Challenging Dogma: Thresholds for Genotoxic Carcinogens? The Case of Vinyl Acetate

Abstract

Although many questions remain unanswered, the general principle of the sequence of events leading to cancer after exposure to genotoxic carcinogens has become increasingly clear. This helps to understand the parameters that influence the shape of the dose-effect curve for carcinogenesis, including metabolic activation and inactivation of carcinogens, DNA repair, cell cycle control, apoptosis, and control by the immune system. A linear dose-response relationship with no observable threshold seems to be a conservative but adequate description for the carcinogenic activity of many genotoxic carcinogens, such as aflatoxin B1, the tobacco-specific nitrosoketone NNK, and probably N,N-diethylnitrosamine. However, extrapolation models connecting the high-level risk to the zero intercept have clearly resulted in overestimations of risk. Vinyl acetate is an example that is discussed extensively in this review. At extremely high and toxic doses, vinyl acetate is carcinogenic in rats and mice and causes chromosomal aberrations. In tissues of contact, vinyl acetate is converted to acetic acid and acetaldehyde. Only when threshold levels are achieved do critical steps in the mechanism ultimately leading to cancer become active, namely pH reduction in exposed cells of more than 0.15 units leading to cytotoxicity, damage to DNA, and regenerative proliferation. Consistent with the known exposure to endogenous acetic acid and acetaldehyde, tissues sustain a certain level of exposure without adverse effects. Physiological modeling shows that the conditions necessary for carcinogenesis are in place only when threshold levels of vinyl acetate are exceeded. The example of vinyl acetate underlines the importance of toxicological research that unequivocally identifies genotoxic carcinogens acting through a threshold process.

Comparison of Carcinogenic and in vivo Genotoxic Potency Estimates

“…Recently, a good agreement has been observed between hazard characterization based on animal studies using the T25 method and epidemiological studies (Sanner & Dybing 2005). The assumption of a linear dose response without threshold is supported in a plausible manner for a number of carcinogens (Hengstler et al 2003). Other carcinogens may behave differently, but the precise nature of the dose response at low doses has not been sufficiently established.…”

Isolation and identification of bovine primary hepatocytes

“…Freshly isolated hepatocytes retain their liver-specific functions and minimize the amount of components required for evaluating hepatotoxicity (Shen et al, 2006). In vitro systems with primary hepatocytes are frequently applied for 1) prediction of in vivo metabolism of test substances, 2) identification of hepatotoxic and/or genotoxic substances, and 3) identification of substances that cause enzyme induction or inhibition (Hengstler et al, , 2003Osterod et al, 2002;Ringel et al, 2002). Strong correlations have been observed between data obtained in vitro using hepatocytes and in vivo observations (Li et al, 1999;Hengstler et al, 2000a,b).…”

A comprehensive review about micronuclei: mechanisms of formation and practical aspects in genotoxicity testing

“…The micronucleus test is one of the most frequently applied assays in genotoxicity testing and is also one of the most popular assays used by our authors (Hothorn and Gerhard 2009;Serpeloni et al 2010;Lima et al 2010;Westphal et al 2009;Angeli et al 2009;Dorn et al 2008;Krishnamurthi et al 2008;Bolt et al 2004;Hengstler et al 2003). The increasing relevance and distribution of the micronucleus test can easily be demonstrated by entering the terms ''micronucleus or micronuclei'' into ISI Web of Knowledge: In 1992, there were less than 2,000 hits.…”