We studied the alpha-radiation risks in patients who received injections of Thorotrast, an X-ray contrast medium used in Europe, Japan, and the United States from 1930 to 1955. Thorotrast was composed of thorium dioxide (ThO2) and Th-232, a naturally occurring radionuclide. Because the physical half-life of ThO2 is 14 billion years and Thorotrast is hardly eliminated from the body, tissues in which it was deposited are irradiated by alpha-radiation for the entire lifetime of the subject. The dosimetry of Thorotrast patients is very complicated, but currently its reliability is quite high compared with other irradiated populations. The major causes of the death of Thorotrast patients are liver cancer, liver cirrhosis, leukemia, and other cancers. Three histologies of liver cancer are found: cholangiocarcinoma, hepatocellular carcinoma, and angiosarcoma. Although cholangiocarcinoma is the most frequent, angiosarcoma is characteristic of alpha-radiation. Among blood neoplasms with a higher incidence of increase than the general population, erythroleukemia and myelodysplastic syndrome were remarkable. Thorotrast patients exhaled a high concentration of radon (Rn-220), a progeny of Th-232, but no excesses of lung cancer in the patients of Japan, Germany, and Denmark were reported. Mutation analyses of p53 genes and loss of heterozygosity (LOH) studies at 17p locus were performed to characterize the genetic changes in Thorotrast-induced liver tumors. Interestingly, LOH, supposedly corresponding to large deletions was not frequent; most mutations were transitions, also seen in tumors of the general population, suggesting that genetic changes of Thorotrast-induced cancers are mainly delayed mutations, and not the result of the direct effects of radiation.
The Canadian Environmental Protection Act (CEPA) authorizes the Ministers of the Environment and of Health in Canada to investigate a wide variety of substances that may contaminate the environment and cause adverse effects on the environment and/or on human health. Under the Act, assessments have been completed for 44 environmental contaminants on the first Priority Substances List, including four metals and their compounds. The principles developed for the assessment of risk to human health for priority substances under CEPA are outlined, with specific emphasis on the metals. These include general aspects such as estimation of total exposure from all media, the development of exposure potency indices for carcinogens in lieu of low-dose risk estimates, and incorporation of toxicokinetic and toxicodynamic data, where available, to modify traditionally adopted uncertainty factors for development of tolerable intakes, or concentrations, for nonneoplastic effects. Aspects of the approach to human health risk assessment more specific to the metals considered under CEPA (i.e., arsenic, cadmium, chromium, and nickel) and implications for the subsequent strategic options process are also addressed, including the extent to which various chemical forms could be assessed (i.e., speciation) and essentiality.
One prospective epidemiologic study of asbestos cement workers with radiological small opacities has been cited as a rationale for attributing excess lung cancer to asbestosis. This approach could have considerable practical value for disease attribution in an era of decreasing exposure. However, a recent International Agency for Research on Cancer review concludes that the mechanism of production of asbestos-related lung cancer are unknown. Asbestosis, therefore, cannot be a biologically effective dose marker of lung cancer susceptibility. Asbestosis nonetheless would be useful in identifying asbestos-attributable lung cancer cases if it could be proven an infallible exposure indicator. In this study, we tested this hypothesis in the chrysotile miners and millers of Quebec, Canada. We examined exposure histories, autopsy records, and lung fiber content for 111 Quebec chrysotile miners and millers. If the hypothesis of an asbestosis requirement for lung cancer attribution were accurate, we would expect as asbestosis diagnosis to separate those with lung cancer and high levels of exposure from those with lower levels of exposure in a specific and sensitive manner. This is the first such study in which historical job-based individual estimates based on environmental measurements, lung fiber content, exposure timing, and complete pathology records including autopsies were available for review. We found significant excesses of lung tremolite and chrysotile and estimated cumulative exposure in those with lung cancer and asbestosis compared to those with lung cancer without asbestosis. However, when the latter were directly compared on a case-by-case basis, there was a marked overlap between lung cancer cases with and without asbestosis regardless of the measure of exposure. Smoking habits did not differ between lung cancer cases with and without asbestosis. In regression models, smoking pack-years discriminated between those with the without lung cancer, regardless of asbestosis status. Most seriously, the pathologic diagnosis of asbestosis itself seemed arbitrary in many cases. We conclude that although the presence of pathologically diagnosed asbestosis is a useful marker of exposure, the absence of this disease must be regarded as one of many factors in determining individual exposure status and disease causation.
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A number of chemicals encountered predominantly in occupational settings have been causally linked with cancer in humans; furthermore, several industrial processes and occupations have been associated convincingly with increased rates of cancer, although the specific carcinogens remain to be identified. The tissues affected are mainly the epithelial lining of the respiratory organs (nasal cavity, paranasal sinuses, larynx and lung), and urinary tract (renal parenchyma, renal pelvis and urinary bladder), the mesothelial linings, the bone marrow and the liver. During the period 1970-84, almost 4 million people (3.7 million men and 0.2 million women) in the Nordic countries were potentially exposed to above-average levels of one or more verified industrial carcinogens. It is expected that these exposures will result in a total of about 1,900 new cases of cancer every year in the Nordic countries around the year 2000, with 1,890 among men and fewer than 25 among women. The proportions that could be avoided if industrial carcinogens were eliminated would be 70% of mesotheliomas, 20% of cancers of the nasal cavity and sinuses, 12% of lung cancers, 5% of laryngeal cancers, 2% of urinary bladder cancers, 1% of the leukaemias, and 1% of renal cancers. Overall, it is estimated that verified industrial carcinogens will account for approximately 3% of all cancers in men and less than 0.1% of all cancers in women in the Nordic countries around the year 2000. No attempt was made to estimate the potential effects of suspected carcinogens in the workplace.
Genes that metabolize the rate of clearance of environmental carcinogens may be candidate genes for cancer susceptibility. There is some data to suggest that exposure to environmental pesticides and other organochlorine pollutants is a risk factor to breast cancer. It is therefore reasonable to ask if variants in the genes responsible for the metabolic activation of organochlorines are associated with different tissue burdens of organochlorines and if these variants modify the risk of breast cancer in the population. We conducted a case-control study of women who underwent an excision biopsy for suspected breast cancer in a Toronto hospital from 1995 to 1997. Patients are residents of the Greater Toronto Area and are primarily Caucasian of European descent. Cases were women with invasive breast cancer (n = 70) and controls (n = 69) were women diagnosed with benign disease, frequency matched by age to cases. Levels of organochlorines were measured in benign breast tissue and seven polymorphisms in five candidate genes were genotyped. In general, women who carried inactive alleles of the GSTM1 had higher levels of breast organochlorines, and were at modestly increased risk of breast cancer (odds ratio = 2.2; 95% CI = 1.1-4.4). However, multiple comparisons were made and generally our data do not support the hypothesis that organochlorines increase the risk of breast cancer among subgroups of women with specific metabolic genotypes.