The Mesothelioma Research Foundation of America
The usual gross and microscopic features of malignant mesolthelioma 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 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.
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:
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.
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.
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.2 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."
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? 4 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.5 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.6 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.7 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 with cumulative 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."11 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.14 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.19 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
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.
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.
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:
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.
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
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.
Asbestos Legislation Update
Research Interest in Asbestos-Related Cancer Intensifies
Nine Questions and Answers on Chrysotile and Health
Abstracts Found in Various Medical Journals Concerning Peritoneal Mesothelioma
Asbestos and Cancer - The First Thirty Years
Asbestos and Cancer - The International Lag
Asbestos in Drinking Water and Cancer Incidence in San Francisco
Asbestos Concentration On Marine Vessels
Asbestos in Strange Places: Two Case Reports of Mesothelioma Among Merchant Seamen
Asbestos in the Workplace and the Community
Asbestos-Related Disease in Plumbers and Pipefitters Employed in Building Construction
Malignant Mesothelioma of the pleura: current surgical pathology
Call for an International Ban on Asbestos
Chrysotile Asbestos is the Main Cause of Pleural Mesothelioma
Environmental asbestos exposure and malignant pleural mesothelioma
For questions related to the foundation and to make contributions please contact:
(800) 909-Meso (6376)
3011 Townsgate Rd, Suite 450
Westlake Village, CA 91361
For more information and other questions contact:
©2013 Mesothelioma Research Foundation Of America