Differentiating between local cytotoxicity, mitogenesis, and genotoxicity in carcinogen risk assessments: the case of vinyl acetate

Abstract Understanding the mode of action of carcinogens is critical to scientifically assessing exposure-related risk. Regulatory hazard classification schemes and dose–response assessment paradigms generally require basic knowledge of genotoxic potential to guide decisions on which scheme or paradigm is most appropriate. Although convention suggests that classification and dose–response assessment of genotoxic chemicals should be assessed using conservative assumptions of no threshold, several examples, such as vinyl acetate, exist that challenge this assumption. Vinyl acetate is carcinogenic at portals of entry (nasal cavity and upper gastrointestinal tract). Local metabolism of vinyl acetate produces DNA-reactive acetaldehyde but also produces acetic acid and protons, which contribute to intracellular acidification, cytotoxicity and cell proliferation. This paper reviews their relative contributions to the overall mode of action. Elevated cellular proliferation, well understood to be a risk factor for carcinogenesis, is observed at concentrations associated with tumor formation. Cytotoxicity and compensatory tissue regeneration is one pathway for stimulating cellular proliferation while intracellular acidification is a mitogenic stimulus. Both of these pathways may be operative in nasal tissues while mitogenic proliferation alone appears to be induced in the upper gastrointestinal tract. Using a physiologically-based pharmacokinetic model, quantitative relationships between critical tissue dosimeters and tissue responses are developed to assess the relative importance of genotoxicity and cell proliferation in the overall mode of action of vinyl acetate. This approach supports the concept that intracellular acidification is the sentinel response that precedes cytotoxicity and cellular proliferation. Secondarily, the carcinogenic potential of vinyl acetate is expressed only when tissue exposure to acetaldehyde is high and when cellular proliferation is simultaneously elevated. This mode of action suggests that exposure levels that do not increase intracellular acidification beyond homeostatic bounds will be adequately protective of adverse downstream responses including cancer. These mechanistic insights provide the scientific basis for a cancer classification that incorporates thresholds for cytotoxic and/or mitogenic cell proliferation secondary to intracellular acidification.