mesothelioma cancer

Historical Background

It was the Conference on the Biological Effects of Asbestos at the New York
Academy of Sciences, organized by Irving Selikoff in November 1964 (1), that put
both mesothelioma and asbestos on the map. Before that meeting, few people in
the scientific or general community had much knowledge of either subject. There
they learned the nature and numerous essential industrial uses of a group of
naturally occurring mineral fibers, collectively known as asbestos, although in
fact com¬prising at least five distinct materials, chemically, physically, and
geologically. Of these, chrysotile, a serpentine mineral mined mainly in Quebec
and the Ural mountains of Russia, made up over 90%. Of the remainder the two
most important were crocidolite and amosite, produced mainly in South Africa and
Australia, both amphibole min¬erals with distinctive qualities valuable for heat
insulation, naval marine use, and the production of large-bore cement pipes. Two
other amphibole mineral fibers were anthophyllite, of limited production in
Finland, and tremolite, little used, though by far the most widespread
geologically. Presenters at the conference stated that within some 20 years of
the first industrial exploitation of asbestos in the 1880s, workers heavily
exposed to airborne fiber and dust developed a dis¬tinctive, seriously disabling
and sometimes fatal diffuse pulmonary fibrosis, later termed asbestosis. Little
was done to limit exposure until the late 1930s, when after a well-conducted
survey of four asbestos textile plants in North Carolina, Dreessen et al (2) and
others of the U.S. Public Health Service recommended in 1938 that a workplace
dust con¬centration of 5 million particles per cubic foot (about 15 fibers/mL)
should not be exceeded. Mainly because of the Second World War, this
recommendation was not implemented; and probably for the same reason it went
unnoticed that there were case reports by some German pathologists (3) of
malignant tumors of the pleura and peritoneum in men with asbestosis. Thus it
was only in the 1950s that the causal asso¬ciation of asbestos exposure with
lung cancer in the United Kingdom (4), and later with mesothelioma in South
Africa (5), was recognized.

Until that time even the very existence of primary malignancies of the
mesotheleum was questioned by reputable pathologists. Looking back, however, a
review by Saccone and Coblenz (6) in 1943 had included the identification of
over 40 cases in autopsies published since 1870, and referred to two cases of
“endothelioma” reported in 1767 by Lieutaud in France among 3000 autopsies. That
mesothelial cancers in low frequency probably occurred well before the
industrial use of asbestos is discussed more fully later. Indeed, a low
background inci¬dence of unknown etiology has almost certainly continued,
affecting both children and adults.

The Link with Asbestos

Two key events were undoubtedly responsible for organizing the New York
Conference. The first was the report in 1960 by Wagner et al (5) of 33 cases of
pleural mesothelioma in the northwest Cape Province of South Africa, 28 of which
occurred in persons who had either worked in the crocidolite mines or lived
close to them, even as children. The second was a study by Hammond et al (7) of
307 deaths in a small cohort of 632 New York insulation workers, including four
from pleural and six from peritoneal mesothelioma. At the end of the conference,
an expert working group of the International Union Against Cancer (UICC), after
review of the evidence presented, made a number of recommendations for
epidemiologic studies, in particular into the importance of asbestos fiber type,
especially in mining industries rather than in manufacturing, to avoid the
complication of exposure to mix¬tures (8). At the request of the Canadian
Federal Government, and with support from the Research Institute of the Quebec
Asbestos Mining Association, a comprehensive university-based scientific program
was established almost at once (9). Elsewhere, only in the chrysotile mine of
Belangero in northern Italy was anything done to implement these recommendations
until over 20 years later. As a result, the lack of infor¬mation on amphibole
exposure, comparable to that for chrysotile, greatly delayed our understanding
of mineral fiber carcinogenicity.

Early Case-Control Studies

Data from two important case-control studies in the United Kingdom were
presented at the New York Conference and published more fully the following
year. The first of these was by Elmes et al (10), who studied 42 male cases of
pleural mesothelioma and 42 closely matched controls in Belfast, Northern
Ireland, with detailed work histories taken from those still living or from
relatives of those who had died. Thirty-seven cases had been exposed to
asbestos, mainly in plumbing, insulation, and shipyard work, not all heavily and
without mention of fiber type, compared with nine controls. The second study, by
New-house and Thompson (11), was of 83 cases, half in men and half in women, who
had died between 1917 and 1950, 56 from pleural and 27 from peritoneal
mesothelial tumors, close to the large Cape Asbestos

Company’s factory that opened in 1913 in London’s East End. Their control series
comprised patients admitted later to the hospital with other diseases, matched
for sex and age. The authors acknowledged that neither these control measures
nor the interview methods were ideal, but concluded that the case-control
comparisons of occupational and residential histories were probably valid. Of 76
pairs, 18 cases (24%) had been employed at the Cape Asbestos factory, five (7%)
at other asbestos plants, and eight (11%) as insulators or laggers, com¬pared
with one (1%) and four (5%) controls respectively. A further nine cases (12%)
were in persons who had lived in the same house as an asbestos worker and were
indirectly exposed, compared with one control (1%). Only crocidolite from South
Africa was used in the Cape Asbestos factory until 1926, when small quantities
of chrysotile and amosite were introduced.

During the next few years, six more case-control studies were published in
addition to the two studies cited above, all with a sub¬stantially increased
relative risk associated with occupational asbestos exposure (Table 17.1).
Little attention was given to fiber type explicitly, but it can be seen that
five of the eight studies were in shipyard areas where amphibole use was common.
Rather different from the other seven, and perhaps more generally informative,
was the study across Canada by McDonald et al (13). This entailed an approach to
all 423 of the country’s pathologists, whereby 165 known deaths from
mesothe-lioma in 1959 to 1968, diagnosed by autopsy or biopsy, were registered
(i.e., 1 per million population per annum). Of this total, 65% were in men; 70%
were pleural, 27% peritoneal, and 3% pericardial. Detailed occupational and
residential histories of exposure to asbestos and six other materials used
industrially were obtained “blind” from relatives and friends in 90% of the
cases, and from two matched case-control series, one of primary and one of
secondary lung cancer, selected from the same autopsy records. An association
with definite or probable occupational exposure to asbestos was clearly
demonstrated—indeed with the highest relative risk (7.0) of all eight
case-control studies—but only 20% of men and one woman had any such contact.
Almost all the excess was in the manufacturing and industrial application of
asbestos, rather than in mining or milling. No association was found with lesser

degrees of occupational exposure or residence in asbestos-mining areas, but
there was a small excess of possible domestic exposures. The smoking histories
in the mesothelial tumor and male control groups were almost identical, and
considerably lower than those in cases of primary lung cancer, implying that
unlike asbestos-related lung cancer, smoking did not contribute to this disease.

In 1972 the survey was repeated, with extension to all pathologists in North
America (some 7000 of them), almost all of whom agreed to contribute cases
identified at autopsy or biopsy for the one year only (18). A control subject
with death from metastatic lung disease from a primary tumor outside the chest,
matched for date, sex, and age, was selected from the same pathology file as the
case. Relatives were inter¬viewed usually by a public health nurse who was not
informed about the case-control status, and detailed residential and
occupational his¬tories were recorded. Jobs were also coded blind, using a list
compiled by four expert international groups, according to the probability of
asbestos exposure. Of 344 male cases of mesothelioma, 188 (55%), com¬pared with
78 (23%) controls, fell into one of the five exposed cate¬gories: insulation
work, an infrequent occupation in controls, had the highest relative risk
(46.1); asbestos production and manufacture were next in line (6.1), followed by
employment in heating trades (exclud¬ing insulation work), shipyards, and
construction (3.4). Subjects from this survey were subsequently used as the base
in a case-control analy¬sis of lung burden with the fibers identified and
concentrations estimated by electron microscopy. The results of this study are
summarized later, together with those from other lung burden analyses.

In the Canadian surveys, 1960 to 1966, the average annual incidence was one case
per million persons—about 1.5 for males and 0.8 for females; however, there may
have been underreporting during these early years. In 1966 to 1972, the
incidence in Canada was 2.9 per million males and 1.4 per million females, and
in the United States in 1972 the corresponding rates were 2.7 and 0.8 per
million. These estimates were used in 1975 in a geographical analysis of all
known cases of mesothe-lioma worldwide in areas where reported cases could be
linked to population estimates. By applying age- and sex-specific rates found in
Canada, the number of mesotheliomas expected on this basis was com¬pared with
the numbers observed (19). High observed-to-expected ratios were found in many
European shipyard cities, notably Walcheren, the Netherlands (23.3),
Wilhelmshaven, Germany (21.5), and Plymouth, UK (14.3). In two locations with
large asbestos product manufacturing industries, there were also high ratios:
Dresden, Germany (16.8) and the Manville-Somerville area of New Jersey (26.5).

In the early 1970s, mesothelioma mortality in North America was already two or
three times higher in males than females. This pattern soon became apparent in
most industrialized countries and was fol¬lowed by a steady upward trend in male
mortality, which still contin¬ues. The steep rise in males, which probably began
in the 1940s, reflects a parallel increase in the industrial use of asbestos,
from about 1910,

having taken account of a 30- to 40-year latency. As a result of this steady
increase, mesothelioma is now responsible for some 20 deaths per million male
population in Western Europe and North America compared with an estimated 1 to 2
per million 30 to 40 years ago. In early studies, only a minority of male cases
were attributable to occu¬pational exposure, whereas now up to 90% are.

Occupational Risk

Apart from the early case-control studies just described, the main body of
information on risks from exposure to airborne asbestos fibers in the workplace
is contained in over 40 historical cohort mortality studies reported during the
past 30 years. These studies have varied in quality and in the extent to which
exposure has been assessed in duration, intensity, or asbestos fiber type. In
fewer than 10 cohorts had there been any attempt to estimate exposure intensity
for each cohort member, and in very few cohorts indeed was there exposure to
only one type of asbestos. These serious deficiencies, given the potentially
great difference in carcinogenicity between chrysotile and the amphi-boles,
render almost uninterpretable the results of the many cohorts exposed to
mixtures where one type, usually chrysotile, was said to predominate.

Despite this lack of specificity, cohort surveys, by being prospective, have
provided more useful information on occupational risk than was usually obtained
from retrospective case-referent studies. This is more true, however, of lung
cancer and nonmalignant respiratory disease (NMRD) than of mesothelioma.
Standardized mortality ratios (SMRs) can usually be calculated by age, sex, and
exposure variables for the former but not the latter, as even now mortality
rates for mesothelioma in the general population are seldom available, let alone
reliable. Inves¬tigators have had to fall back instead on measures of
proportional mortality, though these depend enormously on age composition of the
cohort and length of follow-up. For example, in the large cohort of Quebec
chrysotile miners and millers, described more fully below, the proportion of all
deaths ascribed to mesothelioma rose steadily from 3 of 2413 (0.12%) in 1966 to
38 of 8009 (0.47%) in 1992 (20). Even so, in the absence of any better index,
proportional rates interpreted with care can be useful. Thus, in Table 17.2,
where the salient findings from the 43 main cohort mortality studies published
before 1999 are summa¬rized, the differences in proportional mortality for
mesothelioma are large and systematic. This is especially so when differences
between chrysotile and amphibole exposure within the same industrial sector are
considered in more detail.

The largest and most complete of the mining cohorts was of all 10,918 men born
in 1891 to 1920 who, in 1966, had served for 1 month or more in the Quebec
chrysotile production industry, either as miners or millers in the town of
Asbestos or region of Thetford Mines, or in a small asbestos products factory
(23). Excluding losses, almost all before 1935 and in men with very short
employment, 8009 (82%) of 9780

At both the town of Asbestos and the region of Thetford Mines, the average
duration of employment for mine, mill, and factory workers was about 10 years,
and of those traced, 76% had worked for more than 1 year. No case occurred among
some 4400 men employed less than 2 years; eight were in men employed 2 to 5
years, and the remaining 30 in men employed 20 to 49 years. All employees in the
factory were also potentially exposed to crocidolite and amosite, mainly used in
cement and friction product manufacture. Among these were two cases in men who
in 1939 to 1942 worked on the carding of pure crocidolite for military gas mask
filters. The exposures, shown in f/mil.y, are approx¬imate and were obtained by
conversion from cumulative exposures expressed in million dust particles per
cubic foot.y (mpcf.y), accumu¬lated by workers to age 55.

The cohort of 7317 white South African amphibole miners was estab¬lished in 1981
from records of men employed since 1925 (28). Only some 45% of the cohort were
employed for more than 1 year, and 8% for more than 10 years. Excluding 167 lost
to follow-up, 1225 of the remaining 7150 had died; 30 (2.4%) probably from
mesothelioma, distributed as follows by type of exposure:

The cohort of Australian crocidolite miners and millers comprised 6505 men first
employed between 1943 and 1967, with 4653 (72%) traced to the end of 1980; by
then 820 were known to have died, 32 (3.9%) from mesothelioma (27). Their median
cumulative exposure was estimated at 6 fibers per cc/year; their median duration
of employment was only 4 months, but their exposure was described as intense.
Despite the far lower cumulative exposure experienced by South African and
Australian workers than the men in Quebec, their proportional mor¬tality from
mesothelioma was about 10 times higher.

Most of the other industry-specific comparisons present much the same pattern.
In friction product manufacture, for example, although 11 mesothelioma deaths
were observed by Newhouse and Sullivan (45) in a large cohort of over 9000,
virtually all of whom were exposed only to chrysotile, 10 of the 11 were
definitely, and one possibly, members of a small group who worked for a short
time on a special crocidolite contract. In the textile industry, the two cohorts
studied by McDonald et al (40,42) were in plants owned by the same company and
similar in every way, except that in the one with 14 deaths from mesothelioma,
crocidolite was also used. Even more dramatic results were obtained from the two
cohorts employed briefly during the early years of the Second World War in
Canada (49) and in England (50) on the manu¬facture and assembly of filter pads
made with pure crocidolite for mil¬itary gas masks. Cases of mesothelioma began
to appear in both cohorts 18 years later, with PMRs reaching 16% and 17%,
respectively. A disaster of similar severity affected a small group of employees
in the United States engaged in the manufacture of cigarette filters, of all
things, from crocidolite. In contrast, a study of 570 British workers employed
in manufacturing civilian gas masks using chrysotile filters produced only one
case, an employee previously exposed to crocido-lite (52).

In summary, of 11,538 deaths in the chrysotile cohorts, 44 were from
mesothelioma (PMR per thousand 3.8), whereas in the amphibole-related cohorts of
19,622 deaths, 590 were from mesothelioma (PMR per thousand 30.1). While the
carcinogenic potency of crocidolite thus seems clear, that of amosite,
particularly in mining, is less so. High rates of mesothelioma were observed
nevertheless in the manufacturing of insulation materials and among insulation
workers, both groups heavily exposed to amosite. In none of the reports on
cohorts in Table 17.2, however, is there any reliable indication of risk in
relation to esti¬mated intensity of exposure to any specified fiber type; the
interpreta¬tion of the PMRs, therefore, entails several assumptions.

A further point of interest concerns the general parallel exhibited in Table
17.2 between levels of mesothelioma and lung cancer excess mor¬tality in all
industries except textile manufacture. In the four cohorts shown, two of which
were in the same plant, there were only two mesothelioma deaths in all, whereas
for lung cancer the general pattern was reversed (40,41). In the other two
textile plants in which crocido-lite was also used, there were 24 deaths from
mesothelioma, but with only modest SMRs for lung cancer (42,43). This anomaly,
which is con¬fined to the use of chrysotile in this particular plant, has never
been satisfactorily explained (60), and is all the more important in that it did
not apply to mesothelioma.

Other Causes

Mention has been made of the occurrence of possible cases of mesothe-lioma in
autopsy series at the end of the 19th century. Given the long latency of this
disease (20 to 50 years or longer), it is unlikely that they

could have resulted from the industrial exploitation of asbestos, which began in
the 1880s and then only on a small scale. This evidence in itself is not
conclusive, but there are stronger grounds for both the existence of a low
background incidence of mesothelioma of unknown etiology, and for causation by
at least one environmental mineral other than asbestos.

Fibrous Erionite

The evidence against fibrous erionite is virtually confined to the dis¬astrous
occurrence of unequaled mortality from these tumors in a localized area of
central Turkey. The population of three villages in Cappadocia had been exposed
since birth to airborne fibers of erionite, a zeolite mineral quite unrelated to
asbestos, though with fibers having some physical similarities to crocidolite.
The fibers are derived from volcanic rock, or tuff, which is used in the area
for construction of houses and other buildings. In the three affected villages,
29 of 125 deaths during a defined period were from pleural mesothelioma, and
four others from peritoneal disease (61). Investigation showed that air¬borne
fiber concentrations were higher in the villages affected than in one that was
not; also sputum samples from residents in the former contained ferruginous
bodies with an erionite core. In most cases expo¬sure was from birth, with death
occurring 27 to 40 years later. In common with amphibole fibers, electron
microscopic studies of lung tissue showed erionite to be highly biopersistent.
Deposits of fibrous erionite occur in volcanic areas elsewhere, for example in
some Rocky Mountain states; there has also been some synthetic production for
industrial catalytic purposes. No clear link with mesothelioma mortal¬ity has
been shown with either of these possible sources; perhaps because nowhere other
than in Cappadocia has volcanic tuff been used for domestic buildings, resulting
in exposure of young children. It is worth adding that deaths from mesothelioma
have also been recorded in Scandinavia and other parts of Turkey among former
residents of the affected villages.

Apart from asbestos and erionite, no other environmental agent has been
incriminated with any certainty. Some suspicion has rested on the long, thin
silica fibers created by the burning of sugar cane in India (62) and in the
southern states of the United States (63). A similar process might also arise in
forest fires, but none of these suggestions has been supported by experimental
or lung burden evidence.

Mesothelioma in Children

Despite diagnostic uncertainties, greater even than in adults, it is evident
that mesothelioma does occur in children. In a review of 80 cases, reported from
1969 to 1986 (64), the ratio of males to females, aged 1 to 19 years (mean 9.7
years) was 1.4:1 and only two had a pos¬sible exposure to asbestos. Of these,
68% were pleural, 25% peritoneal, and 8% pericardial. Given that the latency of
mesothelioma is very seldom less than 20 years, and in the Turkish cases at
least 27 years, it is most unlikely that childhood cases could be due to
asbestos expo-

sure. The incidence of mesothelioma in persons younger than 20 years of age can
be roughly estimated from three studies (65). In the Canadian survey from 1960
to 1968, four fatal cases were ascertained by systemic inquiry from all
pathologists—a rate of about 0.7 per 10 million per annum. A very similar figure
can be derived from 13 cases identified among death certificates in the United
States from 1965 to 1968. Finally, data from the Surveillance, Epidemiology, and
End Result (SEER) program in the United States, estimated the case incidence
from 1973 to 1984, at 0.5 per 10 million. As mesothelioma in children may well
be underdiagnosed, a conservative estimate for the annual case incidence in
North America may well reach 1 per 10 million, but even so, appreciably lower
than any comparable estimate for adults.

Statistical Extrapolation

In Canada, annual incidence rates based on cases of mesothelioma ascertained
through pathologists, when extrapolated backward, suggest that male and female
rates were similar at or before 1950, at a level of about 1 per million
population. This pattern is similar to trends found in the SEER cancer
surveillance program in the United States, and for mortality observed in
Britain, Finland, Norway, and Denmark, where an increasing male excess appears
due to the more frequent history of occupational asbestos exposure in men than
in women. In the SEER program, regions with higher age-adjusted incidence rates,
presumably attributable to work-related asbestos exposure, had higher ratios of
male to female cases than regions with lower rates, and linear extrapolation
would suggest that, at the point where the sex ratio is equal, the incidence
might be as high as 5 per million, though with wide confidence limits. In Los
Angeles County, equal numbers of cases in men and women were without history of
exposure to asbestos, sug¬gesting a background incidence of about 2 per million.
In France, careful inquiry failed to identify any opportunity for asbestos
exposure in younger subjects with mesothelioma, with equal numbers of males and
females. In all these various studies, efforts to detect a cause other than
asbestos have been largely unsuccessful (65).

Lung Burden Analyses

Valuable though cohort mortality surveys have been in assessing the health
effects of asbestos in selected industries, they have not con¬tributed much to
knowledge concerning risk in relation to intensity of exposure to specific types
of fiber. In diseases such as mesothelioma, the relevant exposures took place
many years before adequate mea¬surements of respirable dust particles, let alone
fibers, had been made. Any such estimates remain at best a rough surrogate for
what an individual worker inhaled and retained. Thus the development in the
1970s of electron microscopy with energy-dispersive analysis, to iden¬tify,
count, and size mineral fibers in lung tissue, held great potential, though also
with limitations. Apart from selective biases resulting from the availability
and nature of lung samples obtained for analysis, fibers

seen at autopsy or biopsy may not reflect what were present years earlier; much
depends on the ability of fibers to penetrate the airways, and on their
subsequent durability and biopersistence. As it is precisely in these latter
qualities that chrysotile and the amphiboles differ, any epidemiologic study of
lung burden must be carefully controlled and the results interpreted with
considerable caution.

Despite these difficulties, there have been several well-designed case-control
studies of reasonable quality in Europe, Australia, and America that, though not
conclusive, have provided consistent evi¬dence implicating amphibole fibers
rather than chrysotile in most cases of mesothelioma (Table 17.3). The two most
recent studies from Germany (72) and the United Kingdom (73) are particularly
informa¬tive in that they addressed risk in relation to fiber concentration in
lung tissue, i.e., retained dose. In both these studies, a highly significant
linear relationship was observed between odds ratios and concentra¬tions of
amphibole fiber, but not with chrysotile. In the German study, risk was greatest
with fibers longer than 15mm, and in the British, short, medium, and long fibers
were all associated with risk, but most closely with those in the longest
category (≥10mm). In the latter study, the strong linear trend shown by
crocidolite, amosite, and tremolite when combined suggested that their effects
were probably additive (Table 17.4). Overall, these analyses indicated that some
80% of cases studied were attributable to amosite or crocidolite, and 7% to
tremolite. The contribution of chrysotile could not be reliably assessed because
of its low biopersistence, but as over 90% of all asbestos used is chrysotile,
for which tremolite is a valid marker, it must be small.

The British study just described was based on a larger number of cases reported
by chest physicians in a national surveillance scheme in men younger than 50
years of age at time of diagnosis. It was thought that most, if not all, of the
occupational exposures would have been since 1970 when the importation of
crocidolite to the UK was virtually eliminated. In fact, it was found that
almost all the cases were in men who had started work several years before that
date. Of 37 occupations analyzed, odds ratios against expected values obtained
from the census were significantly raised in only eight, of which five were in
the con¬struction industry: carpenters, plumbers, electricians, insulators, and
unskilled workers. The remaining three categories at increased risk were workers
in shipbuilding, cement, and mineral product manufac¬turing, all less important
in this than in earlier surveys (74).

The Tremolite Factor

When we began in 1965, at the behest of the UICC Working Group, an extensive
program of epidemiologic research in the Quebec asbestos mining industry, it was
in the belief that we were dealing with expo¬sure to chrysotile only. Clear
evidence was found of a systematic relationship between quantitative estimates
of airborne dust particle exposure and all measures of morbidity and mortality
of primary inter¬est, including lung cancer, radiographic change, lung function,
and

respiratory symptoms (75). Except at very high exposure levels, these adverse
health effects were not severe, and even among 2413 deaths in a cohort of some
10,000 men, only three (0.12%) were ascribed to mesothelioma. This seemed in
marked contrast to the findings of Selikoff et al (56) of 22 deaths (5.8%) from
this cause among 380 deaths in a small cohort of 632 American insulation workers
(76).

It was observed at the outset, and by local physicians for many years, that
pleural thickening and calcification were much more frequent among workers in
the Thetford Mines region of Quebec than in the town of Asbestos, some 60 miles
away. In a detailed study of pleural calcification Gibbs (77), who was
responsible for the environmental aspects of our research program, noted in 1972
that these radiographic changes were considerably more prevalent in some mines
than in others, suggesting to him that minerals other than chrysotile might be
responsible. Over the next few years, a series of studies was published with
results based on electron microscopic analyses of lung tissue at autopsy, which,
taken together, indicated that the exposure experi-

enced by workers with Quebec chrysotile was much more complicated than had
previously been supposed.

First came the observations of Pooley (78), and then of Rowlands et al (79), who
found that, in the lungs of former Quebec miners at autopsy, chrysotile and
tremolite fibers were present in surprisingly similar concentrations (Fig.
17.1). Later, further analysis of data from these studies suggested that
tremolite concentrations were perhaps two to three times higher in the region of
Thetford Mines than in the town of Asbestos (80). There followed a much larger
investigation by Sébastien et al (81) that, though undertaken for an entirely
different purpose, added considerably to several aspects of the tremolite
ques¬tion. The primary objective of this study was to explain the much greater
risk of lung cancer, though not of mesothelioma, in asbestos textile workers in
Charleston, South Carolina, than in Quebec miners

and millers both exposed to chrysotile from the same source. One hundred
sixty-one lung tissue samples from deceased cohort members (72 from Charleston
and 89 from Thetford Mines) were collected for analysis by transmission electron
microscopy. Altogether 1828 chrysotile and 3270 tremolite fibers were
identified; in both cohorts tremolite predominated and fiber dimensions were
closely similar. Analyses that took account of duration of employment, exposure
inten¬sity, and time from last employment to death concluded that none of these
variables could explain the higher lung cancer risks observed in textile
workers. The possible co-carcinogenic role of mineral oil used to control dust
in textile plants was an alternative explanation, which has yet to be adequately
tested. However, the findings from this large survey made it possible to address
several other questions.

reported by Wagner et al (85) in laboratory rats after inhalation of amosite and
chrysotile.

In his earlier study of pleural calcification in the region of Thetford Mines,
Gibbs (77) had noted that these changes were more common among miners than
millers, and particularly in men who had worked in a localized group of mines
near the center of the town rather than in other mines located peripherally. He
concluded that the cause might be related to some mineral closely associated
with chrysotile, possibly mica, talc, or brünnerite, but he did not include
tremolite, which even Riordan (86) had rarely mentioned in his comprehensive
description of the geology of the region in 1957. Much later, when, by 1992, 38
prob¬able cases of mesothelioma had been identified in the Quebec cohort among
over 8000 deaths from all causes, it became clear that even at Thetford Mines
they too were unevenly distributed. As mentioned in the previous section, among
4125 deaths in miners and millers at Thet-ford Mines, there were 25 (0.61%) from
mesothelioma; at the town of Asbestos among 3331 deaths, the corresponding
figure was 8 (0.24%). At Thetford, however, the cases were more common in
miners, whereas at Asbestos the few cases were all in millers. A further
detailed examination of work histories of the cases at Thetford showed that
man-years of employment were concentrated in a localized area of five mines
centrally located (area A), compared with 10 mines located peripherally (area B)
(20). These were much the same as those observed by Gibbs for pleural
classification. A more detailed analysis was then made of the data for the 83
subjects in Thetford Mines from the study of Sébastien et al (84), using
available records of the specific mines in which each man had worked. This
showed that the concentration of tremolite fibers, but not of chrysotile, were
some four times higher among 58 men in area A (32/mg) than among 25 men in area
B (7/mg) (p = .0002). A strictly controlled study of deaths from mesothelioma
and other cancers, with analysis by logistic regression, was therefore
under¬taken (87). This showed that the odds ratios (OR) for work in the central
mines (area A) were raised substantially and significantly for mesothe-lioma [OR
= 2.55; 90% confidence interval (CI) 1.52–4.27] and lung cancer (OR = 1.98; 90%
CI 1.53–2.57), but not in area B or for cancer at other sites in either area.
Reanalysis by Sébastien of fibers from his earlier study (81) also confirmed
that there was no important difference in their dimensions or composition
between the two areas.

None of these findings would necessarily have incriminated tremo-lite, as
opposed to some other mineral with similar geographic distri¬bution, in the
absence of independent evidence of the carcinogenicity of fibrous tremolite. The
strongest indication of this has been the expe¬rience of vermiculite miners and
millers in Libby, Montana, exposed to contaminating amphibole fibers in the
tremolite series, but to no other form of asbestos. In the early 1980s, parallel
but independent studies of mortality and morbidity among the employees of the
Libby plant were undertaken by us and the National Institute for Occupational
Safety and Health (NIOSH). The results obtained by the two groups provided very
similar evidence of high excess mortality from non-malignant respiratory
disease, lung cancer, and mesothelioma (88),

and an increased prevalence of small radiographic opacities of between 6% and
10% per 100F/mL years (89).

As these findings on mortality were based on very small cohorts, a further
follow-up to the end of 1998 has recently been completed, allowing a more
reliable assessment of risk in relation to estimated exposure. Total deaths to
the end of 1998 were lung cancer 44 (SMR 2.40), NMRD 51 (SMR 3.09), all causes
285 (SMR 1.27); included among the total were 12 deaths attributed to
mesothelioma (PMR 4.21%) (90) (Table 17.5). Adjusted linear relative risks (per
100 F/mL.y), estimated by Poisson regression, were lung cancer (0.36, 95% CI
0.03–1.20), NMRD (0.38, 95% CI 0.12–0.96), and all causes (0.14, 95% CI
0.05–0.26). The 12 deaths from mesothelioma, though with a typical latency range
of 22 to 47 years (median 35.5 years) showed only a limited relation¬ship to
estimated exposure. The all-cause linear model would imply a 14% increase in
mortality for mine workers exposed occupationally to 100F/mL.y or 3.2% for a
general population exposed for 50 years to an ambient concentration of 0.1F/mL
(90).

Synthesis

Over 40 years have passed since 1960, when 33 cases of pleural mesothelioma were
described by Wagner et al (5), almost all from the crocidolite mining region in
the northwest Cape Province of South Africa. In the same year, 10 cases of
peritoneal mesothelioma were reported by Keal (91) among textile employees of
the Cape Asbestos Company in London, exposed to crocidolite from the same
source. Recognizing therefore the importance of asbestos fiber type, the UICC
Expert Group in 1964 had put priority on epidemiologic studies of miners and
millers engaged in the production of the three main types of asbestos rather
than on employees in manufacture and industrial application, usually entailing
chrysotile-amphibole mixtures. During the next 20 years, unfortunately, most
research focused on the latter

and, until the late 1980s, the only production workers studied were miners and
millers in Quebec and Italy, both with similar and reassur¬ing results for
chrysotile. The first amphibole mine workers for whom there were comparable data
were, in fact, the Libby vermiculite employees, exposed incidentally to
contamination by fibrous tremolite (26,90). Only later were mortality data
published in 1988 on crocidolite miners in Australia (27), and in 1992 on
crocidolite and amosite miners in South Africa (28), but in the meantime a
considerable number of cohort study results based on workers in the
manufacturing industries or in asbestos product use were published. Exposure in
all of these cohorts was mainly to chrysotile, but in most of them also to
varying proportions of crocidolite or amosite.

Investigators familiar with the disastrous experience of insulation workers in
North America, where exposure had also been to chrysotile, and possibly amosite,
found it difficult to believe that all types of asbestos were not equally
harmful. This view was supported by exper¬imental evidence, which showed that
all fiber types were equally carcinogenic, without appreciating that
biopersistence and durability would be far more important in humans, with a much
longer life span, than in laboratory animals. Against a background of much
suspicion and recrimination, the results of the several important cohort studies
published in the 1980s failed to have much effect on entrenched and conflicting
views. For those who saw chrysotile as a mineral fiber of low carcinogenicity,
the findings summarized in Table 17.2 confirmed this opinion. Others, with
legitimate concern for control rather than sci¬entific niceties, found little
difficulty in maintaining their disbelief. Uncertainties associated with mixed
exposures, lack of information on exposure intensity, and statistical chance
were often cited; other reasons were less flattering (3).

Some resolution of this unpleasant and unhelpful controversy came with the use
of lung tissue analyses in epidemiologic research. Despite difficulties in
interpretation of results and the absolute need for prop¬erly selected controls
(92), these studies demonstrated two things and revealed a third. First, was the
clear evidence of an overwhelming predominance, with dose-response, of amphibole
fibers in mesothe-lioma cases; second, that amphibole fibers persist in lung
tissue, whereas chrysotile does not. The short life span of laboratory animals
could not deal adequately with tumors in humans of long latency. Third, it has
only been by analyzing lung tissue that the varying pres¬ence of fibrous
tremolite has been demonstrated in commercial chrysotile.

Although the recent update on mortality in the Libby vermiculite cohort has
indicated that the ability of fibrous tremolite to cause mesothelioma is on a
par with crocidolite, it remains almost impossi¬ble to estimate the contribution
it makes to the carcinogenicity of commercial chrysotile, which greatly varies
in level of tremolite content, both geographically and in time. There are two
main reasons for this. First is our ignorance of how best to assess exposure to
a car-cinogenic agent that is biopersistent. Cumulative exposure clearly
underestimates the potential effect of a retained carcinogen. The expo-

sure index that appeared to do best in the Libby cohort was one in which the
estimated fiber concentration at any year was weighted by residence time.
Although conceptually reasonable, such an index was largely determined by
estimated airborne fiber concentrations 30 to 50 years before death, for which
only the most crude approximations can be guessed in this or any other mortality
study. With only 12 mesothe-lioma deaths in a cohort of 406 men, a statistically
significant discrim¬ination between risk and any type of exposure index was not
possible. Second, there is the analogous problem that results from a total
igno¬rance of the tremolite concentrations to which Quebec miners and millers
were exposed, as far back as 1918, when men who later devel¬oped mesothelioma
were first employed. These cases were miners rather than millers, and in the
relevant period there were almost 30 dif¬ferent mining companies, in few of
which were any dust measurements made. Exposure to tremolite would certainly
have been intermittent, as evidenced by the fact that mesothelioma risk in the
Quebec cohort was related to duration of employment but not to intensity of dust
exposure.

Thus, to obtain any kind of answer to the question, we must take account of
other types of evidence. For example, there was no case of mesothelioma in the
Quebec cohort in men employed less than 2 years, and in the 21 of 38 men with
mesothelioma whose lungs were exam¬ined at autopsy, amphibole fibers—mostly
tremolite and in high concentration—were present in them all (20). In the eight
studies of lung fiber burden in mesothelioma cases and controls (Table 17.3),
little or no evidence of risk was observed with chrysotile only; indeed,
amphibole fibers were present in most cases. Finally, the recent case-referent
study in the United Kingdom of young adults with mesothe-lioma showed that
crocidolite and amosite, singly or additively, could account for about 80% of
cases, and tremolite for about 7%, leaving very few for chrysotile alone.

Compared with amphibole fibers, pure chrysotile is removed much more rapidly
from human tissue, but it is not without some biopersis-tence. It would be
unreasonable, therefore, to conclude that when inhaled in sufficient quantity it
carries no mesothelioma risk. It should be remembered, nevertheless, that the
epidemiologic evidence reviewed in this chapter reflects exposure levels some 40
or more years ago, orders of magnitude higher than those that prevail today or
that should be readily achievable. Unfortunately, past failure to discrimi¬nate
between the carcinogenicity of chrysotile and the amphiboles allowed the latter
to be inadequately controlled too long.

Conclusion

In the discussion session on mesothelioma that followed the presenta¬tions by
Selikoff, Wagner, Newhouse, Elmes, and others at the New York Conference in
1964, Scheepers (93), a principal discussant, raised two prophetic questions
that it has taken 40 years to answer. First, with regard to 11 cases of lung
cancer with which he was familiar and whose

predominant exposure had been to chrysotile, he questioned the logic of
attributing them to chrysotile when all had “at one time or another also been
exposed to other forms of asbestos, mainly amosite or croci-dolite.” His next
paragraph then began with the words “What about tremolite?”! This chapter has
been devoted almost entirely to these two questions. As far as mesothelioma is
concerned, the number of cases in which exposure has been to commercial
chrysotile only, let alone to pure chrysotile, is few; almost all were also
exposed to crocidolite, amosite, or chrysotile-amphibole mixtures. The potential
importance of amphibole fibers in the tremolite series is only now being
appreciated. Its carcinogenicity appears similar to that of crocidolite and,
either as a frequent contaminant of chrysotile or as a general environmental
pollutant in certain localities, its effects, though yet to be fully assessed,
could be very large.

References

1. Selikoff IJ, Churg J. Co-chairmen, Conference on the Biological Effects of
Asbestos. Ann NY Acad Sci 1965;132:1–766.

2. Dreessen WC, Dallavalle JM, Edwards TI, Miller JW, Sayers RR. A study of
asbestosis in the asbestos textile industry. Public Health Bulletin No. 241.
Washington, DC: United States Government Printing Office, 1938.

3. McDonald JC, McDonald AD. The epidemiology of mesothelioma in his¬torical
context. Eur Respir J 1996;9:1932–1942.

4. Doll R. Mortality from lung cancer in asbestos workers. Br J Ind Med 1955;
12:81–86.

5. Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos
exposure in the North Western Cape Province. Br J Ind Med 1960; 17:260–271.

6. Saccone A, Coblenz A. Endothelioma of the pleura. Am J Clin Pathol 1943;
13:188–207.

7. Hammond E, Selikoff IJ, Churg J. Neoplasia among insulation workers in the
United States with special reference to intra-abdominal neoplasia. Ann NY Acad
Sci 1965;132:519–525.

8. Working Group on Asbestos and Cancer. Report and recommendations of the
Working Group convened under the auspices of the Geographical Pathology
Committee of the International Union Against Cancer. McDonald JC, Working Group
Member. Arch Environ Health 1965;11:221– 229.

9. McDonald JC. Research on asbestos and health: a progress report to employers
and employees of the Quebec Asbestos Mining Industry. McGill Reporter
1970;2:18–19.

10. Elmes PC, McCaughey WTE, Wade OL. Diffuse mesothelioma of the pleura and
asbestos. Br Med J 1965;1:350–353.

11. Newhouse ML, Thompson H. Mesothelioma of pleura and peritoneum fol¬lowing
exposure to asbestos in the London area. Br J Ind Med 1965;22: 261–269.

12. McEwen J, Finlayson A, Mair A, Gibson AAM. Mesothelioma in Scotland. Br Med
J 1970;4:575–578.

13. McDonald AD, Harper A, El Attar OA, McDonald JC. Epidemiology of primary
malignant mesothelial tumours in Canada. Cancer 1970;26:914– 919.

14. Rubino GF, Scansetti G, Donna A, Palestro G. Epidemiology of pleural
mesothelioma in north-western Italy (Piedmont). Br J Ind Med 1972;29: 436.

15. Ashcroft T. Epidemiological and quantitative relationships between
mesothelioma and asbestos on Tyneside. J Clin Pathol 1973;26:832–840.

16. Hain E, Dalquen P, Bohlig H, Dabbert A, Hinz I. Retrospective study of 150
cases of mesothelioma in Hamburg area. Int Arch Arbeitsmed 1974;33:15– 37.

17. Zielhuis RL, Versteeg JPJ, Planteydt HT. Pleural mesothelioma and expo¬sure
to asbestos. A retrospective case-control study in the Netherlands. Int Arch
Occup Environ Health 1975;36:1–18.

18. McDonald AD, McDonald JC. Malignant mesothelioma in North America. Cancer
1980;46:1650–1656.

19. McDonald JC, McDonald AD. Epidemiology of mesothelioma from esti¬mated
incidence. Prev Med 1977;6:426–446.

20. McDonald AD, Case BW, Churg A, et al. Mesothelioma in Quebec chry-sotile
miners and millers: epidemiology and etiology. Ann Occup Hyg 1997;41:707–719.

21. McDonald JC. Asbestos. In: McDonald JC, ed. Epidemiology of Work Related
Diseases, 2nd ed. London: BMJ Books, 2000.

22. Piolatto G, Negri E, La Vecchia C, Pira E, Decarli A, Peto J. An update of
cancer mortality among chrysotile asbestos miners in Balangero, Northern Italy.
Br J Ind Med 1990;47:810–814.

23. Liddell FDK, McDonald AD, McDonald JC. The 1891–1920 birth cohort of Quebec
chrysotile miners and millers: development from 1904 and mor¬tality to 1992. Ann
Occup Hyg 1997;41:13–36.

24. Meurman LO, Kiviluoto R, Hakama M. Mortality and morbidity among the working
population of anthophyllite asbestos miners in Finland. Br J Ind Med
1974;31:105–112.

25. Brown DP, Dement JM, John M, Wagoner JK. Mortality patterns among miners and
millers occupationally exposed to asbestiform talc. In: Lemen R, Dement JM, eds.
Dusts and Disease (Occupational and Environmental Exposures to Selected Fibrous
and Particulate Dusts). Park forest South, Illinois: Pathotox Publishers,
1979:317–324.

26. McDonald JC, McDonald AD, Armstrong B, Sébastien P. Cohort study of
mortality of vermiculite miners exposed to tremolite. Br J Ind Med 1986;
43:436–444.

27. Armstrong BK, De Klerk NH, Musk AM, Hobbs MST. Mortality in miners and
millers of crocidolite in Western Australia. Br J Ind Med 1988;45:5–13.

28. Sluis-Cremer GK, Liddell FDK, Logan WPD, Bezuidenhout BN. The mor¬tality of
amphibole miners in South Africa, 1946–80. Br J Ind Med 1992;49: 566–575.

29. Weiss W. Mortality of cohort exposed to chrysotile asbestos. J Occup Med
1977;19:737–740.

30. Thomas HF, Benjamin IT, Elwood PC, Sweetnam PM. Further follow-up study of
workers from an asbestos cement factory. Br J Ind Med 1982; 39:273–276.

31. Ohlson C-G, Hogstedt C. Lung cancer among asbestos cement workers. A Swedish
cohort study and a review. Br J Ind Med 1985;42:397–402.

32. Gardner MJ, Winter PD, Pannett B, Powell CA. Follow-up study of workers
manufacturing chrysotile asbestos cement products. Br J Ind Med 1986;
43:726–732.

33. Hughes JM, Weill H, Hammad YY. Mortality of workers employed in two asbestos
cement manufacturing plants. Br J Ind Med 1987;44:161–174.

34. Finkelstein M. Mortality among employees of an Ontario asbestos-cement
factory. Amer Rev Respir Dis 1984;129:754–761.

35. Alies-Patin AM, Valleron AJ. Mortality of workers in a French asbestos
cement factory 1940–1982. Br J Ind Med 1985;42:219–225.

36. Magnani C, Terracini G, Bertolone GP, et al. Mortalita per tumori e altre
malattie del sistema respiratorio tra i lavoratori del cemento-amianto a casale
Monferrato. Una studia di coorte storico. Med Lav 1987;6:441– 453.

37. Raffn E, Lynge E, Juel K, Korsgaard B. Incidence of cancer and mortality
among employees in the asbestos cement industry in Denmark. Br J Ind Med
1989;46:90–96.

38. Albin M, Jakobsson K, Attewell R, Johansson L, Welinder H. Mortality and
cancer morbidity in cohorts of asbestos cement workers and referents. Br J Ind
Med 1990;47:602–610.

39. Neuberger M, Kundi M. Individual asbestos exposure: smoking and mor-tality—a
cohort study in the asbestos cement industry. Br J Ind Med 1990; 47:615–620.

40. McDonald AD, Fry JS, Woolley AJ, McDonald JC. Dust exposure in an American
chrysotile textile plant. Br J Ind Med 1983;40:361–367.

41. Dement JM, Brown DP, Okun A. Follow-up study of chrysotile textile workers:
cohort mortality and case-control analyses. Am J Ind Med 1994;26: 431–447.

42. McDonald AD, Fry JS, Woolley AJ, McDonald JC. Dust exposure and mor¬tality
in an American factory using chrysotile, amosite, and crocidolite in mainly
textile manufacture. Br J Ind Med 1983;40:368–374.

43. Peto J, Doll R, Hermon C, Binns W, Clayton R, Goffe T. Relationship of
mor¬tality to measures of environmental asbestos pollution in an asbestos
textile factory. Ann Occup Hyg 1985;29:305–355.

44. McDonald AD, Fry JS, Woolley AJ, McDonald JC. Dust exposure and mor¬tality
in an American chrysotile asbestos friction products plant. Br J Ind Med
1984;41:151–157.

45. Newhouse ML, Sullivan KR. A mortality study of workers manufacturing
friction materials: 1941–86. Br J Ind Med 1989;46:176–179.

46. Seidman H, Selikoff IJ, Hammond EC. Short-term asbestos work exposure and
long-term observation. Ann NY Acad Sci 1979;330:61–89.

47. Acheson ED, Gardner MJ, Winter PD, Bennett C. Cancer in a factory using
amosite asbestos. Int J Epidemiol 1984;13:3–10.

48. Levin JL, McLarty JW, Hurst GA, Smith AN, Frank AL. Tyler asbestos workers:
mortality exposure in a cohort exposed to amosite. Occup Environ Med
1998;55:155–160.

49. McDonald AD, McDonald JC. Mesothelioma after crocidolite exposure during gas
mask manufacture. Environ Res 1978;17:340–346.

50. Jones JSP, Smith PG, Pooley FD, et al. The consequences of exposure to
asbestos dust in a wartime gas-mask factory. In: Wagner JC, ed. Biological
Effects of Mineral Fibres 2. IARC Scientific Publications No 30. Lyon, France:
IARC, 1980:637–653.

51. Talcott JA, Thurber RN, Kantor AF, et al. Asbestos-associated diseases in a
cohort of cigarette-filter workers. N Engl J Med 1989;321:1221– 1223.

52. Acheson ED, Gardner MJ, Pippard EC, Grime LP. Mortality of two groups of
women who manufactured gas masks from chrysotile and crocidolite asbestos: a
40-year follow-up. Br J Ind Med 1982;39:344–348.

53. Newhouse ML, Berry G, Wagner JC. Mortality of factory workers in East London
1933–80. Br J Ind Med 1985;42:4–11.

54. Enterline PE, Hartley J, Henderson V. Asbestos and cancer: a cohort followed
up to death. Br J Ind Med 1987;44:396–401.

55. Elmes PC, Simpson MJC. Insulation workers in Belfast (1940–1975). A further
study of mortality due to asbestos exposure. Br J Ind Med 1977; 34:174–180.

56. Selikoff IJ, Hammond EC, Seidman H. Mortality experience of insulation
workers in the United States and Canada 1943–1976. Ann NY Acad Sci
1979;330:91–116.

57. Järvholm B, Sandén Å. Lung cancer and mesothelioma in the pleura and
peritoneum among Swedish insulation workers. Occup Environ Med 1998; 55:766–770.

58. Rossiter CE, Coles RM. HM Dockyard, Devonport: 1947 mortality study. In:
Wagner JC, ed. Biological Effects of Mineral Fibres 2. IARC Scientific
Publications No. 30. Lyon, France: IARC, 1980:713–721.

59. Kolonel LN, Yoshizawa CN, Hirohata T, Myers BC. Cancer occurrence in
shipyard workers exposed to asbestos in Hawaii. Cancer Res 1985;45: 3924–3928.

60. McDonald JC. Unfinished business: the asbestos textiles mystery. Ann Occup
Hyg 1998;42:3–5.

61. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 42.
Silica and Some Silicates. Lyon, France: IARC, 1987:225–239.

62. Das PB, Fletcher AG, Deodhare SG. Mesothelioma in an agricultural com¬munity
of India: a clinicopathological study. Aust NZ J Surg 1976;46:218– 226.

63. Rothschild H, Mulvey JJ. An increased risk for lung cancer mortality
asso¬ciated with sugar cane farming. J Natl Cancer Inst 1982;68:755–760.

64. Fraire AE, Cooper S, Greenberg SD, Buffler P, Langston C. Mesothelioma in
childhood. Cancer 1988;62:838–847.

65. McDonald JC, McDonald AD. Mesothelioma: is there a background? Eur Respir
Rev 1993;3(11):71–73.

66. Jones JSP, Roberts GH, Pooley FD, et al. The pathology and mineral content
of lungs in cases of mesothelioma in the United Kingdom in 1976. In: Wagner JC,
ed. Biological Effects of Mineral Fibers. Proceedings of a Sym¬posium held at
Lyons, 25–27 September, 1979, vol 1. IARC Scientific Pub¬lications No. 30. Lyon,
France: IARC, 1980:187–199.

67. McDonald AD, McDonald JC, Pooley FD. Mineral fiber content of lung in
mesothelial tumours in North America. Ann Occup Hyg 1982;26:417–422.

68. Mowe G, Gylseth B, Hartveit F, Skaug V. Fibre concentration in lung tissue
of patients with malignant mesothelioma. A case-control study. Cancer
1985;56:1089–1093.

69. Gaudichet A, Janson X, Monchaux G, et al. Assessment by analytical
microscopy of the total lung fiber burden in mesothelioma patients matched with
four other pathological series. Ann Occup Hyg 1988;32(suppl 1):213–223.

70. McDonald JC, Armstrong B, Case BW, et al. Mesothelioma and asbestos fiber
type: evidence from lung tissue analyses. Cancer 1989;63:1544–1547.

71. Rogers AJ, Leigh J, Berry G, Ferguson DA, Mulder HB, Ackad M. Relationship
between lung asbestos fiber type and concentration and rela¬tive risk of
mesothelioma—a case-control study. Cancer 1991;67:1912– 1920.

72. Rödelsperger K, Woitowitz H-J, Brückel B, Arhelger R, Pohlabeln H, Jöckel
K-H. Dose-response relationship between amphibole fiber lung burden and
mesothelioma. Cancer Detect Prev 1999;23(3):183–193.

73. McDonald JC, Armstrong BG, Edwards CW, et al. Case-referent survey of young
adults with mesothelioma: I. Lung fiber analyses. Ann Occup Hyg
2001;45(7):513–518.

74. McDonald JC, Edwards CW, Gibbs AR, et al. Case-referent survey of young
adults with mesothelioma: II. Occupational analyses. Ann Occup Hyg
2001;45(7):519–523.

75. McDonald JC, Becklake MR, Gibbs GW, McDonald AD, Rossiter CE. The health of
chrysotile mine and mill workers of Quebec. Arch Environ Health 1974;28:61–68.

76. McDonald JC, McDonald AD, Gibbs GW, Siemiatycki J, Rossiter CE. Mor¬tality
in the chrysotile asbestos mines and mills of Quebec. Arch Environ Health
1971;22:677–686.

77. Gibbs GW. Etiology of pleural calcification: a study of Quebec asbestos
miners and millers. Arch Environ Health 1979;34:76–82.

78. Pooley FD. An examination of the fibrous mineral content of asbestos in lung
tissue from the Canadian chrysotile mining industry. Environ Res
1976;12:281–298.

79. Rowlands N, Gibbs GW, McDonald AD. Asbestos fibers in the lungs of
chrysotile miners and millers—a preliminary report. Ann Occup Hyg 1982;
26:411–415.

80. McDonald JC. Epidemiological significance of mineral fiber persistence in
human lung tissue. Environ Health Perspect 1994;102(suppl 5):221– 224.

81. Sébastien P, McDonald JC, McDonald AD, Case B, Harley R. Respiratory cancer
in chrysotile textile and mining industries: exposure inferences from lung
analysis. Br J Ind Med 1989;46:180–187.

82. Sébastien P, Plourde M, Robb R, Ross M, Nadon B, Wypruk T. Ambient air
asbestos survey in Quebec mining towns: Part 2. Main study. Report EPS
5/AP/RQ-2E. 1986.

83. McDonald JC, McDonald AD. Epidemiology of mesothelioma. In: Liddell FDK,
Miller K, eds. Mineral Fibers and Health. Boca Raton, FL: CRC Press,
1991:143–164.

84. Sébastien P, Bégin R, Case BW, McDonald JC. Inhalation of chrysotile dust.
In: Wagner JC, ed. The Biological Effects of Chrysotile. Philadelphia: JB
Lip-pincott, 1987:19–29.

85. Wagner JC, Berry G, Skidmore JW, Timbrell V. The effects of the inhalation
of asbestos in rats. Br J Cancer 1974;29:252–269.

86. Riordon PH. The Asbestos belt of South Eastern Quebec: the asbestos deposits
of Thetford Mines, Quebec: the British Canadian Mine: Nor-mandie and Vimy Ridge
Mines. In: The Geology of Canadian Industrial Mineral Deposits: 6th Commonwealth
Mining and Metallurgical Congress. 1957:1–30.

87. McDonald JC, McDonald AD. Chrysotile, tremolite and carcinogenicity. Ann
Occup Hyg 1997;41:699–705.

88. Amandus HE, Armstrong BG, McDonald AD, McDonald JC, Sébastien P, Wheeler R.
Mortality of vermiculite miners exposed to tremolite. Ann Occup Hyg
1988;32:459–465.

89. Armstrong BG, McDonald JC, Sébastien P, Althouse R, Amandus HE, Wheeler R.
Radiological changes in vermiculite workers exposed to tremo-lite. Ann Occup Hyg
1988;32:469–473.

90. McDonald JC, Harris J, Armstrong B. Mortality in a cohort of vermiculite
miners exposed to fibrous amphibole in Libby, Montana. Occ Environ Med
2004;61(4):363–366.

91. Keal EL. Asbestosis and abdominal neoplasms. Lancet 1960;2:1211– 1216.

92. McDonald JC. Tremolite, other amphiboles and mesothelioma. Am J Ind Med
1988;14:247–249.

93. Scheepers GWH. Section VIII, Discussant, Conference on the Biological
Effects of Asbestos. Ann NY Acad Sci 1965;132:596.