64, 95 percent CI = 40, 97,
p <0.05), local rates (38.13 expected, SMR = 52, 95 percent CI = 33, 80,
p <0.05), and regional rates (36.90 expected, SMR = 54, 95 percent-CI = 34, 82,
p <0.05). Using national, regional, or local rates, there was insufficient
power to detect a 50 percent increased mortality from lung cancer, laryngeal
cancer, or NMRD. No deaths from mesothelioma were reported.
Since cancer mortality 1n the area where the plant was located was known
to be higher than that of the national population, the Investigators used local
rates as the comparison group for analyses of cancer mortality data. When
cancer mortality data were analyzed by latency period (<5, 5 to 15, 15 to 25,
and >25 years), duration of exposure (<10, 10 to 20, and >20 years), age at
first exposure (<25, 25 to 34, 35 to 44 and >45 years), and cumulative exposure
(unexposed, <0.03, 0.03 to 0.10, 0.10 to 0.30, and >0.30 fibers/cm -months), no
Julv 1988 ft-^s n&AFT--nn urn nnnrp OP nTF
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significant trends were found except for laryngeal cancer, which was signifi-
cantly elevated among those with 25 or more years of latency (3 observed, 0.32
expected, SMR = 938, 95 percent CI = 238, 2551, p <0.005); with 20 or more
years of exposure (2 observed, 0.24 expected, SMR * 833, 95 percent CI = 140,
2753, p <0.05); whose first exposure was before age 25 (2 observed, 0.13
expected, SMR = 1,538, 95 percent CI * 258, 5083, p <0.01); and whose cumula-
tive exposure was greater than or equal to 0.30 fibers/cm -months (3 observed,
0.20 expected, SMR e 1500, 95 percent CI * 381, 4082, p <0.005). The investi-
gators also found that all four workers with laryngeal cancer were first
employed before 1960 when FG wool rather than continuous FG filament was
produced. In addition, the results showed a consistent, significant increase
among those most heavily exposed.
The investigators concluded that the excess risk of laryngeal cancer
following exposure to FG seemed biologically plausible and was estimated in
comparison with a population having similar socioeconomic conditions as well as
an elevated background risk. According to the investigators, the small number
of laryngeal cancer cases upon which the excess was based, the absence of an
excess in previous epidemiologies! studies, and incomplete control of confound-
ing variables limit the findings of this study. Generally, SMRs based on five
or fewer observations are subject to chance fluctuation. This also applies to
cases where, because no deaths were observed, SMRs are zero. In both of these
cases, the 95 percent confidence intervals reflect a wide range of possible
risk.
Bertazzi et al. (1986) extended the followup period of their previous
study for an additional 3 years (December 31, 1983). However, it cannot be
determined why the size of the cohort was reduced from 1158 male production
workers in the previous study to 1098 in this study. Because there are marked
variations In cancer mortality rates across different regions in Italy, inves-
tigators used local rather than national rates to study cancer mortality.
Between 1944 and 1960, FG wool was produced. After 1960, production was
limited to continuous FG filament. Resin binders were used since 1944. There
was no reported use of asbestos. The concentrations of respirable fibers
reported ranged from 0.005 to 0.048 fiber/cm with a median length, as
determined by scanning electron microscopy, of 3.7 to 7.5 urn and a median
diameter of 0.3 to 0.7 urn. No asbestos fibers were detected in any of the
samples. There was a maximum exposure period of 30 years from 1944 to 1973.
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Since the observation period was from 1944 to 1983, allowing a maximum followup
of 40 years, there were 10 years without overlapping exposure and observation
periods.
Vital status of former employees was ascertained through the Population
Statistics Office nearest • worker's nost recent residence or place of birth.
Of the 1098 workers, 956 (87.1 percent) were alive; 130 (11.8 percent) had
died; and only 12 (1.1 percent) were lost to followup. Death certificates
were obtained for all 130 of the decedents. Therefore, there was a very high
degree of followup and • 100 percent trace rate. Deaths were coded according
to the 8th Revision of the ICO.
SHRs were not consistent between national and local rates. They tended to
be higher when national rates were used. The significantly increased mortality
from all causes compared to national rates (130 observed, 106.4 expected,
SMR = 122, 95 percent CI « 102, 145) was no longer significant when local rates
were used (126.1 expected, SMR = 103, 95 percent CI « 86, 122). Using either
national or local rates, there was insufficient power to detect a 50 percent
increased mortality from lung cancer, laryngeal cancer, and NMRD. Deaths from
cardiovascular disease (CVD) were significantly decreased using either national
(21 observed, 35.0 expected, SMR = 60, 95 percent CI = 37, 92) or local rates
(42.1 expected, SMR = 50, 95 percent CI = 31, 76), as one would expect for a
group of factory workers. No deaths from mesothelioma were reported.
Using local rates as the comparison group, cancer mortality data were
analyzed by latency, duration of exposure, period of exposure, end cumulative
exposure. No significant trends were observed except for laryngeal cancer
among those with 25 or more years of latency (3 observed, 0.5 expected, SMR =
591, 95 percent CI * 150, 1608, p <0.05, Power = 4 percent). When the cohort
was analyzed by period of first employment, all laryngeal cancer occurred
before 1960 when glass wool was produced. When the data were analyzed by
cumulative exposure, three of the four laryngeal cancers were observed in the
highest exposure group.
The investigators concluded that (1) mortality from all causes was signif-
icantly elevated based on national but not local mortality rates; (2) analysis
by latency, duration of exposure, period of exposure, and cumulative exposure
failed to confirm the hypothesis of an association between lung cancer deaths
and exposure to MMMF; (3) increased laryngeal cancer mortality was statisti-
cally significant after 25 or more years of latency and 15 or more years of
July 1988 8-51 DRAFT—DO NOT QUOTE OR CITE
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exposure among those hired before aged 25, having the highest cumulative
exposure, and first employed before 1960 when airborne concentrations of fibers
were higher than during the production of continuous filament; and (4) exoge-
nous risk factors associated with laryngeal cancer, such as smoking, alcohol,
and asbestos, do not appear to be present. The investigators cautioned that
although biological plausibility exists for the excess laryngeal cancer risk,
the study findings are limited by the small number of laryngeal cancers, the
lack of histopathological characterization of these cases, and the lack of
information on an individual's other possible risk factors.
This study was strengthened by the excellent followup and 100 percent
trace rate. Despite the low power and small number of deaths, the detection of
rare tumors such as laryngeal cancer attests to the importance of thorough
disease ascertainment among decedents. It is not possible to conclude that the
excess laryngeal cancer is causally related to the low levels of FG exposure
because four cases are too few to exclude the effects of chance. Because other
studies have lacked this degree of followup and disease ascertainment, laryn-
geal cancers associated with FG exposure may have gone undetected.
Gardner et al. (1986) conducted a historical prospective mortality study
of two FG factories in the United Kingdom. One cohort consisted of 4734 male
and female (25 percent) workers employed for at least 1 year between April 1,
1946, and December 31, 1978, in an English FG wool factory. After the cohort
was assembled from payroll records, data were supplemented by pension and
medical records. Vital status was determined from the National Health Service
Central Register and Department of Health and Social Security.
The other cohort consisted of 1910 male and female (37.4 percent) workers
employed at any time between January 1, 1956, and December 31, 1978, in a
Northern Ireland continuous glass filament factory. After the cohort was
assembled from job application forms, personnel files, and medical records,
vital status was determined from the Central Services Agency in Belfast.
Copies of death certificates were obtained through the General Register Office.
Persons not identified from these sources were traced through the plant medical
officer and/or their own physicians. For those who emigrated to England, vital
status was determined through the National Health Service Central Register and
Department of Health and Social Security.
After using a computerized life-table method developed to obtain
person-years at risk of dying, the expected numbers of deaths were calculated
-------
by age, sex, cause, and calendar-year specific national rates. Local adjust-
ment factors were applied to txpected numbers for the English cohort using SMRs
for the period 1968 to 1978 from the locality containing the factory. Since
local rates were unavailable for the Irish cohort, the national rates for
Northern Ireland were used to calculate expected deaths.
From employment records, dates of employment and descriptions of all
recorded jobs in the factory were abstracted. Workers were categorized as
preproduction, production, secondary processes, less dusty secondary processes,
maintenance, general staff, and office staff. Short-term industrial hygiene
surveys of dust levels were performed by the Edinburgh Institute of Occupa-
tional Medicine during 1977 for the English factory and during 1979 for the
Irish factory. Samples were collected on membrane filters and analyzed by
"interference" microscopy. Fiber levels were reported to have been low,
especially for the continuous filament process in Northern Ireland, with mean
concentrations of less than 0.1 fibers/cm for each job category. Mean respi-
rable concentrations were highest in the secondary processes category of the
3
English factory at 0.073 fibers/cm and in the secondary processes category of
the Irish factory at 0.002 fibers/cm'
By the end of the followup period, December 31, 1984, of the 4734 English
cohort members, 3932 (83.1 percent) were alive; 622 (13.1 percent) had died;
180 (3.8 percent) were lost to followup. Of the 1910 Irish cohort members,
1,729 (90.5 percent) were alive; 156 (8.2 percent) had died; 25 (1.3 percent)
were lost to followup. For the English cohort, exposure occurred between 1S46
and 1978, for a maximum exposure of 33 years, and followup occurred between
1946 and 1984, for a maximum observation period of 39 years. For the Irish
cohort, exposure occurred between 1956 and 1976 for a maximum exposure of
23 years, and followup occurred between 1956 and 1984, for a maximum observa-
tion period of 29 years. For both cohorts, there were 5 years without overlap-
ping exposure and observation periods. Deaths were coded according to the 8th
Revision of the ICD.
For both sexes of the English cohort, total deaths were similar to national
mortality rates but lower than local mortality rates. Among male workers, a
significant deficit was observed from accidents, poisoning, and violence when
compared to national rates (21 observed, 33 expected, SMR = 64, 95 percent CI -
40, 98, p <0.05). Among female workers, a significant excess of stomach cancer
was found compared to national rates (6 observed, 2 expected, SMR = 277, 95
percent CI = 102, 604, p <0.05). Because there were few lung cancer deaths
8-53 DRAFT—DO NOT QUOTE OR CITE
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among female workers, analysis of lung cancer mortality was restricted to
males, who were further restricted to exclude office workers. Among male
production workers, a significant excess of lung cancer was found only when
compared to national rates (66 observed, 50.8 expected, SMR = 130, p <0.05).
When this group was analyzed by latency and duration of employment, none of the
excesses was significant compared to local rates. No trends were associated
with latency or duration of exposure. In addition, when data for both sexes
were analyzed by degree of exposure, no statistically significant excess deaths
from lung cancer occurred. Although the cohort was large enough to have
sufficient power to detect lung cancer or NMRD, the power was too low to detect
either lung cancer or NMRD when the data were divided into multiple
subcategories.
Among males in the Irish cohort, significant excesses were found from all
other causes of death (112 observed, 89 expected, SMR = 125, 95 percent CI =
103, 151, p <0.05) and accidents, poisoning, and violence (27 observed, 15
expected, SMR = 174, 95 percent CI = 115, 254, p <0.05). Among women, investi-
gators found a significant deficit from all causes (21 observed, 32 expected,
SMR 65, 95 percent CI = 40, 99, p <0.05). There was insufficient power to
detect either lung cancer or NMRD in either sex. When lung cancer mortality
among males was analyzed by duration of exposure, length of employment, and
occupational category, no trends were identified. Of the nine lung cancer
deaths, four occurred among males who worked in the factory for less than 1
year (4 observed, 1.1 expected, SMR = 378, p <0.05). No mesothelioma deaths
were reported in either factory.
The investigators concluded, for the English cohort (1) no excess mortal-
ity existed, except for lung cancer when compared to national rates; (2) no
relationship existed between length of employment, duration of exposure, level
of exposure, or occupational classification; (3) the absence of any important
relationship between lung cancer and latency, duration, or degree of exposure
suggests that the excess using national rates was unrelated to employment at
the factory; and (4) the excess stomach cancer among women was significant
compared to national but not local rates because of high local stomach cancer
rates. They concluded that in the Irish cohort, no excess mortality existed
for either sex, except for accidents, poisoning, and violence among males,
which can be ascribed to the high rate of violent deaths in Northern Ireland.
They concluded that for both cohorts (1) low FG fiber levels were measured in
both factories as compared to U.K. asbestos control limits; (2) no excess lung
July 1988 8-54 DRAFT—DO NOT QUOTE OR CITE
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cancer mortality was found for workers with long followup; and (3) the statis-
tical power to detect laryngeal cancer was only 38 percent (level of risk not
reported).
The conclusion that no relationship exists between lung cancer and job
classification, latency, duration, and degree of exposure 1s weakened by
several limitations. First, although there was sufficient power to detect a SO
percent increased risk of lung cancer among English males, there was insuffi-
cient power to detect lung cancer among English females or Irish males or
females. The deficits that occurred when the data were analyzed by duration,
latency, and degree of exposure could t»ave resulted from the low power to
detect a 50 percent excess of lung cancer deaths, if such an excess really
existed. The same holds true for NMRD. Second, although the investigators
claimed no excess of lung cancer with long followup, it was not possible to
determine the percent of the cohort with 20 or more years of exposure and 30 or
more years of observation. Third, fiber levels may have been too low to detect
a weak carcinogenic response, if it existed.
Saracci et al. (1984) -rondvrrtrt t tisttm'ca* prospective mortality and
morbidity study of 25,146 persons employed between 1900 and 1955 and
December 31, 1977. The cohort essentially consisted of workers employed in 1
of 13 plants producing MMMF in the seven European countries described above.
Selection criteria for including a plant's work force in the study were (1) no
loss or destruction of personnel records, so that the total cohort was identi-
fiable; (2) MMMF production for at least 20 years; (3) facilities available for
mortality and morbidity ascertainment; and (4) exclusion of plants that pro-
cessed asbestos. As a result of mailed questionnaires followed by site visits,
13 factories (7 rock wool, 4 glass wool, and 2 continuous filament) were
selected for the study. In each country, a national research team supervised
the identification and transcription of workers' names and job histories at
each plant as well as the followup. A worker was considered to have entered
the cohort on the date of first employment 1n one of the factories ranging from
1900 to 1955. At four plants, however, because of missing essential informa-
tion on short-term employees, those employed for less than 1 year were excluded
from the cohort.
After using a modified life-table procedure to generate person-years at
risk, each country's national age, sex, cause, and calendar-time specific
mortality rates and age, sex, site, and calendar-time specific national cancer
incidence rates where available were applied to person-years at risk to obtain
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the expected numbers of deaths or cancer cases. Person-years and expected
values for 5-year age and calendar-year groups were computed from the first
year in which national rates were available for each country, which ranged from
1942 to 1953 for mortality and from 1943 to 1958 for cancer incidence. For all
but one plant, the Edinburgh Institute of Occupational Medicine conducted an
environmental survey to measure concentrations of fibers present at the time of
the study collected from personal samples during an 8-hour work shift. Within
each factory, jobs were classified into six occupational categories: (1) not
specified; (2) office; (3) preproduction; (4) production; (5) secondary pro-
cesses; and (6) maintenance. Concentrations of respirable fibers at the time
of the study analyzed by phase-contrast microscopy were below 1 fiber/cm and
ranged from 0.01 to 0.1 fiber/cm . Exposure and observation periods were
concurrent.
Vital status was ascertained through national facilities or local con-
tacts. The followup period ended on December 31, 1977, for 10 plants;
December 31, 1978, for 1 plant; and December 31, 1979, for 2 other plants.
Of the 25,146 total cohort numbers. 23,487 (93.4 percent) were alive; 1,659
(6.6 percent) had died; and 745 (3.0 percent) were lost to followup. The
followup of individual plants ranged from 3 to 10 percent. Causes of death
and cancer diagnosis were coded according to the ICD in use at time of death,
but for ease of presentation, all codes were converted to the 7th Revision of
the ICD.
Among males, a significant excess of deaths occurred from accidents,
poisoning, and violence (246 observed, 205.8 expected, SMR = 120, 95 percent
CI = 105, 135, p <0.05), but significant deficits from all causes (1505
observed, 1666.4 expected, SMR * 90, 95 percent CI = 86, 95, p <0.05), prostate
cancer (14 observed, 25.9 expected, SMR = 54, 95 percent CI * 30, 91,- p <0.05),
circulatory system disease (538 observed, 715.1 expected, SMR » 75, 95 percent
CI = 69, 82), and bronchitis and asthma (36 observed, 50.7 expected, SMR = 71,
95 percent CI s 50, 98). Although laryngeal cancer was not significantly
elevated among workers from the combined 13 MMMF plants, four of the seven
deaths occurred in one factory (4 observed, 1.0 expected, SMR = 408, 95 percent
CI = Hi, 1024, p <0.05, Power = 7 percent). The investigators did not state
the location of the plant or the type of fiber produced there. One death from
mesothelioma was reported. Among females, significant deficits were found frotr,
all causes (154 observed, 219.6 expected, SMR = 70, 95 percent CI = 59, 82,
p <0.05), all malignant neoplasms (49 observed, 70.1 expected, SMR ~ 70, 95
Julv 1988 8-56 DRAFT—DO NOT QUOTE OR CITE
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percent CI = 52, 92, p <0.05), intestinal cancer (0 observed, 5.1 expected, 95
percent C.I = 0, 72), and circulatory system disease (44 observed, 76.9 expected,
SMR s 57 95 percent CI * 42, 77, p <0.05). However, because of the small
number of cancer deaths in women, further analysis was restricted to men.
When the cohort was analyzed by time since first employment and by process
(rock wool, glass wool, or continuous filament), neither significant excesses
nor deficits were associated with increasing latency. Among glass wool work-
ers, significant deficits were associated with all causes (487 observed, 679.2
expected, SMR » 72, 95 percent CI * 66, 78, p <0.05), which remained signifi-
cantly elevated among those with 19 or less, 20 to 29, or 30 or more years
since first exposure. There also were significant deficits from all neoplasms
(119 observed, 155.5 expected, SMR = 77, 95 percent CI = 63, 97, p <0.05),
especially among those with 20 to 29 years since first employment (28 observed,
45.0 expected, SMR = 62, 95 percent CI s 41, 90). Among continuous filament
workers, however, there were significant excesses from all causes (212
observed, 171.6 expected, SMR = 124, 95 percent CI = 108, 141, p <0.05), espe-
cially among those with 19 or less years since first employment (173 observed,
137.1 expected, SMR = 126, 95 percent CI = 108, 146, p e_n tNBurT. . r\*> »i*» »• i^^-r «n rTTC
-------
the low power to detect lung cancer precluded meaningful analysis, presumably
because of an absence of airborne fiber measurements in one factory and missing
job classifications for others. To further explore a potential dose-response
relationship, the investigators performed a nested case-control study using
male lung cancer deaths observed in the study as cases. Controls surviving to
each case were matched by factory and date of birth (up to 40 controls per
case). The population from which controls were drawn was not specified.
Duration of exposure of each case was compared with that of controls up to the
time of death of the cases. The investigators reported that they found no
statistically significant trend with increasing risk and increasing duration of
exposure in any of the three production processes.
When cancer incidence was analyzed by time since first employment in rock
wool or glass wool factories, investigators found a significantly decreased
incidence from all neoplasms in FG wool workers (62 observed, 104.3 expected,
SIR = 59, 95 percent CI = 46, 76, p <0.05), especially among those with 19 or
less years since first employment (32 observed, 54.4 expected, SIR = 59, 95
percent CI = 40, 83, p <0.05) and 20 to 29 years since first exposure (19
observed, 34.4 expected, SIR = 55, 95 percent CI = 33, 86, p <0.05).
Finally, when lung cancer mortality data were pooled from all 13 factories
and analyzed by latency, a significant excess of lung cancer was found among
those with 30 or more years since first exposure (17 observed, 8.9 expected,
SMR = 192, 95 percent CI = 117, 307, p <0.05, Power * 36 percent).
The investigators concluded that (1) the mortality and cancer incidence
analyses showed no consistent trends except for lung cancer; (2) the signifi-
cant excess of lung cancer observed 30 years after first employment when data
from the 13 plants were pooled suggests that an increased risk was associated
•with exposure to MMMr 30 or more years ago; (3) participation of five more
factories would have increased the study population by 30 percent; (4) while
this study used national rates to assess cancer mortality, and while the use of
local rates tends to lower overall SMRs, local rates do not appear to affect
SMRs in the longest periods since first employment; and (5) although informa-
tion on potential confounding variables, such as smoking, was unavailable,
asbestos does not appear to be a confounding variable because asbestos exposure
would have excluded participation of a plant in this study.
Pooling the data increased the sample size so that sufficient power
existed among the males to detect lung cancer or NMRD. However, when the data
were subdivided into multiple categories, the power was too low to detect lung
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cancer or NMRD. This study was further limited by the overlapping exposure and
observation periods, Inadequate followup in some plants (as high as 10 per-
cent), the small number of deaths fn the cohort, «nd the failure to analyze the
data by length of exposure. All of these deficiencies could result in underes-
timating the risk of lung cancer and NMRD 1n the study group. In addition, it
was not possible to determine the percent of the cohort with 20 or more years
of exposure and 30 or more years of observation since first exposure to MMMF.
Nevertheless, despite only 2.9 percent of the person-years for both sexes
accumulated in the 30 or more years since first exposure category, and despite
low power, a twofold excess of lung cancer mortality was found among male
cohort members after 30 years of latency.
Simonato et al. (1986a) extended the followup of the cohort studied by
Saracci et al. (1984) for 5 additional years by conducting a historical pro-
spective mortality study of 21,967 male and female workers ever employed in the
13 European factories manufacturing various types of MMMF. As in the previous
study, those employed for less than 1 year at four plants were excluded. The
cohort was reduced from 25,146 to 21,967 by calculating person-years from date
of first exposure to MMMF rather than from the date of first employment in one
of the 13 plants and by excluding office workers from the cohort. As described
earlier, factories in countries where no followup could be performed, that were
recently opened, or that had asbestos exposures were excluded. Expected deaths
were calculated using age, sex, cause, and calendar-year specific mortality
rates for each of the seven countries. In addition, local lung cancer mortal-
ity rates were estimated by adjusting the expected numbers by a factor equiva-
lent to the local lung cancer SMR.
Because past exposure data were unavailable, based on the use of dust
suppressants (mineral oil, resin binders, and pitch) and potential exposure to
MMMF in different periods of industrial activity, production processes were
divided into three qualitatively distinct technological phases. In the first,
the early technological phase, airborne concentrations of MMMF were highest
because of the absence of dust suppressants and/or batch processing with
labor-intensive methods. In the second, the -intermediate technological phase,
production methods with and without dust suppressants were used. In the third,
the late technological phase, mineral oil and resin binders were used as dust
suppressants with modern mechanized production methods.
Simonato et al. (1986a) reported significant excesses from all causes
(2719 observed, 2457.0 expected, SMR = 111, 95 percent CI = 107, 115, p <0.05),
-------
all malignant neoplasms (661 observed, 597.7 expected, SMR = 111, 95 percent CI
= 102, 119, p <0.05), and lung cancer (189 observed, 151.2 expected, SMR = 125,
95 percent CI = 108, 144, p <0.05). One death from mesothelioma was reported.
Expected values were estimated to have ranged from one to three deaths from
mesothelioma.
When the cohort was analyzed by latency, investigators found significant
excesses from all causes among those with less than 10 to 19, and 20 to 29
years since' first exposure, from all malignant neoplasms among those with 10 to
19 and 20 to 29 years since first exposure, and from lung cancer among those
with 30 or more years since first exposure (29 observed, 16.8 expected, SMR =
173, 95 percent CI * 116, 248, p <0.05, Power * 54 percent). The excess lung
cancer mortality was further analyzed by time since first exposure and by
process using both national and local rates. While the excess among those with
30 or more years since first exposure persisted even in comparison to local
rates (19.1 expected, SMR = 152, p <0.05), the excess lung cancer mortality in
the whole cohort was no longer significant when compared to local rates. No
significant excess lung cancers were found among rock wool workers, but signif-
icant excesses of lung cancer were found among all glass wool workers, espe-
cially those with 30 or more years since first exposure compared to national
rates (17 observed, 9.8 expected, SMR = 173, p <0.05, Power = 40 percent), and
among continuous filament workers with less than 10 years since first exposure
compared to national rates (9 observed, 4.0 expected, SMR = 224, p <0.05, Power
= 15 percent).
When lung cancer mortality among those with 30 or more years since first
exposure were analyzed by year of followup, lung cancer mortality was signifi-
cantly elevated among the total cohort for either period, up to 1977 (14
observed, 5.7 expected, SMR * 246, p <0.05) or up to 1982 (29 observed, 16.8
expected, SMR = 173, p <0.05). Lung cancer mortality was significantly ele-
vated up to 1977 (7 observed, 2.8 expected, SMR * 251, p <0.05), but not up to
1982 in rock wool workers, and up to the end of 1982 in glass wool workers (17
observed, 9.8 expected, SMR - 173, p <0.05). Although no lung cancers were
observed among continuous fiber workers with 30 or more years since first
exposure, the power was only 8 percent or less.
When lung cancer mortality was further analyzed by time since first
exposure and by technological phase at first exposure, significant excesses
were found among rock wool workers of the early technological phase compared to
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either national rates (10 observed, 4.7 expected, SMR = 214, p <0.05, Power =
18 percent) or local rates (3.9 expected, SMR = 257, p <0.05, Power = 24
percent), especially among those with 30 or more years since first exposure (6
observed, 2.0 expected, SMR « 295, p <0.05, Power « 8 percent), and among glass
wool workers in the intermediate technological phase compared to national rates
(68 observed, 48.8 expected, SMR = 139, p <0.05, Power = 93 percent), espe-
cially among those with 10 to 19 years since first exposure (29 observed, 17.7
expected, SMR * 164, p <0.05, Power * 57 percent). The authors reported that
among those with 20 years since first exposure, based on national rates, a
significant excess of lung cancer existed in the early technological phase
(SMR - 254; 95 percent CI = 122, 467, p <0.05), and 1n the intermediate phase
(SMR = 176, 95 percent, CI = 88, 315, p <0.05), but not in the late phase
(SMR = 92, 95 percent, CI = 49, 157). They also reported a statistically
significant (p <0.01) decreasing trend of SMRs from early to late phase (data
not provided) and an 80 percent power to detect an 80 percent increased risk of
lung cancer among the late phase subcohort.
Within rock wool processes, a batch process used in the early technologi-
cal phase at four plants in three countries was considered to have had poten-
tially high historical fiber levels. Among 223 workers employed at these
plants during the period of batch operation, investigators reported a signifi-
cant excess of lung cancer using national rates for those with 20 to 29 years
(4 observed, 1.0 expected, SMR = 402, p <0.05) and 30 or more years since first
exposure (6 observed, 1.8 expected, SMR = 330, p <0.05).
When lung cancer mortality among those with 20 or more years of latency
were analyzed by duration of employment per process, a significant lung cancer
excess was restricted to glass wool workers employed from 1 to 4 years. (19
observed, 9.7 expected, SMR * 197, 95 percent CI = 119, 308, p <0.05) and frorr.
"10 to 19 years (15 observed, 7.9 expected, SMR * 190, 95 percent CI = 106, 314,
p <0.05). The authors stated that duration of employment did not appear to
increase the risk of lung cancer.
The investigators concluded that (1) the elevated mortality from lung
cancer among rock wool workers was associated with employment during the early
technological phase when dust suppressants were not 1n use; (2) after consider-
ing potential confounding factors, such as smoking and asbestos, the concen-
tration of excess lung cancer among those with the highest levels of exposure
to respirable fibers points to MV as a risk factor; (3) no increased risk was
found in the late technological phase after full introduction of dust
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suppressants; (4) the absence of an excess of the same magnitude present in
glass wool workers is consistent with the presumed low exposure to respirable
fibers; and (5) there is no increased risk of mesothelioma.
This study was enhanced by pooling data from the 13 plants, thereby
increasing the number of deaths, analyzing of the data from first exposure
rather than first employment, and adding 5 years to the followup. On the other
hand, although there was sufficient power to detect lung cancer overall, the
low power to detect lung cancer in glass wool workers when they were subdivided
into multiple categories may have impeded the detection of an increased risk of
lung cancer in the early and late phases of glass wool production. Similarly,
the conclusion that no evidence exists for an increased risk of death from
mesothelioma is weakened by the low power (17 percent based on an estimated
maximum expected value of three deaths) to detect a 50 percent increased
incidence of mesothelioma. "
Simonato et al. (1986b) further analyzed the mortality and cancer morbid-
ity experience of the European cohort of 21,967 male and female (14.6 percent)
production workers. The 21,967 production workers consisted of 10,115 workers
in the rock wool/slag wool subcohort, 8,286 workers in the glass wool subcohort,
and 3,566 workers in the continuous glass filament subcohort (Simonato et al.,
1987). Expected deaths and incident cancer cases were derived by applying
national mortality rates adjusted for age, sex, and calendar-year to person-
years at risk. Correction factors for regional lung cancer mortality were also
used, except for two factories where no adjustments were made because of small
national populations, and for two others where immediate local area mortality
rates were used. The exposure assessment was based on the results of a histor-
ical environmental investigation reported by Cherrie et al. (1986) and Cherrie
and Dodgson (1986). Simonato et al. (1987) estimated the highest cumulative
dose in the early technological phase of rock wool/slag wool processes to have
been in the range of 27 to 70 fibers/cm . After a conversion table was pre-
pared at the International Agency for Research on Cancer (IARC) to allow
pooling of results over different ICO Revisions, deaths were reported according
to the 8th Revision of the ICD. National cancer morbidity data were reported
according to the 7th Revision of the ICD.
The end of the followup period varied by plant from 1981 to 1983. Of the
combined 24,609 office and production workers, by the end of the followup
period, 83.3 percent were alive, 11.5 percent had died, and 5.2 percent were
lost to followup. Since vital status was not reported for the production
.!•••»» IQBO 8-62 DRAFT—DO NOT QUOTE OR CITE
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workers, It was not possible to determine the percent alive, dead, or lost to
followup. However, death certificates were obtained for all but 46 (1.7
percent) of the 2719 decedents who had been production workers. Less than 1
percent of the cohort had accrued person-years at risk 30 or more years since
first exposure with 20 or more years' exposure to MMMF. The average duration
of employment was 3.8 years for rock wool workers and 5.6 years for glass wool
workers.
Because the investigators Included both males and females in this analy-
sis, all data were presented for both sexes. Although this analysis focussed
on production workers, the investigators also examined the overall mortality of
office workers compared to national mortality rates and found a significant
excess of bladder cancer (4 observed, 1.0 expected, SMR = 396, 95 percent
CI = 108, 1014, p <0.05, Power = 7 percent) and significant deficits from
accidents, poisoning, and violence (13 observed, 23.9 expected, SMR =54, 95
percent CI = 29, 93, p <0.05, Power = 71 percent), and all causes (117 observed,
158.6 expected, SMR =74, 95 percent CI = 61, 88, p <0.05, Power « 100 percent).
Among the production workers, compared to national rates investigators found
significant excesses from all causes (2719 observed, 2457.0 expected, SMR =
111, 95 percent CI = 107, 115, p <0.05), all malignant neoplasms (661 observed,
597.7 expected, SMR = 111, 95 percent CI = 102, 119, p <0.05), lung cancer (189
observed, 151.2 expected, SMR = 125, 95 percent CI « 108, 144, p <0.05, Power =
100 percent), and accidents, poisoning, and violence (406 observed, 264.8
expected, SMR = 153, 95 percent CI « 139, 169, p <0.05), including suicides
(110 observed, 84.6 expected, SMR = 130, 95 percent CI = 107, 157, p <0.05).
While there was sufficient power to detect lung cancer or NMRD among production
workers, there was only 24 percent power to detect laryngeal cancer and 42
percent power to detect buccal cavity and pharyngeal cancers.
To examine the mortality experience of short-term workers, the data were
analyzed by duration of employment of less than or more than 1 year. Among
short-term workers, investigators found significant excesses from all causes
(741 observed, 504.08 expected, SMR = 147, p <0.05), malignant neoplasms (143
observed, 120.17 expected, SMR * 119, p <0.05, Power = 80 percent), NMRD (36
observed, 26 expected, SMR - 150, p <0.05, Power - 71 percent), digestive
diseases (40 observed, 23.39 expected, SMR * 171, p <0.05, Power = 66 percent),
violent deaths (200 observed, 82.64 expected, SMR = 242, p <0.05), and other
known causes (80 observed, 60.15 expected, SMR = 133, p <0.05). Compared to
local rates, these excesses were reduced, but remained significantly elevated
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at the p = 0.05 level in a subsequent update by Simonato et al. (1987): all
causes (SMR = 142); malignant neoplasms (SMR = 115); NMRD (SMR = 146); diges-
tive diseases (SMR = 165); and violent deaths (SMR = 227). Among those employed
for more than 1 year. Investigators found significant excesses from malignant
neoplasms (518 observed, 475.23 expected, SMR * 109, p <0.05, Power = 100
percent), lung cancer (154 observed, 120.31 expected, SMR * 128, p <0.05,
Power e 100 percent), and violent deaths (206 observed, 176.07 expected, SMR =
117, p <0.05). While the highest risk of death among short-term workers was
from violent causes of death, the highest risk among those employed for at
least 1 year was from lung cancer. According to the authors, short-term
workers included from 9 of the 13 factories constituted one-third of the
cohort.
Next, the investigators analyzed lung cancer mortality by time since first
exposure and found significant excesses from all causes among those with less
than 10, 10 to 19, and 20 to 29 years since first exposure, all malignant
neoplasms among those with 10 to 19 and 20 to 29 years since first exposure,
and lung cancer among those with 30 or more years since first exposure (29
observed, 16.8 expected, SMR = 173, 95 percent CI = 116, 248, p <0.05, Power =
54 percent), which remained significant even when compared to local rates (19.1
expected, SMR = 152, p <0.05, Power = 57 percent). Although there were no
significant excesses from NMRD, there was only 71 percent power to detect NMRD
among those with 30 or more years since first exposure. Except for lung
cancer, the authors stated that no relationship existed between all malignant
neoplasms and time since first exposure.
When lung cancer mortality compared to both national and local rates was
further analyzed by time since first exposure and by process, significant
excesses were found among glass wool workers (93 observed, 73.3 expected, SMR =
127, p <0.05, Power = 99 percent), especially among those with 30 or more years
since first exposure (17 observed, 9.8 expected, SMR = 173, p <0.05, Power = 40
percent) when compared to national, but not local, rates and among continuous
filament workers with less than 10 years since first exposure compared to
national rates (9 observed, 4.0 expected, SMR = 224, p <0.05, Power = 15
percent). When lung cancer mortality was analyzed by factory and by process,
significant excesses were found in Factory 4 (rock wool) compared to both
national (7 observed, 1.9 expected, SMR * 360, p <0.05) and local rates (2.3
expected, SMR = 300, p <0.05); in Factory 9 (rock wool) compared to local rates
(8 observed, 2.9 expected, SMR = 275, p <0.05); and 1h Factory 10 (glass wool)
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compared to national rates (71 observed, 50.6 expected, SMR = 140,. p <0.05).
When lung cancer mortality was analyzed by occupational category among those
with 20 or more years of latency, investigators found a significant excess
among production/preproduction rock wool workers compared to local rates (11
observed, 5.3 expected, SMR = 209, p <0.05, Power * 28 percent). For glass
wool workers in all job categories combined, • significant excess was found
only when compared to national rates (46 observed, 33.1 expected, SMR = 139,
p <0.05, Power = 81 percent). When the excess lung cancer among rock wool
workers with 20 or more years of latency were analyzed by duration of employ-
ment, a significant excess was found among those employed in early and interme-
diate technological phases compared to both national (21 observed, 10.2
expected, SMR = 206, p <0.05, Power = 37 percent) and local rates (9.4 expected,
SMR s 223, p <0.05, Power = 34 percent), showing a dose-response relation-
ship, particularly among those employed from 1 to 4 years when compared to
local rates (7 observed, 2.7 expected, SMR = 257, p <0.05, Power = 11 percent).
Similarly, when the excess lung cancer among glass wool workers with 20 or more
years of latency was analyzed by duration of employment, significant excesses
were found among those employed from 1 to 4 years (19 observed, 9.7 expected,
SMR = 197, p <0.05) and 10 to 19 years (15 observed, 7.9 expected, SMR = 19C,
p <0.05) only when compared to national rates. All of these deaths occurred
among those first employed in the early and intermediate phases. Those employed
from 1 to 4 years during the early and intermediate phases had a significant
excess only when compared to national rates (19 observed, 10.0 expected, SMR =
191, p <0.05). While sufficient power existed to detect lung cancer among
those with 20 or more years since first exposure, the insufficient power to
.detect lung cancer in each of the duration of employment categories may account
for the absence of trends.
When lung cancer mortality was analyzed by latency and technological
phase, the excess was concentrated among rock wool workers first employed in
the early phase with 30 or more years of latency when compared to local rates
(6 observed, 2.0 expected, SMR * 295, p <0.05, Power « 8 percent). The authors
reported, for those with 20 or more years of latency, a significant decreasing
trend for lung cancer from the early to late technological phases of rock wool
production (chi-square s 6.5 based on national rates and 9.8 based on local
rates). Because none of the SMRs was significant, however, the most that can
be concluded is that the data suggest a trend. For glass wool workers, the
significantly elevated lung cancer was restricted to those first employed in
i..i,. ieoo p-ce, nctcr—nn wnr nunrp f)R CITE
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the intermediate phase with 10 to 19 years of latency compared to national
rates. Only one case of mesothelioma was found. Because referent values were
unavailable, the authors estimated expected values of mesothelioma ranging from
one to three deaths.
In addition to lung cancer, the investigators analyzed bladder cancer by
latency and by process. The Investigators reported a significantly Increasing
trend (p <0.05) with Increasing latency among rock wool workers. Because none
of the SMRs was significant, however, the most that can be concluded is that
the data are suggestive of a trend. Concerning other elevated causes of death,
mortality from laryngeal cancer was not significantly elevated among the total
exposed cohort (9 observed, 6.3 expected, SMR = 143, 95 percent CI « 66, 272).
However, not only did all nine deaths occur 1n male production workers
(Simonato et a!., 1986b), but Simonato et al. (1986c) reported that six of the
nine deaths occurred in the Italian FG wool cohort previously studied by
Bertazzi et al. (1984, 1986). This excess from laryngeal cancer was statisti-
cally significant (6 observed, 1.5 expected, SMR = 400, p <0.05, Power = 8
percent). In the other .plants, there were 3 observed deaths versus 4.8
expected with only 19 percent power. Simonato et al. (1986c) concluded that
these data confirm the previous findings by Bertazzi et al. (1984, 1986) of an
elevated laryngeal cancer risk in this Italian FG wool cohort.
When cancer incidence was examined, a significant excess of buccal
cavity/pharyngeal cancer was found (28 observed, 17.0 expected, SIR ~ 164, 95
percent CI = 109, 238, p <0.05, Power = 57 percent). Analysis of these cases
by latency and by process revealed significant excesses in the rock wool
workers (24 observed, 12.2 expected, SMR = 197, 95 percent, CI = 126, 2S3,
p <0.05, Power = 47 percent), especially among those with 10 to 19 (11 observed,
4.6 expected, SMR = 238, 95 percent CI = 119, 426, p <0.05) and 20 to 29 years
of latency (7 observed, 2.6 expected, SMR = 272, 95 percent CI = 109, 55S,
p <0.05). In the subsequent study, however, Simonato et al. (1987) did not
explain why there were two less observed cases of buccal cavity/pharyngeal
cancer. Nevertheless, the excess remained significant (26 observed, 17.0
expected, SMR = 153, 95 percent CI = 100, 224, p <0.05) especially among those
with 20 to 29 years of latency (9 observed, 3.9 expected, SMR = 231, p <0.05).
Although there were no trends when lung cancer incidence was analyzed by
latency and by process, there was low power in each of the four categories
since first exposure. Similarly, when further analyses were performed by
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technological phase at first exposure, there were no visible trends with such
low power. Moreover, analysis of lung cancer for the few cases where histology
was reported by country did not demonstrate any patterns.
To analyze potentially confounding variables, Simonato et al. (1986c)
presented additional data whereby lung cancer aortality was analyzed in rela-
tion to the use of slag as a raw atatefial, bitumen or pitch as a dust
suppressant, minor use of asbestos in some plants, and formaldehyde.
First, because of potential exposure to arsenic, lung cancer mortality
among rock wool workers was analyzed by latency and by use of slag, especially
copper slag, as a raw material. Although the investigators stated that the use
of slag appeared to be associated with increasing lung cancer mortality after
20 years of latency, the data did not support this claim. In the subsequent
1987 study, this analysis was confined to those with 20 or more years of
latency. Simonato et al. (1987) found an increased risk of lung cancer among
those with 20 or more years since first exposure to rock wool during the use of
slag (23 observed, 12.2 expected, SMR = 189, 95 percent CI « 120, 283,
p <0.005), especially ««*ong t^o*e -witt, 30 cr inort ye-ars since first exposure
(9 observed, 3.5 expectad, SMR = 254, 95 percent CI « 116, 481, p <0.0 1) and
among those with 20 or acre years since first exposure during the use of slag
without copper (18 observed, 10.2 expected, SMR « 176, 95 percent CI = 104,
278, p <0.05). Furthermore, when Simonato «t al. (1987) examined the use of
slag as a raw material during the early technological phase, there was a
significant excess of lung cancer among workers in factories with limited or no
use of slag (6 observed, 1.8 expected, SMR = 341, p <0.0 1), but not in those
factories which used only slag as a raw material (4 observed, 1.4 expected,
SMR = 295).
Second, because of potential exposure to polycyclic aromatic hydrocarbons,
lung cancer mortality was analyzed by latency and use of bitumen as a dust
suppressant. Although the investigators claimed that there was no clear
difference with or without the presence of bitumen after 20 years of latency in
either rock wool or -glass wool workers, among glass wool workers with potential
exposure to bitumen, there was a significant excess of lung cancer (56 observed,
38.5 expected, SMR = 145, 95 percent CI = 110, 189, p <0.05), especially among
those with 10 to 19 years of latency (23 observed, 12.8 expected, SMR = 183, 95
percent, CI = 114, 270, p <0.05). In the subsequent 1987 study where this
analysis was confined to those with 20 or more years of latency, no significant
excesses were found (Simonato et al., 1987).
+ i+i*r** f\ f^ nn J» tTT_ _r\^ *ir«T rsitnTr Att ^ T TT
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Third, when lung cancer and potential exposure to asbestos were examined,
there was a significant excess among rock wool workers with 30 or more years of
latency without the potential presence of asbestos (10 observed, 4.6 expected,
SMR = 218, 95 percent CI = 105, 401, p <0.05) and increasing SMRs with increas-
ing latency in the same group. In the subsequent study, the excess was slightly
higher (SMR « 242, p <0.01) when confined to those with 20 or more years of
latency (Simonato et a!., 1987). A similar excess was apparent in glass wool
workers (17 observed, 9.4 expected, SMR * 181, 95 percent CI = 105, 290,
p <0.05). One would expect to observe these excesses because the presence of
asbestos was a criterion for excluding a plant from participating in the study.
However, in the subsequent study, this excess was no longer significant (SMR =
142) when analysis was restricted to those with 20 or more years since first
exposure (Simonato et al., 1987).
Finally, the investigators examined the potential effect of formaldehyde
on lung cancer mortality and found no excess mortality among those with high
(up to 5 pptn) or intermediate levels of formaldehyde. In fact, a significant
excess was seen among those with low levels of exposure to formaldehyde (61
observed, 62.13 expected, SMR = 130, 95 percent CI « 104, 162, p <0.05),
especially those with 10 to 19 years of latency (38 observed, 22.6 expected,
SMR = 168, 95 percent CI = 119, 231) and those never exposed with 30 or more
years of latency (11 observed, 5.2 expected, SMR = 208, 95 percent CI = 104,
373, p <0.05). However, in the subsequent study where this analysis was
confined to those with 20 or more years of latency, no significant excesses
were found (Simonato et al., 1987).
The investigators concluded the following: (1) no excess mortality from
NMRO was found in any of three production processes; (2) an elevated mortality
.from lung cancer was associated with employment during the early technological
phase of rock wool production (exposures such as smoking or previous employment
were unlikely to account for this excess); (3) the concentration of a lung
cancer excess in the group with the potential for highest levels of MMMF dust
Indicates that the association may be of a causal nature; (4) since respirable
fibers were a significant component of workroom air, 1t 1s possible that MMMF
exposure during the early production phase of rock wool, either alone or in
combination with other factors, may have contributed to the observed lung
cancer excess (no excess was observed after the full introduction of dust
suppressants); (5) there was no excess of the same magnitude in glass wool
workers; and (6) there is no evidence of an increased risk of mesothelioma.
i ooo
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The limitations listed for the previous study (Simonato et al., 1986a)
such as low power in wany subcategon'es, are pertinent here as well. With
improved ascertainment of cause of death from death certificates and additional
followup, additional lung cancer deaths among glass wool workers might be
detected.
Two additional epidemiologies! studies were conducted in European workers.
These studies were not part of the category of European cohorts reviewed by
Saracci et al. (1984) and Simonato tt al. (1986a,b,c, 1987).
Moultn et al. (1986) conducted a historical prospective morbidity study
with 1374 active or retired male employees who had worked in a French FG wool
plant for at least 1 year between January 1, 1975, and December 31, 1984. From
company records, the investigators assembled the cohort and reconstituted
workers' occupational histories in the factory from date of hire. After
computing person-years at risk of dying for this period, the expected numbers
of cancer cases for calculating SIRs were derived from French regional age,
sex, and calendar-specific cancer incidence rates for 5-year age groups for the
period 1975 through 1984. Cancer cases in this cohort were identified from the
company's social insurance records. Diagnoses were ascertained by histologies!
reports, hospital records, or from attending physicians' reports. Of the 1374
cohort members, 101 (7.35 percent) were lost to followup. These individuals
were considered to be alive and contributed to person-years through 1984.
Cancer cases were coded according to the 8th Revision of the ICO.
Production at this FG thermal insulation factory started in 1940. The
manufacturing processes generate discontinuous FG fibers coated with a
thermosetting binder consisting of water, phenol, formaldehyde, ammonia, urea,
and oil. The mean diameter of the fibers produced at this factory is 6.4 uir,;
30 percent have diameters less than 3 pm, and 10 percent have diameters less
than 1 urn. Two exposure monitoring surveys performed 1n 1981 identified
occupational groups according to place of work. Results of personal monitoring
samples from the exposure monitoring surveys showed low fiber concentrations:
the average respirable fiber concentrations were less than 0.2 fibers/cm .
Tobacco consumption was estimated from Information on 966 active employees in
1983. No data on alcohol consumption could be obtained.
In 1984, the mean age of the cohort was 44.4 years (SO = 11.3), the mean
length of employment was 16.6 years (SO s 8.8), and 25 percent of the
person-years had accrued among those with 20 or more years since first employ-
ment. Results of the inquiry on tobacco consumption indicated no difference in
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tobacco consumption between the cohort and the French male population of the
same age in 1979 and no differences inside the factory according to occupation.
Of 41 cancer cases identified among the 1374 cohort members, 19 were
located in the upper respiratory or alimentary tract. Histopathological
reports available for six cases found squamous cell carcinomas. Of these 19
cancer cases, 9 were buccal cavity cancers, 5 were pharyngeal cancers, and 5
were laryngeal cancers. Compared to French regional cancer incidence rates,
there was a significant excess of upper respiratory and alimentary tract
cancers (19 observed, 8.71 expected, SIR * 218, 95 percent CI = 131, 341,
p <0.005, Power = 33 percent), particularly from buccal cavity and pharyngeal
cancers (14 observed, 4.41 expected, SIR * 317, p <0.001, Power = 22 percent).
When the upper respiratory and alimentary tract cancers were examined by
specific cancer site, there was a significantly elevated incidence of buccal
cavity cancer (9 observed, 2.99 expected, SIR = 301, p <0.005, Power = 17
percent). However, the increased incidences of laryngeal cancer (5 observed,
2.17 expected, SIR - 230, Power = 11 percent) and pharyngeal cancer (5 observed,
3.57 expected, SIR = 140, Power = 17 percent) were not significantly elevated,
perhaps due to low power to detect tumors at these sites. In addition, although
there was no significantly elevated lung cancer incidence, the power to detect
lung cancer in this cohort was only 32 percent.
When the cohort was divided into administrative staff, maintenance staff,
and production workers, the excesses of upper respiratory and alimentary tract
cancers were confined to production workers, particularly among those exposed
for more than 10 years (Table 8-4).
The investigators concluded that (1) a significant excess of cancer of the
upper respiratory and alimentary tract was observed, which appears to be
associated with duration of exposure to FG wool; (2) the excess may be underes-
timated because of the 101 workers lost to followup; and (3) the increase in
cancer incidence cannot be explained by an excess of alcohol or tobacco
consumption.
The evidence of a causal relationship between upper respiratory and
alimentary tract cancers and exposure to FG wool was strengthened by data on
smoking histories that indicated no significant differences 1n tobacco consump-
tion between the cohort and the French male population or between different
segments within the cohort itself. Despite low power to detect a 1.5-fold risk
of buccal cavity cancer, there was a significant excess of cancer from this
site alone. All other studies have reported observed and expected deaths from
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TABLE 8-4. CANCER INCIDENCE ANALYSIS BY SITE AND
DURATION OF EXPOSURE
JJpj>er respiratory and alimentary tract cancers
Group
Administrative staff
Maintenance staff
Production workers
Unexposed
Exposed 1-9 years
Exposed 10-19 years
Exposed >70 years
Total
Observed
.
1
1
3
7
7
19
Expected
••
1.41
0.60
1.49
2.30
2.10
8.71
SIR
0
71
167
202
304**
333***
218***
95% CI
0-461
2-398
4-929
41-584
122-627
134-687
131-341
Power (X.)
•
6
6
6
14
10
33
""Significantly different from regional cancer incidence rates: p <0.01.
***Significantly different from regional cancer incidence rates: p <0.005.
Source: Moulin et el. (1986).
the combined category of buccal cavity and pharyngeal cancers. In addition, as
the investigators pointed out, the large number of workers lost to followup
(7.4 percent) might account' for an underestimation of the true risk of laryngeal
and pharyngeal cancers. However, this also holds true for lung cancer anc may
account for the absence of a significant excess of cancer from this site.
Engholm et al. (1987) conducted a historical prospective mortality and
morbidity study and a nested case-control study designed to control for con-
founding variables, such as asbestos and silica exposures, smoking, and popula-
tion density. The cohort consisted of 135,026 male Swedish construction
workers who had first participated in regular health examinations from 1S71
through 1974. It was estimated that approximately 80 percent of all workers
undergo such examinations. There was no discussion of past or present exposure
levels to MMMF. Expected numbers of death were based on mortality statistics
for Sweden by age, sex, cause of death, and calendar year. Expected numbers of
cancer incidence were based on rates for Sweden by age, sex, cancer diagnosis,
and calendar year.
Vital status was determined through record linkage of computerized data
bases. The cohort was followed for mortality to December 31, 1983, and for
cancer morbidity to December 31, 1982, by linkage to the Swedish national vital
statistics file and the Swedish Cancer Registry. The average followup for
mortality was 10.4 years and for cancer morbidity was 9.4 years. The 8th
TQRR
8-71
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Revision of the ICD was used to code mortality, and the 7th Revision was used
for cancer morbidity.
By the end of the mortality followup period, December 31,. 1983, 127,009
(94.1 percent) of the 135,026 cohort members were alive; 7,356 (5.4 percent)
had died. Eleven subjects lost to followup were excluded from analysis. It
1s unclear whether the 661 (0.5 percent) emigrants accrued person-years or
whether they were excluded from analysis.
Overall mortality 1n this cohort was significantly less than in the
general Swedish population (7,356 observed, 10,896 expected, SMR * 68, 95
percent CI = 66, 69, p <0.05). The healthy worker effect was further demon-
strated by the significantly lower deaths from all cancers (2153 observed, 2553
expected, SMR = 84, 95 percent CI * 81, 88, p <0.05), lung cancer (444 observed,
513 expected, SMR * 86, 95 percent CI « 79, 95, p <0.05), and NMRD (193
observed, 418 expected, SMR = 46, 95 percent CI = 40, 53, p <0.05). For
overall mortality and for each of the above causes of death, there was 100
percent power to detect a 50 percent increase in mortality. The only signifi-
cant excess was from industrial accidents (data not reported).
When cancer incidence was examined, there was a significant deficit from
all cancers (3910 observed, 4067 expected, SIR = 94, 95 percent CI = 91, 97,
p <0.05, Power = 100 percent), but a significant excess from cancers of the
pleura, all of which were classified by the Cancer Registry as mesotheliomas
(23 observed, 11 expected, SIR = 213, 95 percent CI * 135, 320, p <0.05, Power
= 39 percent).
In the nested case-control study, cases were all subjects who after a
first health examination had been diagnosed with primary cancer of the respira-
tory system. For each of the 518 cases, five controls were selected from among
those who had not developed respiratory cancer with Individual matching for age
and year of first examination. Controls were selected from a file of all
subjects who had developed respiratory cancer, sorted by year of first examina-
tion, and by date of birth. For each case, controls were first selected at
random from among those with the same year of examination and year of birth and
alive up to the time of diagnosis of respiratory cancer in the corresponding
case. Where five controls could not be found in this group, controls were
drawn from those born 1 year earlier than the case. A subject could be
selected as a control for only one case. Cases and controls were then classi-
fied into categories based on self-reported exposure to MMMF and asbestos and
on estimates of average intensity of exposure to MMMF and asbestos in 160
July 1988 6-72 DRAFT—DO NOT QUOTE OR CITE
-------
different types of construction tasks. To control for confounding variables,
detailed smoking habit Information was obtained and each subject was classified
according to population density.
A total of 18 cases of Individuals diagnosed with a primary tumor of the
respiratory tract included 23 cases of mesothelioma and 424 cases of lung
cancer; 16 subjects diagnosed with lung cancer following primary diagnosis of
another cancer were excluded. These Investigators found that neither
self-reported exposure to HMMF nor exposure to asbestos was associated with
lung cancer. In fact, subjects in the cohort appeared to have been unaware of
their exposure to asbestos. The strong association between asbestos exposure
and MMMF exposure made it difficult to separate the effects of the two expo-
sures upon respiratory cancer. Subjects categorized as heavily exposed to MMMF
did not have a significantly higher incidence of respiratory cancer than
unexposed subjects. The investigators concluded that the results did not
support a relationship between MMMF and increased risk of lung cancer. Because
the risk appeared to be related to asbestos exposure rather than to MMMF
exposure, they concluded that the results appeared compatible with the known
effect of asbestos exposure on lung cancer incidence.
Although there appeared to be a high degree of followup, failure to
determine the vital status of the 661 emigrants could result in an underestima-
tion of the risk of lung cancer and NMRD. Furthermore, additional deaths or
tumors could have occurred among 20 percent of the construction workers who
chose not to participate in the regular health examinations, thereby further
underestimating the risk of lung cancer and NMRD. These potential biases were
minimized, however, because even though only 5 percent of the cohort had died,
there was sufficient power to have detected excesses from lung cancer and NMRD
in this cohort.
8.1.1.2.4 Epidemiological study combining U.S.. Canadian, and European workers.
In an overview of the hazards of MMMF following exposure in U.S., Canadian, and
European workers, Doll (1987) collated the results from the three major cohorts
of MMMF workers previously studied by Enter!ine et al. (1987), Shannon et al.
(1987), and Saracci et al. (1984) and Simonato et al. (1987). Taken together,
these studies provide data on 7,682 deaths In 41,185 workers in the U.S.,
Canada, and Europe, many of whom were first employed in the 1940s. To include
workers with presumed exposure to MMMF in production plants, i.e., production
and maintenance employees, Doll (1987) excluded office workers, who had previ-
ously been included in the Canadian cohort. Because the European work force
July 1988 8-73 DRAFT—DO NOT QUOTE OR CITE
-------
included women and because it was not possible to determine men and women
employed in European plants for more than 1 year, Doll (1987) excluded
short-term workers, i.e., those exposed for less than 1 year. This served to
make the European data more comparable with the U.S. data. Expected deaths
were based on national or local rates when available for the U.S. and European
cohorts and provincial rates for the Canadian cohort. Doll (1987) pointed out
that the SMRs for specific causes of death were low because expected deaths
prior to 1950 were based on the national mortality rates for the early 1950s.
This resulted in a potential underestimate of causes of death that became more
common, such as lung cancer, and a potential underestimate of diseases that
became less common (Doll, 1987).
All workers included in the study were observed for at least 5 years. Of
the 41,185 workers, 7,862 (19 percent) had died. According to Doll (1987), all
three studies succeeded in determining the mortality experience of 96 percent
of the defined populations, i.e., 4 percent were lost to followup. Death
certificates were obtained for all but 191 (2.4 percent) of the 7862 decedents.
U.S., Canadian, and European workers experienced mortality rates similar
to those expected for all causes, cancers other than lung cancer, and nonmalig-
nant diseases other than NMRD (Table 8-5). Lung cancer mortality, however, was
significantly elevated for the U.S. cohort compared to national rates (SKR =
116), for the Canadian cohort compared to provincial rates (SMR = 174), for the
European cohort compared to national rates (SMR * 128), and for the three
cohorts combined (SMR = 121).
To control for potentially confounding variables, such as smoking and
other etiological agents that may vary with geography, Doll (1987) used local
mortality rates available for the U.S. and European cohorts to calculate
expected deaths (Table 8-6). When compared to local rates, the excess lung
cancer mortality was reduced below the level of significance for the U.S. and
the European cohorts but remained significantly elevated for the combined U.S.
and European cohorts (SMR * 109).
Next, Doll (1987) analyzed the lung cancer mortality by process, i.e.,
rock wool or slag wool (MW), fibrous glass wool (FG wool), or continuous
fibrous glass filament (continuous FG filament). For this analysis, Doll (1967)
categorized U.S. workers in plants where both FG wool and continuous FG fila-
ment were made concurrently with workers making FG wool only. It appears that
July 1988 8-74 DRAFT—DO NOT QUOTE OR CITE
-------
smart? cw»sr-swrinr wmiAiHv 'on Nmniir.MnN wtwKiir, tnnN tin H.V. tANAniAN. uranrtAN. AWI cnmimf> conoirts
United Stales C.uia.l.i
ise of death Ohs.
causes 4906
>q canter 3/0
wr raiMrrrs
'ticliiiliixi lour
•snlhel ionias) 677
«er respiratory
isease 314
ler disease 30/5
lernal causes 405
-------
the greatest risk of lung cancer appears in MW workers (SMR = 128, p <0.01), an
intermediate, nonsignificant risk in FG wool workers (SMR = 110), and an
absence of risk in continuous FG filament workers (SMR « 93; see Table 8-7).
To determine whether the lung cancer excess could be ascribed to occupa-
tional hazards, lung cancer mortality in the three cohorts was analyzed by
process and time since first exposure (Table 8-8). Compared to local rates,
there was a significant excess of lung cancer among MW workers for all periods
since first exposure (SMR = 128, p <0.01), particularly among those with 30 or
more years since first exposure (SMR = 148, p <0.05).
To compare relative excesses among those holding different jobs within a
plant, Doll (198?) presented data from Enterline et al. (1987) on respiratory
cancer among workers exposed to small-diameter FG fibers compared to those in
the same plants, as well as those employed in other FG plants, not exposed to
small-diameter FG fibers. No significant excesses were found among those
TABLE 8-6. COMPARISON BETWEEN U.S. AND EUROPEAN SMRs FOR LUNG
CANCER DERIVED FROM NATIONAL AND LOCAL RATES
Cohort
location
U.S.
Europe
Combined
Observed
deaths
370
189a
559
National
Expected
deaths
319
151
470
Rates
SMR
116**
125**
119***
Local Rates
Expected
deaths
339
172
513
SMR
109
110
109*
alncludes those with less than 1 year of employment.
*Significantly different from comparison group: p <0.05.
**Significantly different from comparison group: p <0.01.
***Significantly different from comparison group: p <0.001.
Source: Doll (1987).
exposed to small-diameter fibers, and no increasing trends of respiratory
cancer were associated with increasing time since first exposure when compared
to local rates (Table 8-9). However, the small number of deaths (22 observed)
and insufficient power (57 percent) to detect respiratory cancer among those
exposed to small-diameter fibers precluded meaningful analysis of these data.
July 1988 8-76 DRAFT—DO NOT QUOTE OR CITE
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tMUl fl-r. HINT. CANTIR WIRIAI IIY ItY PHOtl S%
Rock or Slag Wool
ml
it inn Otis.
iria
e
l» 1 ant s
<|t. SM«
74 YO
HI. 9
90. 1
144 . %
or,
01
l»9
l/4»
KM
III)
Pnwf r
too
i;
inn
iwi
(III', (up.
r.4 r.'i 6
..
IS 15. 5
f> 114 9
il.HW»nts
SMR
9?
--
9/
91
(X)
98
..
55
99
•ce: Doll (1987)
1AHIE fl-fl.
irs
n e
•si
'Mire
0
19
?'
r
per i ods
Obs.
19
43
4?
37
141
HINT. CANCER MORI All IV
Rock or
E«p.
in. 6
33.1
33.6
75.0
110. Z
Slag Wool
SMR
10?
130
175
148*
i?a"
AMONG THE
Power
(X)
60
81
83
74
100
iiinrf coMntNio COINIRIS nv
Otis.
76
88
140
175
1/9
Proress
1 ilirmis (ilA
f«P
37 I
77.9
179. f.
105 0
344.5
PROCISS ANO
ss Won!
SMH
ni
113
Km
119
no
Power
(*)
/4
99
too
inn
ion
1IHI SINCE rtRSI
Glass E
obs. r»p.
IS 10.9
1', 74.6
Jh 37.4
11 If. 5
79 H5.0
EXPOSURE
llanenls
SNR
138
61
111
79
93
Power
(X)
„
71
76
59
100
;pir*t«ry cancer for U.S. plants.
iqntricantly different fro* local »orlallty rate*: p <0.05.
i«|nificatitly different fro* local Mortality rates: p
-------
tAmr ni BISNRAKWV r.wir.m MINIM m nv IXI-OMIRI in '.MAIJ-IHAMMIN WAV, wmii nnrns ANII tint Mucr HUM IMPIOVMNI
Ivpr exposed in
•••» niip nf four plants MitufKluHmf Movri- r»piiM-s. I «p '.MH (t) 01.s Op. SMR (X) Obs. l«p SHU (t)
10 I I M f.1 II -
II / S.«1 17H ?l -
"> n / ».? iii'i 3f. -
• h 3.01 |9fl IB -
?? II. 1 |?4 5; mi I7S ? I OS 100
::•»: I>«M (I9W7); pKpPclprt values for respiratory canrrr t.,i-,c(l mi lo«..il imirt.il il.y r.il«-s.
-
-
-
119
4?
96
9/
94 ?4S
39.fi
nn.r
H/.4
2?6.9
lor.
ion
in
ion
im
ion
ino
too
-------
To compare relative excesses of lung cancer among those exposed to differ-
ent amounts of MMMF, Doll (1987) presented data from Simonato et al. (1987) in
which significantly elevated SMRs were found in workers employed in the early
and intermediate technological phases of the MW industry (21 observed, 9.4
expected, SMR * 223, p
-------
tAtiir n-in siilctrn tAMrin MOIMAIIIY urn u.v Ktm MMIOPMN r.oiicwis
Mle
a
iiral cavity/
'iiaryttx
i»|>httf]iis
.nmach
iliin
•i linn
nynx
os 1 ate
l.idili-r
>nrs
•itl«>*i a
liter lymphatic
.mil lii'm.ilo-
Itoielic
,i
Ofos.
370
35
75
47
81
36
15
68
79
2
35
68
f.p
319
?8. T
71.9
43.5
91.0
30.8
14.4
63.6
77.6
5.7
38.9
57.1
SMR
II6«*
17?
114
108
89
117
104
107
105
35
90
119
P
100
t
75
65
91
99
80
41
97
7?
74
88
96
Ol.s
189
11
14
f,4
37
3.1
1
31
74
r,
I/
33
1.,..
IM 7
10.6
II 0
Ml II
10 7
77.0
(>. 3
31.4
17.9
1.1
71 1
79.5
'.Mil
175"
171
KIM
'II
91
177
M.I
91
1 11
IM
HO
II7
P
lim
41
49
'III
ll'l
/I
74
117
59
71
66
76
Dliv
559
40
.19
III
tin
!>')
74
99
5.1
8
57
101
I.,,.
4/07
39 3
14.0
117. 1
111. 1
58 0
70. 7
97 1
45. .1
9.6
60 5
86 3
'.Mil
118-**
177
117
99
90
119
116
102
117
8.1
86
117
P
100
Rfl
87
100
100
96
67
99
97
37
97
99
i ohorl includes those employed less than I year; U.S. anil I uri»|MMn exper.trd vslup% lor limq cancer based
on national rales.
**Si(|nif icanlly different frow CMpartson group p <0.0).
**Sii|nif icantly different fro» conparison group p
-------
IAIIII n n MnniAtm i ROM NMRti nv cmmnl
Cause of Oe.ilh
Acute upper respiratory
inter V. inn
Influrn/a ami pneumonia
other respiratory
disease (includinn,
piMMMMx: on i os i s )
(Ironed it is, emphysema.
and asthma
All NHRD
United States
|>
Obs. fxp. SHR (*.)
--
B4 109. 1 77* 100
730 174.7 13?" 10(1
314 787.8 111 100
1 .m.iil.l | nrni
P
Otis. l»|i SHR (1) 01. s. tup.
7 75
1 5.f. in»* 7.1 7J 75. J
74 M.I
1 7.4 171 If. Mi 7.1.3
4 fl.7 4T .IS Ifi5 lfi!»
1*
SHR
80
97
170*
.<
90
100
P
(t)
18
99
46
99
100
If S. ami flirope combined
~ ' ' •"••' P
Ohs. t«p. SHR (X)
-
157 184. 7 85 ion
370 767.3 177'" 100
479 447.7 107 |OO
*%ii|iti f iranlly di((rr«nt fro« national norlality rates fnr llii> llnltril States ami I nrope ami nrnvlncial •orlallly rates for Canada: p <0.05.
**Sii|nificantly different fro«i national Mortality rales for tli« United St.ilrs and liirnp* and provincial •ortallly rates for Canada: p <0.01.
•"•Sii|ni f itanl ly different Iron national Mortality rates for the United Sidles ami furnpe and provincial mortality rates for Canada: p
-------
of respirable fibers were probably tenfold higher than current levels. Con-
cerning asbestos exposure as a confounding variable, Doll (1987) stated that
because neither excesses of lung cancers nor mesotheliomas were found among
those employed when asbestos exposure was most likely to have occurred, asbestos
is not likely to have accounted for the excess lung cancer in MW workers.
While other carcinogens may have been present, 1t fs unclear to what extent
they could have accounted for the difference between MW and FW workers. In
addition, it was not possible to determine the confounding effects of bitumen
and mineral oil, arsenic in slag, and polycyclic aromatic hydrocarbons from
furnaces upon the excess lung cancer observed in MW workers.
Conflicting evidence exists regarding the relationship between exposure to
MMMF and respiratory disease. In favor of a causal relationship between MMMF
and lung cancer, Doll (1967) pointed out the positive animal data, the gradient
of fiber counts in MW, FG wool, and continuous FG filament, and the higher
mortality among FG workers exposed to small-diameter fibers compared to those
who were not. Against a causal relationship are the failure to observe a
relationship between risk and duration of employment, lack of clear evidence of
a quantitative relationship between mortality and estimated cumulative dose,
and low level of fiber counts in the workplace. Doll (1987) concluded that
(1) the risk of lung cancer among those employed in the early periods of MW and
FG wool sectors of MMMF production is 25 percent above that expected after 30
years since first employment; (2) the risk of lung cancer is greater in the MW
than in the FG industry; (3) no risk of lung cancer was demonstrated in the
continuous FG filament sector; (4) a variety of carcinogens might have contrib-
uted to the lung cancer hazard; (5) uncertainty of fiber counts in the early
production periods and the extent of the contribution of other carcinogens
precludes a precise quantitative estimate of the likely effect of exposure to
current fiber levels; (6) no specific hazard other than lung cancer has been
established; and (7) MMMF are less carcinogenic than asbestos fibers.
However, nonsignificant increases from lung cancer based on small numbers
of deaths and low power preclude the purported greater risk of lung cancer
among those exposed to small-diameter FG fibers. Similarly, the small numbers
of deaths and low power preclude Doll's claim that no risk exists in the
continuous FG filament sector. In addition, the low power to detect NMRD in
the Canadian cohort contributed to the inability to detect a hazard from NMRD.
Despite the significant excesses from other respiratory disease in the combined
.i,.iv, IP** 8-82 DRAFT—DO NOT QUOTE OR CITE
-------
U.S./European cohort, it is unclear why Doll (1987) concluded that no NMRD risk
exists. Aside from the limitations discussed above, the healthy worker effect
in this study was minimized by a long observation period.
8.1.1.2.5 Integration of human health effects data by fiber and by carcinogenic
and noncarcinogenic effects. Table 8-12 summarizes the najor epidemiological
studies available on MMMF, placing special emphasis upon malignant and nonmalig-
nant respiratory disease (NMRD). All of these studies are historical pros-
pective in design and have been critically reviewed and analyzed above in
depth.
Concerning noncarcinogenic effects following exposure of workers to
microfibers (fine-diameter FG, i.e., <1 un> in diameter), Enterline et al.
(1983) found an excess of NMRD among workers never exposed to microfibers
(SMR = 130.1, p <0.05), especially among those in Plant 9 (SMR = 136.4,
p <0.05). The apparent absence of a nonmalignant respiratory disease risk
among those ever exposed to microfibers was from small numbers of NMRD deaths
and insufficient power to detect a 50 percent increased risk of NMRD. In a
followup study, Enterline et al. (1986) again found that en excess of NMRD was
concentrated among those never exposed to microfibers (SMR = 133.5, p <0.01).
Bayliss et al. (1976) evaluated the pathogenicity of microfibers in a nested
case-control study of NMRD. There was no association between cases of NMRD and
work in operations involving exposure to microfibers. Thus, it appears that
there was no association between NMRD and exposure to microfibers. In the few
available studies that explored noncarcinogenic effects following exposure to
microfibers, the small number of deaths among those ever exposed contributed to
the low power to detect NMRD in that group.
Concerning noncarcinogenic effects following exposure to respirable glass
fibers (FG wool <3 urn 1>n diameter), Enterline et al. (1983) found excess NMRD
among those employed in FG wool and continuous FG filament plants combined (SMR
= 129.6, p <0.01), which increased after 20 or more years of latency (SMR =
135.5, p <0.01). The highest risk of NMRD (SMR * 136.1, p <0.05), was found in
those with the lowest cumulative exposure to respirable FG fibers, i.e.,
2.14 fibers/cm -month. This seems to indicate that there was no association
between NMRD and exposure to FG wool and/or continuous FG filament. In the
followup study, Enterline et al. (1986) found a slightly higher excess from
NMRD in plants that produced FG wool and continuous FG filament after 20 or
more years of latency (SMR = 141.8, p <0.01). The low power to detect NMRD in
individual plants may have precluded detecting NMRD in these studies. Bayliss
July 1988 8-83 DRAFT—DO NOT QUOTE OR CITE
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I iftatnrs
I I her
I i nr and
'» (I'm?}
line el al.
MW and FG
n-i? SUMMARY nr rARtiNotiiMit AND NONrAPr.iNnr.rNlr Uriels mi*
PlNIM'f CIIVI MOHIIIIIIIY AMI) HdMIAIIIY MllHM S IN WIIHKI RS I xl'OSI II III
Cohort si/r and
minimum iluYatioti
of exposure
Mi-.ui I ilii-r
Invi-ls
(I il.rrAm')
7049 male production
and maintenance
workers employed
for at (past. I ye.ir
(6 monlhs for llmsn
in Iwn plants
exposed to tine-
diameler 1C)
16,/SO Male produc-
tion and n«inlpnancp
workers (l.fUf, MW;
I4.RR4 TO) rm|ilnyrd
(or at least 1 ypar
(6 months for those
in two plants
to fine-dianeter
II. Jin lor MW;
(Ml? I lor Hi
Mean ciimilat ive exposure
{I iher/em" •mntlis):
SJ 71. for MW, 4.47 for If,
tare Inoifenic endpolnl*
Ixiess of respiratory syste*
t:ancer (site-specific cancers
not reported) limited to
Plant /. Increased risk was
cfreater amonq those with ?0
or more years since first
exposure |ntficant excess for
combined MW and FG workers.
Noncarc Inoitenlc
enilpnints
None delected.
[xcess nf NMRO in
combined MW and 1C.
workers (SMR = 1.1?. 1")
appeared unchanged
after 20 or metre years
since first employment
(SMR = 1.37. !••).
1C wool and
1C. filament
Ixcess of respiratory system
cancers (site-specific cancers
not re-reported) found In MW
workers (SMB = 160.!»•). luces*
was qreatest In Plant 7 (SMR =
4M.J") and Increased 70 or
more years since first employ-
ment (SMR-fl6B.5**). the highest
risk occurred In those with 21.B8
to 99.99 fiber/cn'-months of
cumulative exposure to resplrable
MW fihers (SMR = 178.2«).
None delected.
Excess of NMRO In MW
plant 3 (SMR = ?2I«)
appeared unchanged
after 20 or more years
since first employment
(SMR - 219.9*).
Excess of NMRO In all FG
planls (SMR = 129.6")
Increased after 20 or
•ore years since lirst
employment (SMR =
I.1S.S**). Ihe hlohesl
risk of NMRD (SMR -
13n.I*) was found in
those with lowrst
exposure to rpspiralile
1C, fillers. <2. M
f ibers/c.m^-monlhs.
(continued on the following paqe)
-------
1MIII n 17 (r.nnliniHMl)
Invesl iq.tlnrs
Interline pt al.
(U.S.)
(ti.nt. )
Cohort sire ami
• iniwM ilnral inn
f lh?r of exposure
IG fine dlaaeler 6 (mnths «iini«nini
duration of pw)ili>y-
•ent tor those in
two plants
HP.III fil.ri
I.-V.-I-.
|l ilwr/im'
Iliter Iine p|
( 11111,)
(H. V)
at.
MW and fG
on
i
CO
en
fG wool and
IG filament
rr. rine-
16.661 nalr produc-
tion antt •ainfrii.tricp
workers raploypit lor
at Ipast I y«-.>r (f.
«mnth« tor thnsp in
two plants
to
fG).
Not fi*piiff.pil
6 Month*
duration of p«i|>lfiy-
•pnt for those in
two plants
t.irtlnof|enlc endpolnt*
None
of respiratory tystc*
cancer (SMR = IIS. 6**) Increased
altrr 70 or Mire years after
since first exposure (SHU =
fxcess of lung cancer (SMI «
IK.*) Increased after 20 or
•ore years since first exposure
(SUB = m.«").
txcess of respiratory tystew
cancer found in IW workers
after fO or anre years since
first exposure (SUB « M6. I*).
fur.ess was greater anong those
MM workers with 30 *ore years
since first exposure (SMI =
I5I./M.
F»cess of respiratory systea
cancer after 20 or More years
since first exposure (SHR -
129.%*). Slonlficant
increasino trend of SHBs with
increaslnq latency; excess
aoomi those with 30 or awre
years since first exposure
(SMI - 137.0**) increased
after 20 to 29 years of
e«|>loyiwnt (SHR = 160.1*).
Nonp rfptpcled.
MoncarcInoqenlc
erw (points
(xcess of NNRO l
to fG workers nevpr
exposed to I Inp-iliameler
fG (SMP = 130. I*).
especially thoip in
Plant 9 (SMS = 1.16.4*).
Iherefore. no associa-
tion between NMRD and
f ine-diaaeler filters.
(xcess of MHffO (SMW =
132.3**) remains
unchanged after 20 or
•ore years since first
exposure
-------
fiber
i*rl inp pi at.
inn
'.S.)
MW and
Cohort sl/e •niil
• I n I KIM duration
nl exposure
(Mill It-1?, (rnnllnupil)
Mr .in I ilipr
ir ve Is
(I ihri/in')
CarclnnctPnlc emfpotntt
Honearclnoi|pnlc
endpoinls
16,f>M m*\r prnilur-
llon ami Maintenance
workers pmploypd (or
at Iras I I yp.»r
(f> i*nnths (or those
in two plants
exposed to (inp-
If.)
p«pnsurp li-wpls:
It; - ll.tll; MW - !.!»
l.rlorr !•»/!,. H 1
IM1f, IIMI. (I. III .liter
I'M.O
0. 3S?
FR wool ami
in filament
0. OVJ
tier I inp Anil
•tiller', on
I I'I/S»
[H S. )
-Insulation"
|rr. wool]
with a mean lpni|lh
of SPrvie* of ypvirs
?.1.< ypars
Not roportpil.
Allpr ?n< ypars of latency,
ol»sprvp«l excpss of respiratory
syslpi* canrpr slqnlfleant
«:niii|>arpd to national rates
C.MH = l?«.3"). but not to
IIM.A! rales (112.3). t«cess
ol liini) cancer after 20* years
of latency siqnlf leant coaipared
to national (SMR = I2S.4**) or
loral rates (112.7"). this
shows lite strength of the
lunq cancer hazard, which
appears to be responsible for
Hie respiratory cancer excess.
I xcess of respiratory tystew oncer
found In MW workers after 20*
ypars of latency significant
compared to national (SMA =
Mr. I**), but not to local rates
(SUB = 130.9). fhe greatest
PKCPSS of respiratory cancer
occurred aamng MW workers
compared to either national
(SHK = I4R.4**) or local rates
(SMR = IJ3.6*). this shows the
respiratory cancer haiard awong
MMMI workers Is concentrated In
the MW suhcohort. •
lucess of respiratory syste*
cancer found after 20 years
significant compared to
national (SMR = 129.S**) but not
local rates (3MM = 110.6).
liicess of respiratory cancer aanng
those with 30* years of latency
siipilf leant compared to national
(SMR = I.1/.8**) but not local
ralPS (SMR = 110.8).
Nonp detected.
txcess of NMRD (SMR =
132. .!••). Ho further
analyses of NMRR.
None detected.
(continued on the following pane)
-------
IW1K n 17. (rontlttupil)
eslli)at«r«
llss ft al.
9/f.)
S. )
Hber
"Insulation"
(ff, wool]
Cohort si/e ami
Minimum dural inn
of exposure
I44B while males
employed for S or
more years
Mfitn 1 ilwr
Inypls
(lil male production
workers employed (or
at .least 1 year
2S76 current and
former male workers
employed for more
than 3 months
2557 current and
former male workers
employed for more
than 3 months
?3Si males without
regard for minimum
duration of employ-
ment: I.BIS (//»)
In one of three MW
plants; S46 (7«)
in one fO plant
Not
l year In any four
plants (SIK = 233*).
None detected.
None deleeled.
None deleeled.
None detected.
None delected.
(continued on the following page)
-------
lAlllf II I? (rnnl iniii-d)
gators
f ihrr
•ii and
>rk (nnr.)
MW
holm and
i|pr (1'JHn)
i-.i)
and Jensen
)
.irk)
MW or fC wool
rl al
.)
PI.II k )
and
it™ ( I'tW,)
I .in.l)
1C wool
Cohort si/c 4i«l
Mi ni mini rlnr.il inn
of exposuYf
3600 male and female
(2HX) p>'odiirlion
employees who had
worked »t leasl
1 year in one of two
MW plants or in a 10
wool p!int
5169 «ale and fewtle
(flX) employee! with-
out regard (or
• iniwMi duration of
e«ploynent
5317 *ale ami fenale
(ftT) pmfiloypp*. with-
out rei|.»ril lor
minimm ittir.il inn of
enpfoynienl.
94| ma IP and fpn.ilp
worlriT < V.il 1 wm-llrr'.
p*i|ilnypil .ls
( 1 ilirr/i «')
Not ic|iorlp eslim.iti
for |i.ist <*»poMirrs
Hot rpported
r.ir« lom|piilc endpnlnls
I »c«".s of intestinal cancer
iui idrnce in MW workers
pn>|ili>ypd >l yi>ar (MR = 196*).
I xi rss nf luiii| cancer inei-
iIt-in I? in one MW plant (rnck
w,,ol) (MR = 799*). which was
wiiri1 prnnniinced when shorl-
Iprn ('I yr) workers were
excluded (SIR = 3n6**).
Ixcrss of lung cancer Incl-
dpnr.c in the three MW ptants
appeared after 70» years since
first exposure (SIR = 199*),
which was concentrated among
those employed for 1 or more
years (SIR = 706*).
Ixcess of lung cancer among those
with I to 4 years of employment
and 30 or more years since first
exposure In MW production (SMR =
HHII""") or in fG wool production
(SMR = 345").
Ixcess of digestive organ/
peritoneum cancer Incidence
amniHf male and female pro-
duction workers during the
first 10 years after Initial
employment (SIR = 15?*).
Excess of lung cancer Incidence
among male and female production
workers after 70 or more years
since first employment (SIR =
?0'l*) was concentrated among
male production workers (SIR =
19V).
Among male production workers.
excess incidence from huccal
i:avily/pharyni|pal cancer (SIR =
710*) and digestive organ cancer
-------
lAlllt n 17 (mnllnued)
itigators
fiber
Cohort si/e and
Minimum duration
of exposure
le and
il/el-Beyme
14)
.1 del-many)
le and
iliel-fleymo
If,)
•st Germany)
HW
ittl el a).
»«»
• ly)
FG wool before
I960; continuous
10 filament after
i960
Mi et
i.)
IV)
al.
fG woof before
I9MI; continuous
1C filament
alter |<»r.O
2096 male prndmlion
and maintenance
employees without
regard for minimum
duration of employ-
menl
2092 male product loo
and mainlenance
employees without
regard for minimum
duration of emplny-
menl
11S8 oale production
workers e«ptoyed at
least 1 year
i098 male firmhirtion
workers eiqiloyrd at
at least I year
Mean 1 ilier
levels
Not reported
Not reported
Resplralile fraction:
II.not to 0.0?3 (median
diamvler 0.) to 0. 1 )«•)
fraction:
II ("I*. I It.018 (median
diam-I.er 0. .1 to O. 7 |IM)
r.arclnoc|«nlc endpolnts
NoncarcInoqenic
endpolnts
I »te-.s of stomach cancer among
production workers after ?0 to
79 years since first employment
(SMH = 2/34).
production and maintenance
workers hired before the intro-
duction of resin binders In 1969.
excesses of stomach cancer after
70 to 79 years since first e«po-
sure (SHU = ?6I«) and lung
cancer after 10 to 19 years
since first exposure (SMA = 272*).
Maintenance workers had • tlgnl-
f leant excess of lung cancer
after 70 to 79 years since first
exposure (SMR = 249*).
Using Internal controls as the
reference group, there was an
increased relative risk fro*
pancreatic cancer (MR = 6.76*).
txcess of larynqeal cancer compared
to national rates (SMR = 400*) but
not local or regional rates.
Compared to local rates, exposure
of taryngeal cancer among those
with 75 or more years of latency
(SMR = 938***). with 20 or more
years of exposure (SMR * 833*).
whose first exposure was before
aue ?S (SMR = 1*3B**). and whose
cumulative exposure was >0. 30
f ibers/cm'-wmths (SMR = 1SOO*").
All four cases were first
employed before I960 when FG wool
ralher than FG filament was
produced, these results show •
consistent, significant Increase
among those most heavily exposed.
Using local rales, excess of
larynqeal cancer among those with
?S or more years of lalency (SMR =
All laryngeal cancer deaths
occurred lielore I'»M> when If. wool
was |irn
-------
lAPIf «- \f. {continued)
(colors
f Ihpr
irr Pt al.
Mi)
I ami-IG wnnl;
Ihprn Irplaitd-
limmtis
.imrnt)
in wool or
continuous fG
I ilament
ace I el al.
'.)»* )
irrnpe )
MM and FG
el
MM ami
I in opp)
Cohort 'sl/P ami
minimum duration
of exposure
4734 Males anil
females (?SX)
employed lor at
least I ypar in
an I no, list* 1C wnnl
factory; 1910 males
and (pica les (.17 «»
employed at any
limp in • Norlliprn
Ireland cont unions
1C filament factory
75.146 »ale and
female and employees
of one of 13 HMHF
plants (7 MM plants.
4 fG wool. ? contin-
uous ff, fllampnt);
for four plants.
those caploypd !p fraction:
' I »;
fl (11 to 0. I
CarctmMienlc endpolnts
Noiw.«rclno<|pnlc
pndpnints
Iirpss of stomach cancer aeong
tltp fpiiiale work force of the
Lnqlish factory compared to
national (SMR = 777*) hut not
local rates. Excess of lung,
cancer aiwinq male production
workers of the English factory
('.MB = 110*) only when compared
to national rates. In this
sa*p qroini, there were some
excesses of lung cancer when
the data were analyied by
latency and duration, but
these were not significant
compared to local rates.
No site-specific cancer
excesses were detected In the
Northern Ireland factory.
When the data fro* all 1) plants
were pooled, compared to
national rates, excess of lung
cancer annmf men with 30 or (rare
years since first employment
(SHR = 1931).
Excess of lung cancer compared
to national but not local rates
(SNR - 175*). Excess of lung
cancer Increased after 30 or
more years since first exposure
to M** compared to cither
national (SMR = 183*) or local
rates (SHU = I5?«).
Excess lung cancer among MM workers
compared to national (SMR = 714*)
and local rates (SHU = 757*) during
the early technological phase.
especially among those with 30 or
more years since first exposure to
MM diirimi the early phase (SMR =
None detected In either
InglIsh or Irish
cohorts.
None detected.
Not applicable because
analysis restricted to
lung cancer mortality.
(continued on the following
-------
I Mil I Ml? (con! I mini)
Htipr
Cohort *!/«• and
minimum dur.it {mi
ol exposure
M«».in I ilii-r
li»v«» Is
(I ilirr/rm')
et
( I 'IW..1 )
(I |.p)
( • tint )
If. wool
rr. wool
Simonaln fl a I.
(i'mr.h.c;
(I urnpi*)
Continuous
IT. filament
MM and
2I.967 male and
female (14. fit) pro-
duction workers;
worker employed ' I
year In four plants
were excluded.
in, i is MM, B.?n6 to
wool, and 3.bM> con-
tinuous fC
workers
<)I>SP in
of
MM
iMK ?/ In /(I
pndpolnt*
Noncarcoints
l«r.pss lunq cancvr aw>ng fC wool
wnrkrrs rmnparpd to national rates
only (SMR = 1?^*). especially
.iminci Ihnsp with 30 or »or« years
sinrp first exposure to 1C wool
(SMH = 113").
fxcess lim«j cancer Mom) FC wool
workers compared to national
ral.ns only during; the Intermediate
tprhnoloqical phase (SMR = 139*),
particularly mong those after
in to 19 years since first
exposure and local rates
(SMR = IS?*), fhe highest risk
of ileath aiming short-tera
workers was from violent causes.
whereas the highest risk amng
those employed for at least
I year was lung cancer.
Increased Incidence of hoccal
ravity/pharyngeal cancer (SIR =
IM*) among production workers
exposed to MMMf, remained
siipiK itanl compared to local
r;il.-% (SIR - IV>«).
(•cess of MMRD among
short-term (employed
-------
(AMI I fl-l? (ronlliuipil)
sliqatnrs
I I her
Cohort slfe .mil
minimum duration
of
Mi« an I iliri
N've Is
(ftl>.-t/<«.'
nato el at.
"Mt.c; I'm/)
rope)
nl )
rr. wool
Carcinogenic enrfpolnts
fxcess of lung cancer In MW
factory 4 compared to national
(SMR = jr.O*) and local rates
(KM)*) and in factory 9 compared
to local rates (SMR = 140*).
Among those with 20 or more
years of latency, excess of lung
cancer in preproduction/
production rock wool workers
compared to local rates (SMR =
711')*). Among workers with ?0 or
more years of latency, excess of
lung cancer during the early and
intermediate phases compared to
national (SMB = 706*) and local
rates (SMR = ??3*). showing a
dose-response relationship of
decreasing SMRs with Increasing
duration of employment, this
lung cancer excess was concen-
trated in rock wool workers first
employed In the early phase
(SMD = ?S/*), particularly among
those with 30 or more year* of
latency (SMR = 295*) compared to
local rates.
txcess Incidence of buccal cav.lly/
pharynqeal cancer was limited to
rock wool workers (SIR * 19?*).
especially among those with 10 to
19 years of latency (SIR = 238")
and 70 to 29 years of latency
(SMR = 2/2").
Ixcess of lung cancer compared to
national rates only (SMR * 177*).
especially among those with 30
or more years since first
exposure (SMR = 1/3*).
Noncarcinoqenlc
emlpoinls
(continued on the following page)
-------
estimator*
iber
Cohort sl/r ami
minimum idir.il ion
of e«|i«Mirr
Mfll I fl-17. (r:nnt innwtf
Mo.ln t ilii-r
li-wrls
(lih.-r/.V)
wtti.lto ft a I.
•iiiMi.r.; inni)
nrn|>f*)
mil. )
fO wool
I In et al.
inr.)
ranee)
Continuous
rfi filament
FC wool
1)74 active or
retired •Ales
••ployed for at
least I year
Respiralilr (railIon:
07 (mr-aii diameter -
6.4 inn; JirX < I |im;
Kit ' I |im)
C*rclnoi|enlc endnolnts
None arc InoqenIc
emlpoints
to national rates, excess
of liini| c.incer United to those
•••tiluypil in the intermediate
l<-(hmilo<|iral phase (SMR = 139*).
p.irt it ul^rly annnq those with
III lo \>) years since first
ritposiire (SMU = I6«s). No
r«i rssrs of lung cancer Mono,
It; workers were found using
local rates, txcess of
larymieal cancer (SHft = 400*)
limited to Male production
workers in an Italian FC wool
cohort. Intension of follow-up
continued previous excess of
larynqeal cancer.
I xcess of lung cancer umony those
with less than 10 years of latency
was significant only when compared
to national rates (SMR = 224*).
Increased Incidence of upper
respiratory and alimentary
tract cancers (SMR = 2I8"«)
particularly buccal cavity/
pharyngeal cancer (SIR =
3 1 /••••) compared to regional
rates. Increased Incidence of
nuccat cavity cancer (SIR -
Not applicable because
study was limited to
cancer incidence.
holm el al.
TO/)
135.0?6 aale SwedUh
construction workers
without reqarrf to
•titralinn of enptny-
•ent
Hot rppnrtPil
Excesses of upper respiratory
and alimentary tract cancers
were confined to production
workers exposed fro* 10 to
19 years (SIR = 304**) or for
20 or more year* (SIR = 3)3***).
Increased Incidence of
mesolhrliomas (SIR = 213*).
None detected.
(continued on the following pane)
-------
Investigators
I iber
Cohnrl sl/f> .«»IIS. Co^iared to local
rales, excess lunq cancer
rcnainerf significantly elevated
lor combined U.S. and European
cohorts
-------
et al. (1976) found an excess of NMRD in U.S. male FG wool workers (SMR = 189,
p <0.05, Power = 34 percent), which increased among those with 10 or more years
of latency (SMR = 200, p <0.01). Several studies, however, were unable to
detect excesses from NMRO even if such excesses did, in fact, exist. These
include Enterline and Henderson (197S), Morgan et •!. (1984), Shannon
-------
to im'crofibers, the small numbers of deaths and low power precluded meaningful
analysis of microfiber exposure and respiratory cancer.
To further explore whether exposure to small-diameter fibers produced in
four different plants was related to an excess of respiratory cancer, Enter!ine
et al. (1986, 1987) examined mortality from respiratory cancer by plant among
those exposed and never exposed. Contrary to expectations, the only signifi-
cant excess of respiratory cancer appeared in workers 1n one plant who were
never exposed to microfibers as compared to national mortality rates (SMR =
120.2, p <0.05). The apparent absence of a respiratory cancer risk among those
ever exposed to microfibers was from small numbers of respiratory cancer deaths
and insufficient power to detect a 50 percent increased risk of respiratory
cancer in this group. When investigators further categorized the respiratory
cancer deaths among those ever exposed to microfibers by both latency and
length of exposure, they found that this analysis supported a causal relation-
ship between exposure to respiratory cancer and microfiber exposure. On the
contrary, because there were too few deaths and insufficient power to permit
meaningful analysis of the data in this manner, the author's hypothesis of a
causal relationship is not supported by the data. In addition, Bayliss et al.
(1976) evaluated the pathogenicity of microfibers in a nested case-control
study of malignant respiratory disease. No association was found between cases
of malignant respiratory disease and work in operations involving exposure to
microfibers. Thus, it appears that no association existed between excess
respiratory cancer and exposure to microfibers.
Concerning carcinogenic effects following exposure of workers to FG wool,
Enter!ine et al. (1986) found an excess of respiratory system cancer in U.S.
male production and maintenance workers after 20 or more years since first
exposure to both FG wool and continuous FG filament (SMR = 129.5, p <0.01). A
significant, increasing trend of SMRs was associated with increasing latency.
An excess of respiratory cancer among those with 30 or more years of latency
(SMR = 137.8, p <0.01) increased after 20 to 29 years of employment (SMR =
160.1, p <0.01). In the subsequent update, Enterline et al. (1987) found that
the excess of respiratory system cancer after 20 years of latency was reduced
and no longer significant compared to local rates (SMR = 110.6). Similarly,
the excess of respiratory cancer seen among those with 30 or more years of
latency was reduced and no longer significant compared to local rates (SMR =
110.8). This suggests that no relationship existed between exposure to FG wool
and continuous FG filament and respiratory cancer.
-------
In Canada, Shannon et al. (1986, 1987) found an excess of lung cancer in
male production workers with the highest exposure to FG wool (SMR = 199,
p <0.005). In addition, an excess of lung cancer was found among those with
the longest duration of exposure and the longest tine since first exposure (SMR
= 182, p <0.05). This suggests a causal relationship between exposure to FG
wool and lung cancer that was correlated with latency and duration of exposure.
In Europe, Bertazzi tt al. (1984) found a fourfold excess of laryngeal
cancer among male FG wool production workers compared to national rates, but
not regional or local rates. However, using local rates, excesses of laryngeal
cancer were found among those with 25 or more years of latency (SMR = 938,
p <0.005), with 20 or more years of exposure (SMR = 833, p <0.05), whose first
exposure was before age 25 (SMR =1538, p <0.01), and whose cumulative exposure
was >0.30 fibers/cm -months (SMR = 1500, p <0.005). All four cases were first
employed before 1960 when FG wool rather than FG filament was produced.
Despite the small number of observed deaths upon which these analyses were
based, the results show a consistent, significant increase among the FG wool
workers who were most heavily exposed. In a subsequent update, Bertazzi et al.
(1986) found a sixfold excess of laryngeal cancer among those with 25 or more
years of latency. All laryngeal cancer deaths occurred before 1960 when FG
wool was produced.
Gardner et al. (1986) found an excess of stomach cancer among female
employees of an English FG wool plant compared to national (SMR = 277, p <0.05)
but not local rates. In the same factory, an excess of lung cancer was found
among male production workers (SMR = 130, p <0.05) when compared to national
rates. Additional excesses of lung cancer were found when the data from male
production workers were analyzed by latency and duration of employment, but
• these were not significant compared to local rates.
Simonato et al. (1986a) found an excess of lung cancer among FG wool
workers compared to national rates (SMR * 127, p <0.05), especially among those
with 30 or more years since first exposure to FG wool (SMR = 173, p <0.05). An
excess of lung cancer was found for the intermediate phase of FG wool produc-
tion (SMR = 139, p <0.05), particularly after 10 to 19 years of latency (SMR =
164, p <0.05), but these excesses were no longer significant compared to local
rates. Among those with 20 or more years of latency, excesses of lung cancer
were found for those employed from 1 to 4 years (SMR = 197, p <0.05) and from
10 to 19 years (SMR * 190, p <0.05); local rates not reported. In subsequent
updates, Simonato et al. (1986b,c, 1987) found that the above excesses of lung
July 1988 8-97 DRAFT—DO NOT QUOTE OR CITE
-------
cancer were significant only when compared to national rates. However, con-
cerning other elevated causes of death, Simonato et al. (1986b) found that all
nine laryngeal cancer deaths occurred in male production workers, and that six
of the nine deaths occurred fn the Italian FG wool cohort studied by Bertazzi
«t al. (1984, 1986) and Simonato et al. (1986c). This excess from laryngeal
cancer was statistically significant (6 observed, 1.5 expected, SMR « 400,
p <0.05, Power = 8 percent). In other plants, the apparent lack of an excess
from laryngeal cancer mortality could be attributed to the insufficient power
to detect a 50 percent increased risk of death from laryngeal cancer. Based on
the additional deaths identified after increased followup, Simonato et al.
(1986c) concluded that these data confirmed the previous findings by Bertazzi
et al. (1984, 1986) of an elevated laryngeal cancer risk in the Italian FG wool
cohort.
Moulin et al. (1986) reported an increased incidence of upper respiratory
and alimentary tract cancer among active or retired French FG wool workers (SIR
= 216, p <0.005), particularly buccal cavity/pharyngeal cancers (SIR = 317,
p <0.001) compared to regional rates. There was a threefold excess of buccal
cavity cancer alone. Excesses of upper respiratory and alimentary tract cancer
were confined to production workers exposed for 10 to 19 years (SIR = 304,
p <0.01) or for 20 or more years (SIR = 333, p <0.005).
Thus, it appears that among FG wool workers, there were significant
excesses from respiratory cancer (Enterline et al., 1986), including lung
cancer (Shannon et al., 1986, 1987; Gardner et al., 1986; Simonato et al.,
1986a); from laryngeal cancer (Bertazzi et al., 1984, 1986; Simonato et al.,
1986a,b); from stomach cancer (Gardner etal., 1986); and from buccal
cavity/pharyngeal cancer (Moulin et al., 1986), especially from buccal cavity
cancer (Moulin et al. , 1986).
Concerning carcinogenic effects following exposure of workers to continu-
ous FG filament, Simonato et al. (1986a) found an excess of lung cancer among
male and female Europe production workers with less than 10 years of latency
compared to national rates (SMR = 224, p <0.05), but not compared to local
rates (Simonato et al., 1986b.,C, 1987). However, there was insufficient power
to detect lung cancer in this cohort. Enterline et al. (1986, 1987) found no
excess respiratory cancers among those producing continuous FG filament, even
when the cohort was subdivided by latency and length of exposure. Although
there was sufficient power to detect respiratory cancer in the total continuous
FG filament cohort (Power = 91 percent), there was insufficient power to detect
.1,-iw TQfip 8-98 DRAFT—DO NOT QUOTE OR CITE
-------
a 50 percent Increase in respiratory cancer when the cohort was subdivided by
latency and length of exposure. Bertazzi et al. (1984, 1986) found that the
excess laryngeal cancer cases were first employed before 1960 when only FG wool
was produced rather than after 1960 when only continuous FG filament was
produced. There was insufficient power to detect site-specific cancers among
those employed after 1960. Gardner et al. (1986) found no site-specific cancer
excesses in a Northern Ireland continuous FG filament factory. There was
insufficient power to detect lung cancer in this cohort. Thus, at this time,
it appears that no relationship exists between cancer and exposure to continu-
ous FG filament.
Concerning carcinogenic effects following exposure to MW (mineral wool and
rock and/or slag wool), interline and Marsh (1982) found an excess of respira-
tory system cancer in one MW plant of eight U.S. MW or FG plants. A ninefold
risk was found among jnale production or maintenance workers with 20 or more
years of latency compared to a 2.5-fold risk among those with less than 20
years of latency, even though the power to detect a 50 percent increase in
respiratory cancer mortality was low (12 and 4 percent, respectively). In the
second in a series of four studies of U.S. MMMF production and maintenance
workers, Enterline et al. (1983) reported an overall excess of respiratory
system cancer among all MW workers (SMR = 160.1, p <0.01). As in the previous
study, the excess was greatest in Plant 7 (SMR = 451.3, p <0.01) and resulted
in a ninefold increase after 20 or more years of latency even though there was
insufficient power to detect respiratory cancer in MW workers. In the third
study, despite low power, Enterlin* et al. (1986) found a 46 percent increase
in respiratory cancer among workers after 20 or more years of latency. The
excess was slightly higher after 30 or more years of latency (SMR « 151.7,
p <0.05). In the fourth study, Enterline et al. (1987) found that the 46
percent increase in respiratory cancer among MW workers after 20 or more years
of latency was no longer significant when compared to local mortality rates.
However, as in the previous studies, there was Insufficient power to detect a
50 percent increased risk of death from respiratory cancer among those with 20
or more years of latency. Compared to FG wool and continuous FG filament, the
greatest respiratory cancer hazard was found among MW workers (SMR « 148.4,
p <0.01), which remained significantly elevated compared to local mortality
rates (SMR * 133.6, p <0.05). The respiratory cancer excess among MW workers
is above background rates, thereby taking into account etiological agents such
as smoking and regional mortality differences, which could influence the
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magnitude of the risk. Robinson et al. (1982) found a 3.33-fold increase from
digestive tract cancer among Bale MW production workers after 20 or more years
of employment. There was insufficient power to detect excess mortality from
any site-specific cancer mortality.
In Europe, Andersen and Langmark (1986) found a twofold increase in
Intestinal cancer Incidence among male -MW workers employed at least 1 year.
There was insufficient power to detect this excess as well as excess lung
cancer. Nevertheless, there was a threefold increase in lung cancer incidence
in one rock wool plant, which became more pronounced when short-term workers,
i.e., those employed for less than 1 year, were excluded (SIR = 386, p <0.01).
A twofold increase in lung cancer incidence three MW plants after 20 or more
years of latency was concentrated among those with 1 or more years of employ-
ment. Westerholm and Bolander (1986) found an 8.8-fold excess from lung cancer
among male and female MW production workers with 1 to 4 years of employment and
30 or more years of latency, even though there was insufficient power to detect
lung cancer. Olsen and Jensen (1984) found a 52 percent increased incidence of
digestive organ/peritoneum cancer among male and female MW production workers
during the first 10 years after initial employment. They also found a twofold
increase in lung cancer incidence «»ong male and female production workers
after 20 or more years of latency (Power = 20 percent). This increase was
concentrated among male production workers. In a followup study, Olsen et al.
(1986) found an increased incidence from buccal cavity/pharyngeal cancer (SIR =
210, p <0.05, Power = 24 percent) and from digestive organ cancer (SIR = 150,
p <0.05, Power = 90 percent) among male production workers. Claude and
Frentzel-Beyme (1984) found an excess of stomach cancer among male production
workers after 20 to 29 years of latency (SMR = 273, p <0.05), despite low
power. In a followup study among male production and maintenance workers hired
before the introduction of resin binders in 1953, Claude and Frentzel-Beyme
(1986) found excesses from stomach cancer after 20 to 29 years of latency (SMR
= 261, p <0.05), thereby confirming the previous finding, and from lung cancer
after 10 to 19 years of latency (SMR = 272, p <0.05, Power « 12 percent).
Maintenance workers had a 2.5-fold excess of lung cancer after 20 to 29 years
of latency. Using internal controls as a reference group, there was a
sevenfold increase in relative risk from pancreatic cancer. Pooling data from
the European studies, Simonato et al. (1986a) found excess lung cancer among MW
workers first employed during the early technological phase of MMMF production
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compared to both national (SMR * 214, p <0.05, Power = 14 percent) or local
rates (SMR = 257, p <0.05, Power = 24 percent). This excess was even greater
after 20 or more years since first exposure to MW during the early phase (SMR =
295, p <0.05, Power « 8 percent). In followup studies, Simonato et-al.
(1986b,c, 198?) found lung cancer excesses in Factory 4 (rock wool) compared to
both national (SMR = 360, p <0.05) and local rates (SMR e 300, p <0.05). Among
those with 20 or more years of latency, a twofold excess of cancer was found in
preproduction/production rock wool workers compared to local rates (Power = 28
percent). Among rock wool workers with 20 or more years of latency, a twofold
excess of lung cancer was found for the early and intermediate technological
phases compared to both national and local rates. This lung cancer excess was
concentrated among rock wool workers first employed in the early phase (SMR =
257, p <0.05), particularly after 30 or more years of latency, compared to
local rates (SMR = 295, p <0.05). Despite low power, Simonato et al. (1986fc,c,
1987) also found a twofold increased incidence of buccal cavity/pharyngeal
cancer in rock wool workers (SIR - 197, p <0.05), which increased with increas-
ing latency. The low power to detect site-specific cancers in many subcatego-
*
ries that was found in several of the individual European studies pertained to
the Simonato studies even when the data were pooled from the 13 plants.
Combining U.S. and European MW workers, Doll (1987) found that compared-to
local rates, the lung cancer excess among MW workers was greatest among those
with 30 or more years of latency (SMR = 148, p <0.05, Power * 74 percent).
This excess was concentrated among those employed in the early and intermediate
technological phases but only significant when compared to national rates (SMR
= 223, p <0.001).
Thus, it appears that among MW workers, significant excesses existed from
respiratory system cancer (Enterline and Marsh, 1982; Enterline et al., 1983,
1986, 1987), including lung cancer (Andersen and Langmark, 1986; Westerholm and
Bolander, 1986; Olsen and Jensen, 1984; Claude and Frentzel-Beyme, 1986;
Simonato et al., 1986a,b,c, 1987; Doll, 1987); from digestive tract cancer
(Robinson et al., 1982), including stomach cancer (Claude and Frentzel-Beyme,
1984, 1986), digestive organ/peritoneal cancer (Olsen and Jensen, 1984),
digestive organ cancer (Olsen et al., 1986), Intestinal cancer (Andersen and
Langmark, 1986), and pancreatic cancer (Claude and Frentzel-Beyme, 1986); and
from buccal cavity and pharyngeal cancer (Olsen et al., 1986; Simonato et al.,
1966b,c, 1987). Additional excesses of buccal cavity/pharyngeal cancer occurred
-------
in Norwegian MW and FG wool workers (Andersen and Langmark, 19B6), but it was
not possible to attribute the excess to one or the other group.
8.1.2 Ceramic Fibers
8.1.2.1 Cross-Sectional Studies. Clinical Evaluations, and Case Reports
8.1.2.1.1 Respiratory effects. Limited information was found on the health
effects of ceramic fibers. Gantner (1986) determined the exposure levels
resulting from conversion of ceramic fiber to cristobalite and the dust gener-
ated by removal of ceramic fiber insulation from heat treatment furnaces.
Ceramic fiber insulation consists of alumina-silicate fibers that are vitreous
in their initial, manmade state. When subjected to high temperatures over
extended periods of time, however, the fibers devitrify and are converted into
cristobalite, a form of free silica. Temperature appeared to be the control-
ling factor in transformation of ceramic fiber, with highest percentages of
Cristobalite present closest to the hot face and none found beyond the 4-inch
layer. During removal of the insulation, personal respirable dust levels
exceeded the threshold limit value (TLV) in. 75 percent of the samples. Per-
sonal total dust samples exceeded the TLV in 80 percent of the samples. TLV
was calculated using the average percentage of cristobalite found in total dust
and respirable dust samples. Workers appeared to be at significant risk for
cristobalite exposure. According to Ziskind et al. (1976), who studied workers
occupationally exposed to silica, silicosis may be caused by exposure to
elevated levels of cristobalite over extended periods of time. Silicoses are
associated with rapid deterioration of pulmonary function characterized by
restriction of lung volume with a reduction of total lung capacity, vital
capacity, and pulmonary diffusing capacity.
8.2 SYNTHETIC FIBERS
8.2.1 Aramid Fibers
No information was available concerning the human health effects of this
fiber.
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8.2.2 Carbon Fibers
8.2.2.1 Cross-Sectional Studies, Clinical Evaluations, and Case Reports
8.2.2.1.1 Respiratory effects. Jones et al. (1982) conducted radiograph!c,
spirometric, and respiratory questionnaire exams of 88 workers from a carbon
fiber plant. Little variation had occurred over the years in the levels of
respirable dust concentrations, which varied from a mean of 0.03 to 0.16 tng/m
in different production areas. Diameters ranged from 8 to 10 urn. No evidence
existed that carbon fibers caused any 111 effects in the lungs of exposed
workers.
8.2.2.1.2 Effects from surgical introduction. Rosenthall (1987) studied the
effect of a knee prosthesis with carbon fiber-reinforced polyethylene surfaces
on production of an inflammatory reaction. A foreign body reaction in three
patients with total knee arthroplasties was demonstrated by technium-99rc
methylenediphosphonate (MDP) deposition in the intra-articular space. However,
there was no visible uptake of Ga citrate. The inflammation was shown to be
due to a synovia! joint cell foreign body reaction to particulate carbon fiber
debris in one patient with correlating data from a histological examination of
the synovium.
8.2.3 Polyolefin Fibers. No information was available concerning the human
health effects of this fiber.
8.3 MINERALS
8.3.1 Attapulgite and Sepiolite
8.3.1.1 Cross-Sectional Studies, Clinical Evaluations, and Case Reports
8.3.1.1.1 Respiratory effects. Limited information exists on the effects of
attapulgite and sepielite in humans. In a cross-sectional morbidity study,
Gamble et al. (1985) examined the prevalence of respiratory symptoms, pneumoco-
niosis, and reduced pulmonary function 1n U.S. attapulgite workers. The study
population consisted of 705 men from two attapulgite mining and milling
companies (355 men from Company A and 310 men from Company B) who were similar
in age, tenure, and smoking habits. Over 50 percent of the workers in Company
6 had been employed in dusty occupations other than attapulgite mining and
milling, most for less than 5 years. Mean estimates of cumulative exposure to
total and respirable dust were calculated from environmental survey date.
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Total dust concentrations varied between 0.09 and 22.96 mg/m , and respirable
dust varied between 0.05 and 2.71 mg/m3. Medical examinations, performed by
the two companies, consisted of a respiratory questionnaire, chest x-rays, and
spirometry. Lung function data included the maximal forced vital capacity
(FVC), forced expiratory volume in 1 second (FEV^, and FEVj/FVC x 100 (FEVj
percent). Logistic regression was used for analysis of the association between
exposure and respiratory symptoms and radiographic findings. The observed
prevalence of symptoms and the odds ratio (OR) by exposure category were
calculated, controlling for race, age, height, and smoking in each model. No
consistent relationship was found between exposure and respiratory symptoms.
FVC and FEV- were generally lower in the medium* and high-exposure groups, but
the differences were not statistically significant.
A total of 701 x-rays obtained from both companies were read for evidence
of pneumoconiosis. The prevalence of pneumoconiosis was elevated in the older
age categories and the prevalence was consistently increased in the highest
exposure groups, but these trends were not significant. There was no associa-
tion between reduced FVC and FEV- and radiographic findings. The authors
concluded that their data did not provide evidence for a relationship between
attapulgite exposure and respiratory morbidity.
Bignon et al. (1980) described case reports of two individuals exposed to
attapulgite fibers, one by inhalation and the other by ingestion. A 41-year-old
French worker with lung fibrosis had been exposed to attapulgite dust for 3
years while mining and processing the mineral for use in the pharmaceutical
industry. Attapulgite fibers were found in lung washing fluid following
bronchoalveolar lavage at a concentration of 42,000 fibers/cm . The mean
length and diameter of the fibers were 1.5 pm and 0.11 urn, respectively.
Attapulgite fibers, at a concentration of 300,000 fibers/cm , were also detected
in the urine of a 60-year-old woman who had been treated for gastrointestinal
disease for 6 months with 9 g/day of a drug containing attapulgite (Attapul-
gite® consisting of 3 g activated Mormoiron attapulgite In a 6-g pack). No
adverse effects attributable to the fibers were reported.
Baris et al. (1980) performed mass photofluorograms of the inhabitants of
four Turkish villages where mining and processing of sepiolite had occurred for
more than 100 years. A clinical and radiologic survey was also conducted on 63
sepiolite workers whose exposure duration ranged from 1 to 30 years with a mean
of 11.9 years. Mineral fiber-related pleura! diseases were not detected in the
villagers exposed to sepiolite dust. Calcified pleura! plaques, pleura!
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thickening, and mesothelioma observed in the villagers were attributed to the
home use of a stucco finish that contained tremolite asbestos. Pulmonary
fibrosis was found in 10 of 63 workers. However, more than half of the 10
workers resided 1n dusty rural regions where asbestos and zeolites were
present, 3 had previous occupational histories that nay have been responsible
for or contributed to the pulmonary disorders, and all were smokers exhibiting
symptoms of chronic bronchitis. Therefore, no causal relationship between
pulmonary fibrosis and sepiolite dust inhalation could be established.
8.3.1.2 Epidemiologies! Studies. Waxweiler et al. (1985) conducted a histori-
cal prospective mortality study of employees of a large U.S. attapulgite mining
and milling facility. The cohort consisted of 2302 white and nonwhite male
miners and millers employed at least 1 month between January 1, 1940, and
December 31, 1975. Expected deaths were based on U.S. age, race, and calendar
year-specific mortality rates. Vital status was determined through information
obtained from the Social Security Administration, Internal Revenue Service,
state bureaus of motor vehicles, state vital statistics offices, and other
sources. Of the 2302 workers, 1847 (80.2 percent) were alive, 315 (13.7
percent) had died, and 140 (6.1 percent) were lost to followup. Death certifi-
cates were obtained for all but 19 (6.0 percent) of the decedents. Deaths were
coded by a qualified nosologist and converted to the 7th Revision of the ICD.
Jobs were classified from analysis by dust exposure levels into high-exposure
(1.15 to 1.60 mg/m respirable dust), low-exposure (0.45 mg/m respirable
dust), and intermittent-exposure (occasional work in high-exposure jobs)
categories. Although there was a maximum followup of 36 years, exposure and
observation periods were concurrent, thereby underestimating the risk of lung
cancer.
Personal exposure data were unavailable for the cohort, but area monitor-
ing data were collected in 1976. The monitoring survey indicated that airborne
fibers in the plant were generally short 1n length, I.e., 0.1 to 2.5 um, and
narrow in diameter, I.e., 0.02 to 0.1 pm. Fiber aspect ratios (length to
diameter) were generally greater than 10:1. Respirable dust concentrations in
all of the monitored work areas were less than the Mine Safety and Health
Administration (MSHA) nuisance dust standard of 5 mg/m .
There were no significant Increases in cause-specific mortality for the
whole cohort. When the cohort was divided into white and nonwhite workers, a
significant excess of lung cancer was seen in white males (16 observed, 8.3
expected, SMR = 192, p <0.05, Power = 37 percent), but a significant deficit of
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lung cancer was seen in nonwhite males (5 observed, 9.4 expected, SMR = 53,
Power = 34 percent). This excess in white males persisted after 10 years since
first employment (16 observed, 7.2 expected, SMR = 222, p <0.05), but was
limited to those employed from 1 month to 5 years (10 observed, 4,3 expected,
SMR = 233, p <0.05) rather than those with 5 or »ore years of employment
(long-term workers). A threefold excess of lung cancer was observed among
white males employed In the high- and intermittent-exposure job categories
after 20 or more years of latency (6 observed, 2.0 expected, SMR = 300,
p <0.05), which was greater among long-term employees (3 observed, 0.7 expected,
SMR =429, p <0.05, Power * 9 percent).
The investigators concluded that (1) whereas white employees experienced a
twofold excess of lung cancer, nonwhites had a lung cancer risk approximately
half of that expected based on U.S. mortality rates; (2) lung cancer was not
altered by dust exposure level, latency period, or duration of employment,
except for those employed at least 5 years in high-exposure jobs; and (3) the
deficits from NMRD are consistent with the hypothesis that short fibers are not
fibrogenic. The investigators stated that the study was limited by (1) the
absence of smoking histories; (2) the incomplete enumeration of the cohort;
(3) the large number of individuals lost to followup; (4) the missing race on
50 persons; (5) the lack of longitudinal person-specific dosimetry; (6) the fe«
expected deaths among those with 20 or more years of latency; and (7) use of
national rather than local mortality rates as a comparison group.
In addition to the above limitations, the power to detect site-specific
cancers, such as lung cancer, as well as NMRD, was insufficient; there was a
low trace rate; and exposure and observation periods were concurrent. All of
these limitations served to underestimate the true risk of lung cancer and NMnD
among this group of workers. Despite the low power, since exposure to asbestos
or other lung carcinogens was not mentioned, it appears that attapulgite was
associated with excess lung cancer mortality. Without local mortality rates
for lung cancer, however, this cannot be stated with certainty.
8.3.2 Erionite
Results from several cross-sectional morbidity and mortality studies have
shown that erionite induces pleura! and peritoneal mesotheliomas among adult
inhabitants from three Turkish villages. The annual crude death rate from
malignant mesothelioma (both pleura! and peritoneal) was 8 deaths per 1000
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inhabitants of the three affected villages. In addition, radiological data
Indicate a higher prevalence of pleura! changes in villages affected with a
high prevalence of mesothelioma as compared to a control village. The presence
of asbestos did not correlate with the distribution of mesothelioma in these
villages. Turks who emigrated to Sweden exhibited immunological effects
similar to those found in asbestos-exposed Individuals.
8.3.2.1 Cross-Sectional Studies. Clinical Evaluations, end Case Reports
8.3.2.1.1 Respiratory effects. Baris et al. (1987) conducted a
cross-sectional Morbidity and mortality study and reported 16 new coses of
pleura! disease between 197S and 1976 from Karain, a remote village located in
the Anatolian region of Turkey. The study group consisted of 575 residents of
Karain, whose name translated from Turkish means "abdominal pain." Because no
formal records were kept by a vital statistics office for the period up to
1970, the investigators relied upon information obtained from relatives and
from hospital admissions from Karain. Survey radiographs taken in 1971 and
available information on deaths between 1970 and 1974 were reviewed. For the
period from 1975 to 1976, the investigators studied physical and socioeconomic
conditions and performed geological, biological, and chemical tests to detect
environmental toxicants in Karain and neighboring villages. These tests
included sampling airborne dust; performing elemental analysis of soil and
rock; sampling food, drink, and water supplies; and conducting a health survey
of the inhabitants of Karain and neighboring villages. The health survey
included chest x-rays and physical examinations and clinical tests of hospital
admissions. Occupational, domestic, and familial medical histories were
obtained for new cases of chest disease that developed between 1975 and 1976.
The investigators stated that causes of death during 1975 and 1976 were
recorded and verified to the maximum extent possible.
Although most of the information sources up to 1975 were anecdotal, more
recent information from medical records showed that serofibrinous or
serohemorrhagic pleural effusion was present among respiratory disease admis-
sions. Tests for tuberculosis were negative, and antituberculosis treatment up
to 1975 proved ineffective. In 1974, for Karain's 604 inhabitants, 11 of the
18 deaths that occurred were attributed to pleural mesotheliomas. Comparison
of total deaths in Karain and eight neighboring villages in 1974 revealed
significant excesses from all causes of death in Karain (18 observed, 6.60
expected, SMR » 273, p <0.001) and in Akcaoren (11 observed, 5.94 expected. SMR
e 185, p <0.05). Although the source of the expected number of deaths was not
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identified, the investigators stated that these two villages had a signifi-
cantly higher death rate (chi-square * 30.45, 8 degrees of freedom) than the
other villages. Of greater importance, however, was the concentration of 11
pleura! mesotheliomas in Karain and the absence of mesotheliomas in each of the
eight other villages. When the investigators compared results of chest x-rays
taken during health surveys of 1971 and 1975, they found no significant change
in the general pattern of chest diseases 1n Karain.
The investigators also reported that some of the men from Karain were
smokers; women never smoked. The village has no asbestos deposits and asbestos
brought in from other areas has not been processed. Arsenic, uranium, nickel,
and chromium were present in trace amounts. Extracts of soil, dust, and stucco
were negative for benzo(a)pyrene. No significant radioactivity was found in
the village or surrounding soil or rocks. Tests for aflatoxins in various
foods were negative. Some water supplies contained small quantities of uniden-
tifiable fibers. Actual exposure levels were unavailable.
The mass radiographic survey showed no significant change in the preva-
lence of chest disease between 1971 and 1975. During 1975 and 1976, 16 new
cases of pleura! disease were found. The final diagnosis of mesothelioma was
based on radiological evidence in 11 of the 16 cases and on histologies!
evidence for 7 of the cases. The five other cases were diagnosed with chronic
fibrosing pleurisy. The cases mainly had agricultural occupations.
Geneological information from medical histories indicated that blood relation-
ship was not a prerequisite for mesotheliomas within a family; the authors
suggested a common environmental etiology.
The investigators concluded that apart from a few asbestos fibers identi-
fied in the drinking water and in two of five samples of pleura! tissue, no
obvious environmental or occupational source of asbestos exposure existed in
Karain. They suggested that a patient might have been exposed to asbestos frorr,
an undetected source or that tapwater might be the source of asbestos. However,
they did not explain why, if asbestos were the causative agent, the excess
malignant respiratory disease was limited to Karain despite the proximity of
other villages.
Ban's et al. (1979) reported the results of cross-sectional morbidity and
mortality studies of asbestos-related diseases, primarily calcified pleura!
plaques (CPP), chronic fibrosing pleuritis (CFP), and malignant pleura! meso-
thelioma (MPM) in Turkish villages with or without asbestos deposits. Because
certain parts of Turkey are rich in asbestos minerals, this study was to expand
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previously conducted surveys in areas surrounding asbestos mines and mi 11s into
rural regions of Turkey. The investigators summarized their findings for six
Anatolian regions of Turkey by stating that CPP, CFP, and MPM are endemic to
some villages with or without asbestos deposits. Although asbestos in building
materials had been postulated as a cause, environmental samples in villages
where CPP 1s endemic revealed the absence of asbestos. In fact, the prevalence
of CPP did not appear to be correlated with asbestos-containing building
•aterials. Because erionite was detected 1n soil, rock, and lung tissue
samples in areas where asbestos is absent and where the diseases have shown a
geographical distribution, the investigators stated that CPP, CFP, and MPM may
be related to zeolite minerals rather than to asbestos. When additional soil
samples near Tuzkby revealed respirable zeolite fibers, Baris et al. (1979)
concluded that tumor induction by asbestos contamination of drinking water,
previously postulated ty Baris et al. (1978), was highly improbable. Actual
exposure levels were not reported.
Baris et al. (1981) conducted a cross-sectional morbidity and mortality
study of Karain (population 554) and its neighboring village of Karlik (popula-
tion 479) to determine whether erionite might be responsible for the very high
rates of mesotheliomas and at which concentrations erionite might be associated
with this excess. The investigators compared the inhabitants of the two
villages for several demographic characteristics, assessed the prevalence of
radiological chest abnormalities, and estimated concentrations of mineral
fibers in air and water samples and their size and, composition. Demographic
data were abstracted from health center registers, which contained birth and
death rates. Death rates were obtained by a direct age-adjustment procedure,
with the combined populations of the two villages as a standard. No medically
certified cause of death was recorded. All persons aged 20 and over were
invited to participate in the interview, chest x-ray, and physical examination
portions of the study: 89.8 and 90.8 percent of the men and women, respec-
tively, in Karain, and 83.4 and 77.1 percent of the men and women, respectively,
in Karlik participated. Interviews conducted by a local resident lasted
approximately 4.5 minutes and Included questions on personal, family, residen-
tial, and occupational history. Less than 2 percent of the interviews were
discarded as unreliable by an observer. Full-size posterior-anterior chest
x-rays were taken; films were read blind by Baris. Respirable and total
environmental dust was measurable for 8 to 10 hours per day over a minimum of 3
days. Samples were analyzed by optical and electron microscopy.
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The sex and age compositions of the two villages in 1978 were similar.
Whereas no significant differences were found for educational status, occupa-
tion, lifelong residence, proportion of consanguinous marriages, original
residence of spouse, and cigarette smoking habits, life expectancy was signifi-
cantly reduced in Karain (p <0.01) by 14 years and adult mortality was 70 to 80
percent higher than 1n Karlik. However, Investigators found no statistically
significant differences In pleura! radiological abnormalities. The prevalence
of mesothelioma diagnosis by x-ray in Karain adults was 3.4 percent (11/325) in
1979. Concentrations of respirable fibers from the street atmosphere, from
work and recreational areas, and from indoor locations were uniformly low in
Karlik (at or below 0.1 fibers/cm ) and higher in some samples from Karain,
with erionite representing 80 percent of the fibrous material. Neither
asbestiform nor erionite fibers were detected in the three water samples. The
investigators concluded that these findings were compatible with the hypothesis
of a causal association between endemic mesothelioma and inhalation of erionite
fibers, but the fiber concentrations in all samples were so low that the role
of erionite as an etiological agent is questionable.
Ban's et al. (1987) updated and completed previously published results
(Baris et al., 1981) of an association between exposure to naturally occurring
fibrous erionite and malignant mesothelioma. In 1979, the adult populations
(aged 20 or more) of Karain, with known high numbers of mesothelioma, and of
Karlik, with no known cases of mesothelioma, were selected for a
cross-sectional morbidity and mortality study. In 1980, a third village,
Sarihidir, was included because of the presence of erionite fibers in soil
samples but with no mesotheliomas reported up to 1980. Adults were interviewed
and given chest x-rays and physical examinations. X-rays were read without
knowledge of village at the International Agency for Research on Cancer (IARC)
in Lyon. Although there was no followup of study subjects, health center-
records, hospital clinical records, and other sources were used to establish a
list of deaths that occurred between June 1979 and July 1983 in Karain and
Karlik and between July 1980 and July 1983 in Sarihidir. For the mortality
portion of the study, a fourth village in the same province, Turkey, was
included for deaths that occurred between 1980 and 1983. Only deaths among
those aged 20 and older were included in the analysis. Comparison groups were
the 1978 populations of Karain and Karlik, the 1979 population of Sarihidir,
and the 1980 population of Tuzkb'y.
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Airborne levels of respirable (diameter <3 um) and total dust were mea-
sured in all four villages. More than 150 samples were obtained by the method
recommended by the Asbestos International Association (AIA) and analyzed by
transmission electron microscopy. The U.S. Environmental Protection Agency
(U.S. EPA) analyzed two water samples from Karain, one from Karlik, and two
from Sarihidir. Lung tissues from sheep 5 or »ore years old from all area
villages except Karain, which had no sheep, were analyzed for mineral content.
The study group consisted of 32? people from Karain, 228 from Karlik, and
337 from Sarihidir. Participation 1n the study was 89.8 and 90.8 percent males
and females, respectively, 1n Karain; 83.6 and 77.1 percent males and females,
respectively, in Karlik; and 93.3 and 83.2 percent males and females, respec-
tively, in Sarihidir. The age structure of the three villages was similar. No
major differences were found between the villages, except that consanguineous
marriages and illiteracy were higher in Sarihidir. The major occupation was
farming, which ranged from 89.6 to 100 percent in the three villages. None of
those interviewed had experienced either known or suspected exposure to asbes-
tos. In all three villages, more than 50 percent of the males were either
current or ex-smokers; only 2 of 482 (0.4 percent) of the females smoked.
Among current smokers, 70 percent smoked 20 or more cigarettes per day.
The entire population was x-rayed in Karlik except for 1.8 and 3.0 pe'—
cent, respectively, who were x-rayed in Karain and Sarihidir. Round opacities
of category 1/0 or more were more common in males from all three villages;
males from Sarihidir exhibited a significantly higher prevalence (p <0.01) than
those from Karain and Karlik. Calcifications of the diaphragm were more
frequent among both males and females from Karain and Sarihidir than among
those from Karlik; this difference was statistically significant (p <0.01) for
males from Sarihidir as compared to males from Karlik.
During the study period, 141 deaths were recorded in the four villages:
29 from malignant pleura! mesotheliomas, 4 from malignant peritoneal mesothe-
liomas, 17 from lung cancers, 1 from laryngeal cancer, 21 from unspecified
cancers, 59 from other causes, and 10 from unknown causes. Irrespective of
sex, the largest number of deaths from pleura! mesotheliomas (21 out of 29)
occurred in Karain. There were three pleura! mesotheliomas from Sarihidir, but
no peritoneal mesotheliomas, and five pleura! and four peritoneal mesotheliomas
limited to women from Tuzkby. Lung cancer prevalence was highest in Sarihidir.
No cancer deaths occurred in Karlik. When age- and sex-specific death rates
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were calculated, Karain had the highest overall death rate and the highest
death rate from malignant mesothelioma.
Zeolite fibers constitute the major portion of dust 1n the clouds of
Karain, Tuzkby, and Sarihidir. Tremolite was observed 1n Karain and Karlik at
less than 0.001 fiber/cm3. In Sarihidir, chrysotile and tremolite fibers <5 »n
in Itngth contributed up to 10 percent of the fibers in this size range. In
Tuzkby, no asbestos fibers were detected; the shorter fibers aainly consisted
of zeolite, calcite, and Muscovite. Thus, airborne fiber concentrations were
low but showed a higher proportion of erionite In villages affected by mesothe-
lioma than in the control village. The same pattern was found in fiber levels
from the lung tissues of sheep from villages affected and unaffected by meso-
thelioma. Analysis of water samples performed by the U.S. EPA showed that none
of the samples contained asbestos, zeolite, or other mineral fibers above the
detection limit of 50,000 fibers per liter.
The investigators concluded that the results of this study confirm previ-
ous findings of an extremely high rate of malignant mesotheliomas in some
villages of central Turkey. They further concluded that (1) the cancer mortal-
ity excess was not limited to pleura! mesotheliomas (peritoneal mesotheliomas
and lung cancer were also found); (2) the similarity of the demographic charac-
teristics of the villages enabled morbidity and mortality comparisons;
(3) radiological data indicate a higher prevalence of pleural changes in
villages affected by high prevalence of mesotheliomas compared to the control
village; (4) the annual crude death rate from malignant mesothelioma was 6
deaths per 1000 inhabitants of the three affected villages; (5) because
measurements showed higher airborne erionite levels in affected versus control
villages, the prevalence of mesothelioma and lung cancer was related to expo-
• sure to erionite fibers, and (6) some documented exposure to asbestiform fibers
does not appear to correlate with the distribution of the disease.
Artvinli and Ban's (1979) conducted a cross-sectional morbidity and
mortality study and described three hospital admissions from Tuzkby. Tuzkby is
50 km from Karain, the village where Baris et al. (1978) previously found
excesses from malignant pleural mesothelioma (MPM). The reference population
was drawn from the neighboring village of Kizilkb'y. Both Tuzkby and Kizilkby
are located in the city of Nevsehir. For the cross-sectional study, persons at
least 25 years old were selected and divided by age and sex into four 15-year
age groups, i.e., 25 to 39, 40 to 54, 55 to 69, and 70*. Through stratified
sampling, 312 persons (145 males, 167 females) from Tuzkby and 95 persons (45
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males, 50 females) from Kizilkby were included in the study. A questionnaire
on smoking habits and personal and family medical history completed for each
person was followed by physical examinations, x-rays, and lung function stud-
ies. In addition, chemical analyses of water samples and mineralogical analy-
ses of building materials and soil samples were performed.
Of the three hospital admissions, one 42-year-old male fanner had MPM, a
31-year-old male salt-miner had a malignant epithelial tumor, and a 36-year-
old male had chronic fibrous pleuritis. No ferruginous bodies were found in
the lung tissues; among the study group, x-ray examinations yielded 53 cases
(17 percent) of pleura! calcification, 33 cases (10.5 percent) of pleura!
thickening, 47 cases (15 percent) of obscured costodiaphragmatic angle, and 3E
cases (12.1 percent) of interstitial pulmonary fibrosis. In addition, two
cases of MPM were found in this group. Among the control villagers, no cases
of malignant diseases or pathological conditions upon x-ray examination were
found.
No differences between the water samples from the study and control
villages were found. No fibrous minerals were found in the water samples.
Soil samples from Tuzkb'y, on the other hand, contained multiple fibers, usually
30 to 40 pm long and 1 to 2 pm in diameter, which were classified as zeolite
minerals, i.e., mordenite, erionite, or chabayite. These same fibrous minerals
had been identified in soil samples from Karain and were also present in lung
samples from the three hospital admissions. However, no fibrous zeolites were
present in the control village. No types of asbestos were present in either
village. Exposure concentrations were unavailable.
The investigators concluded that zeolites were responsible for the MPM and
other respiratory disorders in Tuzkb'y. They estimated an incidence and preva-
lence of MPM in Tuzkoy of 6.5 cases per year or 22 cases per 10,000 people.
Compared to the annual incidence of MPM in Pennsylvania (1 case per million),
in Finland (1 per million), and in the United Kingdom (2.3 per million), they
further estimated that the annual Incidence of MPM in Tuzkb'y 1s at least 942
times higher than expected.
Artvinli and Baris (1982) updated their previous cross-sectional morbidity
and mortality study (Artvinli and Baris, 1979) of 312 residents of Tuzkoy
compared to 95 residents of Kizilkb'y. In addition, they analyzed the number of
deaths among those aged 15 or older in both villages from January 1, 1976,
until December 3, 1980. The methodology remained the same as that used in the
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previous study; only new results win be reported here. Exposure concentra-
tions were unavailable.
Physical examination revealed that the Tuzkby group had diminished breath
sounds (p <0.01). Ronchi and rales occurred more frequently in the Tuzkby
group than in controls (p <0.05). All abnormal x-ray findings, except inter-
stitial pulmonary fibrosis, were significantly less common in housewives
compared to other occupational groups, e.g., farmers, salt-miners, civil
servants, and other unspecified occupations. Among 1780 Tuzkb'y inhabitants who
were at least 15 years old, 67 died between 1976 and 1980; of these, 41 (61.2
percent) of the deaths resulted from malignant diseases (15 from pleura!
mesothelioma, 12 from peritoneal mesothelioma, 8 from lung cancer, 2 from
gastric cancer, 2 from colon cancer, 1 from laryngeal cancer, and 1 from
leukemia). Of the remaining 26 decedents, 19 died from nonmalignant causes,
and 7 died from unknown causes. In the control village during the same period,
only 2 of 325 individuals aged 15 years and over died; both deaths were from
nonmalignant causes. No x-ray abnormalities or deaths resulting from malignan-
cies were found in the control group.
The investigators concluded that (1) pathological x-ray findings, i.e.,
calcified pleura! plaques, pleura! thickening, obscured costophrenic angles,
and diffuse interstitial pulmonary fibrosis, were observed more frequently in
the Tuzkb'y group than in the control village; (2) the majority of deaths frorr
Tuzkby were attributable to malignant diseases (pleural and peritoneal
mesotheTioma and lung cancer); (3) the incidence of cancer in Tuzkby is greater
than that of asbestos insulation workers; and (4) because zeolite rather than
asbestos was found in soil samples and in building materials from Tuzkby, but
not in the control village, and because zeolite was detected in lung and
pleural biopsies of patients from Tuzkby, zeolite was considered the agent
responsible for these pulmonary and pleural malignancies.
Artvinli and Ban's (1982) reported the results of a cross-sectional
morbidity study of 327 persons over the age of 20 from Karain, 312 over the age
of 25 from Tuzkby, and 302 over the age of 25 from Sarihidir. Study subjects
were identified through x-ray screening studies. For each subject, question-
naires, physical examinations, and respiratory function tests were obtained.
Those with abnormal findings were admitted to a hospital for further clinica!
evaluation. Environmental and tissue samples were also obtained. Deaths from
malignant diseases were reported for those over age 15 from Karain between 1975
-------
and 1980, for those over age 15 from Tuzkby between 1978 and 1980, and for
persons from Sarihidir of unspecified ninimum age at death between 1978 and
1979. All death certificates were evaluated in these villages by an unspeci-
fied person. For each of the three villages under study, an unspecified
control village with a similar population was chosen as the comparison group.
In Karain, 64 (19.6 percent) of the 327 study subjects had abnormal x-ray
findings; specifically, 51 of the 327 (15.6 percent) had pleura! thickening.
Malignant pleural mesothelioma accounted for 38 of the 47 (80.8 percent) deaths
from 1975 to 1980 among those 15 and older. In Tuzkb'y, 171 (54.8 percent) of
the 312 study subjects had abnormal x-ray findings; specifically, 53 (17
percent) had pleural calcifications, 33 (10.5 percent) had pleural thickening;
47 (15.0 percent) had obscured costophrenic angle; and 38 (12.1 percent) had
diffuse interstitial pulmonary fibrosis. Malignant pleural mesothelioma
accounted for 15 (22.3 percent) and malignant peritoneal mesothelioma accounted
for 12 (17.9 percent) of the 67 deaths from 1978 to 1980 among those 15 and
older. In addition, eight lung cancer deaths occurred. In Sarihidir, 65 (21.5
percent) of the 302 study subjects had abnormal x-r«y findings; specifically,
25 (8.1 percent) had pleural thickening. Investigators found three malignant
pleural mesotheliomas, two malignant peritoneal mesotheliomas, two gastrointes-
tinal malignancies, and one lung cancer for the period between 1978 and 1979.
However, neither abnormal x-ray findings nor deaths from malignant diseases
(period unspecified) were found in control villages. While neither asbestos
nor erionite was detected in any control village, environmental samples and
tissue samples from patients of the three villages under study contained
erionite. No environmental concentrations were reported.
The investigators concluded that (1) the existence of asbestos-related
radiological findings and diseases in three villages in the absence of asbes-
tos suggests a cause other than asbestos; and (2) since all samples have shown
the presence of erionite fibers, erionite rather than asbestos was responsible
for the same pathological changes seen in those exposed to asbestos.
Recently, a number of Investigators have found several different
asbestiform minerals in addition to zeolite in environmental and lung tissue
samples from Karain and Tuzkb'y. These findings have raised the question of
whether asbestos alone or a synergistic effect involving both asbestos and
zeolite may be causing the high prevalence of respiratory diseases in this
region.
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Rohl et al. (1982) conducted a detailed analysis of environmental samples
(including house dust, soil samples, and building materials) obtained from the
Turkish villages (Karain, Tuzkb'y, Sarihidir) where mesothelioma was known to
occur. In addition, lung tissue specimens of patients diagnosed with mesothe-
lioma who lived in these villages were also analyzed. Detailed examination of
environmental samples snowed that they contained several different forms of
fibrous minerals, Including asbestos minerals and fibrous erionite. In one
sample collected near Karain, up to 30 percent, by weight, consisted of
tremolite and chrysotile. Analysis of pleura! and parenchyma! tissues revealed
that the lungs contained both asbestos and eripnite fibers. Approximately 90
percent of the fibrous particles in the lung tissue had a composition consis-
tent with that of erionite. A small amount (approximately 1 to 5 percent by
volume) of fibrous mineral was identified as tremolite with a length typically
less than 10 urn. Chrysotile, both in fiber bundles and unit fiber form, was
also found in small amounts. In addition, tremolite fibers were observed in
dust samples from Tuzkby. In lung tissue specimens obtained from pleura!
disease patients from this village, zeolite fibers predominated but tremolite
fibers were also found.
Sebastien et al. {1981) analyzed lung tissue samples from two malignant
pleura! mesothelioma patients from Tuzkby and found ferruginous bodies and
uncoated fibers. The numerical concentration of the ferruginous bodies per
gram of dried lung tissue was in the range of 10 . Characterization of these
bodies revealed that they contained a central core of zeolite. Analysis
p
indicated about 10 uncoated fibers per gram of dried lung tissue, and 93
percent were identified as zeolite fibers with a mean length of about 3.7 urn.
Only 3 percent of the fibers were longer than 8 urn or thinner than 0.25 urn.
Two other types of fibers, found less frequently, were also characterized.
These were identified as titanium oxide and an amphibolelike fiber having a
chemical composition similar to that of tremolite and actinolite.
Boman et al. (1982) analyzed lung tissue samples from two mesothelioma
patients who had emigrated from Karain to Sweden. Transmission electron
microscopic and microcheirrical analysis revealed that 64 and 75 percent, respec-
tively, of the fibrous minerals present in the tissue samples were zeolite
fibers. In addition, several asbestiform minerals including chrysotile (9 and
5 percent) and tremolite (27 and 9 percent) were also identified. The authors
suggested a synergistic effect involving both zeolite and asbestos.
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In the United States, fibrous erionite noted in samples of road dust from
•n area in Nevada prompted Rom et al. (1981) to evaluate chest x-rays obtained
from a local community hospital. All chest x-rays (275) of patients over the
•ge of 25 in 1968 and 1975 and over the age of 50 during the first 8 months of
1980 were examined. Seventeen (6.2 percent) of the radiographs showed signs of
pleura! thickening that Included blunting of one or both costophrenic angles,
and five (1.8 percent) had pleural plaques. No pleural tumors were noted.
Although the prevalence of the pleural changes was age related, the authors
found no unusual occurrence of pleural chest disease.
Casey et al. (1985) described a case report of a 52-year-old man with
pleural thickening and pulmonary fibrosis. The patient, who lived and worked
in an area of Nevada rich in zeolite deposits, had no known occupational
exposure to asbestos. A lung biopsy revealed both fibrous and nonfibrous
particles. The particles were studied using energy-dispersive x-ray analysis;
the analytic pattern of the particles was identical to that produced by a
sample of fibrous erionite. No asbestos fibers could be identified. The
authors suggested that exposure to erionite may be associated with the patient's
pulmonary disease.
8.3.2.1.2 Immunological effects. Ozesmi et al. (1986) conducted a cross-
sectional morbidity study of 74 individuals who emigrated from Karain, the
Turkish village with the high incidence of MPM, to Sweden. Because the minere-
logical characteristics and the adverse effects of fibrous zeolite (irionite)
are similar to those of asbestos, and because immunological aberrations have
been found in those with asbestosis, the investigators searched for possible
disturbances in the immune systems of the former residents of Karain. From a
list of participants in an earlier study identified by Boman et al. (1982),
former residents of Karain currently living in Stockholm were invited to
participate. The 74 study subjects underwent clinical examinations and chest
radiography. Blood samples and personal and family medical histories were also
taken. Healthy blood donors were used as controls.
Of the 74 study group members (36 males and 38 females), seven had pleural
plaques upon x-ray examination. Compared to controls, the mean percentages of
Leu4* cells and Leu 3a* cells were significantly decreased (p <0.01, respec-
tively), whereas the mean percentage of Leu 2a cells was normal. This lead
to a significant reduction (p <0.05) of the Leu 3a:Leu 2a ratio in the study
group. In addition, the mean percentage of B cells (Leu 12* cells) was signi-
ficantly decreased (p <0.05) in the study group. No correlation was found
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between percentages of different lymphoid cells and age, sex, family history of
mesothelioma, or duration of residence in Karain.
The investigators concluded that these findings indicate that exposure to
fibrous zeolite causes a numerical imbalance between two phenotypically differ-
ent T cell subsets similar to that found in Individuals exposed to asbestos.
6.3.2.2 Epidemiological Studies. No analytical epidemiological studies were
available for erionite.
8.3.3 Talc
8.3.3.1 Cross-Sectional Studies. Clinical Evaluations, and Case Reports.
Increased respiratory symptoms, higher prevalence of pleural thickening or
calcification and pneumoconiosis, and decreased pulmonary function have been
reported in workers exposed to talc containing various amounts of tremolite,
anthophyllite, or silica fibers. The extent of these effects increased with
age of workers, intensity of smoking, and duration of exposure. These effects
were less pronounced with exposure to talc free of asbestiform fibers.
8.3.3.1.1 Respiratory effects. The results of a study of 93 New York miners
and millers exposed to talc containing tremolite and anthophyllite fibers
indicated increased respiratory symptoms, x-ray abnormalities, and decreased
pulmonary function when compared to a population of potash miners (Gamble
et a!., 1979). Among the talc workers, higher respiratory symptom rates were
found for those who had worked for less than 15 years and those with 15 years
or more of employment. However, most of the workers with symptoms were eithe-
smokers or ex-smokers. Mean pulmonary function values (FEV., FVC, and maximum
respiratory flow at 50 and 75 percent) of talc workers were significantly
decreased in comparison to those of the potash workers. These decreases
remained after controlling for age, height, smoking, and number of. years of
employment. An association was found between decreased pulmonary function and
fiber and particulate exposure and the number of years worked. The prevalence
of pleural calcification and pneumoconiosis 1n talc workers with 15 or more
years of employment was higher than 1n potash miners. The greatest difference
between the two groups was the Increased prevalence of pleural thickening in
talc workers. Among the talc workers, pleural thickening occurred in 1.6
percent of workers with less than 15 years of employment and in 31 percent of
those with more than 15 years employment. Corresponding values for potash
miners were 0.5 percent and 4.0 percent, respectively.
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A cross-sectional study of 299 workers from Montana, Texas, and North
Carolina, who were exposed to talc containing low levels of silica and
tremolite and antigorite fibers, was conducted by Gamble et al. (1982). The
mean age of the study population was 40, and the nean duration of exposure to
talc dust was less than 10 years. The average concentration of airborne dust
ranged from 0.28 to 2.64 »g/m . Respiratory symptoms did not show any
consistent association with years worked or cumulative exposure. There were no
significant Increases 1n pneumoconiosis aimong the study group or significant
reductions in lung function. An increased prevalence in bilateral pleura!
thickening was found in some exposed workers. The prevalence was related to
age and smoking habits and was greater (23 percent) in those employees working
10 years or more when compared to those working less than 10 years (2.5 per-
cent). Moreover, workers with bilateral pleura! thickening had higher average
and cumulative exposures than those with no pleura! thickening. All pulmonary
function values of these affected workers were reduced when compared to unaf-
fected workers.
Evidence of fibrosis in workers exposed to talc containing minimal amounts
of crystalline silica and asbestiform minerals was reported in a pulmonary
pathology study by Vallyathan and Craighead (1981). Pulmonary tissue from
seven deceased Vermont talc workers exhibited various degrees of pulmonary
fibrosis. The severity of the fibrosis increased with duration of employment
and concentration of heavy mineral deposits in fibrotic lesions of the lung.
X-ray crystallographic studies of lung digestates revealed that the predominant
mineral in the lungs was talc.
A study of 202 talc (purity not specified) workers in India showed a
significant increase (p <0.001) in respiratory symptoms among the workers when
compared to 101 matched control subjects of the same socioeconomic status but
not engaged in any dusty trade (Bachani and Agarwal, 198S; Bachani, 1984).
Exposure levels were not reported. Signs and symptoms Included pain and
burning of the nose and throat, increased phlegm production, difficulty in
breathing, and chest pain. Clinical examinations revealed a higher number of
workers with nasal and pharyngeal iiucosal congestion and scattered rhonchi.
Over 13 percent of the workers »nd 9 percent of the controls had clinical
evidence of chronic airflow limitation (CAL). The prevalence of CAL was
related to age and smoking history. A positive correlation was found between
the prevalence of CAL and duration of exposure to talc dust. In addition, the
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presence of eosinophils in sputum samples of 13 of 38 workers and none in the
control subjects suggested that talc exposure may induce an allergic-type
pathology.
Changes in ventilatory functions in response to industrial grade talc dust
exposure (no levels given) were investigated in 202 workers (Oamodar et al.,
1983). Smoking habits were graded by duration In years times frequency per
day. FVC, FEV^, and FEV. percent were measured. All indices decreased with
increasing age, intensity of smoking, and duration of exposure. A significant
decrease in pulmonary function was found for workers who smoked compared to
control subjects who smoked. No significant difference was found between
workers and control subjects who did not smoke. The authors postulated a
complementary effect of smoking on talc-induced changes in lung function.
A cross-sectional study of the respiratory function of 116 Vermont miners
and millers of talc ore, free from asbestos and silica, was performed by Wegman
et al. (1982). Exposure levels were found to be below 3.0 mg/m respirable
dust with a geometric mean exposure of 1.8 mg/m respirable dust. In addition,
a 1-year followup evaluation of pulmonary function was performed on 103 work-
ers. A significant reduction in pulmonary function was found in workers who
smoked. After adjusting for smoking, the effect of exposure to talc was not
statistically significant, although there was evidence of an exposure-related
effect in workers with an annual dust exposure of 1.5 mg/m . Effects on
pulmonary function in nonsmokers was not associated with exposure. Talc
exposure was also associated with small, rounded, and irregular opacities seen
on chest x-rays. An annual loss in pulmonary function occurred in the workers
at a rate greater than expected. However, the loss did not correlate with
exposure to talc dust.
A microscopic analysis of the lung and lymph node dust samples from 12
deceased Austrian workers occupationally exposed to talc dust revealed a
slightly increased concentration of real fibers and elongated particles in
comparison to normal individuals (Friedrichs, 1987). The ratio of length to
diameter was inconsistent throughout the diameter range examined and was not
comparable to that found in asbestos workers with mesothelioma. It was con-
cluded that the carcinogenic potential of the fibers was not very high since
neither of the two factors postulated to be important in assessing the carcino-
genic hazard of a fiber, i.e., increased numbers of very fine fibers <0.01 urn
in diameter and high numbers of fibers in the Stanton range, appeared to be
related to the disease state.
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Talc is considered to be hazardous when inhaled in large quantities. The
hazard is acute in cases of accidental Inhalation and chronic in cases of
industrial exposure or prolonged use of commercial products. However, since
talc is not always a uniform substance, the association between talc exposure
and adverse health effects nay be related in some instances to the presence of
contaminating ninerals such as asbestos and silica. Most reports describing
acute and chronic effects of talc exposure Include little characterization of
the talc involved.
Infants and small children have died from cardiorespiratory arrest,
pulmonary edema, and pneumonia within hours after inhaling talcum powder
(Cotton and Davidson, 1985; Motomatsu et el., 1979; Gould and Barnardo, 1972;
Anonymous, 1969). The powder dries the mucous membranes of the bronchioles,
thus disrupting pulmonary clearance and clogging the small airways. Victims
usually display dyspnea, tachypnea, tachycardia, cyanosis, and fever. Broncho-
pulmonary lavage is not effective, since talc is insoluble in water. Gould and
Barnardo (1972) described the case of a 7-year-old girl who survived a massive
aspiration of powdered talc and later developed bronchiectasis of the left
lung.
Lund and Feldt-Rasmussen (1969) described the case of a child who survived
a massive aspiration of talc but only after exhibiting cyanosis, tachypnea with
intercostal retractions, and tachycardia. There was fine crepitation over the
lungs, and x-rays revealed signs of bronchitis and peribronchitis with atelec-
tases. Clinical treatment provided a gradual regression back to normal.
In addition to the effects of a massive acute inhalation, cases of talc
pneumoconiosis or chronic sarcoidosis characterized by foreign body granulomas
and interstitial fibrosis have been reported as a result of chronic use of
cosmetic talcum powder (Tukiainen et el., 1984; Wells et al., 1979). Signs and
symptoms included dyspnea, productive cough, and weakness. Abnormal chest
radiographs and decreased pulmonary function were also observed.
8.3.3.1.2 Effects from dermal application. An analogy between asbestos-
produced mesotheliomas and talc-produced ovarian cancers was originally based
upon the close relationship between talc and asbestos. Additional supporting
evidence for this analogy is derived from the similarity 1n origin and histol-
ogy between mesotheliomas and ovarian cancers (Longo and Young, 1979).
In a case-control study of 215 white females with epithelial ovarian
cancers and 215 controls from the general population, 92/215 (42.8 percent)
cancer cases regularly used talc either as a dusting powder on the perineum or
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on sanitary napkins compared with 61/215 (28.4 percent) of controls (Cramer
«t al., 1982). The relative risk adjusted for parity and menopausal state was
1.92 (p <0.003). A total of 32/215 (14.9 percent) of cancer cases regularly
used talc both on the perineum and on sanitary napkins compared with 13/215
(6.0 percent) of the controls. Women with both exposures therefore had the
greatest adjusted relative risk of 3.28 (p <0.001).
An extraction-replication technique (Griffiths «t al., 1973; Henderson,
1972; Henderson etal., 1973; Henderson and Griffiths, 1975) was used to
examine tissue from patients with ovarian tumors. No asbestos particles were
found in any of the tissues studied (Henderson «t al., 1971). Particles of
talc were identified in approximately 75 percent (10/13) of the ovarian tumors.
Talc particles were found localized deep within the tumor tissue; some were as
small as 1000 angstroms in size, but they were generally within a range from
1000 angstroms to 2 pm.
In a letter to the editor, Hartge et al. (1983) refuted the association
between talc use and ovarian cancer. The data collected were part of a
case-control interview study of epithelial ovarian cancer conducted on 197
women with pathologically confirmed primary epithelial ovarian cancer from 19J
to 1977. The control population consisted of 197 women treated at the same
hospital for conditions other than gynecologic, psychiatric, or malignant
diseases or pregnancy. Questions about talc were added to the questionnaire
after the study began so that 135 cases and 171 controls were questioned about
talc exposure. No increase was found in the relative risk to women who used
talc as a body powder or on diaphragms. A reliable estimate of relative risk
in women who used talc specifically on sanitary napkins, underwear, or the
genital area was not possible, however, because of the small numbers of women
involved.
Granulomas of the skin postulated to be caused by entrance of talc through
the skin at sites of draining or incised furuncles were reported by Tye et al.
(1966).
8.3.3.1.3 Effects from intrapleural Instillation. Adverse systemic effects,
including dyspnea followed by acute respiratory failure and bilateral pleura!
effusion with interstitial infiltrates, was reported 1n a patient a few hours
after talc pleurodesis (Bouchama et al., 1984). The patient improved with
corticosteroid therapy.
A total of 210 cases of patients who had undergone pleurodesis with
iodized talc or kaolin 14 to 40 years previously were traced, and the number's
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of deaths from all causes and cancer of the lung and pleura were compared to a
control death rate derived from age- and year-specific tables from England and
Wales (Research Committee of the British Thoracic Association and the Medical
Research Council Pneumoconiosis Unit, 1979). No increase was found in the
incidence of lung cancer in these patients, and no cases of mesothelioma were
reported.
8.3.3.1.4 Effects from surgical "introduction. Inadvertent Introduction of
talc into the body has been shown to produce granulomas. A granuloma that
completely obstructed the ureter of a 53-year-old woman was attributed to the
introduction of talc as a glove powder 20 years previously during a hyster-
ectomy operation (Joannides, 1978). However, the possibility that the causitive
agent may also have been either starch granules or Lycopodium spores was noted.
Sahi et al. (1967) reported that granuloma formation on the bowel and perito-
neum was believed to be the result of talcum powder use during a previous
surgical intervention. Fienberg (1937) reported two cases of granuloma forma-
tion caused by talc introduced during surgical procedures.
8.3.3.1.5 Effects from intravenous administration. Intravenous abuse of
stimulant drugs intended for oral administration can lead to the embolization
of insoluble tablet fillers such as talc to the pulmonary vasculature. The
vasculature acts as a filter in most cases, thereby restricting talc-induced
pathologic lesions to the lungs. Blockage of pulmonary perfusion by the
passage of intravenously injected talc particles can result in pulmonary
hypertension with the formation of arterio-venous. shunts. The venous blood can
then bypass the lungs and enter the arterial system, lodging particles in
various organs such as the eye. The resulting peripheral retinal neovascular-
ization has been noted after injection of talc emboli (Lederer and Sabates,
1982). Particles smaller than 7 own can travel to the retina via the pulmonary
capillary bed. Bilateral intraretinal talc emboli were reported in 23 patients
by Tse and Ober (1980). A case of talc retinopathy that included vitreous
hemorrhage and retinal detachment was reported by Bluth and Hanscom (1981).
The effects of talc particle injection resulted 1n blindness In this case.
Granulomatous lesions found in lungs, liver, spleen, bone marrow, and
systemic lymph nodes as a result of systemic talc embolization were reported by
Mariani-Costantini et al. (1982). Larger talc crystals (10 to 17 urn) remained
localized in the lungs; small crystals (2 to 10 urn) spread systemically. No
crystals were found in numerous sections of the central nervous system, and
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only a few were present in the myocardium, retina, optic nerve, and kidneys.
The talc particles were present in urine, demonstrating that they may have been
able to pass through the glomerular capillary bed. Self-induced pulmonary
granulomatosis was described by Waller et al. (1980). Cases of intravenous
talc granulomatosis (Tao et al., 1984), liver talc granulomas (Molos et al.,
1987), and systemic talc granulomatosis (Lewis et al., 1985) have been reported
in association with intravenous drug abuse.
8.3.3.2 Epidemiological Studies. Several historical prospective mortality
studies have been conducted to identify potential relationships between expo-
sure to talc and nonmalignant respiratory disease (NMRD). An increase in
respiratory cancer and NMRD was observed in several studies. However, workers
were simultaneously exposed to talc containing asbetos, silicates, carbonates,
or radon. Results from one study indicate that exposure to pure talc was net
associated with increased NMRD or respiratory cancer.
Kleinfeld et al. (1967) conducted a proportionate mortality study of 220
talc miners and millers employed between 1940 and 1965 who had achieved at
least 15 years of exposure to talc dust. In addition to talc, exposure also
included tremolite and anthophyllite (asbestiform and nonasbestiform fibers),
carbonate dusts, and a small amount of free silica. Data for this cohort
concerning employment and health histories as well as deaths were obtained from
a number of sources, including plant records, death certificates (when avail-
able), private physician records, state health department files, hospital
records, and autopsy records (procured for 35/91 deaths). The degree of
completeness for disease ascertainment of the study population and the criteria
for classifications of morbidity and mortality were not specified. The refer-
, ence population used for calculating expected mortality was U.S. white males
for the year 1957, which was the median year of death for the 91 total deaths
occurring out of 220 workers. An analysis of the 91 deaths by cause yielded a
significant increase in the proportional mortality of the total observed deaths
from cancer of the lung and pleura (11 observed, 3.2 expected, Proportionate
Mortality Ratio (PMR) = 344, p <0.01, Power « 21 percent). When the cohort was
analyzed by age group (<40, 40 to 59, 60 to 79, 80+ years), a significant
increase in cancer of the lung and pleura occurred in the subgroup 60 to 79
years old (17 observed, 3.9 expected, PMR « 436, p <0.01, Power = 24 percent).
The authors expressed concern that this finding was at variance with the
results from asbestos workers who had a similar duration of exposure during a
similar period. Increased respiratory cancer incidence was found in both the
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40 to 59 and 60 to 79 age groups of asbestos workers. A possibility exists
that the discrepancy -in these findings could be due to a greater carcinogenic
potential and/or greater exposure levels in the case of asbestos workers.
However, since the power to detect a carcinogenic risk in the 40 to 59 age
group of talc workers was inadequate (21 percent), no definite conclusions
could be drawn. An analysis of Individuals with carcinoma of the lung or
pleura, by duration of txposure, found that all these Individuals were Ini-
tially exposed prior to the institution of wet drilling (a period of heavy
exposure before 1945) with an average duration of exposure of 14.6 years.
Environmental dust exposure concentrations before 1945 ranged from 120 to 818 x
106 particles/ft3 for wines and 69 to 1227 x 106 particles/ft3 for mills, and
between 1946 and 1965 ranged from 5 to 9 x 10 particles/ft for mines and 25
to 73 x 10 particles/ft3 for mills. No direct relationship was observed,
however, between the duration of exposure before wet drilling and the occur-
rence of pulmonary carcinoma.
Of the 91 total deaths, 28 were attributed to pneumoconiosis or complica-
tions or both. Nineteen of the 28 were due to cor pulmonale, which was
reported as a major cause of death among talc workers. Because of the absence
of adequate data, the role of smoking in the causation of pulmonary carcinoma
could not be ascertained in this study.
Findings from an update of this previous study through 1969 further
supported the increased incidence of cancer of the lungs and pleura (Kleinfeld
et al., 1974). The criteria for inclusion in the cohort remained the same for
the followup study. The total number of workers studied was 260, and the
analysis used was a comparison of observed proportional mortality rates from
specific causes with expected rates. Expected mortality for the total group
represented the proportion of deaths among white men in the U.S. due to spe-
cific causes in 1955 (median year of death among the total 108 deaths). For
each of the 5-year periods, median years 1942, 1947, 1952, 1957, and 1962 were
selected. Data for the cohort were obtained from the same sources as those in
the previous study. The total number of deaths out of 260 workers was 108, and
•n analysis of these deaths by cause yielded results consistent with the
previous study; there was a significant increase in proportional mortality from
respiratory cancer in the 60 to 79 age group (16.6 observed, 3.6 expected,
PMR =461, p <0.05).
Insufficient power to detect an increase in other age groups was still a
confounding problem in this analysis. An analyses of carcinoma of the lung and
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pleura as related to six 5-year periods (1940-44, 1945-49, 1950-59, 1960-64,
and 1965-69) revealed significant increases in the observed proportional
mortality for respiratory cancer for three periods: 1945-49 (observed * 11.7,
expected = 3.1, PMR * 377, p <0.05, Power = 18.9 percent); 1950-54 (12.5
observed, 4.3 expected, PMR « 291, p <0.01, Power * 20 percent); and 1955-59
(observed = 20.0, expected « 5.7, PMR * 351, p <0.05, Power * 24 percent).
Investigators found no differences in mortality for respiratory cancer occur-
ring after 1960 and no correlation between respiratory cancer deaths and age or
years of exposure. Ten of the 13 deaths from respiratory tract cancer occurred
in the period between 15 and 24 years of exposure to talc dust. However, a
prolonged exposure of >25 years did not produce any additional risk.
Although they remained major causes of death, deaths attributable to
pneumoconisis and its complications decreased by more than 50 percent in the
last 5-year period studied (decrease from nine to four deaths).
The only historical prospective mortality study conducted with very pure
talc was reported by Rubino et al. (1976). The cohort consisted of 1514 talc
miners and 478 talc millers, who began work in the years between 1921 and 1950,
and who had been employed for at least 1 year in talc operations of the
Germanasca and Chisone Valley. Because millers were exposed to very pure talc,
whereas miners' exposures included a certain amount of inhalable silica parti-
cles, miners and millers were analyzed separately. Data for each worker were
obtained from payrolls and records of a mining company of Pinerolo.
Age-matched control subjects were chosen from the population of the town of
Alba, which represented similar ethnic, social, and economic conditions.
Follow-up for the study cohort was 88.9 percent complete for miners and 91.6
percent complete for millers. The cause of death was obtained from death
certificates for exposed and control persons and was coded according to the 8th
Revision of the ICO. For both internal and external controls, an age- adjusted
modified life-table technique was used to compute expected deaths. The age
intervals used were <30, 30 to 50, 51 to 70, and >70, and the latency periods
were 1 to 10, 11 to 20, 21 to 30, 31 to 40, 41 to 50, and >50.
Cumulative exposure (millions particles per ft /years, mppcf) was computed
by multiplying dust level for a period by number of years exposed and summing
the resulting values for each period. Three exposure levels were then classi-
fied for miners (exposure 1 s 566 to 1,699; exposure 2 = 1,700 to 5,665;
exposure 3 = 5,666 to 12,750) and millers (exposure 1 - 25 to 141; exposure
2 = 142 to 424; exposure 3 = 425 to 906). Analysis of mortality data indicated
1988 8-126 DRAFT—DO NOT QUOTE OR CITE
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a significantly lower mortality for talc miners and millers than expected
(miners « 704 observed, 791.2 expected, SMR * 89, p <0.01, Power = 100 percent;
millers = 227 observed, 258.4 expected, SMR = 88, p <0.01, Power = 100 percent).
When the overall Mortality was subdivided by cause of deaths, deaths from all
NMRD 1n miners were significantly higher than in controls (140 observed, 101.8
expected, SMR = 136, p <0.01, Power = 99.8 percent). Among malignant diseases,
deaths from lung cancer were significantly lower than 1n controls (9 observed,
19.7 expected, SMR * 46, p <0.01, Power * 63.7 percent). An analysis of cause
of death by exposure levels in miners showed a trend of Increasing deaths with
increasing exposure from NMRO (Exposure Level 1 * 26 observed, 36.9 expected,
SMR =70, p <0.05, Power = 86 percent; Exposure Level 2 = 38 observed, 36.3
expected, SMR s 105, not significant, Power * 85.8 percent; Exposure Level
3 = 76 observed, 67.1 expected, SMR * 113, p <0.05, Power « 97.9 percent). No
clear trends, by exposure level, were observed for deaths from any other cause
in miners or millers. When mortality by cause of death was analyzed by latency,
the only significant increase found was for NMRD after 20 to 40 years of
latency (76 observed, 54.4 expected, SMR * 140, p <0.01, Power « 95 percent);
and after >40 years of latency (36 observed, 23.9 expected, SMR = 151, p <0.01,
Power = 151). No significant increase in observed deaths by latency was found
for millers.
The choice of the control population was discussed by the authors as a
confounding factor that could contribute to the observed differences. It was
not possible to verify the appropriateness of this reference group. In addi-
tion, smoking data were unavailable; therefore, it was assumed that the control
and exposed groups were similar in this respect. An internal comparison of
groups of workers by increasing dose and latency period produced a pattern of
excess mortality for respiratory causes of death in miners. This trend, plus
the different incidence of silicosis 1n miners (62 observed, 30.9 expected, SMR
= 201, p <0.01, Power = 80 percent), led the authors to conclude that the
increased risk of death from NMRO was due to silica rather than talc. The lack
of increased risk from any cause of death 1n talc-exposed millers led the
authors to conclude that no evidence from the study supported the role of pure
talc in carcinogenesis. It should be noted, however, that the power to detect
lung cancer in the study population of millers was inadequate.
Brown et al. (1979) conducted a historical prospective mortality study
involving 398 white males initially employed some time between January 1, 1947,
and December 31, 1959, at a talc mine and mill in upper New York State
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(Gouverneur region). Vital status for cohort members as of June 30, 1975, was
determined through government records -Including the SSA, State Vital Statistics
offices, and State Motor Vehicle Registration. Death certificates were obtained
and causes of death were interpreted by a qualified nosologist and converted to
the 7th Revision of the ICD. A wodified life-table technique was used to
obtain person-years at risk of dying by 5-year time periods, 5-year age groups,
duration of employment, and number of years since Initial employment. The
reference population used was U.S. white Bales. Vital status was determined
for 96 percent of the exposed cohort.
No significant difference in overall mortality was observed. However, a
significantly higher mortality from all malignant neoplasms was detected (19
observed, 10.6 expected, SMR = 180, p <0.01, Power = 42 percent). This was
ascribed, in part, to the significant increase in deaths due to bronchogenic
cancer (9 observed, 3.3 expected, SMR = 270, p <0.05, Power = 13 percent). In
addition, investigators found an increase in deaths from NMRD, excluding
influenza, pneumonia, bronchitis, and acute upper respiratory infection (5
observed, 1.3 expected, SMR = 380, p <0.05, Power = 13 percent). An analysis
of the association between bronchogenic cancer and latency revealed a signifi-
cant increase in the interval 20 to 28 years since onset of employment (6
observed, 1.3 expected, SMR = 460, p <0.01, Power = 13 percent).
The study of mortality patterns in workers exposed to talc from the
Gouvernour mining area demonstrated an excess 1n mortality from both NMRD and
bronchogenic cancer. However, this study included several confounding vari-
ables. Smoking histories were unavailable for this cohort. Data on other
occupational exposures were also missing. In addition, an industrial hygiene
analysis showed that the amphibole fiber exposure characteristics between a
neighboring talc operation known to have asbestiform talc and the study mine
and mill were essentially the same. Fiber exposures, when measured in 1975,
were found to exceed Occupational Safety and Health Administration (OSHA)
asbestos standards. The authors postulated that the exposure to asbestiform
tremolite and anthophyllite may have been responsible for the results observed.
A confounding problem with the study cohort was the relatively short duration
of employment for many of the workers: 50 percent were employed less than 1
year, and less than 25 percent were employed >10 years. Of the 10 deaths from
bronchogenic cancer, 4 were found 1n workers employed less than 1 year. Only
two of these four were known to have been previously exposed to talc containing
asbestiform minerals.
•> •-*• r\fM>rT. _nr\ uAT AllATC HP
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Selevan et al. (1979) conducted a historical prospective mortality study
of 392 white male talc workers wt>o had been radiographed as part of the Vermont
Health Department annual surveys. The workers were employed by five companies
in the Vermont talc industry for at least 1 year between January 1, 1940, and
December 31, 1969. Follow-up was begun from the Initial radiographic examina-
tion, when 1 year of employment was achieved, or January 1, 1940, whichever was
later, and was continued through December 31, 1975. Vital status ascertainment
was performed through government records including Social Security Administra-
tion, State vital statistics offices, and State motor vehicle registration
files. Vital status was unknown for 1.0 percent (4 of 392 workers) of the
cohort. Death certificates were obtained, and causes of death were classified
by a qualified nosologist and converted to the 7th Revision of the ICD. A
modified life-table technique was used to obtain person-years of observation by
5-year time periods, 5-year age groups, 5-year exposure groups, and 5-year
latency groups. The study cohort was divided Into two groups, milling (225
workers) and mining (163 workers). A minimum of 1 year of employment in the
work area was required for inclusion; 47 workers (12 percent of the total
population) qualified for inclusion in both groups. U.S. rates were used for
calculation of expected values. In addition,. Vermont rates were used for
comparison in the cases of NMRD and respiratory cancer deaths, since Vermont
rates are higher for these causes.
An analysis of exposure revealed that both airborne dust and bulk samples
of talc from the mines and mills were similar in composition: no asbestos was
detected; free silica was below 0.25 percent for nearly all samples; and the
minerals magnesite, chlorite, and dolomite were present in significant quanti-
ties. Although no cumulative exposures could be calculated, it was not uncom-
mon for past levels to exceed the OSHA and Mine Safety and Health
Administration (MSHA) standard of 20 nppcf. Miners, but not millers, may also
have been exposed to serpentine rock and radon.
The mortality analysis of the total cohort showed that the only signifi-
cant excess occurred from NMRD (excluding influenza and pneumonia) (11 observed,
1.79 expected, SMR = 615, p <0.01, Power « 14 percent), particularly among
| millers (7 observed, 0.89 expected, SMR =787, p <0.01, Power = 5 percent). A
significant increase in respiratory cancer mortality was observed only among
miners (5 observed, 1.15 expected, SMR = 435, p <0.05, Power = 10 percent).
These two significant excesses were maintained when expected numbers of deaths
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from the Vermont population were used (NMRD, 1.33 expected, p <0.01; respira-
tory cancer, 1.22 expected, p <0.05). To confirm that the excess of NMRD
deaths in millers was from talc exposure, chest radiographs for 8 of the 11 men
who died from this disease were examined for pneumoconiosis. Of the eight
radiographs, six (75 percent) had indications of pneumoconiosis. When 2 of the
11 workers with prior dust exposure were included, five of the six (83.3
percent) radiographs were read as having pneumoconiosis. Qualitative radio-
graph readings by the Vermont Health Department provided information on three
deaths with missing radiographs; all three had evidence of pneumoconiosis,
which provided a total of 9 of 11 deaths with readings consistent with pneumo-
coniosis. This supported the association between talc exposure and NMRD.
The authors stated that the possibility of a selection bias was small
because workers who were missed by the radiographic surveys were for the most
part short-term workers. An examination of NMRD mortality by latency resulted
in a pattern of significant excess after 15 years (2 observed, 0.31 expected,
SMR = 645, p <0.05, Power = 8 percent), and after 30 years (5 observed, 0.41
Expected, SMR = 1220, p <0.01, Power « 3 percent), but not before 15 years.
This suggested that no selection bias toward less healthy workers existed. No
data were available on the smoking histories of workers. In addition, the
confounding problem of small cohort size resulted in a lack of adequate power
to detect increased risk in many of the disease categories.
Stille and Tabershaw (1982) conducted a historical prospective mortality
study of 655 white male workers employed between January 1, 1948, and December
31, 1977, at one talc mine and mill (TMX) in upper New York State. Exposure
data were not included. Due to small numbers and lack of talc exposure, women
were excluded from analysis. The cohort was followed until December 12, 197S.
Data on the workers were retrieved from employment records. Vital status was
unknown for 36 members (5.5 percent) of the cohort. Death certificates were
obtained and coded according to the 8th revision of the JCD by a trained
nosologist. Expected values were based on the U.S. white male population by
means of a modified life-table method.
The mortality analysis of the cohort revealed no significant increases in
deaths from all causes, from cancer of the respiratory tract and lung, from
NMRD, or from other causes of death. The cohort was divided into workers with
a prior work history before TMX employment and workers with no known prior work
experience. Investigators found no significant difference in mortality rates
for all disease categories in workers without prior employment. However,
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workers with prior work histories did show significant increases in deaths
attributable to a number of causes including respiratory cancer (9 observed, 4
expected, SMR * 228, p <0.05, Power « 15 percent) and NMRD (9 observed, 2.9
expected, SMR = 307, p <0.01, Power « 15 percent). The authors postulated that
the observed mortality cancer was from exposures that occurred in the workers'
previous jobs.
An analysis of the dose-response relationship of the lung cancer cases
observed in the entire cohort and cumulative dose as Measured by years of
exposure resulted in an Inverse dose-response relationship. Investigators
found a clustering of 9 out of 12 cases within the first 5 years of employment
at TMX. In addition, a calculation of the average latency time for lung cancer
among TMX workers was 19.9 years. The authors cited the lack of a dose-
response relationship and the short latency period as evidence that the prior
occupational exposures and not exposures at TMX may have been the cause of
subsequent cancers.
Confounding variables in the study included the small cohort size and
inclusion of short-term (<1 year) employees. Although the U.S. white male
population was used as a reference group, the authors pointed out that the New
York State cancer death rate is substantially higher (199.24 compared to
174.04). Lack of data concerning smoking histories and incomplete work histo-
ries were also limitations of this study.
Thomas and Stewart (1987) conducted a historical prospective mortality
study of 2055 white males employed for at least 1 year between January 1, 1935,
and January 1, 1966, at three plants of a ceramic plumbing fixture company.
More than 60 percent of the cohort was employed for 10 or more years. Nonwhite
males and females were excluded from the cohort due to small numbers. Vital
status was determined from company, Social Security Administration, credit
bureau, and department of motor vehicle records. As of January 1, 1981, 1394
(67.8 percent) of the 2055 cohort members were alive; 578 (28.1 percent) had
died; and 83 (4.0 percent) were lost to followup. Death certificates were
obtained for all but 1.7 percent of the decedents and coded by a qualified
nosologist using the 8th Revision of the ICO. Expected numbers of deaths were
calculated using rates for U.S. white males. Because exposure data for talc
dust were unavailable, exposure classifications were based on the potential
exposure to silica dust (none, low, high). All jobs involving talc exposure
had high silica exposure and were further classified into no talc, nonfibrous
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talc, and fibrous talc exposures; no talc was the lowest exposure, and fibrous
talc was the highest exposure. No information on smoking patterns was known
for this cohort.
The mortality analysis showed a significant increase in deaths from lung
cancer (52 observed, 36.3 expected, SMR * 143, p <0.05, Power « 85.5 percent)
and NMRD (64 observed, 37.0 expected, SMR s 173, p <0.05. Power * 86 percent).
The increase 1n NMRD deaths was mainly from respiratory disease other than
pneumonia or emphysema, which Included 23 deaths nosologically classified as
pneumoconiosis from silica and silicates (41 observed, 14.1 expected, SMR =
290, p <0.05, Power = 46 percent). An analysis of lung cancer and NMRD by year
of hire showed a significant increase in lung cancer among workers hired
between 1940 and 1949 (22 observed, 11.4 expected, SMR = 193, p <0.05, Power =
45 percent) and a significant increase in NMRD among workers hired before 1940
(55 observed, 24.5 expected, SMR = 224, p <0.05, Power = 68 percent). Analysis
of mortality by exposure category for lung cancer and NMRD revealed a signifi-
cant excess only in workers in the high silica exposure category (44 observed,
24.3 expected, SMR = 181, p <0.05, Power » 68 percent), particularly among
those exposed to nonfibrous talc (21 observed, 8.3 expected, SMR = 254,
p <0.05, Power = 37 percent). In addition, a significant increase in NMRD was
found among those exposed to high silica with no talc exposure (36 observed,
13.7 expected, SMR = 264, p <0.05, Power = 49 percent) and to nonfibrous talc
(16 observed, 7.3 expected, SMR = 220, p <0.05, Power = 31 percent). An
analysis by duration of exposure and years since first silica exposure revealed
an increase in NMRD mortality by duration of exposure (15 to 29 years: 21
observed, 12.1 expected, SMR = 173, p <0.05, Power = 45 percent; and 30* years:
36 observed, 12.8 expected, SMR = 281, p <0.05, Power = 49 percent) and years
since first exposure (50 observed, 22.0 expected, SMR * 227, p <0.05, Power =
66 percent). Lung cancer mortality did not increase with duration of exposure,
but there was an increase in years since first exposure (30* years: 32
observed, 20.6 expected, SMR = 156, p <0.05, Power = 65.8 percent). The
analysis by duration of exposure and years since first exposure to nonfibrous
talc revealed an increased mortality from lung cancer with duration of exposure
(5 to 14 years: 11 observed, 4.0 expected, SMR = 276, p <0.05, Power = 15 per-
cent; and 15* years: 8 observed, 2.2 expected, SMR = 364, p <0.05, Power = 12
percent) and with years since first exposure (5 to 14 years: 8 observed, 2.9
expected, SMR = 281, p <0.05, Power = 15 percent; and 15* years: 13 observed,
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4.7 expected, SMR = 275, p <0.05, Power = 16 percent). Mortality from NMRD was
not affected by duration or time since first exposure to nonfibrous talc.
The excess NMRO was elevated among workers with exposure to high levels of
silica regardless of nonfibrous talc exposure. This risk decreased over time,
suggesting a reduction to silica exposure. Risk of NMRD was also unaffected by
duration or time since first exposure to nonfibrous talc. The authors con-
cluded an association between silica dust rather than talc exposure with this
disease. The excess in lung cancer found in this study, however, occurred
primarily in workers exposed to both nonfibrous talc and silica. Risk of lung
cancer occurred only ajnong those hired after 1940 and increased with increasing
duration of exposure to nonfibrous talc but not with duration of silica expo-
sure. This suggested that exposure to nonfibrous talc was related to lung
cancer risk. However, the confounding problem of simultaneous silica exposure
prevented any conclusions as to their respective roles in the disease.
8.3.4 Venrnculite
8.3.4.1 Cross-Sectional Studies. Clinical Evaluations, and Case Reports.
Results of two studies indicated an association between past fiber exposure and
parenchyma! and pleura! radiographic abnormalities, but no correlation with
pulmonary function tests.
8.3.4.1.1 Respiratory effects. In a review on nonasbestos fibrous materials,
Lockey (1981) concluded that vermiculiHe itself did not produce adverse health
effects but noted that vermiculite ore may contain asbestos fibers. In a more
recent study (Lockey et al., 1984), workers exposed to vermiculite contaminated
with fibrous tremolite were examined. A total of 530 employees in a plant
processing vermiculite ore to its expanded form were studied. Industrial
hygiene sampling of airborne fibers was initiated in 1972, 15 years after the
plant had begun using vermiculite. Particles with a length >5 urn, a diameter
<3 urn, and aspect ratio of 3:1 or greater were counted as fibers. A
high-exposure group was Identified and compared with the chemical processing
facility where exposure was low. The highest cumulative fiber exposure for an
employee was 39 fibers/cm -year; only 9.6 percent had an exposure greater than
10 fibers/cm3-year, and 10.7 percent had been employed 20 years or more since
initial exposure. A cluster of 12 cases of pleura! effusions was identified in
the high-exposure group of 194 workers. Radiographic changes correlated with
exposure when age-matched groups and groups with comparable smoking habits were
Ju1y i988 8-133 nRAFT-.nn NOT nnniF np ri-rr
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compared. The prevalence of pleuritic changes was significantly related to
fiber exposure, but no correlation was found between fiber exposure and various
pulmonary function tests.
Amandus at al. (1987b) conducted a cross-sectional morbidity study of 191
men employed for at least 5 years between 1975 and 1982 at a vermiculite ore
mine and mill near Libby, MT. Radiographic examinations had been administered
by a local hospital to all active workers in 1959 and annually since 1964.
Questionnaires on smoking habits and respiratory symptoms had been administered
by the company to most active workers employed after 1975. Chest radiographs
were available for 184 workers, and questionnaires about smoking and respira-
tory symptoms were available for 121 workers. Radiographic findings were
independently interpreted by three readers blinded to other data. The
radiographic readings indicated that the prevalence of small opacities was 10
percent, any pleura! change was 15 percent, pleura! calcification was 4 per-
cent, and pleura! thickening on the wall was 13 percent. Fiber exposure, as
measured by fiber-years, was significantly related to small opacities, any
pleura! change, and pleura! thickening on the wall (p <0.05). The prevalence
of small opacities was related to age and fiber-years but not significantly
related to smoking. The confounding effect of smoking could not be accurately
assessed, however, due to the small number of nonsmokers (25 overall).
8.3.4.2 Epiderciologica! Studies. Amandus and Wheeler (1987) conducted a
historical prospective mortality study of 575 men hired prior to 1970 and
employed at least 1 year at the vermiculite ore mine and mill near Libby, KT.
Vital status was ascertained for 569 of the 575 cohort members (99 percent) as
of December 31, 1981. Death certificates were obtained for all but two of the
decedents (1.2 percent) and coded according to the 8th Revision of the 1CD.
Expected deaths were calculated from the U.S. white male death rates. Individ-
ual cumulative fiber exposure estimates (fiber-years) for the cohort were
computed for 25 "location-operations" (LO) for the years after 1968 by using an
arithmetic average of fiber concentrations (fibers/cm ) and for the years
before 1968 by using an arithmetic mean of dust concentrations (mppcf).
Vermiculite ore was found to be contaminated with fibrous tremolite-actinolite
(Amandus et al., 1987a).
The results of the mortality analysis indicated a significantly increased
risk of mortality for lung cancer (20 observed, 9.0 expected, SMR = 223.2,
p <0.01, Power = 38 percent) and NMRD (20 observed, 8.2 expected, SMR = 243.0,
p <0.05, Power = 35 percent). An analysis by exposure, measured as fiber-years
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(f*y)i showed a significant increase in mortality in the highest exposure
category (>399 f-y) for both lung cancer (10 observed, 1.7 expected, SMR =
575.5, p <0.01, Power = 12 percent) and NMRD (7 observed, 1.8 expected; SMR =
400.7, p <0.1, Power = 14 percent). Mortality from NMRD was also significantly
elevated in the lowest exposure category (<150 f-y) (8 observed, 3.6 expected,
SMR « 220.0, p <0.05, Power * 18 percent). Mortality from lung cancer and
NMRD was further evaluated by f-y and years of latency. No clear pattern
emerged with respect to latency for lung cancer, although the significant
increases occurred in the highest f-y exposure category (>399) at <10 years
latency (2 observed, 0.2 expected, SMR = 1370.2. p <0.05, Power * 4 percent)
and £20 years latency (7 observed, 1.0 expected, SMR = 671.3, p <0.01, Power =
7 percent). No exposure-response association was found for NMRD; significant
effects occurred after 10 to 19 years of latency for 100 to 399 f-y
(3 observed, 0.6 expected, SMR = 459.9, p <0.05, Power « 6 percent) and >399
f-y (4 observed, 0.5 expected, SMR * 774.5, p <0.01, Power = 4 percent)- At
£20 years, only the lowest exposure category (<50 f-y) was significant
(7 observed, 2.1 expected, SMR = 327.8, p <0.05, Power = 10 percent). There
was insufficient power to detect significant increases in risk at other expo-
sure and latency periods. In addition to small cohort size and insufficient
power to.detect lung cancer and NMRD among the whole cohort, another confound-
ing variable in this study included the effect of smoking. The proportion of
current and former smokers among 161 vermiculite workers was found to be
15.5 percent higher than that among U.S. white males in 1975. Another source
of bias may have been the use of the national mortality rates rather than state
or county rates.
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Winkelmann, R. ; Westerholm, P.; Winter, P. D.; Zocchetti, C. (1986c) The
man-made mineral fiber European historical cohort study. Scand. J. Work
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Simonato, L. ; Fletcher, A. C. ; Cherrie, J. W.; Andersen, A.; Bertazzi, P.;
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(1987) The International Agency for Research on Cancer historical cohort
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the follow-up. Ann. Occup. Hyg. 31: 603-623.
Skuric, 2.; Stahuljak-Beritic, D. (1984) Occupational exposure and ventilatory
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Stille, W. T.; Tabershaw, I. R. (1982) The mortality experience of upstate New
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Stokholm, J. ; Norn, M. ; Schneider, T. (1982) Ophthamologic effects of man-made
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Tao, L.-C.; Morgan, R. C. ; Donat, E. E. (1984) Cytologic diagnosis of intrave-
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Teppo, L. ; Kojonen, E. (1986) Mortality and cancer risk among workers exposed
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9. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
The quantification of toxicological effects of a chemical consists of
separate assessments of noncarcinogenic and carcinogenic effects. Noncarcino-
genic effects are believed to occur via a threshold mechanism for which concen-
trations that produce adverse health effects can be identified, while
carcinogenic mechanisms are assumed to act without a threshold. The procedures
used to quantify toxicological effects are based on guidelines proposed by the
U.S. Environmental Protection Agency (1986, 1988) for inhalation exposure or
oral intake. No guidelines are available for intraperitoneal or intrapleural
administration. These procedures are summarized below.
9.1 PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS
9.1.1 Noncarcinogenic Effects
In the quantification of noncarcinogenic effects, a Reference Dose (RfD)
is calculated. The RfD is an estimate (with an uncertainty spanning perhaps an
order of magnitude) of a daily exposure of the human population (including
sensitive subgroups) that is likely to be without an appreciable risk of
deleterious health effects during a lifetime.
RfDs are typically calculated using a single exposure level and uncer-
tainty factors that account for specific deficiencies in the toxicity date
base. Both the exposure level and the uncertainty factors are selected and
evaluated in the context of all available chemical-specific literature. After
all toxicological, epidemiologic, and supporting data have been reviewed and
evaluated, a key study Is selected that reflects optimal data on the critical
effect. Dose-response data points for all reported effects are examined as a
component of this review.
The threshold concept is the basis for the derivation of the RfD. Essen-
tially, an experimental exposure level is selected from the available studies
that represents the highest level tested in which an adverse effect was not
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demonstrated. This chosen No-Observed-Adverse-Effect Level (NOAEL) represents
the first quantitative basis for the scientific evaluation of the risk posed to
humans by systemic toxicants. The RfD is operationally derived from this NOAEL
or from the Lowest-Observed-Adverse-Effect Level (LOAEL) by consistent applica-
tion of general order-of-magnitude uncertainty factors (UFs) that reflect the
second quantitative basis of this scientific evaluation of risk. Uncertainty
factors are associated with various specifically recognized uncertainties
(i.e., toxicity data base deficiencies) when extrapolating from the type of
study from which the RfD is estimated. Suggested uncertainty factors for
extrapolation follow:
Human to Sensitive Human
Animal to Human
Subchronic to Chronic
LOAEL to NOAEL
Incomplete to Complete
Use a 10-fold factor when extrapolating from valid
experimental results of studies using prolonged
exposure to average healthy humans. This factor is
intended to account for the variation in sensitivity
among the members of the human population.
Use an additional 10-fold factor when extrapolating
from valid results of long-term studies on experi-
mental animals when results of human exposure stucies
are not available or are inadequate. This factor isi
intended to account for the uncertainty in extrapo-
lating from animal data to the case of humans.
Use up to an additional 10-fold factor when extrapo-
lating from less than chronic results on experimental
animals when there are no useful long-term human
data. This factor is intended to account for the
uncertainty in extrapolating from less than chronic
NOAELs to chronic NOAELs.
Use up to an additional 10-fold factor when deriving
an RfD from a LOAEL instead of a NOAEL. This factor
is intended to account for the uncertainty in extrap-
olating from LOAELs to NOAELs.
Use up to a 10-fold factor when extrapolating from
valid results in experimental animals when the data
are "incomplete." This factor is intended to account
for the inability of any single animal study to
adequately address all possible adverse outcomes in
humans.
An additional modifying factor (MF) reflects professional judgment of the
entire data available on the specific agent and is usually >0 and <10.
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The inhalation RfD is derived from the NOAEL as:
RfD = NOAEL/UF x MF
where:
UF « an uncertainty factor suited to the characteristics of the data.
MF - a modifying factor, based on professional judgment of the entire
data base (e.g., sample size).
9.1.2 Carcinogenic Effects
9.1.2.1 Studies in Humans. Evidence of carcinogenicity from human studies
comes from case reports, descriptive or cross-sectional studies, and analytical
epidemiology or case-control and cohort studies. The weight of evidence for
carcinogenicity from studies in humans is classified as follows:
1. Sufficient evidence of carcinogenicity, which indicates that a
causal relationship exists between the agent and human cancer.
2. Limited evidence of carcinogenicity, which indicates that a
causal interpretation is credible, but that alternative explana-
tions, such as chance, bias, or confounding, could not be
adequately excluded.
3. Inadequate evidence, which indicates that there were few avail-
able studies with little pertinent data, which while showing
evidence of association, did not exclude chance, bijs, or
confounding, and therefore, a causal interpretation is not
credible.
4. No data, which indicates that data are not available.
5. No evidence, which indicates that no association was found
between exposure and an increased risk of cancer in well-
designed and well-conducted independent analytical epidemi-
ologic studies.
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9.1.2.2 Studies in Animals. Evidence of carcinogenicity in animals is classi-
fied into five groups:
1. Sufficient evidence of carcinogenicity, which indicates an
increased incidence of malignant tumors or combined malignant
and benign tumors (1) in multiple species or strains; or (2) in
multiple experiments (e.g., with different routes of administra-
tion or using different dose levels); or (3) to an unusual
degree in a single experiment with regard to high incidence,
unusual site or type of tumor, or early age at onset.
Additional evidence may be provided by data on dose-response
effects, as well as information from short-term tests or on
chemical structure.
2. Limited evidence of carcinogenicity, which means that the data
suggest a carcinogenic effect but are limited because (1) the
studies involve a single species, strain, or experiment and do
not meet criteria for sufficient evidence; (2) the experiments
are restricted by inadequate dosage levels, inadequate duration
of exposure to the agent, inadequate period of followup, poo-
survival, too few animals, or inadequate reporting; or (3) there
is an increase in the incidence of benign tumors only.
3. Inadequate evidence, which indicates that because of major
qualitative or quantitative limitations, the studies cannot be
interpreted as showing either the presence or absence of a
carcinogenic effect.
4. No data, which indicates that data are not available.
5. No evidence, which indicates that no increased incidence of
neoplasms has been found in at least two well-designed and
well-conducted animal studies in different species.
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The EPA categorizes the carcinogenic potential of a chemical, based on the
overall weight of evidence, according to the following scheme:
• Group A: Human Carcinogen. Sufficient evidence exists from
epidemiology studies to support a causal association
between exposure to the chemical and human cancer.
• Group B: Probable Human Carcinogen. Sufficient evidence of
carcinogenicity in animals with limited (Group Bl) or
inadequate (Group 62) evidence in humans.
• Group C: Possible Human Carcinogen. Limited evidence of
carcinogenicity in animals in the absence of human data.
• Group D: Not Classified as to Human Carcinogenicity. Inadequate
human arid animal evidence of carcinogenicity or for
which no data are available.
• Group E: Evidence of Noncarcinogenicity for Humans. No evidence
of carcinogenicity in at least two adequate animal tests
in different species or in both adequate epidemiologic
and animal studies.
If lexicological evidence leads to the classification of the contaminant
as a known, probable, or possible hunan tBrcinogsn, mathematical models are
used to calculate the estimated excess cancer risk associated with exposure to
the chemical. The data used in these estimates usually come from lifetime
exposure studies in animals. To predict the risk for humans from animal date,
animal doses must be converted to equivalent human doses. This conversion
includes correction for noncontinuous exposure, less-than-lifetime studies, and
for differences in size. The factor that compensates for the size difference
is the cube root of the ratio of the animal and human body weights. It is
assumed that the average adult human body weight is 70 kg.
Chemical levels are correlated with a carcinogenic risk estimate by
employing a cancer potency (unit risk) value together with the assumption for
lifetime exposure via inhalation or ingestion. The cancer risk is usually
derived from the linearized multistage model with • 95 percent upper confidence
limit providing a low-dose estimate; that is, the true risk to humans, while
not identifiable, is not likely to exceed the upper limit estimate and, in
fact, may be lower. Excess cancer risk estimates may also be calculated using
other models such as the one-hit, Weibull, logit, and probit. There is little
basis in the current understanding of the biological mechanisms involved in
i.,i,, TQDP Q-n noj&rT—nn wni nnnic nP fTTF
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cancer to suggest that any one of these models is able to predict risk more
accurately than any other. Because each model is based on differing assump-
tions, the estimates that are derived for each model can differ by several
orders of magnitude. However, a model that incorporates low dose linearity in
tumor formation, such as the multistage, is preferable as it is more scientif-
ically plausible.
The scientific data base used to calculate and support the setting of
cancer risk rate levels has an inherent uncertainty due to the systematic and
random errors in scientific measurement. In most cases, only studies using
experimental animals have been performed. Thus, there is only uncertainty when
the data are extrapolated to humans. When developing cancer risk rate levels,
several other areas of uncertainty exist, such as the incomplete knowledge
concerning the health effects of chemicals in the environment; the impact of
the experimental animal's age, sex, and species; the nature of the target organ
system(s) examined; and the actual rate of exposure of the internal target
organs in experimental animals or humans. 'Dose-response data usually are
available only for high levels of exposure, not for lower levels of exposure,
levels that are closer to the standard and closer to levels to which humans are
exposed. When there is exposure to more than one contaminant, additional
uncertainty results from a lack of information about possible synergistic or
antagonistic effects.
9.2 MANMADE MINERAL FIBERS
9.2.1 Human Health Effects
The carcinogenicity of crocidolite asbestos fibers in both humans and
animals has been well-established. The available epidemiological evidence
clearly demonstrates an association between exposure to asbestos and the
subsequent development of carcinomas of the lung and diffuse mesotheliomas of
the pleura and peritoneum. According to the International Agency for Research
on Cancer (IARC), following a long latency period, an increased risk of pleura!
and peritoneal mesotheliomas with increasing duration of exposure has been
reported in persons occupationally or environmentally exposed to asbestos
fibers (National Research Council, 1984). The epidemiological study of
respiratory diseases and asbestos exposure has detected low to moderately-
increased risk ratios (two- to fivefold) for lung cancer, laryngeal cancer,
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gastrointestinal cancer, and colorectal cancer, as well as high risk ratios
(ninefold) for lung cancer among those with asbestosis. In addition, there is
a we 11-documented synergistic relationship between asbestos exposure and
smoking for the development of lung cancer. However, the risk of mesothelioma
appears to be independent of smoking.
Because of the physical similarities between WIMP and asbestos fibers and
because of the widespread and Increasing use of HMMF, numerous epidemiological
studies have been conducted to determine whether a causal relationship exists
between exposure to MMMF and malignant and nonmalignant respiratory disease.
These studies, all of which are historical prospective in design, have been
critically reviewed in Chapter 8 and summarized in Table 8-12. No epidetniologic
studies were found for ceramic fibers.
Limitations in the epidemiologies! method in elucidating occupational and
environmental hazards are more often a result of an absence of available
information rather than a flaw in methodology. In the case of MHMF, many
well-conducted studies exist when evaluated in the context of adequate design
and followup. However, factors such as low estimated levels of exposure or
short duration of exposure, coupled with insufficient power to detect a
50 percent increased incidence of cancer, NMRD, or mesothelioma when the data
are divided into multiple subcategories, make the observed risk sufficiently
low to be masked by background mortality rates. This especially holds true for
lung cancer, which has a high background rate. Therefore, since an epidemio-
logical study, like any other screening test, is an instrument of limited
sensitivity, however well a study is conducted it can only detect effects
within the limits of sensitivity of the experimental design.
While the overall quality of the epidemiological studies on MMMF is good,
because no actual exposure data on historical levels of MMMF exist with which
to establish a dose-response relationship, these data are unsuitable for the
quantification of risk. A summary of the weight of evidence for causal rela-
tionships between exposure to various MMMF and NMRD and carcinogenic effects is
presented in Table 9-1.
9.2.1.1 Fibrous Glass
9.2.1.1.1 Qualitative evaluation of noncarcinogenic effects. An evaluation
of noncarcinogenic effects following exposure of workers to glass microfibers
indicates no association between exposure to glass microfibers and subsequent
development of NMRD. Similarly, it appears that no association exists between
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TABLE 9-1. SUMMARY OF THE WEIGHT OF EVIDENCE FOR CAUSAL RELATIONSHIPS
BETWEEN EXPOSURE TO MMMF AND CARCINOGENIC AND NONCARCINOGENIC EFFECTS
Fiber
Effect
Weight
of Evidence
Glass microfibers
Fibrous glass wool
Continuous fibrous glass
filament
Mineral wool
Ceramic fibers
NMRDa
Respiratory cancer
NMRD
Lung cancer
Laryngeal cancer
Buccal cavity cancer
NMRD
Lung cancer
NMRD
Respiratory cancer
Lung cancer
Digestive system cancer
Stomach cancer
Buccal cavity and
pharyngeal cancer
b
Inadequate
Inadequate
Limited
Limited
Limited
Limited
Inadequate
Inadequate
Inadequate
Limited
Limited
Limited
Limited
Limited
Nonmalignant respiratory disease.
5No data are available.
exposure to fibrous glass wool and subsequent development of NMRD. In both
cases, the apparent absence of an association, however, is limited by the
sensitivity of the studies to detect a 50 percent increase in NMRD. Enterline
et al. (1983, 1986) found excess NMRD in the combined fibrous glass wool/
continuous fibrous glass filament category, but did not find an excess of
NMRD associated with fibrous glass wool or continuous fibrous glass filament
when the data were analyzed by fiber. Only one study (Bayliss et al., 1976)
detected an excess of NMRD in fibrous glass wool workers (SMR = 189, p <0.05,
Power = 34 percent), which increased among those with 10 or more years of
latency. This twofold excess was limited to one study and is insufficient for
establishing a causal relationship. Therefore, the weight of evidence for a
causal relationship between fibrous glass wool and NMRD is limited. The
evidence is inadequate to establish a causal relationship between continuous
fibrous glass filament and NMRD.
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9.2.1.1.2 Characterization of carcinogenic effects. An evaluation of carcino-
genic effects following exposure of workers to glass microfibers indicates no
association between exposure to glass microfibers and subsequent development of
cancer. Only four studies focused on workers in MMMF plants who were most
likely to have been exposed to nicrofibers. Neither the series of studies by
interline et al. (1983, 1986, 1987) nor the study by Bayliss et al. (1976)
found significant excesses of respiratory or other cancers associated with
exposure to microfibers. The relationship between the calculated SMRs for
respiratory cancer and exposure to nricrofibers reported in the studies by
Enter!ine et al. (1986, 1987) and Bayliss et al. (1976) led the authors to
conclude that these data supported the hypothesis of an association between
microfiber exposure and respiratory cancer. Since the excesses reported were
not statistically significant, however, and nay have been elevated because of
random variation or as a result of chance, such excesses could not be used to
establish a causal relationship. The lack of statistical significance, how-
ever, might be attributed to the insufficient sensitivity to detect a 50 per-
cent increase in respiratory cancer, if it did, in fact, exist among workers
exposed to glass microfibers. Thus, the weight of evidence for a causal
relationship between microfibers and respiratory cancer was inadequate.
Concerning carcinogenic effects following exposure of workers to fibrous
glass wool, investigators found excesses from respiratory cancer, including
lung cancer and laryngeal cancer; from stomach cancer; and from buccal
cavity/pharyngeal cancer, especially buccal cavity cancer. Enterline et al.
(1986) found an excess of respiratory system cancer in U.S. male production and
maintenance workers after 20 or more years of latency following exposure to
both fibrous glass wool and continuous fibrous glass filament (SMR = 129.5,
p <0.01), which in the subsequent study (Enterline et al., 1987) was decreased
and no longer significant compared to local mortality rates (SMR = 110.6).
Similarly, an excess of respiratory cancer among those with 30 or more years of
latency following exposure to both fibrous glass wool and continuous fibrous
glass filament (SMR = 137.8, p <0.01), and which increased after 20 to 29 years
of employment (SMR = 160.1, p <0.01) (Enterline et al., 1986), was no longer
significant compared to local mortality rates (Enterline et al., 1987). Since
local mortality rates are more appropriate than national rates as comparison
groups for respiratory cancer, these results suggest that no relationship
existed between respiratory cancer and exposure of workers to fibrous glass
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wool In combination with continuous fibrous glass filament. While there was
sufficient power to detect respiratory cancer among those exposed to both
fibrous glass wool and continuous fibrous glass filament, there was
insufficient power when the cohort was subdivided by latency or duration of
exposure. Therefore, the weight of evidence for a causal relationship between
combined exposure to fibrous glass wool and continuous fibrous glass filament
and respiratory cancer is inadequate.
In Canada, Shannon et al. (1986, 1987) found a twofold excess (p <0.005,
Power = 36 percent) of lung cancer in male production workers with the highest
exposure to fibrous glass wool when compared to provincial mortality rates. In
addition, an excess of lung cancer was observed among those with the longest
duration of exposure (>S years) and the longest time since first exposure
(>10 years) (SMR = 182, p <0.05, Power = 28 percent). This suggests a causal
relationship between exposure to fibrous glass wool and lung cancer that also
was associated with increasing latency and duration of exposure. In England,
Gardner et al. (1986) found a 30 percent increase in lung cancer mortality
(p <0.05, Power = 95 percent) among male fibrous glass wool production workers
when compared to national rates. Although additional excesses were found when
the data from male production workers were analyzed by latency and duration of
employment, these excesses were not significant compared to local mortality
rates. However, the low power to detect lung cancer when the data among male
production workers were analyzed by duration of employment and by latency may
have contributed to the apparent absence of a lung cancer risk using local
mortality rates. Pooling data from 13 European MMMF plants, Simonato et al.
(1986a,b,c) found an excess of lung cancer among fibrous glass wool workers
compared to national rates (SMR = 127, p <0.05), especially among those with 30
or more years since first exposure to fibrous glass wool (SMR « 173, p <0.05).
There was an excess of lung cancer during the intermediate phase of fibrous
glass wool production (SMR » 164, p <0.05). Among those with 20 or more years
of latency, lung cancer did not appear to increase with increasing length of
exposure. In subsequent studies, however, Simonato et al. (1986b,c, 1987)
reported that the above excesses from lung cancer were no longer significant
compared to local mortality rates. Again, the apparent absence of a lung
cancer risk using local mortality rates may be attributable to the insufficient
power to detect a 50 percent increase in lung cancer when the data were sub-
divided into latency and duration groups. Therefore, the data are equivocal:
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a twofold significant excess of lung cancer among Canadian fibrous glass wool
workers, which was associated with latency and duration, supports a causal
relationship between lung cancer and exposure to fibrous wool. The failure to
sustain significant excesses of lung cancer among English and other European
fibrous glass wool workers when compared to local rates refutes such a rela-
tionship. Thus, the weight of evidence for a causal relationship between
fibrous glass wool and lung cancer is limited.
Concerning other carcinogenic effects following exposure to fibrous glass
wool, in Italy, Bertazzi et al. (1984) found a fourfold excess of laryngeal
cancer among male fibrous glass wool production workers compared to national
but not local or regional rates. Despite low power and only four observed
laryngeal cancer deaths, compared to local mortality rates, a consistent,
significant increase was observed among the fibrous glass wool workers who were
most heavily exposed. The excesses ranged from eightfold among those with 20
or more years of exposure to fifteenfold for those whose first exposure was
before age 25. All four cases were first employed before 1960 when fibrous
glass wool rather than continuous fibrous glass filament was produced, thereby
indicating a temporally correct association. This excess was confirmed in a
followup study by Bertazzi et al. (1986) that detected nine deaths from
laryngeal cancer, all of which occurred in male production workers. Six of the
nine deaths occurred in the Italian fibrous glass wool cohort studies by
Bertazzi et al. (1984, 1986) and Simonato et al. (1986a,b,c) and resulted in a
fourfold increase (6 observed, 1.5 expected, SMR = 400, p <0.05, Power =
8 percent). In other plants, the apparent lack of an excess from laryngeal
cancer mortality could be attributed to the insufficient power to detect
50 percent increased risk of death from laryngeal cancer. The additional
deaths identified by Simonato et al. (1986c) after increased followup con-
firmed the previous findings by Bertazzi et al. (1984, 1986) of an elevated
laryngeal cancer risk in the Italian fibrous glass wool cohort. The strength
of the association despite low power, I.e., large SMRs that increased with
increasing latency and length of exposure, the significant findings after
comparison with high local rates of laryngeal cancer that would control for
exogenous risk factors such as smoking and alcohol consumption, the additional
cases among male production workers identified by Simonato and colleagues that
were consistent with previous excesses identified by Bertazzi and colleagues,
and the biological plausibility for the excess laryngeal cancer risk, suggest
-------
that a causal relationship existed between exposure to fibrous glass wool and
laryngeal cancer. However, the excess is apparently limited primarily to
Italian workers and is based on only six deaths. Therefore, the weight of
evidence for a causal relationship between exposure to fibrous glass wool and
laryngeal cancer is limited at the present time.
In England, Gardner et al. (1986) found an excess of stomach cancer among
female employees of a fibrous glass wool plant compared to national (SMR = 277,
p <0.05, Power = 8 percent), but not local, mortality rates. No excesses of
stomach cancer were found in other studies following exposure to fibrous glass
wool. A threefold excess of stomach cancer limited to one study is insuffi-
cient for establishing a causal relationship. Therefore, the weight of evi-
dence for a causal relationship between exposure to fibrous glass wool and
stomach cancer is inadequate.
In France, Moulin et al. (1986) found a twofold increased incidence of
upper respiratory and alimentary tract cancers among active or retired fibrous
glass wool workers (SIR = 218, p <0.005, Power = 33 percent) compared to
regional rates. Despite low power, investigators found a threefold excess from
buccal cavity cancers (SIR = 317, p <0.001, Power = 22 percent). Significant
excesses were greater among production workers in the two highest latency
groups, 10 to 19 years (SIR = 304, p 20 years (SIR = 333,
p <0.005). Although a threefold excess of buccal cavity cancer provides strong
evidence for a causal relationship, it is limited to only one study. There-
fore, the weight of evidence for a causal relationship between exposure to
fibrous glass wool and buccal cavity cancer is limited.
Concerning carcinogenic effects following exposure of workers to continu-
ous fibrous filament, Simonato et al. (1986c) found an excess of lung cancer
among male and female production workers from the combined European cohort with
less than 10 years of latency compared to national rates (SMR = 224, p <0.05,
Power = 15 percent) but not compared to local rates (Simonato et al., 1986b,c,
1987). The appearance of an excess after so short a latency period argues
against a causal relationship. Other studies of continuous fibrous glass
filament workers found no excess site-specific cancers (Enterline et al., 1986,
1987; Bertazzi et al., 1984, 1986; Gardner et al., 1986); none of these had
sufficient power to detect lung cancer or.laryngeal cancer in this group of
workers. A twofold excess of lung cancer after an inadequate latency period is
insufficient for establishing a causal relationship. Therefore, the weight of
- - -««<•> O.T? noarT-.nn wni nnniF DR CITE
-------
evidence for a causal relationship between exposure to continuous fibrous glass
filament and respiratory cancer is Inadequate.
9.2.1.2 Mineral Wool
9.2.1.2.1 Qualitative evaluation of noncarcinogem'c effects. An evaluation of
noncarcinogenic effects following exposure of workers to mineral wool indicates
that only one study (Enter!ine et a!., 1983} detected an excess of NMRD in male
workers employed in a single plant (SMR = 221, p <0.05, Power = 30 percent).
This excess appeared unchanged after 20 or more years of latency (SMR = 219.9,
p <0.05, Power = 25 percent) and did not persist in the 1986 study after
additional years of followup (Enterline et al., 1986). A twofold excess
limited to one study, which did not increase after 20 years of latency, is
insufficient for establishing a causal relationship. Therefore, the weight of
evidence is inadequate for a causal relationship between mineral wool and NMRD.
Therefore, no association appears to exist between noncarcinogenic effects
and exposure to glass microfibers, fibrous glass wool, continuous fibrous glass
filament, or mineral wool. There are numerous reasons why an association was
not detected. First, there may be no such relationship. Second, exposure
levels may have been too low to induce a response. Third, a relationship may
have been undetected because of insufficient power to detect a 50 percent
increase in NMRD if it did exist. Based on these limitations, the most that
can be concluded is that the available studies failed to demonstrate NtfRD
within the limits of statistical sensitivity imposed by their respective study
designs. The absence of a dose-response relationship or increased mortality
from NMRD does not establish the safety of the individual fiber types studied.
9.2.1.2.2. Characterization of carcinogenic effects. An evaluation of carci-
nogenic effects following exposure of workers to mineral wool indicates signif-
icant excesses from respiratory cancer including lung cancer; from digestive
tract cancer including digestive organ and peritoneal cancer, digestive organ
cancer, stomach cancer, intestinal cancer, and pancreatic cancer; and from
buccal cavity and pharyngeal cancer. In the United States, Enterline and Marsh
(1982) found a 2.5-fold excess of respiratory cancer (p <0.05, Power =
12 percent) among male production and maintenance workers in one mineral wool
plant out of eight MMMF plants with less than 20 years of latency. After 20 or
more years of latency, this excess increased to ninefold (p <0.05, Power =
4 percent). Enterline et al. (1983) found that the respiratory cancer excess
was no longer limited to Plant 7, but included all mineral wool workers (SMR =
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160.1, p <0.01, Power = 64 percent). As in the previous study, the greatest
excess was found in Plant 7 (SMR = 451.3, p <0.01, Power « 14 percent) and also
resulted in a ninefold excess after 20 or more years of latency (p <0.01,
Power = 3 percent). A 46 percent excess of respiratory cancer among all
mineral wool workers after 20 or more years of latency found by Enter!ine et
al. (1986) was no longer significant when compared to local mortality rates in
a later analysis (Enter!ine et al., 1987). However, as in the previous studies
by Enterline and colleagues, there was insufficient power to detect a 50 per-
cent increased risk of death from respiratory cancer among mineral wool
workers with 20 or more years of latency. Evidence of a respiratory cancer
hazard following mineral wool exposure was strengthened when Enterline et al.
(1987) found a significant excess of respiratory cancer among mineral wool
workers (SMR = 148.4, p <0.01, Power = 89 percent) even when compared to local
mortality rates (SMR ~ 133.6, p <0.05, Power « 91 percent). This shows that
with adequate power, respiratory cancer is significantly elevated compared to
background rates, thereby taking into account etiologies! agents such as
smoking and local mortality differences that could influence the magnitude of
the risk as well as social, economic, ethnic, and cultural factors related to
disease. The strength of the association despite low power, i.e., SMRs that
increased with increasing latency, and the significant findings among all
mineral wool workers compared to both national and local mortality rates,
suggest that a causal relationship existed between mineral wool and respiratory
cancer. However, one cannot completely rule out other etiological agents that
might be capable of inducing similar effects. Therefore, the weight cf
evidence for a causal relationship between mineral wool and respiratory cancer
is limited at the present time.
In Europe, despite low power, Andersen and Langmark (1986) found a three-
fold increase in lung cancer incidence compared to national rates among male
mineral wool workers in a rock wool plant, which became more pronounced when
short-term workers, i.e., those employed for less than 1 year, were excluded
(SIR = 386, p <0.01). They also found a twofold increase in lung cancer
incidence (p <0.05, Power = 21 percent) among those employed for 1 or more
years in one of three mineral wool plants after 20 or more years of latency.
Westerholm and Bolander (1986) found a ninefold excess (p <0.005) of lung
cancer compared to national rates in male and female mineral woo! production
workers with 1 to 4 years of employment and after 30 or more years of latency,
July 1988 9-14 DRAFT-DO NOT QUOTE OR CITE
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even though there was insufficient power to detect lung cancer (Power = 4 per-
cent). Olsen and Jensen (1984) found a twofold increase in lung cancer
incidence among male and female production workers after 20 or more years of
latency compared to national rates (p <0.05, Power = 20 percent). This excess
was concentrated among male production workers (SIR = 195, p <0.05). Claude
and Frentzel-Beytne (1986) found a threefold excess among male production and
maintenance workers who were hired before the introduction of resin binders in
1953 and who had 10 to 19 years of latency compared to national rates (p <0.05,
Power = 12 percent). Pooling data from the European studies, Simonato et al.
(1986a) found an excess of lung cancer among mineral wool workers first
employed during the early technological phase of MMMF production compared to
both national (SMR =214, p <0.05, Power * 14 percent) or local mortality rates
(SMR * 257, p <0.05, Power = 24 percent). This excess was even greater after
20 or more years since first exposure to mineral wool during the early
technological phase (SMR = 295, p <0.05, Power = 8 percent). Subsequent studies
by Simonato et al. (1986b,c, 1987) confirmed these excesses even when compared
to local rates. Combining U.S. and European mineral wool workers, Doll (1987)
found that compared to local mortality rates, the lung .cancer excess was
greatest among mineral wool workers with 30 or more years of latency (SMR = 148,
p <0.05, Power = 74 percent). Despite low power, the following factors suggest
that a causal relationship existed between exposure to mineral wool and lung
cancer: the strength of the association, ranging from two- to ninefold; the
significant excesses in nine studies, even when compared to local mortality
rates; the appearance of the excesses during the early technological phase of
MMMF production; and the concentration of excesses among production workers
employed for at least 1 year. Therefore, similar to respiratory cancer, the
weight of evidence for a causal relationship between exposure to mineral wool
and lung cancer is limited at the present time.
Investigators found numerous excesses from digestive tract cancer follow-
ing exposure to mineral wool. In the United States, Robinson et al. (1982)
found a 3.3-fold increase in digestive system cancer among male mineral wool
production workers with 20 or more years of employment (p <0.05, Power =
8 percent). In Europe, Olsen and Jensen (1984) found a 52 percent incidence
of digestive organ and peritoneal cancer among male and female mineral wool
production workers during the first 10 years after initial employment (p <0.05,
Power = 53 percent). In a followup study, Olsen et al. (1986) found a
.iniu TQftfi Q-l*; neari-.nn WOT nunrc np TTTF
-------
50 percent increased incidence of digestive organ cancer among male production
workers (p <0.05, Power - 90 percent). Claude and Frentzel-Beyme (1984) found
an excess of stomach cancer among male production workers after 20 to 29 years
of latency (SMR = 273, p <0.05, Power = 14 percent). In a followup study,
Claude and Frentzel-Beyme (1986) confirmed their various findings of a cancer
excess and further found that it was concentrated among male production and
maintenance workers who had been hired before the introduction of resin binders
in 1953 and who had 20 to 29 years of latency (SMR = 261, p <0.05, Power =
14 percent). Using internal controls as a reference group, a sevenfold relative
risk of pancreatic cancer was found. Andersen and Langmark (1986) found a
twofold increase in intestinal cancer among male mineral wool workers employed
at least 1 year (p <0.05, Power = 28 percent). Based on excesses of digestive
system cancer among male and female mineral wool production workers from three
studies, two of which showed excesses ranging from 33 to 50 percent in male
production workers alone, a causal relationship appears to exist between
digestive system cancer and exposure to mineral wool. The excesses of stomach
cancer found in two studies of male production workers with sufficient latency
and employed before the introduction of resin binders also support a causal
relationship between stomach cancer and exposure to mineral wool, but these
excesses were limited to one factory. Excesses from pancreatic cancer and frorr,
intestinal cancer were each limited to one study and are probably not causally
related to mineral wool exposure. Therefore, the weight of evidence for a
causal relationship is limited for digestive system cancer and stomach cancer
and inadequate for pancreatic cancer and for intestinal cancer.
In Europe, Olsen et al. (1986) found an increased incidence from buccal
cavity and pharyngeal cancer among male production workers (SIR = 210, p <0.05,
Power = 24 percent). The low power to detect buccal cavity and pharyngeal
cancer in many subcategories, which were found in several of the individual
European studies, remained even when the data from the 13 plants were pooled.
For example, despite low power, Simonato et al. (1986b,c, 1987) found a twofold
increased incidence of buccal cavity and pharyngeal cancer in rock wool workers
(p <0.05), which increased with increasing latency. However, the twofold
excesses, even though detected In multiple studies, are insufficient for
establishing a causal relationship. Therefore, the weight of evidence for a
causal relationship between exposure to mineral wool and buccal cavity cancer
is limited.
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9.2.1.3 Ceramic Fibers. No information was found on the health effects of
ceramic fibers.
9.2.1.4 Quantification of Carcinogenic Effects of Manmade Mineral Fibers. The
minimum requirements for an epidemiclogical study to qualify for a quantitative
risk assessment include the measurement of risk (SMR, PMR, SIR, RR) and corre-
sponding exposure levels, explicit or implicit, with length of exposure or some
measure of duration of employment. The study also should show statistically
significant risk for the exposed compared to reference population, and more
weight should be placed on the study with, larger expected values and
person-years if other factors are equivalent.
The data describing the exposure levels of fibrous glass wool, continuous
glass wool filaments, and mineral wool are based on much speculation concerning
past industry conditions (see also Chapter 3). Accurate values for the concen-
tration of airborne fibers to which workers have been exposed are available
only since the late 1970s. However, it is widely believed that the levels in
earlier years were higher than the current levels. Cherrie and Dodgson (1985)
identified the two most important factors contributing to release of MMMF into
the air as nominal fiber size and the addition of oil to MMMF wool. They
estimated that both factors could alter the airborne concentrations at least
tenfold. Cherrie et al. (1986) reported past exposures to airborne fibers by
conducting a historical environmental investigation in European MMMF factories.
The purpose of the investigation was to assess past exposures to MMMF as well
as other environmental risk factors. They concluded that the production
history of each plant could be classified into two or three distinct techno-
logical phases. In the early technological phase, batches were processed with
no oil added to the fibers. The later technology included more modern produc-
tion techniques, and oil was added to the fibers to prevent them from becoming
airborne. An intermediate phase, in which a mixture of production techniques
was utilized, was identified at some plants. It is assumed that during the
early phase, airborne fiber concentrations in the mineral wool plants were
greater than current concentrations. Cherrie et al. (1986) estimated that the
airborne concentrations existing during the early technological phase were
greater than 10 times the concentrations measured during the late technological
phase. For glass wool plants, a thicker-diameter fiber was manufactured during
the early technological phase. It is assumed that this change in fiber size
would put a greater number of smaller fibers into the air and perhaps cancel
-------
any effect of lowering the concentration with the addition of oil. Hence,
advances in technology may not have changed the airborne concentrations at the
glass wool plants. Cherrie et al. (1986) conclude that it was reasonable to
separate each plant history into an early, intermediate, and late technological
phase, but they give no accurate estimate of past exposure concentrations.
Cherrie et al. (1987) describe a simulation of a mineral wool production
plant operating in the 1940s to estimate the airborne fiber levels before oil
was added to the process to minimize airborne fiber levels. They conclude that
the addition of the oil reduced the airborne fiber concentration by three- to
ninefold in different scenarios.
Dodgson et al. (1987) derive a model to estimate past exposure at mineral
wool and glass wool plants. The model predicts mean airborne concentrations at
mineral wool plants of between 1 to 2 fibers/cm and up to 10 fibers/cm during
the early technological phase. Estimates for glass wool plants remain at about
0.1 fiber/cm for the early and late technological phases.
About the most that can be gathered from these data is a qualitative
assessment that levels during the early technological phase were higher than
they are today, perhaps by one or two orders of magnitude. Oodgson et al.
(1987) caution that potential errors exist in any estimation that has been
performed to measure past exposure to MMMF. Methods of gathering data (i.e.,
self-administered questionnaire) and variability in various factors from plant.
to plant, the extent of which cannot be quantified, can exert great influence
on any estimates. Doll (1987) concluded that the uncertainty in the fiber
counts during the early technological phase and the extent of the contribution
of other carcinogens make it impossible to provide precise quantitative esti-
mates of the effects of exposure to MMMF.
The epidemiologic data likewise provide an inconsistent amount of evidence
to perform a quantitative risk assessment. There is no doubt from a qualita-
tive standpoint that exposure to MMMF 1s limited to various respiratory cancers
as can be seen in the conclusions reached In the previous sections. However,
the ability to quantify the human cancer risk for a given exposure level is not
that straightforward. The available epidemiologic data are overall an incon-
sistent set of data upon which to base quantification of human risk.
Enterline et al. (1987) describe an investigation of workers employed at
17 U.S. manufacturing plants. This study updates earlier reports of the same
cohort (Enterline and Marsh, 1982; Enterline et al., 1983, 1987). They con-
cluded that analyses with various surrogates of fiber exposure did not support
July 1988 9-18 DRAFT-DO NOT QUOTE OR CITE
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a dose-response relationship between exposure and respiratory cancer for
mineral wool workers, fibrous glass wool workers, or continuous fibrous glass
filament workers. While SMRs did increase with time since first exposure for
fibrous glass wool workers (though none were significantly increased), this did
not hold for respiratory cancer and duration of exposure for any of the three
fibers. Cumulative exposures by fiber did not exhibit any increasing dose-
response relationship, and measurements of fiber concentrations during the
early technological phase were not available.
Shannon et al. (1986) extended the followup of previously reported data
(Shannon et al., 1982, 1984) from workers in Ontario, Canada. Analysis of lung
cancer deaths by duration of exposure and time since first exposure yielded too
few deaths and low statistical power for meaningful evaluation.
Bertazzi et al. (1986) found a fourfold excess of laryngeal cancer in a
factory in Italy. As only four cases of laryngeal cancer were described, too
few cases were available to adequately establish a dose-response relationship.
However, three of the four cases were observed in the highest exposure group,
and a significant increase was observed in those with 25 or more years of
latency.
Simonato et al. (1987) extended a study of 13 MMMF plants in Europe. This
cohort had been studied previously by Saracci et al. (1984); the most convinc-
ing evidence of a causal association would establish a relationship between
increasing lung cancer risk and increasing dose of MMMF. No such dose-response
relationship was observed using length of employment as a surrogate for dose.
The authors do qualify the use of length of exposure instead of dose by indi-
cating that improvement in worker exposure may make this factor unreliable as
an estimate of cumulative dose. No dose-response relationship was observed for
mineral wool or fibrous glass workers by duration of employment.
Dose-response relationships were observed for mineral wool workers by
years since first exposure and also by technological phase, but these relation-
ships did not hold for fibrous glass wool workers. However, the effects of
other environmental conditions, such as the use of arsenic-containing slag
during the early technological phase, poor ventilation, and exposure to PAHs,
could not be excluded.
From these data, it appears that the evidence for respiratory cancers due
to exposure to MMMFs is inconsistent. It is not unreasonable to conclude that
conditions during the early years of the MMMF industry have contributed to an
observed excess of cancer risk. The effects of exposure control methods
Julv 1988 9-19 DRAFT—DO NOT QUOTE OR CITE
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employed in the last 20 years may not have been manifested as of yet. It also
seems reasonable to conclude that exposure to mineral wools is a greater risk
than exposure to fibrous glass wool, which carries a greater risk than continu-
ous glass filaments, with the latter being almost risk-free. While qualitative
evidence for cancer has been demonstrated, consistent dose-response relation-
ships necessary for quantification of risk have not been demonstrated in any
cohort investigated.
Because of these inconsistent dose-response relationships, the uncertainty
in exposure concentrations in the early part of the industry and the unknown
effects of exposure to other environmental carcinogens make the quantification
of human risk inappropriate at this time.
9.2.2 Animal Toxicity
9.2.2.1 Characterization of Noncarcinogem'c Effects. Several chronic inhala-
tion toxicity studies conducted with rats, guinea pigs, and hamsters exposed to
MMMF (glass fibers, mineral wool, and ceramic fibers) of varying diameters and
lengths generally indicated some pulmonary damage, but no carcinogenic response.
These studies were reviewed in Chapter 5. The severity.of the pulmonary
response is influenced by fiber dimensions. Thin (<3 um), long (>20 urn) fibers
elicit a more severe response than do either thick (>5 um), long fibers or
short (<5 um) fibers of any diameter. However, unlike asbestos fibers of
similar dimensions that have been shown to be toxic and fibrogenic after
introduction into the lung, manmade mineral fibers generally do not elicit a
pulmonary response more severe than macrophage aggregation and alveolar pro-
teinosis following inhalation exposure or intratracheal instillation. This may
be due in part to the proportion of nonrespirable-to-respirable fibers within
the aerosol and the number of respirable fibers actually deposited in the lung
and alveoli. Fibrous glass and mineral wools have been shown to be cytotoxic
by several investigators, although very limited evidence suggests that ceramic
fibers are not cytotoxic. Again, thin, long fibers proved to be more cytotoxic
than either short fibers of any diameter or thick and long fibers. Therefore,
since manmade mineral fibers have been shown to be cytotoxic in ni vitro
assays, questions remain as to why these fibers are not as toxic as asbestos
following inhalation. One possible explanation may be a lack of durability of
vitreous fibers as compared to that of asbestos. Following introduction into
the lungs, glass fibers have been shown to erode, becoming coarse in appearance
I..1).. idee 9-20 DRAFT—DO NOT QUOTE OR CITE
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after 12 to 24 months. Leaching of components has also been shown to occur,
resulting in weakened fibers that become fragmented, engulfed by macrophages,
and cleared from the lung or dissolved, whereas asbestos (and erionite) fibers
are relatively insoluble and are not readily cleared from the lungs. Further-
more, the dissolution of asbestos fibers generally results in longitudinal
splitting, producing thinner fibers. In addition, inhaled vitreous fibers have
not been shown to migrate to the pleura! surfaces of the lung or the tissues
other than the tracheobronchial lymph nodes. Asbestos, on the other hand, has
been shown to readily penetrate epithelial surfaces to the lung interstitium
and migrate to pleura! surfaces, thus interacting with different target cells
than manmade mineral fibers and eliciting different pulmonary responses includ-
ing tumorigenesis.
Results of the inhalation studies detailed in Chapter 5 indicate that the
mechanism of toxicity for manmade mineral fibers may not be comparable to that
of asbestos, particularly on a dimensional basis alone. Other fiber charac-
teristics, e.g., durability and migration within tissue, must also be consid-
ered. However, to completely assess the toxicity of manmade mineral fibers
following inhalation exposure, more testing of fibers with similar dimensions,
using a range of exposure levels, must be conducted. .
9.2.2.2 Quantification of Noncarcinogenic Effects
9.2.2.2.1 Fibrous glass. Several chronic inhalation toxicity studies were
considered for the derivation of the Reference Dose (RfD) for fibrous glass
(Table 9-2). No more than two exposure levels of a specific fiber were tested
and a dose-response relationship was not demonstrated in any one study. How-
ever, when these studies are considered collectively, it is apparent that a
range of exposure levels using fibrous glass samples of similar dimensions
within the respirable range (<3.5 urn in diameter) were used. Conse.quently, the
results of these studies can be considered together for calculation of the RfD.
The pulmonary lesions resulting from fibrous glass exposure in each study
have been scored by the reviewers using the grading system of McConnell et al.
(1984) described previously (see Section 5.2.1.1.2., Table 5-2). According to
this grading system, a lesion score of 1.0 to 2.9 signifies either no pulmonary
tissue response or scattered macrophage accumulation in the alveoli. Lesion
scores of 3.0 to 3.9 indicate some structural change in the lung architecture
such as development of cuboidal epithelium, reticulin fiber networks at
bronchoalveolar bifurcations, and scattered focal peribronchial fibrosis with
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TABLE 9-2. SUMMARY OF LONG-TERM INHALATION STUDIES CONSIDERED FOR DERIVATION OF THE RfD FOR FIBROUS GLASS
Exposure Mean
level diameter
Species (mg/m3) (pm)
Rat/hamster 0.3 0.45
3.0
Rat/hamster 100 0.5
Rat 5 <3.5
15
Rat/hamster 10 3.1
Rat/hamster 1.2 5.4
12.0
Rat 15 4.6
Rat/hamster 9 6.1
Length
(pm) Pulmonary effects
<20 Dose- related increases in
macrophage aggregation.
Slight increases in bron-
choalveolar metaplasia in
hamsters at 3.0 mg/m-1.
5-20 Increased alveolar protein-
osis; sparse collagenous
fibrnsis in lung, pleura,
and lymph nodes of rats and
hamsters; and laminated,
calcific microliths in
hamsters.
>10 Severe, plaguelike pleural
lesions, mild granulomatous
inflammation, and macrophage
aggregation.
77% Increase in macrophage
>10 aggregation that was more
severe in rats than hamsters.
5-50 Increase in macrophage
aggregation that was more
severe in rats than hamsters.
Slight increase in broncho-
alveolar metaplasia in
hamsters exposed to 1.2 but
not to 12.0 mg/m-1.
>20 No pulmonary response.
50% Increase in macrophage
>80 aggregation.
Lesion
score References
2.1 Smith et al.
2.3 (1984. 1986,
1987)a
3.7-4.0 Gross et al.
(1970)°
3.2 Mitchell et al.
3.5 (1986)c
2.1-2.3 Smith et al.
(1984, 1986,
1987)
1.8-2.4 Smith et al.
1.6-2.1 (1984, 1986,
1987)
1 Mitchell et al.
(1986)
1.9-2.3 Smith et al.
(1984, 19R6,
1987)
exposed for 6 hours/day, 5 days/week for 24 m
and observed for life.
-------
no collagen formation, in addition to moderate to severe dust-laden macrophage
aggregation. Scores of 4.0 or higher denote the development of minimal to
severe collagenous fibrosis, blockage of airways, and destruction of lung
architecture.
Considering only glass microfibers (diameters of 0.45 to 0.5 urn), a NOAEL
of 3.0 mg/m was identified from the studies of Smith et. al. (1984, 1986, 1987)
in which lesion scores of 2.1 to 2.3 we're obtained in both rats and hamsters.
A LOAEL was identified from the study by Gross et al. (1970), in which rats and
hamsters were exposed to fibrous glass (0.5 urn in diameter and 5 to 20 pm in
length) at a total respirable concentration of 100 mg/m . In this study,
exposed rats and hamsters developed sparse focal collagenous fibrosis in the
lung, pleura, and lymph nodes; in addition, hamsters developed calcified,
laminated microliths.
The RfD for a 70-kg adult is calculated as follows:
RfD - <*•*> • 0.03
where:
3.0 mg/m3 - NOAEL, based on data from the studies by Smith et al. (19S4,
1985, 1987).
100 = uncertainty factor, chosen in accordance with EPA guidelines
for use with a NOAEL from an animal study.
For fibers with diameters >0.5 but <3.5 urn, two studies were considered
for derivation of a second RfD. A LOAEL of 5 mg/m was identified from the
study of Mitchell et al. (1986) in which a lesion score of 3.2 was. obtained in
rats. In the second study (Smith et al., 1986), lesion scores of 2.1 to 2.3
were obtained in rats and hamsters, and a NOAEL of 10 mg/m was identified. In
this study, however, the dust cloud had a respirable mass fraction of only
30 percent and contained a high percentage of nonfibrous particles. Therefore,
the study of Mitchell et al. (1986) was chosen for derivation of the RfD value
for fibrous glass having diameters >0.5 but <3 urn. The RfD for a 70-kg adult
is calculated as follows:
RfD = (i0m s 0-005 n>g/m3 (5.0 pg/m')
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where:
5.0 mg/m3 « LOAEL, based on the development of severe plaque! ike lesions
and moderate dust-laden macrophage aggregation in alveoli
and mild granulomatous inflammation In rats exposed to
fibrous glass with a diameter of <3.5 and length of >10 urn
(Mitchell et al., 1986).
1000 = uncertainty factor, chosen in accordance with EPA guidelines
for use with a LOAEL from an animal study.
An RfD value was not calculated for glass fibers with diameters >3 um,
since these fibers are not considered to be respirable. The only pulmonary
response observed was slight macrophage aggregation, and lesion scores of 1 to
2.3 were obtained in rats and hamsters (see Table 9-2).
9.2.2.2.2 Mineral wool
9.2.2.2.2.1 Rock wool. Two long-term inhalation studies were considered
for derivation of the RfD for rock wool (Table 9-3). As with glass fibers,
only one exposure level of rock wool was tested, and since the fibers tested in
each study had approximately the same dimensions, they were considered collec-
3
tively. The data indicate a dose response with a NOAEL of 5 mg/m (respirable
concentration), identified from the study of Le Bouffant et al. (1986). A
LOAEL of 10 mg/m was identified from the study of Wagner et al. (1984), based
on a slight cellular change in lung architecture. The RfD for a 70-kg adult is
calculated as follows:
Rf0 = .gm = 0 05 mg/m3 (50
where:
5.0 mg/m3 = NOAEL, based on data from the study by Le Bouffant et al.
(1986).
100 = uncertainty factor, chosen in accordance with EPA guidelines
for use with a NOAEL from an animal study.
9.2.2.2.2.2 Slag wool. Only one long-term inhalation study was found for
use in the derivation of the RfD for slag wool. In the study by Smith et al.
(1986, 1987), a LOAEL of 10 mg/m was identified, based on a significant
decrease in the lifespan and a slight increase (not statistically significant)
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TABLE 9-3. SUMMARY OF LONG-TERM INHALATION STUDIES CONSIDERED FOR DERIVATION OF
THE RfO FOR ROCK WOOL
Species
Rat
Rat
Respirable
fiber con-
centration
(mg/m3)
10
5
Mean
diameter
(Mm)
87% <2
49% <2
Length
dim)
>5
88% >5
Pulmonary effects
Mild to moderate dust- laden
macrophage aggregation and
some nyperplasia.
Mild macrophage aggregation
and chronic inflammation of
nasal fossae.
Lesion
score References
2.7-3.3 Wagner et al.
(1984)a
2.3 Le Bouffant
et al. (1986b)
aAnima1s were exposed for 7 hours/day, 5 days/week for 12 months and observed for life.
Exposure was for 5 hours/day, 5 days/week for 12 or 24 months. Animals exposed for 12 months were
observed up to 16 months postexposure, and animals exposed for 24 months were observed up to 4 months
postexposure.
-------
in pulmonary fibrosis in rats exposed to slag wool. The RfD for a 70-kg adult
is calculated as follows:
RfD =
where:
10 mg/m3 = LOAEL, based on a significant decrease in lifespan and slight,
nonsignificant increase in pulmonary fibrosis in rats (Smith
et al., 1986, 1987).
1000 = uncertainty factor, chosen in accordance with EPA guidelines
for use with a LOAEL from an animal study.
9.2.2.2.3 Ceramic fibers. Three studies were considered for calculation of
the RfD value for ceramic fibers (Pigott et al., 1981; Davis et al., 1984;
Smith et al., 1987). The data and lesion scores derived using the grading
system of McConnell et al. (1984) are summarized in Table 9-4. Only one
exposure level was tested in each of the chronic studies considered, and no
other suitable studies were found. Therefore, the results from all three
studies were used to assess to LOAEL and NOAEL for ceramic fibers.
Since no effects were observed at either fiber concentration in the stud.>
by Pigott et al. (1981), the higher fiber concentration of 2.45 mg/rr, was
chosen as the NOAEL for ceramic fibers. The results of the study by Davis
et al. (1984) indicated a treatment-related effect at 8.4 mg/m . This
concentration could be considered the LOAEL since no other effects such as
mortality were noted in the exposed animals. The RfD for a 70- kg adult is
calculated as follows:
RfD = -(lo = °-024 m9/n>3 (24.5 ug/m3)
where:
2.45 mg/m = NOAEL, based on the absence of increases in mortality and
pulmonary effects in rats exposed to ceramic fibers (Pigott
et al., 1981).
100 = uncertainty factor, chosen in accordance with EPA guidelines
for use with a NOAEL from an animal study.
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TABLE 9-4. SUMMARY OF LONG-TERM INHALATION STUDIES CONSIDERED FOR DERIVATION OF
THE RfO FOR CERAMIC FIBERS
Species
Rat
Rat
Rat/hamster
Respirable
fiber con- Mean
centration diameter
(mg/m3) (pm)
2.18-2.45 3
8.4 0.3
12 1.8
Length Lesion
(pm) Pulmonary effects score
10.5-62 Aggregation of dust- laden 2.3
macrophages. No fibres is
present.
90% <3 large areas of alveolar 3.2
proteinosis and dust- laden
macrophage aggregation.
Ferruginous bodies were
present.
35 Moderate dust- laden macrophage 2.1-3.0
aggregation and a slightly
increased incidence of fibrosis
were noted in rats. One
mesothelioma was found in
70 hamsters.
References
Pigott et al.
(1981)a
Davis et al.
(1984)°
Smith et al.
(1987)c
^Animals were exposed to refractory Saffilft fibers for 6 hours/day, 5 days/week for 86 weeks.
Animals were exposed to aluminum silicate fibers for 7 hours/day, 5 days/week for 12 months and observed for
?0 additional months.
cExposure to Fiberfraxfc was for 6 hours/day, 5 days/week for 24 months, and the animals were observed for life.
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9.2.2.3 Characterization of Carcinogenic Effects
Several chronic inhalation toxicity studies with rats, guinea pigs, and
hamsters exposed to MMMF of varying diameters and lengths indicate no carcino-
genic response. These studies were reviewed in Chapter 7. The inability of
glass fibers to elicit a carcinogenic response following inhalation exposure to
animals is unclear. However, it nay be Influenced by the proportion of
nonrespirable to respirable fibers and the actual number of respirable fibers
retained in the lungs and alveoli. In addition, the biodisposition of these
fibers from the lung, as previously described for noncarcinogenic responses
(see Section 9.2.2.1), may also influence the effects noted.
In contrast, either intratracheal or intraperitoneal administration of
MMMF into several animal species was carcinogenic. The severity of the carci-
nogenic responses, like that of the noncarcinogenic responses characterized
earlier, was found to be influenced by fiber dimensions. Thin (<3 uir,), long
(>20 urn) fibers were the most potent carcinogens, and thick (>5 urn), long or
short (<5 urn) fibers were less carcinogenic. Stanton (1973) hypothesized that
durable fibers, of which asbestos is one example., cause cancer irrespective of
their physicochemical nature simply because they are fibers, provided they
subscribe to well-defined ranges of diameters and lengths. Stanton1s studies
(Stanton et al., 1977, 1981) indicated that in addition to asbestos, several
other natural and synthetic fibers caused malignant tumors in rats after
intrapleural implantation, and found a good correlation between tumorigenicity
and a fiber length of >8 urn and a diameter <0.25 urn. However, the investiga-
tors did not find a sharp demarcation line in fiber size, and carcinogem'city
probably correlated with fibers of a size that was able to escape phagocytosis
and retain the ability to penetrate into and migrate in tissues.
The "Stanton hypothesis" has been tested, reanalyzed, and criticized, but
it has not been discarded or disproven, and many but not all difficulties have
been resolved.
Bertrand and Pezerat (1980) reanalyzed statistically some of Stanton's
data and concluded from an analysis of the length/diameter variables (aspect
ratio) that carcinogenesis is the result of a continuous function of the
aspect ratios and that the effects of the two variables cannot be separated.
Wagner et al. (1969) were the first to indicate a correlation between
fiber size and carcinogenic potential in their studies on amphibole asbestos.
For a given weight of asbestos injected intrapleurally in rats and assuming
July 1988 9-28 DRAFT-DO NOT QUOTE OR CITE
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that all fibers had approximately the same length of 10 to 20 pm, the carcino-
genic potential, correlated with the thinness of fibers, was as follows:
crocidolite (riebeckite)>amosite>anthophyllite. Milling of fibers decreased
their length and also decreased their carcinogenicity. With three samples of
tremolite, Wagner et al. (1982) found that the Incidence of mesotheliomas was
14/47 in Sprague-Dawley rats after intrapleural Injection of 20 mg of a prepa-
ration in which 56 percent of the fibers were >8 pm and had a diameter of
<1.5 pm (15.4 x 10 fibers/ug). Two other samples of tremolite with 0.7 and
0 percent of fibers in this size category were inactive. Pott and colleagues
(1976) and Pott (1978) found that the maximum biologic activity of glass fibers
was among the fibers with diameters of about 0.25 mm and lengths >10 pm. More
recently, Pott et al. (1987a) found that the length and durability of the
fibers are perhaps of greater significance than diameter in determining the
carcinogenic potential. Several other studies reviewed in Chapter 7 indicate
that fiber size is critical for explaining carcinogenicity of natural and/or
manmade fibers, although all investigators did not give precise measurements,
and all results did not agree with the discrete fiber size.
9.2.2.3.1 Fibrous glass. Several long-term studies have been conducted with
fibrous glass of varying diameters and lengths using several routes of adminis-
tration in various animal species (see Table 7-13). No carcinogenicity was
observed in at least three animal species following inhalation exposure (Smith
et al., 1984, 1986; Gross et al., 1970; Goldstein et al., 1983; Mitchell
et al., 1986), and the results for intratracheal instillation were equivocal.
Negative results were obtained following intratracheal instillation in rats and
hamsters by Smith et al. (1986, 1987). Conversely, results of Pott et al.
(19845; 1987a) and Mohr et al. (1984) indicated that intratracheal instillation
of two different glass fibers resulted in mesothelial tumors in both rats and
hamsters.
In contrast, fibrous glass has been shown to be carcinogenic in laboratory
animals following intrapleural «nd intraperitoneal administration. After
intrapleural injection, glass fibers were found to be carcinogenic in rats and
hamsters but not nice. Mesotheliomas and sarcomas were the predominate tumor
types observed. In general, glass microfibers having diameters <0.5 um and
lengths >5 urn were the most carcinogenic (Smith and Hubert, 1974; Wagner
et al., 1976; Stanton et al., 1977; Smith et al., 1980; Monchaux et al.,
1981).
-------
Intraperitoneal injection of glass fibers has also been shown to result in
carcinogenicity in rats, but limited evidence suggests that glass fibers are
not carcinogenic in hamsters. As seen following intrapleural administration,
the primary tumor types found were mesotheliomas or sarcomas. The majority of
the fibers tested were nricrofibers having diameters <0.05 and lengths <10 um
(Pott and Friedrichs, 1972; Pott et al., 1976, 1987a,b; Muhle et al., 19S6;
Smith et al., 1986).
Thus, the weight of evidence suggests that glass fibers having diameters
<3 |jm and lengths >5 urn are carcinogenic following direct administration to
pleural and peritoneal surfaces. In addition, tumor incidences (mostly meso-
theliomas or sarcomas) increase as the fiber diameters decrease, with glass
microfibers being the most carcinogenic. The results of the Pott et al.
(1984a, 1987a) studies suggest that intratracheal instillation of glass
microfibers results in induction of tumors (mostly mesotheliomas) in the lungs.
However, no strong evidence of carcinogenicity was observed following inhala-
tion exposure. This may be due to small total respirable fiber concentrations
within the dust cloud resulting in small concentrations in the lungs and/or the
biodisposition of the fibers following inhalation. Due to the absence of
methodology to estimate cancer risk from data obtained following intrapleurel
or intraperitoneal administration and the lack of evidence of carcinogenicity
following inhalation exposure, a quantitative analysis of the carcinogenic risk
for glass fibers cannot be made at the present time.
9.2.2.3.2 Mineral wool. Relatively little information on the carcinogenic
potential of mineral wool was found in the available literature (see
Table 7-13). Rock wool was not carcinogenic to rats following inhalation
exposure (Wagner et al., 1984), and no information on the carcinogenicity of
rock wool following intratracheal instillation was found in the available
literature. Only one carcinogenicity study testing the effects of rock wool
following intrapleural administration was available. In this study, rock wool
was found to be carcinogenic, resulting in the development of mesotheliomas in
5/96 rats (Wagner et al., 1984). Rock wool was also found to be carcinogenic
in three intraperitoneal studies (Pott et al., 1984a, 1987a); the tumors
observed were either mesotheliomas or sarcomas. No conclusions regarding the
possible correlation between the physical characteristics and carcinogenicity
of rock wool can be drawn from the data obtained.
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Slag wool was not carcinogenic in rats or hamsters following inhalation
exposure (Smith et al., 1986, 1987). No information on the carcinogenicity of
slag wool following intratracheal or intraperitoneal administration was found
in the available literature. Data on carcinogenicity following intrapleural
administration were equivocal. In a long-term study in rats reported by Wagner
et al. (1984), no tumors were induced in 48 animals. In a second intrapleural
study in rats, however, a 5 percent tumor incidence of mesotheliomas or sarco-
mas was obtained (Pott et al., 1984a). Although the tumor incidence was low,
the development of mesotheliomas and sarcomas following intrapleural adminis-
tration is consistent with the expected pattern of tumor development following
similar exposure to asbestos, and therefore, slag wool was considered to be
carcinogenic in this study. Since there is limited evidence that rock and slag
wools are not carcinogenic following inhalation exposure, and no methodology
exists for estimation of the carcinogenic risk using intrapleural or intra-
peritoneal data, quantification of carcinogenic risk cannot be performed at
this time.
9.2.2.3.3 Ceramic fibers. Six studies addressing the carcinogenic potential
of ceramic fibers were evaluated; the data are summarized in Table 7-13. No
evidence of a significant increase in pulmonary tumors was noted in three
studies utilizing inhalation as the route of ceramic fiber exposure. Chronic
inhalation exposure to refractory ceramic fibers (Fiberfrax ) produced no
tumors in rats and one mesothelioma in 70 hamsters (Smith et al., 1986). The
mesothelioma was noted because of its known association with fiber exposure,
but the possibility that the mesothelioma was a spontaneous event could not be
discounted. The chronic inhalation exposure of rats to refractory ceramic
alumina (Saffil ) fibers in the manufactured or thermally aged form did not
result in any benign or malignant pulmonary tumors in exposed rats (Pigott
et al., 1981). In addition, no significant differences were observed in benign
or malignant tumors at sites other than the respiratory tract. In a chronic
inhalation study by Davis et al. (1984), eight pulmonary neoplasms consisting
of one adenoma, three carcinomas, and four malignant histiocytomas were noted
in 48 rats exposed to aluminum silicate ceramic fibers. An additional six
animals exhibited areas suspected of being preneoplastic. However, the impli-
cation of the reported pattern of tumor development is unknown, since the
finding of malignant histiocytomas in fiber-exposed animals is not consistent
-------
with the expected pattern of tumor development resulting from asbestos expo-
sure. Intratracheal administration of refractory ceramic fibers (Fiberfrax^)
in rats and hamsters did not result in any pulmonary tumors (Smith et al.,
1986).
Administration of ceramic fibers via the intraperitoneal route yielded a
high incidence of mesotheliomas in rats and hamsters (Smith et al., 1986; Pott
et al., 1987b). However, lower tumor Incidences were noted in the study by
Davis et al. (1984): 1 mesothelioma and 2 fibrosarcomas developed in 32 rets
injected with aluminum silicate fibers. Surprisingly, there was no strong
evidence of carcinogenicity in rats for aluminum silicate and large-diameter
alumina and zirconium oxide fibers administered via the intrapleural route
(Wagner et al., 1973; Stanton et al., 1981).
The weight of evidence suggests that ceramic fibers are carcinogenic
following intraperitoneal administration, although no carcinogenic response was
noted in two strains of rats after intrapleural injection. As stated earlier,
no methodology exists for calculation of carcinogenic risk using data from
intraperitoneal studies. In addition, strong evidence indicates that ceramic
fibers are not carcinogenic following inhalation exposure in two animal spe-
cies. Therefore, a carcinogenic risk estimate for ceramic fibers was net
calculated.
9.2.3 Characterization of Carcinogenic Potential Based on Human and Animal
Data
The weight of evidence from both human health effects data and animal
toxicity data, based on the information described in the previous sections (see
also summary in Section 9.5), suggest the following carcinogenic categories for
the MMMF: glass microfibers, B2; fibrous glass, Bl; mineral wool, Bl; ceramic
fibers, C.
9.3 SYNTHETIC FIBERS
9.3.1 Human Health Effects
No epidemiological studies were found for carbon and polyolefin fibers.
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9.3.2 Animal Toxicity
9.3.2.1 Characterization of Noncarcinogenic Effects. The available informa-
tion is too limited to enable an evaluation of the effect of fiber dimensions
on pulmonary response similar to that determined for MMMF. However, the
combined evidence from subchronic and chronic toxicity, as well as cytotoxici-
ty, studies Indicate that respirable aramid fibers are nuch more toxic than
carbon or polyolefin fibers. Aramid fibers have been shown to be cytotoxic and
to cause fibrosis, obliterative bronchiolitis with collagen formation, and
emphysema as well as lung carcinomas in rats following repeated or chronic
inhalation exposure. Inhalation of carbon fibers resulted in macrophage
accumulation but no pulmonary damage in exposed rats, whereas intratracheal
administration of polypropylene to rats resulted in pulmonary granulomas only.
No pulmonary tumors were noted following administration of either fiber. Both
carbon and polyolefin fibers exhibited minimal cytotoxic and hemolytic
activity.
9.3.2.2 Quantification of Noncarcinogenic Effects
9.3.2.2.1 Ararcid fibers. Only one long-term inhalation study was found in the
available literature (Stadler, 1986). In this study, a NOAEL of 0.08 mg/tn3 was
identified in rats, based on cellular changes in lung architecture following
exposure at 0.32 and 0.63 mg/m for 2 years or at 2.23 mg/m for 1 year. These
changes included type II cell hyperplasia, nodular thickening of ridges at
alveolar duct bifurcations, and formation of ciliated columnar epithelial cells
in alveolar ducts. Significant increases in absolute and relative lung weights
were seen at 0.63 and 2.23 mg/m , and emphysema and significant increases in
mortality were noted at 2.23 mg/m . The RfD for a 70-kg adult is calculated as
follows:
RfD s (O
where:
0.08 mg/m3 = NOAEL, based on the absence of cellular change in lung
architecture (Stadler, 1986).
100 = uncertainty factor, chosen in accordance with EPA guidelines
for use with a NOAEL from an animal study.
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9.3.2.2.2 Carbon fibers. No suitable long-term inhalation studies were founa
in the available literature. In a subchronic inhalation study reported by Owen
et al. (1986), no effects were obtained in rats following exposure to 20 mg/m
for 6 hours/day, 5 days/week for 16 weeks. The rats were observed for a
recovery period of 32 weeks. However, the authors did not report the respira-
ble concentration, and the majority of carbon fibers within the aerosol cloud
were beyond the respirable range. Furthermore, a small number of animals were
exposed for the entire 16-week period (20 males), and a range of doses was not
tested. Therefore, this study was not considered suitable for derivation of a
conservative estimate of the RfD. Since no other studies were found, the RfD
for carbon fibers could not be calculated.
9.3.2.2.3 Polyolefin fibers. No inhalation studies were found in the avail-
able literature, and therefore, an RfD for polyolefin fibers could not be
calculated.
9.3.2.3 Characterization and Quantification of Carcinogenic Effects
9.3.2.3.1 Aramid fibers. In a chronic inhalation study conducted by Haskell
Laboratory (Stadler, 1986), cystic keratinizing squamous cell carcinomas were
exhibited in female but not in male rats (see Table 7-12). Groups of 100
animals (50 males, 50 females) were exposed to Kevlar fibers at concentrations
of 0, 0.08, 0.32, or 0.63 mg/m for 2 years or 2.23 mg/m for 1 year (followed
by a 1-year recovery period). These exposure concentrations were approximately
equivalent to 2.4, 25.4, 11.2, and 435.5 fibrils/cm , respectively. Since the
individual animal data were available, a survival analysis was performed tc
determine if the survival of the animals could have an influence on tumor
development. The survival analysis showed that animals exposed to 0.08, 0.32,
and 2.23 mg/m exhibited significantly shorter lifespans (p <0.05) compared to
controls.
Analysis of the tumor incidence data, accounting for differences in
survival between groups, can be performed following procedures described by
International Agency for Research on Cancer (1980) for tumors found in an
incidental context. By this method, the data are separated into time intervals
exhibiting a monotonic increase in tumor incidence across dose groups. This
created a number of time intervals resulting in a time-weighted statistic.
£
Application of this procedure to the Kevlar data resulted in the formation of
only one interval, indicating that there is no advantage in using this method
to adjust for survival differences. Hence, we will not adjust for survival in
the tumor incidence analysis.
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The incidence of lung carcinoma in female rats exhibited a significant
•increasing trend with dose by the Cochran-Armitage Trend test (p <0.01). The
incidence of tumors in the high-dose group was significantly increased compared
to controls (6/69 versus 0/78) by Fisher's Exact test (p <0.05).
The multistage model was used to estimate cancer risk. No adjustments to
dose were made to account for differences in extrapolating from animals to
humans. For purposes of this extrapolation, the high-exposure value was
reduced by half to account for exposure of only 1 year with a 1-year recovery
period. The assumption made here is that the animals were exposed to the same
number of fibers at 2.23 mg/m for 1 year as they would have been had they been
exposed to 1.12 mg/m for 2 years. The cancer unit risk, using the data shown
below, is 9.4 x ID*2 (mg/m3)"1 or 7.5 x 10~4 (fibrils/cm3)"1 . This value is
the 95 percent upper bound on risk. The true value could be as low as zero but.
is unlikely to be higher.
Exposure level (mg/m3)
0.08 0.32 0.63 2.23
Squamous cell carcinoma 0/78** 0/76 0/76 4/79 6/69**
**Sigm'ficant dose-related trend by the Cochran-Armitage Trend test denoted
at controls (p <0.01), and significant increase compared to controls by
Fisher's Exact test denoted at the high dose (p <0.01).
9.3.2.3.2 Carbon fibers. Only one dermal carcinogenicity study using four
types of carbon fibers was found in the available literature (DePass, 19£2).
In this study, CF, MAT, PAN, and PAN-oxidized carbon fibers were not
carcinogenic in mice following dermal exposure, although a few tumors were
present following the dermal application of CF, MAT, and PAN-oxidized carbon
fibers. The incidences were not significantly different from controls, and the
tumor types observed (see Table 7-13) have been shown to occur spontaneously in
this strain of mice. Therefore, the tumor induction was not considered to be
due to the administration of carbon fibers. Since no other suitable studies
were found, an estimate of the carcinogenic risk of carbon fibers was not
calculated.
9.3.2.3.3 Polyolefin fibers. No inhalation or intrapleural studies were found
in the available literature (see Table 7-13). Polypropylene was not carcino-
genic following a single intratracheal injection of 1.25 mg in Long-Evans rats
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(Moreno and Moreno, 1986). Conversely, intraperitoneal injection resulted in
the induction of mesotheliomas or sarcomas in 2/51 female Wistar rats (Pott
et a!., 1987b). However, the increased incidence was not significantly differ-
ent from that of controls.
Very limited evidence suggests that polyolefin, specifically polypropyl-
ene, is carcinogenic following intraperitoneal administration. However, the
lack of inhalation data precludes the quantification of the carcinogenic risk
associated with exposure to polyolefin fibers.
9.3.3 Characterization of Carcinogenic Potential Based on Human and Animal
Data
The weight of evidence from both human health effects data and animal
toxicity data (see also summary in Section 9.5) suggest the following carcino-
genic categories for the synthetic fibers: aramid fibers, B2; carbon fibers,
D; polyolefin fibers, D.
9.4 MINERALS
9.4.1 Human Health Effects
9.4.1.1 Attapulgite
9.4.1.1.1 Qualitative evaluation of noncarcinogem'c and carcinogenic effects.
Only one study (Waxweiler et al., 1985) detected an excess of lung cancer in
white male workers (SMR = 192, p <0.05, Power = 37 percent). This risk in-
creased to threefold (p <0.05) among white males employed in high- and
intermittent-exposure job categories after 20 or more years of latency.
Although no excesses from NMRD were detected, there was insufficient power to
detect either NMRD or site-specific cancers, such as lung cancer, among the
entire cohort. The small number of deaths and low power and absence of smoking
histories precluded meaningful analysis of the data by cumulative dust exposure
and latency or duration of employment, especially among nonwhite employees.
Therefore, the weight of evidence for a causal relationship between exposure to
attapulgite and lung cancer or NMRD is inadequate. The International Agency
for Research on Cancer (1987) has determined that there is inadequate evidence
of human carcinogenicity for attapulgite.
rTTC
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9.4.1.2 Erionite
9.4.1.2.1 Qualitative evaluation of noncarcinogenic and carcinogenic effects.
Cross-sectional mortality studies have demonstrated a high prevalence of deaths
from malignant mesotheliomas, to a greater extent of the pleura arid to a lesser
extent of the peritoneum, in the adult populations from three Turkish villages
where individuals were exposed throughout their lifetimes. Erionite fibers
were identified in soil and air samples from these three villages as well as in
the lung tissues of patients with malignant mesotheliomas. No malignancies of
any type were found in a control village during the same period. Smoking could
not account for the excesses seen; less than 1 percent of the women from the
three contaminated villages smoked, yet a high prevalence of malignant mesothe-
liomas was observed among women.
No apparent sex differences were observed. Tests for other environmental
carcinogens showed that arsenic, uranium, nickel, and chromium were present in
trace amounts. Tests for aflatoxins and radioactivity were negative (Baris
et al., 1978). None of the villagers interviewed had experienced either known
or suspected exposure to asbestos. Since the major occupation in the three
villages was farming, an environmental rather than an occupational agent would
be more likely to be responsible for the malignancies. Although causal rela-
tionships cannot be discerned through either cross-sectional studies or cese
reports, the consistency of the findings from multiple studies and the presence
of erionite rather than asbestos suggests an etiological role for erionite.
The International Agency for Research on Cancer (1987) has determined that
there is sufficient evidence for the carcinogenicty of erionite to humans.
Because of carcinogenic effects, each of the studies examined nonmalignant
pleura! disease. Tests for tuberculosis were negative. Fibrosis of the lung
and pleura were two effects commonly noted. The research by Baris et al.
(1987) culminated in a finding that there was a higher prevalence of pleural
radiological changes in villages affected by mesotheliomas as compared to the
control village. Because cross-sectional studies provide a measure of preva-
lence rather than a measure of incidence (i.e., a measurement of risk), they
cannot be used for quantitative risk assessment.
9.4.1.3 Talc
9.4.1.3.1 Qualitative evaluation of noncarcinogenic and carcinogenic effects.
Health effects seen following occupational exposure to talc included increased
mortality from respiratory cancer and nonmalignant respiratory disease (NMRD).
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In many of the studies, however, workers were simultaneously exposed to contam-
inants such as asbestiform amphiboles, silicates, carbonates, and radon. This
lack of specificity made it difficult to ascribe any of the health effects
solely to talc exposure. Therefore, the weight of evidence for a causal
relationship between exposure to talc alone and lung cancer or NMRD is inade-
quate. International Agency for Research on Cancer (1987) has also determined
that there is inadequate evidence for pure talc.
9.4.1.4 Vermiculite
9.4.1.4.1 Qualitative evaluation of noncarcinogenic and carcinogenic effects.
Chest radiographs from a cross-sectional morbidity study showed some evidence
of pleura! disease in workers employed at least 5 years in a Montana
vermiculite ore mine and mill. The effect of smoking and the presence of
tremolite-actinolite fibers confounded these findings with respect to the
prevalence of pleura! disease in this group of workers.
Results from a historical prospective mortality study of 575 male employ-
ees of the same Montana vermiculite ore mine and mill (Amandus and Wheeler,
1987) found significant excesses from lung cancer (SMR = 223.2, p <0.01,
Power = 38 percent) and NMRD (SMR = 243.0, p <0.05, Power = 35 percent) despite
low power. The highest excesses were found among those in the highest exposure
category (>399 fiber-years) for both lung cancer (SMR = 575.5, p <0.01) and
NMRD (SMR = 400.7, p <0.01). Because vermiculite ore was found to be contarr.i-
nated with fibrous tremolite-actinolite, it is not possible to attribute these
and other excesses to vermiculite exposure. Therefore, the weight of evidence
for a causal relationship between exposure to vermiculite and lung cancer or
NMRD is inadequate.
9.4.2 Animal Toxicity
9.4.2.1 Quantification of Noncarcinogenic Effects
9.4.2.1.1 Attapulgite. No inhalation studies on attapulgite were found in the
available literature, and therefore, an RfD was not calculated.
9.4.2.1.2 Erionite. Although no suitable inhalation toxicity studies were
found for use in quantification of noncarcinogenic effects, erionite has been
shown to be carcinogenic in animals and humans following inhalation exposure
(see Section 9.4.2.2.2 and Chapter 7). Consequently, an inhalation RfD value
was not calculated.
9.4.2.1.3 Talc. Only one inhalation study was found in the available litera-
ture (Wagner et a!., 1977). In this study, groups of rats were exposed to a
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mean respirable concentration of 10.8 mg/m3 talc for 7.5 hours/day, 5 days/week
for 3, 6, or 12 months. The animals were then observed for up to 1 year. At
this concentration, minimal to slight fibrosis was observed in the talc-exposed
rats; the severity increased with increasing length of exposure. Thus, a LOAEL
of 10.8 mg/m was identified, and since this was the only inhalation study
available for consideration, this value was used to calculate the RfO for talc.
The RfD for a 70-kg adult is calculated as follows:
RfD = m = 0.011 mg/m3 (10.8 mg/m3)
where:
10.8 mg/m3 = LOAEL, based on presence of pulmonary fibrosis in rats,
1000 = uncertainty factor, chosen in accordance with EPA guidelines
for use with a LOAEL from an animal study.
9.4.2.1.4 Venm'culite. No inhalation studies were found in the available
literature. Therefore, an RfD for vermiculite could not be calculated.
9.4.2.2 Characterization and Quantification of Carcinogenic Effects
9.4.2.2.1 Attapulgite.. No studies on the carcinogenicity of attapulgite
following inhalation exposure were found in the available literature (see
Table 7-13). Negative results were obtained following intrapleural administra-
tion in rats by Stanton et al. (1981). However, Pott et al. (1974, 19S7a)
reported that attapulgite was carcinogenic when administered via the intra-
peritoneal route, inducing tumors in 40 to 65 percent of the rats injected.
The majority of the tumors were reportedly mesotheliomas. No methodology for
the quantification of the carcinogenic risk using data from intraperitoneal
studies is available and, therefore, a risk estimate was not calculated.
9.4.2.2.2 Erionite. Unlike the other naturally occurring and manmade mineral
fibers mentioned above (see also Table 7-13), erionite was found to be a very
potent carcinogen following inhalation exposure, Inducing mesotheliomas in
27/28 rats (Wagner et al., 1985). Erionite has also been shown to be carcino-
genic after intraperitoneal administration in rats and mice (Suzuki and
Kohyama, 1984; Ozesmi et al., 1985; Pott et al.; 1984a, 1987a) and intrapleural
injection in two strains of rats (Maltoni et al., 1982; Wagner et al., 1965).
Using the multistage model for carcinogenic risk estimation, the unit risk
is 5.56 (mg/m3)"1, based on the tumor incidences obtained from the inhalation
July 1988 9-39 DRAFT--nn KIHT 'nnn-rc nc rm
-------
study of Wagner et al. (1985) given below. This value represents the 95 per-
cent upper bound on risk. The true value could be as low as zero but is
unlikely to be higher. No adjustments were made to account for differences in
extrapolation between animals and humans.
Exposure level (mg/tn3)
10
Mesotheliomas 0/28** 27/28**
""Significant dose-related trend by the Cochran-Armitage Trend test denoted
at controls (p <0.01), and significant increase compared to controls by
Fisher's Exact test denoted at the high-dose group (p <0.01).
9.4.2.2.3 Talc. There is no evidence that talc is carcinogenic following
ingestion, inhalation exposure, or intratracheal, intrapleural, or intraperito-
neal administration in rats, hamsters, or mice. Negative results were obtained
following inhalation exposure in rats and hamsters by Wagner et al. (1977) and
Wehner et al. (1977). Similar findings were observed after intratracheal
instillation in hamsters, although talc proved to be an effective cocarcinogen
when administered with benzo(a)pyrene (Stenback eta!., 1986). No tumor
induction was observed following intrapleural administration in two strains of
rats (Wagner et al., 1977; Stanton et al., 1981), and negative results were
also obtained after intraperitoneal injection of talc in rats and mice (Pott
et al., 1974; Ozesmi et al., 1985).
The weight of evidence indicates that talc is not carcinogenic in labora-
tory animals following inges\ion, inhalation exposure, or intfatracheal,
intrapleural, or intraperitoneal administration. Therefore, an estimate of the
carcinogenic risk for talc was not calculated.
9.4.2.2.4 Vermiculite. The only study on the carcinogenicity of vermiculite.
found in the available literature indicated that vermiculite is not carcinogen-
ic following intrapleural administration in rats (Hunter and Thomson, 1973).
However, since no other carcinogenicity studies were found, an assessment of
the carcinogenic risk of vermiculite cannot be made at this time.
July 1988 9-40 DRAFT—DO NOT QUOTE OR CITE
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9.4.3 Characterization of Carcinogenic Potential Based on Human and Animal
Data
The weight of evidence from both human health effects data and animal
toxicity data (see also the following summary) suggest the following carcino-
genic categories for the minerals: attapulgite, C; erionite, B2; talc, D;
vermiculite, D.
9.5 SUMMARY OF CARCINOGENIC AND NONCARCINOGENIC EVIDENCE
The NOAELs and LOAELs identified from inhalation toxicity studies are
listed in Table 9-5. These values serve as the basis for calculation of the
RfD values. Suitable inhalation toxicity studies were not found for carbon
fibers, polyolefin fibers, attapulgite, and vermiculite. Although an inhala-
tion study was found for erionite, only the carcinogenic effects were described.
The weight of evidence for animal and human carcinogenicity are also listed in
Table 9-5. Most fibers for which data were available showed some carcinogenic
effect when administered via the intrapleural and/.or intraperitoneal route,
except for talc. However, only aramid fibers and erionite are carcinogenic by
the inhalation route.
The weight of evidence for carcinogenicity in humans was limited for
fibrous glass wool (with diameters <3 pm), mineral wool, and erionite. Esti-
mates of cancer risk were not determined because dose-related increases were
not observed, and exposure data were not available. Inadequate evidence was
found for glass microfibers, attapulgite, talc, and vermiculite. Both talc and
vermiculite were found to contain asbestos fibers. Epidemiological studies
were not found for ceramic, aramid, carbon, or polyolefin fibers.
-------
TABLE 9-5. SUMMARY OF CARCINOGENIC AND NONCARCIMOGEN1C EFFECTS FROM ANIMAL AND HUMAN DATA
Fiber
Glass microfibers
Fibrous glass
Rock wool
Slag wool
Ceramic fibers
Aramid fibers
Carbon fibers
Polyolefin fibers
Attapulgite
Erionite
Talc
Vermiculite
Noncarcinoqenic e
(mg/m-1 )
NOAEL LOAEL
3.0 100
~a 5
5 10
10
2.45 8.4
0.08 0.32
—
..
._
—
10.8
..
ffects
RfD Inh.
0.03
0.005
0.05
0.01
0.024
0.0008 *
—
--
—
4
0.011
—
Carcinogenic evidence in
Animal Unit risk Human
Intpl. Intrpr. (mg/m3) ' Inh.
+ * -- Inadequate
+ * Limited
+ + — . Limited
± - — Limited
i *
t 9.4xlO~2
_
-4
± — Inadequate
+ + 5156 Limited
Inadequate
Inadequate
Carcinogenic
classification
82
Bl
Blb
Blb
C
B2
0
D
C
Bl
0
0
No suitable studies were found.
'Human evidence is for mineral wool, i.e., rock and slag wool combined.
Abbreviations: Inh. = inhalation; Intpl. = intrapleural administration; Intrpr. = intraperitoneal injection.
-------
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