Malignant Mesothelioma of the pleura: current surgical pathology

The usual gross and microscopic features of malignant mesothelioma are well described in many standard texts, and require no reiteration
in this volume. Instead, this account concentrates on the unusual or
controversial, on the still-evolving role of immunohistochemistry for
the discrimination between mesotheloma and its look-alikes, and on the
differential diagnosis in pleural biopsies.

Malignant pleural mesothelioma

Malignant mesothelioma (MM) has recently attracted the attention of
the media because of its relationship with professional and
environmental exposure to asbestos. This tumour of the pleura is a
disease which has emerged in significant numbers of patients during the
last 30 years in the industrialized countries and its increasing
incidence makes it of socio-economical interest.

The histological description of MM was first published by E. Wagner
in 1870 and later by Klemperer and Rabin. A literature review of
pathological cases of lung diseases befor 1940 identified 41 out of
46,000 autopsies as possible MM. In this review they mentioned a report
from 1767 by Lieutaud who was the first to describe two possible cases
of MM in an autopsy study. Since then, a number of case reports were
published in which a relationship with asbestos exposure ws considered important but it was the report of J.C. Wagner in 1960
which identified a clear relationship between exposure to crocidolite
mining and the development of MM. From that moment the association
between asbestos exposure and MM ws accepted and a beginning was made
to abandon the productionand processing of asbestos materials.

Mesothelioma: Cases Associated with Non-occupational and LowDose Exposures.

Asbestos: Mesothelioma Mesothelioma is a rare cancer of the
"mesothelial" cells that make up various membranes in a person's chest
or abdominal cavity. This includes the pleura that encases the lungs.
The pleura facilitates lung movement during breathing without motion
sensation or nerve irritation inside the chest. Mesothelioma is not
lung cancer, although it frequently causes respiratory problems as the
tumor grows and spreads along the surface of internal organs along
serosal membranes. When it develops, mesothelioma is almost always
caused by asbestos. There is some evidence that the virus SV40 may also
be a factor in the disease in some people. It is not caused by smoking
of any kind.Mesothelioma most often occurs in two areas, forming
extremely serious malignant tumors: · Pleural Mesothelioma: cancer of
the pleura, the membrane that lines the lungs and the chest cavity, and
· Peritoneal Mesothelioma: cancer of the peritoneum, which is the
serosal membrane lining of the abdomen. MesotheliomaTreatment Options:

• Surgery
• Radiation
• Chemotherapy
• Photodynamic
• Immunotherapy
• PET
• Pain Management
• Treatment Centers
• Physicians

The photo at left shows an actual human mesothelioma tumor (white
rind-looking margins surrounding the dark lung area). It is a
cross-section of a mesothelioma victim's chest cavity with only one
lung remaining. The tumor encases the lung as it tracks the pleura,
causing pain with breathing and creating compromised lung function.

Mesothelioma has a very long "latency" period, i.e., the time
between the first exposure to asbestos and the onset of the symptomatic
disease. This latency period is usually at least 10 to 15 years, and is
reported in the recent medical journals to be as long as over 60 years.
A period of 40 years from exposure to diagnosis is not uncommon.
Mesothelioma can be caused by very brief, low dose exposures to
asbestos. The risk of contracting mesothelioma increases with any level
of exposure. Because there is no "safe" level of exposure, all
preventable contacts with asbestos should be avoided.

Low-Dose Ionizing Radiation, Human Biology and non-Linearity
The prime concern of radiation protection policy since 1959 has been
protecting DNA from damage. The 1995 NCRP Report 121 on collective dose
states that since no human data provides direct support for the linear
nonthreshold hypothesis (LNT), and some studies provide quantitative
data that, with statistical significance, contradict LNT, ultimately,
confidence in LNT is based on the biophysical concept that the passage
of a single charged particle could cause damage to DNA that would
result in cancer. Current understanding of the basic molecular biologic
mechanisms involved and recent data will be examined after presenting
several statistically significant epidemiologic studies that contradict
the LNT hypothesis.

Over eons of time a complex biosystem evolved to control the DNA
alterations (oxidative adducts) produced by about 10E10 free
radicals/cell/d derived from 2-3% of all metabolized oxygen.
Antioxidant prevention, enzymatic repair of DNA damage, and removal of
mis- or unrepaired DNA alterations by apoptosis, differentiation,
necrosis, and the immune system, sequentially reduce DNA damage from
about 10E6 DNA alterations/cell/d to about 1 mutation/cell/d. These
mutations accumulate in stem cells during a lifetime with progressive
DNA damage-control impairment associated with aging and malignant
growth. A comparatively negligible number of mutations, an average of
about 10E7 mutations/cell/d, is produced by low LET radiation
background of 0.1 cGy/y. The remarkable efficiency of this biosystem is
increased by the adaptive responses to low-dose ionizing radiation.

Each of the sequential functions that prevent, repair, and remove
DNA damage are adaptively stimulated by low-dose ionizing radiation in
contrast to their impairment by high-dose radiation. The biologic
effect of radiation is not determined by the number of mutations it
creates, but by its effect on the biosystem that controls the
relentless enormous burden of oxidative DNA damage. At low doses,
radiation stimulates this biosystem with consequent significant
decrease of metabolic mutations. This reduction of gene mutations in
response to low-dose radiation provides a biological explanation of the
statistically significant observations of mortality and cancer
mortality risk decrements, and contradicts the biophysical concept of
the basic mechanisms upon which, ultimately, the NCRP's confidence in
the LNT hypothesis is based.

Background
The best scientific evidence of human radiation effects
initially came from epidemiologic studies of atomic bomb survivors in
Hiroshima and Nagasaki. While no evidence of genetic effects has been
found, these studies showed a roughly linear relationship between the
induction of cancer and extremely high dose-rate single high doses of
atomic bomb radiation. This was consistent with the knowledge that
ionizing radiation can damage DNA in linear proportion to high-dose
exposures and so produce gene mutations known to be associated with
cancer. In the absence of comparable low dose effects it was prudent to
propose tentatively the no threshold hypothesis that extrapolates
linearly from effects observed at very high doses to the same effects
at very low doses. It was accepted in 1959 by the International
Commission on Radiological Protection (ICRP)1 and afterwards adopted by
national radiation protection organizations to guide regulations for
the protection of occupationally exposed workers and the public.

This hypothesis that all radiation is harmful in linear proportion
to the dose, is the principle used for collective dose calculations of
the number of deaths produced by any radiation, natural or generated,
no matter how small. The National Council of Radiation Protection and
Measurements Report 121, quot;Principles and Application of Collective
Dose in Radiation Protection," summarizes the basis for adherence to
linearity of radiation health effects:3 "Taken as a whole, the body of
evidence from both laboratory animals and human studies allows a
presumption of a linear no threshold response at low doses and low-dose
rates, for both mutations and carcinogenesis. Therefore, from the point
of view of the scientific bases of collective doses for radiation
protection purposes, it is prudent to assume the effect per unit dose
in the low-dose region following single acute exposures or low-dose
fractions in a linear response.

There are exceptions to this general rule of no threshold, including
the induction of bone tumors in both laboratory animals and in some
human studies due to incorporated radionuclides, where there is clearly
evidence for an apparent threshold. However, few experimental studies,
and essentially no human data, can be said to prove or even to provide
direct support for the concept of collective dose with its implicit
uncertainties of nonthreshold linearity and dose-rate independence with
respect to risk. The best that can be said is that most [sic] studies
do not provide quantative data that, with statistical significance,
contradict the concept of collective dose. Ultimately, confidence in
the linear no threshold dose-response relationship at low doses is
based on our understanding of the basic mechanisms involved. Genetic
effects may result from a gene mutation, or a chromosome aberration.

The activation of a dominant acting oncogene is frequently
associated with leukemias and lymphomas, while the loss of suppressor
genes appears to be more frequently associated with solid tumors. It is
conceptually possible, but with a vanishing small probability, that any
of these effects could result from the passage of a single charged
particle, causing damage to DNA that could be expressed as a mutation
or small deletion.

It is a result of this type of reasoning that a linear nonthreshold
dose-response relationship cannot be excluded. It is this presumption
[sic], based on biophysical concepts, which provides a basis for the
use of collective dose in radiation protection activities." NCRP Report
121 summarizes that while some studies "provide quantitative data that,
with statistical significance, contradict the concept of collective
dose," "ultimately, confidence in the linear no threshold dose-response
relationship at low doses [LNT hypothesis] is based on our
understanding of the basic mechanisms involved." Current understanding
of the basic biologic mechanisms involved and recent data will be
examined after presenting some of the statistically significant
epidemiologic data that contradict the LNT hypothesis. The biologic
data also contradict "the presumption, based on biophysical concepts,
which provides a basis for the use of collective dose in radiation
protection activities."

Epidemiologic Studies What are some of the statistically significant
epidemiologic studies that demonstrate risk decrements (hormesis) as
predicted by the adaptive responses to low-dose radiation of the DNA
damage-control biosystem? For several decades increased longevity and
decreased cancer mortality have been reported in populations exposed to
high background radiation. Established radiation protection authorities
consider such observations to be spurious or inconclusive because of
unreliable public health data or undetermined confounding factors such
as pollution of air, water and food, smoking, income, education,
medical care, population density, and other socioeconomic variables.
Recently, however, several epidemiologic statistically significant
controlled studies have demonstrated that exposure to low or
intermediate levels of radiation are associated with positive health
effects.

Dr. Zbigniew Jaworowski, past chairman of UNSCEAR, in his current
review of hormesis cites recent data showing hormetic effects in humans
from the former Soviet Union. After radiation exposure from a thermal
explosion in 1957, 7852 persons living in 22 villages in the Eastern
Urals were divided into three exposure groups averaging 49.6 cGy, 12.0
cGy, and 4.0 cGy and followed for 30 years. Tumor-related mortality was
28%, 39%, and 27% lower in the 49.6 cGy, 12.00 cGy, and 4.0 cGy groups,
respectively, than in the nonirradiated control population in the same
region. In the 49.6 cGy and 12.0 cGy groups the difference from the
controls was statistically significant (Figure 1).

Epidemiologic studies showing beneficial effects of low doses of
radiation in atomic bomb survivors (Figure 2) and other populations
were reviewed by Sohei Kondo, Professor of Radiation Biology, Atomic
Energy Research Institute, Kinki University, Osaka, Japan. Included are
the apparently beneficial effects of low doses of external gamma rays
on the life span of radium-dial painters and the significantly lower
mortality from cancers at all sites of residents of Misasa, an urban
area with radon spas, than residents of the suburbs of Misasa (Figure
3). [INLINE] These beneficial effects are consistent with the findings
of B. L. Cohen, Professor of Physics, University of Pittsburgh, that
relate the incidence of lung cancer to radon exposure in nearly 90% of
the population of the United States. The 1601 counties selected for
adequate permanence of residence provide extremely high-power
statistical analysis. After applying the BEIR IV 8 correction for
variations in smoking frequency, the study shows a very strong tendency
for lung cancer mortality to decrease with increasing mean radon level
in homes, in sharp contrast to the BEIR IV theoretical increased
mortality derived by linear no threshold extrapolation of effects in
uranium miners exposed to very high radon concentrations. The
discrepancy between theoretical and measured slopes is 20 standard
deviations (Figure 4).

Rigorous statistical analysis of 54 socioeconomic, seven physical,
and multiple geographic variables as possible confounding factors, both
single and in combination, demonstrates no significant decrease in the
discrepancy. The multiple independent requirements that a possible
unknown confounding factor must meet, make its existence highly
improbable. A reasonable explanation is that stimulated biological
mechanisms more than compensate for the radiation "insult" and are
protective against cancer in a low-dose, low-dose-rate range. The
thirteen-year U.S. Nuclear Shipyard Workers study of the health effects
of low-dose radiation was performed by the Johns Hopkins Department of
Epidemiology, School of Public Health and Hygiene, reported to the
Department of Energy in 1991 9 and reported in UNSCEAR 1994.4 Professor
Arthur C. Upton, who concurrently chaired the NAS BEIR V Committee on
"Health Effects of Exposure to Low Levels of Ionizing Radiation," 10
chaired the Technical Advisory Panel that advised on the research and
reviewed results.

The results of this study contradict the conclusions of the BEIR V
report 10 that small amounts of radiation have risk - the LNT
hypothesis. From the database of almost 700,000 shipyard workers,
including about 108,000 nuclear workers, three closely matched study
groups were selected, consisting of 28,542 nuclear workers with working
lifetime doses 5 mSv (many received doses well in excess of 50 mSv),
10,462 nuclear workers with doses <5 mSv and 33,352 non-nuclear
workers. Deaths in each of the groups were classified as due to: all
causes, leukemia, lymphatic and hematopoietic cancers, mesothelioma,
and lung cancer. The results demonstrated a statistically significant
decrease in the standardized mortality ratio for the two groups of
nuclear workers for 'death from all causes' compared with the
non-nuclear workers. For the 5 mSv group of nuclear workers, the highly
significant risk decrement to 0.76, 16 standard deviations below 1.00,
of the standard mortality ratio for death from all causes is
inconsistent with the LNT hypothesis and does not appear to be
explainable by the healthy worker effect (Figure 5) 4.

The non-nuclear workers and the nuclear workers were similarly
selected for employment, were afforded the same health care thereafter,
and performed the identical type of work, except for exposure to 60 Co
gamma radiation, with a similar median age of entry into employment of
about 34 years. This provides evidence with extremely high statistical
power that low levels of ionizing radiation are associated with risk
decrements. Nevertheless, Professor Arthur C. Upton and others consider
the three-country low-dose radiation and cancer study of Cardis, et
al11,12, to be the best occupational study of nuclear workers (Figure
6). This study concluded, "There was no evidence of an association
between radiation dose and mortality from all causes or from all
cancers. Mortality from leukemia, excluding chronic, lymphocytic
leukemia (CLL) ...was significantly associated withcumulative external
radiation dose (one-sided P value= 0.046: 119 deaths)." The statistical
methods used state, "As there was no reason to suspect that exposure to
radiation would be associated with a decrease in risk of any specific
type of cancer, one-sided tests are presented throughout."

The authors' analysis of the 119 deaths from all leukemias except
CLL excluded 86 deaths in dose categories 1.3.4, and 6 in which there
were fewer deaths than expected. Trend analysis of the remaining 33
deaths in dose categories 2, 5, and 7 for estimated P=0.046 was
obtained "using computer simulations based on 5000 samples, rather than
the normal approximation." The Canadian Breast Cancer Fluoroscopy
Study13 reports the observations of the mortality from breast cancer in
a cohort of 31,710 women who had been examined by multiple fluoroscopy
between 1930 and 1952. The observed rates of mortality are related to
breast radiation doses and presented only in tabular form. The authors
compare linear and linear-quadratic dose-response models fit to the
data and conclude, "that the most appropriate form of dose-response
relations is a simple linear one, with different slopes for Nova Scotia
and the other provinces." On the basis of this linear model that
includes only non-significant data and excludes the data with the
highest confidence limits (Figure 7), the authors predict the lifetime
excess risk of death from breast cancer after a single exposure at age
30 to 1 cGy(1r) to be approximately 60 per million women or 900 per
million women exposed to 15 cGy. The observed data, however,
demonstrate with high statistical confidence, a reduction of the
relative risk of breast cancer to 0.66 (P=0.05) at 15 cGy and 0.85 (P=
0.32) at 25 cGy. The second author, in his 1996 revision of this study,
removed this highly significant contradiction of the LNT hypothesis by
lumping all low-dose data into a single 1-49 cGy category. The study
actually predicts that a dose of 15 cGy would be associated with 7,000
fewer deaths in these million women. Lauriston S. Taylor, past
president of the NCRP, considered application of LNT theory for
calculations of collective dose as, "deeply immoral uses of our
scientific heritage"15.

METABOLIC AND RADIATION DNA DAMAGE CONTROL During the past decade
rapid advances in our knowledge of molecular biology and cell function
enable us to understand why low-dose radiation is associated with
positive health effects in contrast to the carcinogenic effect of
high-dose radiation. Our understanding is based upon current, cellular
molecular biology observations. Estimates are based on published data
and recent personal communications: * Two to three percent of all
metabolized oxygen is converted to free radicals (reactive oxygen
species),16 10E10/cell/d, that produce about 10E6 DNA oxidative
adducts/cell/d.7, 8 These include about 0.5 double strand
breaks/cell/d.17 In addition, a relatively small number of metabolic
DNA alterations are produced by DNA replication and thermal instability.

By comparison, 1 cGy low LET radiation produces 20 DNA oxidative
adducts/cell that include an average of 0.4 double strand
breaks/cell.18,19 * Over eons of time, as multicellular animals
developed and metabolized oxygen, a complex DNA damage-control
biosystem evolved (Fig. 8).17 The damage corresponding to 10E10 free
radicals/cell/d is largely prevented by antioxidants that scavenge
approximately 99% of these free radicals. The resultant 10E6 DNA
oxidative adducts/cell/d are reduced by enzymatic repair to about 10E2
mis/unrepaired DNA alterations/cell/d. Apoptosis, differentiation,
necrosis, and the immune system remove approximately 99% of these
mis/unrepaired DNA alterations so that an average of 1 mutation/cell/d
(possibly up to 2-3) accumulates during the lifetime of a stem cell to
decrease DNA damage-control capability with associated aging and
malignant growth (Figure 8).17 Cancer increases as the third to fifth
power of age. This remarkably efficient biosystem prevents precocious
aging and malignancy unless impaired by genetic defects, or damaged by
high doses of radiation or other toxic agents. 9, 16-19, 22-33 * How
does background radiation add to the metabolic accumulation of
mutations?

A much larger fraction of double strand breaks occurs in DNA
oxidative adducts produced by radiation than in those produced by
metabolism (2x10E-2 vs 5x10E -7).17,21 The mis/unrepaired fraction of
these double strand breaks is also much larger than that of other
metabolic DNA oxidative adducts (10E-1 vs 10E-4). Nevertheless, the
number of metabolic DNA oxidative adducts (10E6/cell/d) is so much
greater than the number of oxidative adducts from low LET background of
0.1 cGy/y (5x10 -3/cell/d), that an average of only 10E -7 radiation
mutation/cell/d is added to 1 metabolic mutation/cell/d (Figure 8).17

Response to Low-Dose Radiation
The activity of the DNA damage control biosystem is decreased
by high-dose radiation, but adaptively responds with increased activity
to low-dose radiation (e.g., 30 cGy) (Figures 9, 10).9, 22,23,26-33 The
efficiency of this biosystem is increased by the adaptive responses to
low-dose ionizing radiation (Figures 9, 10). This is well documented in
UNSCEAR 1994:4 "There is substantial evidence that the number of
radiation-induced chromosomal aberrations and mutations can be reduced
by a small prior conditioning dose in proliferating mammalian cells in
vitro and in vivo. There is increasing evidence that cellular repair
mechanisms are stimulated after radiation-induced damage... Whatever
the mechanisms, they seem able to act not only on the lesions induced
by ionizing radiation but also on at least a portion of the lesions
induced by some other toxic agents. As to the biological plausibility
of a radiation-induced adaptive response, it is recognized that the
effectiveness of DNA repair in mammalian cells is not absolute... An
important question, therefore, is to judge the balance between
stimulated cellular repair and residual damage." This statement applies
not only to the mutations produced by radiation and other toxic agents,
but also to the unmentioned enormous number of daily metabolic
mutations.

The operative effect of reducing metabolic mutations by the adaptive
response of the DNA damage-control biosystem to low-dose radiation is
the critical factor, not reduction of the relatively negligible number
of mutations produced by low-dose radiation. This critical factor must
be considered, "to judge the balance between stimulated cellular repair
and residual damage." Assuming a 20% increased efficiency of biosystem
control in response to a tenfold increase of annual background
radiation from 0.1 cGy/y, to 1 cG/y, radiation mutations would indeed
increase from 1x10-7/cell/d to 8x10-7/cell/d but metabolic mutations
would decrease from 1/cell/d to 0.8/cell/d (Figure 11).17 "The balance
between stimulated cellular repair and residual damage" is a decrease
of mutations from an average of 1 mutation/cell/d to 0.8
mutation/cell/d (Figures 8,11) UNSCEAR did not consider that the
increase of radiation mutations is negligible compared to the operative
effect of the adaptive response to low-dose radiation upon the high
background of metabolic mutations.

The biologic effect of radiation is not determined by the number of
DNA mutations it creates, but by its effect on the biosystem that
controls the relentless enormous burden of oxidative DNA damage.
High-dose radiation impairs this biosystem with consequent significant
increase of metabolic mutations and corresponding risk increments.
Low-dose radiation stimulates the DNA damage-control biosystem with
consequent significant decrease of metabolic mutations and
corresponding risk decrements (Figures 8-11).35 This reduction of gene
mutations in response to low-dose radiation provides a biological
explanation of the statistically significant observations of mortality
and cancer mortality risk decrements, and contradicts the biophysical
understanding of the basic mechanisms upon which, ultimately, the
NCRP's confidence in the LNT hypothesis is based. This article
represents the views of the author and not necessarily those of the
U.S. Nuclear Regulatory Commission.

Mesothelioma: Occupational and Enviornmental Medicine

My comments are being made on the behalf of the Art and Creative
Materials Institute, a non-profit trade organization that represents
the major manufacturers and importers of art materials in the United
States. Talc is a common component of these art materials. I would like
to address several issues discussed in the draft Report on Carcinogens:
Background Document for Talc. Asbestiform and Non-Asbestiform. These
comments are offered to the Report on Carcinogens Subcommittee with the
expectation that this report can be strengthened if it addresses
certain issues in more detail. I will comment on both on studies
concerning both asbestiform and non- asbestiform talc.

Asbestiform Talc
Definition: The draft report discusses the definition of asbestiform
fibers. It would be strengthened if it includes NIOSH’s definition of
these fibers:. NIOSH (Kullman, et al. 1995) defines asbestiform habit
as:

“a specific type of mineral fibrosity in which the growth is
primarily in one dimension and the crystals form naturally as long,
flexible fibers. Fibers can be found in bundles that can be easily
separated into smaller bundles or ultimately into fibrils.”

This definition is important since many of the fibers in asbestiform
talc are cleavage fragments. NIOSH’s definition for asbestiform habit
contrasts with their definition for the nonasbestiform habit :

“These minerals have … crystal habits where growth proceeds in two
or three dimensions instead of one dimension. When milled, these
minerals do not break into fibrils but rather into fragments

resulting from cleavage along the two or three growth planes.
Particles formed by the comminution of these minerals are referred to
as cleavage fragments.”

Respirable fiber size: Although the draft report notes that a
respirable fiber has a diameter of 3-4 mm this is for fibers with a
density of 1. Talc has a specific gravity of 3 and, consequently the
equivalent aerodynamic diameter of respirable talc fibers would be 1/3
of this, on the order of 1 mm (Wylie, et al. 1993). This finding is
particularly important in that the fibers in asbestiform talc are
primarily wider than 1 mm with only 10-11% of fibers in commercial
talcs being <1 mm in diameter.

Fiber size and cancer risk: There are excellent animal models for
the relationship between fiber dimension and risk of both mesothelioma
and lung cancer. For mesothelioma risk, fibers with a dimension of
£0.25 mm in diameter and >8 mm long appear to present the greatest
risk (Stanton, et al., 1981; Oehlert, 1991) with almost no risk
presented by short fibers (Davis, et al. 1986). Most amphibole fibers
in a asbestiform talc mine are shorter than 10 mm (Kelse and Thompson,
1989) and would not be expected to present a risk of mesotheliomas.
Similarly, lung cancer risk also depends on fiber dimensions. Based on
asbestos inhalation studies, Berman et al (1995) found that potency for
lung cancer rested with fibers that were longer than 10 mm and less
than 0.3 mm in diameter. Their model found that fibers that were <10
mm long and had widths from 0.3-5.0 mm were not associated with a lung
cancer risk. Lippmann (1988) performed as similar analysis. He found
that fiber retention drops rapidly as fiber diameter increases from 0.8
to 2.0 mm. No lung cancer risk was associated with fiber length less
than 5 mm. Lung cancer risk was associated with fibers with a diameter
of 0.3-0.8 mm and a substantial fraction >10 mm in length.

Animal Studies: Although IARC considered a number of studies
involving the carcinogenicity of talc in experimental animals, they did
not have access to identification information concerning several of the
fibrous talcs. This is particularly important because talcs form the
Grouvenor Talc Company (GTC), the mine most studied for cancer risk,
have been examined in a number of animal models and have been found to
be non-carcinogenic. Stanton, et al. (1981) examined two asbestiform
talcs from the Grouvenor talc district including one from GTC (Stanton
talc #6) in their pleural implantation rat model. Neither of these
talcs induced mesotheliomas although based on particle dimensions, a
60% incidence of mesotheliomas would have been expected with the GTC
talc. Oehlert (1991) re-analyzed the Stanton data, breaking out potency
assessments not only by particle size but by mineral type. When
compared to asbestos, the author found that talcs were 1/135,000 as
potent for causing pleural tumors. This re-analysis included both the
asbestiform talcs and 5 non-asbestiform talcs studied by Stanton, et al.

Smith, et al. (1979) also studied one GTC talc (FD14) in their
hamster pleural mesothelioma model. This talc, as well as another talc
containing amphibole fibers, was negative in their model.

Wylie, et al. (1997) studied the FD14 talc from the Smith et al.
study in an in vitro system. It was not cytotoxic and did not induce
cell proliferation. Talc samples not containing quartz were not
cytotoxic where asbestos was both cytotoxic and induced proliferation.

Epidemiology: non-asbestiform amphiboles: The primary components of
asbestiform talcs, other than talc, are cleavage fragments of
anthophyllite and tremolite. Since exposure to these cleavage fragments
may be a factor in cancer risk from exposure to asbestiform talc, a
review of epidemiological studies of workers exposed to nonasbestiform
amphiboles is in order and will strengthen this report. Kusiak et al
(1991) looked at a cohort of 54128 gold and nickel miners with
potential exposure to nonasbestiform amphibole fibers. They found an
excess cancer risk in pre-1945 workers but no relationship between
cancer excess and exposure to mineral fibers. The concluded that the
excess was probably related to exposures to arsenic and radon decay
products (radon daughters). Steenland and Brown (1995) studied 3328
gold miners from South Dakota. There was no significant increase in
lung cancer risk in this cohort though there was evidence of excessive
quartz exposure including elevated deaths from immunological diseases,
renal disease and tuberculosis.

The authors suggest that a slight excess in lung cancer rates might
be related to the smoking habits of miners: they smoke more then the
general population. Cooper et al (1992) studied 3444 taconite miners
exposed to silica and nonasbestiform amphibole fibers. The standardized
mortality rate (SMR) for lung cancer was less than expected at 67 and
was not related to duration of employment, exposure level or latency.
When Cooper, et al. eliminated those workers with less than 3 months of
employment from the analysis, the SMR for lung cancer actually
decreased as duration of employment increased.

Epidemiology: asbestiform talc: The association between exposure to
asbestiform talc and lung cancer risk is primarily based on the
findings of increased cancer risk in workers exposed to asbestiform
talc in the Grouvenor talc district (GTD) of upstate New York. A more
detailed description of these studies, as well as inclusion of the
latest (Dezell et al, 1995) study would be in order. Kleinfeld, et al.
(1967, 1974) found a 10 pulmonary and pleural tumors among a study of
all GTD workers. All cases occurred in workers who were exposed prior
to the introduction of exposure control measures ca. 1945. Twenty-nine
of the workers died of pneumoconioses, including 5 who died of a
complication of quartz exposure, tuberculosis. This study had the short
coming that it did not take into account exposures other then to talc,
did not take into account smoking history and did not relate exposure
levels to outcome. Recent data developed by NIOSH (1980) can be used to
estimate respirable quartz exposures to workers in this study. NIOSH
found that for the average dust exposure of 2.9 million particles per
cubic foot (mppcf) in GTC mills, the average respirable quartz exposure
was 11 mg/m3 and that for the average dust exposure of 8.1 mppcf in the
GTC mine the average quartz exposure was 12.4 mg/ m3. Dust exposure
measurements were made for GTD mines and mills in the Kleinfeld, et al.
study. These exposures can be translated to average respirable quartz
exposures as follows:

Pre-1945 1945-1965
Mppcf Qartz (mg/m3) Mppcf Quartz (mg/m3)
Mines: drilling 818 1250 5 8
Mines: other 129 190 5-9 8-14
Mills 69-278 260-1050 27-37 102-140

Exposure levels prior to 1945 were sufficiently high, in both mines
and mills, to result in the pneumoconioses cases described above with
quartz levels in air as great as 10 fold higher than today’s
permissible exposure limit for respirable quartz of 100 mg/m3.
Respirable quartz is a known human lung carcinogen, with elevated risks
particularly when exposures are sufficient to result in silicosis. That
respirable quartz exposures were a concern has been confirmed by
autopsy studies performed by Dr. Jerrold Abraham of 8 GTD workers. Two
of the 5 workers with a history of more than 20 years of talc mining
had silicosis.

The second study that has been used to implicate a risk between
exposure to asbestiform talc and lung cancer is the NIOSH 1979 study of
Grouvenor Talc Company workers. GTC went into operation in the late
1940’s using a wet drilling method that would have suppressed exposure
to respirable quartz dust as noted in the above table. The NIOSH study
has been criticized because of a number of short comings. It would be
important to highlight these short comings since they have been
addressed in later epidemiological studies of these workers. Specific
concerns with this study included its small size; inclusion of all
workers, including those that had only worked days; lack of assessment
of the contribution of prior exposures; no study of exposure-lung
cancer relationships; and no adjustment for smoking effects (Brown, et
al, 1983). Any prior mine work among GTC employees would have likely
involved high level exposures to quartz dust. Stille and Tabershaw
(1982) were able to nearly double the size of the cohort. They found
that the SMR for lung cancer among workers who had only worked at GTC
was less than expected (76) and that tuberculosis, a disease associated
with silicosis, was a significant finding (SMR 680). This study did not
correct for smoking history, exposure or identify non-GTC exposures
that many have been a concern.

Lamm, et al. (1988) presented a re-analysis of the Stille and
Tabershaw (1982) data set in which the occupational histories of
workers dying of lung cancer were presented. 8 of 11 workers who died
of lung cancer had worked in mines other than talc mines or in quarries
elsewhere than at GTC. The SMR for lung cancer in mill workers was 72
for those workers who had worked at least one year at GTC. For those
for workers who worked less than one year and had first worked to GTC
20-24 years prior to their death, the SMR for lung cancer was 1111. The
latter group would have included workers with prior exposures to mine
dust prior to the putting in place of dust control technologies.

Gamble (1993) performed a nested case control study on NIOSH’s
second evaluation of 710 GTC workers (NIOSH, 1990) to address concerns
of confounding. They found that when using fellow GTC workers as
controls, all of the excess lung cancer risk could be ascribed to
smoking. When looking at past exposures they found that essentially all
talc exposure could be ascribed to work at GTC. They were able to give
more complete exposure histories for the lung cancer cases: 8 of the 22
cases had worked as drillers at mines or quarries other than GTC and 17
had worked in metal mines prior to working at GTC. Work in mines would
have been expected to be associated with exposure to either quartz dust
(exposures would have likely been even higher in metal mines than in
talc mines because of quartz content of base rock) or radon daughters,
a known cause of excess lung cancer risk in metal miners. That drillers
may be at particular risk of quartz exposure has been noted by Rubino,
et al. (1976) who found that dust generated from drilling operations my
contain up to 18% quartz, even though talc itself is relatively free
from quartz. In metal mines, drilling dust can contain up to 39% quartz
(McDonald, et al., 1978).

Dezell, et al. (1995) further expanded the cohort to 818 workers and
increased the latency time to an average of 21 years for GTC workers.
They were able to address the concern that prior studies did not
address incorporate an exposure-response analysis by estimating
respirable dust exposures. When compared to past dust measurements,
there was an excellent correlation between the two with a correlation
coefficient of 0.78. They found no relationship between dust exposure
at GTC and lung cancer. Increases in lung cancer were limited to
workers hired prior to 1955 with deaths from non-malignant respiratory
disease concentrated in this group as well. When adjusting for exposure
they found an inverse relationship between lung cancer and exposure to
all subjects, to those workers who were first employed prior to 1955
and to those workers who had worked at GTC for more than one year. The
Gamble and Dezell, et al. studies discount the finding of an
exposure-related risk of lung cancer for GTC workers with smoking
and/or prior exposures to cancer-causing quartz dust or radon being
likely contributors to the risk.

Asbestos and Cancer: An Overview of Current Trends in Europe
Maria Albin,1 Corrado Magnani,2 Srmena Krstev,3 Elisabetta Rapiti,4 and Ivetta Shefer1*
1Department of Occupational and Environmental Medicine, Lund University
Hospital, Lund, Sweden; 2Cancer Epidemiology Unit - CPO Piemonte, S.
Giovanni B. Hospital and University of Torino, Torino Italy; 3Institute
of Occupational and Radiological Health, Belgrade, Yugoslavia;
4Osservatorio Epidemiologico Regione Lazio, Rome, Italy

Abstract
This review assesses the contribution of occupational asbestos exposure
to the occurrence of mesothelioma and lung cancer in Europe. Available
information on national asbestos consumption, proportions of the
population exposed, and exposure levels is summarized. Population-based
studies from various European regions on occupational asbestos
exposure, mesothelioma, and lung cancer are reviewed. Asbestos
consumption in 1994 ranged, per capita, between 0.004 kg in northern
Europe and 2.4 kg in the former Soviet Union. Population surveys from
northern Europe indicate that 15 to 30% of the male (and a few percent
of the female) population has ever had occupational exposure to
asbestos, mainly in construction (75% in Finland) or in shipyards.
Studies on mesothelioma combining occupational history with biologic
exposure indices indicate occupational asbestos exposure in 62 to 85%
of the cases. Population attributable risks for lung cancer among males
range between 2 and 50% for definite asbestos exposure. After exclusion
of the most extreme values because of methodologic aspects, most of the
remaining estimates are within the range of 10 to 20%. Estimates of
women are lower. Extrapolation of the results to national figures would
decrease the estimates. Norwegian estimates indicate that one-third of
expected asbestos-related lung cancers might be avoided if former
asbestos workers quit smoking. The combination of a current high
asbestos consumption per capita, high exposure levels, and high
underlying lung cancer rates in Central Europe and the former Soviet
Union suggests that the lung cancers will arise from the
smoking-asbestos interaction should be a major concern. -- Environ
Health Perspect 107(Suppl 2):289-298 (1999).

http://ehpnet1.niehs.nih.gov/docs/1999/Suppl-2/289-298albin/abstract.html

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