Peter F. Infante

Cadmium-induced Cancers in Animals and in Humans

Abstract Discovered in the early 1800s, the use of cadmium and various cadmium salts started to become industrially important near the close of the 19th century, rapidly thereafter began to flourish, yet has diminished more recently. Most cadmium used in the United States is a byproduct from the smelting of zinc, lead, or copper ores, and is used to manufacture batteries. Carcinogenic activity of cadmium was discovered first in animals and only subsequently in humans. Cadmium and cadmium compounds have been classified as known human carcinogens by the International Agency for Research on Cancer and the National Toxicology Program based on epidemiologic studies showing a causal association with lung cancer, and possibly prostate cancer, and studies in experimental animals, demonstrating that cadmium causes tumors at multiple tissue sites, by various routes of exposure, and in several species and strains. Epidemiologic studies published since these evaluations suggest that cadmium is also associated with cancers of the breast, kidney, pancreas, and urinary bladder. The basic metal cationic portion of cadmium is responsible for both toxic and carcinogenic activity, and the mechanism of carcinogenicity appears to be multifactorial. Available information about the carcinogenicity of cadmium and cadmium compounds is reviewed, evaluated, and discussed.

Beryllium: An etiologic agent in the induction of lung cancer, nonneoplastic respiratory disease, and heart disease among industrially exposed workers

On the basis of the clear demonstration of the carcinogenicity of beryllium in several animal species along with the suggestion of an increased risk of lung cancer mortality in humans exposed to beryllium, an epidemiologic study of workers exposed to beryllium at one production facility was undertaken. Within the limitations imposed by the selection of data for calculation of cause-specific expected mortality (use of U.S. white male cause-specific mortality rates with linear extrapolation of 1965–1967 to 1968–1975 vs use of cause-specific mortality rates for the county in which the study facility and the majority of its workers resided), the study demonstrated a statistically significant increased risk of respiratory disease (neoplastic and nonneoplastic) and of heart disease mortality. A possible explanation other than in terms of beryllium was sought for this excessive risk of cause-specific mortality among beryllium-exposed workers. The excessive risk of lung cancer mortality could not be related to an effect of age, chance, self-selection, study group selection, exposure to other agents in the study facility, or place of residence. On the basis of the frequency of cigarette smoking among those cohort members employed in 1967–1968 and the distribution of histologic types of lung cancer among deceased cohort members, it seems unlikely that cigarette smoking per se could have accounted for the increased risk of lung cancer among beryllium-exposed workers in the study cohort. Lifetime employment histories for members of the study cohort were not available, so that definitive statements about the role of other occupational exposures cannot be made. However, information on usual occupations as indicated on death certificates suggests that it is unlikely that some undefined occupational or environmental exposure other than to beryllium could account per se for the excessive lung cancer mortality. This interpretation is further supported by the residential stability of the study cohort in a county having a lung cancer rate significantly lower than that of the entire United States. The findings of a statistically significant excess of lung cancer mortality among cohort members in general (P < 0.05) and among workers observed 25 or more years since onset of beryllium exposure in particular (P < 0.01), when taken in context with the results of earlier animal bioassay and recent epidemiologic studies, are supportive of the hypothesis that beryllium is carcinogenic to man.

Carcinogenic, mutagenic and teratogenic risks associated with vinyl chloride.

The data presented demonstrate clearly that vinyl chloride (VC) is related to a significant excess of mortality from cancer of the liver, lung and brain among workers occupationally exposed to VC. The risk of dying from cancer of the lymphatic and hematopoietic system also appears to increase with an increase in latency. These cancer sites could have been predicted by the animal bioassay conducted by Maltoni. With regard to the liver, even the histophthologic type of cancer (angiosarcoma) was observed first in experimental animals. A study of cancer mortality among populations residing proximate to VC polymerization facilities also demonstrated an increased risk of dying from CNS and lymphatic cancer. These latter findings raise cause for concern about out-plant emmissions of VC, but without further study these cancers obviously cannot be interpreted as being related to out-plant exposure to VC. Various test systems now have elicited a positive mutagenic response to VC. Thus, our observations of a significant excess of fetal mortality among the wives of males, who were occupationally exposed to VC, raise public health concern that VC may be mutagenic in humans. With regard to the teratogenicity of VC, observations of a significant excess of children born with birth defects were reported among populations residing proximate to VC polymerization facilities. Additional epidemiologic study is needed to determine whether a repeated pattern of excessive numbers of children born with birth defects can be observed in other communities with VC polymerization facilities.

Mortality patterns from lung cancer and nonneoplastic respiratory disease among white males in the Beryllium Case Registry

Study was undertaken of mortality patterns among white males entered into the Beryllium Case Registry (BCR) while alive with a diagnosis of beryllium-related nonneoplastic respiratory symptoms or disease. Analyses demonstrate an excessive risk of lung cancer among those subjects in the BCR who had been previously diagnosed with acute chemical pneumonitis or bronchitis secondary to short-term beryllium exposure. In the evaluation of the excessive lung cancer risk in this population, consideration should be given to the competing effects from the high case fatality rate of nonneoplastic respiratory disease. This excessive risk of lung cancer could not be explained on the basis of cigarette smoking per se. The findings of the present study utilizing subjects in the BCR are consistent with results of animal studies that over 30 years ago first demonstrated beryllium to be a carcinogen and with numerous epidemiologic studies demonstrating an increased risk of lung cancer among workers occupationally exposed to beryllium and its compounds.

Mutagenic and Oncogenic Effects of Chloromethanes, Chloroethanes and Halogenated Analogues of Vinyl Chloride

In the early 1970’s, information bearing on the mutagenicity and carcinogenicity if vinyl chloride (VC) in experimental test systems and in humans came to the attention of the public health community. As a result, emphasis was placed on the evaluation of potential genotoxic and carcinogenic effects of a number of halogenated hydrocarbons structurally related to VC. This response was of particular concern as many of these substances are in high volume production and have a large number of individuals exposed in the occupational setting. As a result of pollution from industrial effluents, many of these substances have been identified in community water supplies. Some of these substances also have been or still are contained in consumer products.

Benzene and Leukemia: The 0.1 ppm ACGIH Proposed Threshold Limit Value for Benzene

Abstract The American Conference of Governmental Industrial Hygienists (ACGIH) has proposed a threshold limit value (TLV) for benzene of 0.1 ppm. Individuals representing the American Petroleum Institute (API) and the Chemical Manufacturers Association (CMA) have argued that 1) the risk assessment by Rinsky et al. which ACGIH partially relied upon for its proposed TLV overestimates the risk; however, at the exposures levels of interest (e.g., 0.1 to 1.0 ppm) for establishing a benzene TLV, the Rinsky et al. assessment provides lower estimates of leukemia risk than most others; 2) ACGIH should not use the Dow study for direct observational evidence of leukemia risk associated with low-level benzene exposure because of confounding exposure; however, it is unlikely that confounding exposures played a role in the excess of leukemia demonstrated in the study, and the Dow cohort was exposed to an average benzene concentration of about 5.5 ppm benzene for 7.0 years (38.5 ppm-years), while some of the individuals...

The Past Suppression of Industry Knowledge of the Toxicity of Benzene to Humans and Potential Bias in Future Benzene Research

Abstract Petrochemical industry representatives often withhold information and misinterpret positive evidence of toxicity of benzene, even from their own research, also discouraging or delaying disclosure of findings of adverse effects to the public. They now appear to be attempting to influence study results in industrys favor by offering predetermined conclusions about study results as part of an effort to draw financial support for the studies. The American Petroleum Institute is currently raising funds for benzene research being conducted in China for which it has already announced the intended conclusions.

Vinyl Chloride Propellant in Hair Spray and Angiosarcoma of the Liver among Hairdressers and Barbers : Case Reports

Abstract Two cases of angiosarcoma of the liver (ASL) are, to the best of our knowledge, the first literature reports of such cases identified among hairdressers and barbers who used hair sprays containing vinyl chloride (VC) as a propellant. The cases were exposed to VC aerosols between 1966 and 1973, for 4–5 year periods. Modeling indicates estimated peak levels of VC exposure ranging from 129 ppm to 1234 ppm, and average exposure ranging from 70 ppm to 1037 ppm, based upon assumptions of use and number of air exchanges per hour. As ASL is a sentinel cancer for exposure to VC, identification of these cases raises concern about the contribution of VC to hepatocellular carcinoma (HCC), a much more common type of liver cancer, as well as other VC-related cancers among hairdressers and barbers. Had manufacturers acted in a responsible manner, VC never would have been introduced as a propellant into consumer products such as hair sprays, pesticides, and paints.

Benzene and leukemia, Pliofilm Revisited: I. An historical review of the leukemia deaths among Akron Goodyear Tire and Rubber Company Employees

Abstract The cohort study of Pliofilm workers exposed to benzene has been used as a primary data source to estimate quantitative dose response for benzene-leukemia. Little attention has focused on the undercounting of leukemia deaths used in the analyses, nor on the behavior of the company toward the Pliofilm workers who contracted leukemia. An historical review of documents related to the Akron portion of the cohort indicates that between two and five workers diagnosed with acute myelogenous leukemia (AML) could be added to the cohort for alternate dose response analyses. In the late 1950s and early 1960s, the company did not inform Pliofilm workers with AML that they had the disease, concealed from the workers, including those diagnosed with AML, and the treating hematologist that benzene was the solvent being used, and denied compensation for AML cases exposed to benzene until forced to do so by the State of Ohio in 1968.

Determination of blood‐lead elimination patterns of primary lead smelter workers

Data for peripheral blood‐lead (PbB) levels for workers of four primary lead smelters in the United States were analyzed to characterize the patterns of PbB elimination. These workers had been removed from their job under the Medical Removal Protection (MRP) provision of the lead standard promulgated in 1978 by the Occupational Safety and Health Administration (OSHA). For each individual removed under the first or second year of the MRP provision, data for blood‐lead levels in relation to length of time removed were applied to four separate mathematical models, namely, linear regression, power curve fit, exponential curve fit, and logarithmic curve fit. The best model was determined by comparing overall correlation coefficients squared (r2) values derived from each model. Separate analyses were also made to test the relationship of PbB elimination rates to PbB levels at the time of the removal, length of occupational lead exposure, and job category. In addition, the duration of the medical removal time un...