1715a Epidemiological evidence for non-linear exposure-responses for occupational carcinogens

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Abstract

Many chemicals are classified as known human carcinogens, based at least in part on epidemiological evidence. However, occupational epidemiological studies often lack detailed and reliable individual-level exposure information, and only may be capable of qualitatively indicating increased risk among ‘exposed’ versus ‘unexposed’ groups. Although this information might be helpful for hazard identification, it is of limited use for risk assessment. Therefore, many investigators have placed greater emphasis on obtaining measurements and deriving quantitative estimates of individual exposures over time. In addition to facilitating the identification of potentially non-linear exposure response relationships, including exposure thresholds for risk, this information helps improve risk assessments. Evidence of nonlinear exposure-response sometimes aligns with knowledge about the agents’ route of exposure, mode of action, metabolism and elimination. Furthermore, the identification and application of sensitive biological markers of exposure can help define groups of workers with exposures that are biologically meaningfully different from those of other groups, allowing more precise characterisation of the risk function and possibly the shape of the underlying dose-response function. For many carcinogens, the exposure-response is becoming clearer, and for some it is not linear. Furthermore, where there is evidence of exposure thresholds, epidemiological data may provide direct evidence of the exposure level where risk is increased, i.e., a meaningful departure from background rates. This presentation will review the epidemiological evidence on several known occupational carcinogens that suggest nonlinear risk functions, drawing on examples such as hexavalent chromium, crystalline silica, ionising radiation, vinyl chloride and benzene. Possible mechanisms that give rise to the observed nonlinear relationships (e.g., production of carcinogenic metabolite, overwhelming clearance pathways or repair mechanisms, etc.) will be discussed, and recommendations on how the integration of evidence from different lines of inquiry holds promise for identifying nonlinear exposure-response relationships for occupational carcinogens.

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