US EPA's TSCA risk assessment approach: a case study of asbestos in automotive brakes.

The United States Environmental Protection Agency (US EPA) is currently refining its approach for risk assessments conducted under the amended Toxic Substances Control Act (TSCA), largely based on recommendations from the National Academies of Sciences, Engineering, and Medicine (NASEM). We identified several issues with the current TSCA risk assessment approach that were not addressed by NASEM in its recommendations. Here, we demonstrate these issues with a case study of the 'Risk Evaluation for Asbestos, Part 1: Chrysotile Asbestos,' which US EPA released in December 2020. In this evaluation, US EPA found that occupational and some consumer uses of automotive brakes and clutches that contain asbestos result in unreasonable risks. These risks were calculated from estimated exposures during brake work and an inhalation unit risk (IUR) developed for chrysotile asbestos. We found that US EPA overestimated risk as a result of unrealistic inputs to both the exposure and toxicity components of the risk equation, and because the Agency did not fully consider relevant epidemiology and toxicity evidence in its systematic review. Our evaluation demonstrates areas in which the TSCA risk assessment approach could be improved to result in risk evaluations that are supported by the available scientific evidence.

Historical state of knowledge of the health risks of asbestos posed to seamen on merchant ships.

We examined the development of knowledge concerning the risks posed by asbestos to seamen working aboard merchant ships at sea (i.e. commercial, rather than naval vessels). Seamen were potentially exposed to "in-place" asbestos on merchant ships by performing intermittent repair and maintenance tasks. We reviewed studies measuring airborne asbestos onboard merchant ships and health outcomes of merchant seamen, as well as studies, communications, and actions of U.S. organizations with roles in maritime health and safety. Up to the 1970s, most knowledge of the health risks of asbestos was derived from studies of workers in asbestos product manufacturing and asbestos mining and milling industries, and certain end-users of asbestos products (particularly insulators). We found that attention to the potential health risks of asbestos to merchant seamen began in the mid- to late 1970s and early 1980s. Findings of pleural abnormalities in U.S. seamen elicited some concern from governmental and industry/labor organizations, but airborne asbestos concentrations aboard merchant ships were found to be <1 f/cc for most short-term repair and maintenance tasks. Responses to this evolving information served to warn seamen and the merchant shipping industry and led to increased precautions regarding asbestos exposure. Starting in the 1990s, findings of modest increases in lung cancer and/or mesothelioma in some epidemiology studies of seamen led some authors to propose that a causal link between shipboard exposures and asbestos-related diseases existed. Limitations in these studies, however, together with mostly unremarkable measures of airborne asbestos on merchant ships, preclude definitive conclusions in this regard.

Electricians' chrysotile asbestos exposure from electrical products and risks of mesothelioma and lung cancer.

Both mechanistic and epidemiology studies indicate chrysotile asbestos has a threshold below which it does not cause mesothelioma or lung cancer. We conducted a critical review to determine whether electricians are at increased risk for these cancers and, if so, whether their exposure to chrysotile in electrical products could be responsible. We found that most, but not all, epidemiology studies indicate electricians are at increased risk for both cancers. Studies that evaluated electricians' exposure to asbestos during normal work tasks have generally reported low concentrations in air; an experimental study showed that grinding or drilling products containing encapsulated chrysotile resulted in exposures to chrysotile fibers far below the OSHA permissible exposure limit and the cancer no observed adverse effect level. Studies of other craftsmen who often work in the vicinity of electricians, such as insulators, reported asbestos (including amphibole) exposures that were relatively high. Overall, the evidence does not indicate that exposure to chrysotile in electrical products causes mesothelioma or lung cancer in electricians. Rather, the most likely cause of lung cancer in electricians is smoking, and the most likely cause of mesothelioma is exposure to amphibole asbestos as a result of renovation/demolition work or working in the proximity of other skilled craftsmen.

A framework for assessing causality and adverse effects in humans with a case study of sulfur dioxide.

Following exposure to a substance, several biological events can occur that may eventually, depending on the exposure dose and duration, lead to adverse effects. We developed a framework to evaluate whether an exposure is causally related to an effect and whether that effect is adverse. An exposure is not likely to be causal if an effect is: not statistically significantly different in exposed and non-exposed study subjects; isolated or independent; secondary; observed because of study limitations; or unrelated to the apical effect and not associated with functional impairment. Adaptive effects are not adverse and, although effects that overwhelm homeostasis often are, this may not be the case if they are transient, early precursors of an apical effect, reversible, or of low severity. We applied the framework to a case study of sulfur dioxide (SO(2)) and conclude that the available evidence supports a short-term exposure threshold of 400 ppb SO(2) for adverse effects on lung function in sensitive individuals. At this concentration, effects are transient, reversible, and of low severity. Below this concentration, effects are isolated or independent and not statistically different in exposed and unexposed subjects in clinical trials, and study limitations affect interpretation of observational studies.

Carcinogenicity assessment of water-soluble nickel compounds.

IARC is reassessing the human carcinogenicity of nickel compounds in 2009. To address the inconsistencies among results from studies of water-soluble nickel compounds, we conducted a weight-of-evidence analysis of the relevant epidemiological, toxicological, and carcinogenic mode-of-action data. We found the epidemiological evidence to be limited, in that some, but not all, data suggest that exposure to soluble nickel compounds leads to increased cancer risk in the presence of certain forms of insoluble nickel. Although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is limited evidence that suggests it may act as a tumor promoter. The mode-of-action data suggest that soluble nickel compounds will not be able to cause genotoxic effects in vivo because they cannot deliver sufficient nickel ions to nuclear sites of target cells. Although the mode-of-action data suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion. The mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all. The weight of evidence does not indicate that soluble nickel compounds are complete carcinogens, and there is only limited evidence that they could act as tumor promoters.