Challenging Dogma: Thresholds for Genotoxic Carcinogens? The Case of Vinyl Acetate
- 1 April 2003
- journal article
- review article
- Published by Annual Reviews in Annual Review of Pharmacology and Toxicology
- Vol. 43 (1), 485-520
- https://doi.org/10.1146/annurev.pharmtox.43.100901.140219
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.Keywords
This publication has 76 references indexed in Scilit:
- Butadiene – progress under the European Union Existing Substances RegulationChemico-Biological Interactions, 2001
- pH effects on the lifespan and transformation frequency of Syrian hamster embryo (SHE) cellsCarcinogenesis: Integrative Cancer Research, 1996
- Cancer Risk of Low-Level ExposureScience, 1996
- Formation and stability of acetaldehyde-induced crosslinks between poly-lysine and poly-deoxyguanosineMutation Research, 1994
- Risk assessments of Low-Level ExposuresScience, 1994
- Induction of protein phosphorylation, protein synthesis, immediate‐early‐gene expression and cellular proliferation by intracellular pH modulationEuropean Journal of Biochemistry, 1993
- Linear dose-response relationship for DNA adducts in rat liver from chronic exposure to aflatoxin B1Carcinogenesis: Integrative Cancer Research, 1990
- Chronic toxicity studies of vinyl acetate in Fischer ratsToxicology and Applied Pharmacology, 1983
- Analysis for organic vapor emissions near industrial and chemical waste disposal sitesEnvironmental Science & Technology, 1982
- Excess Lung Cancer Risk in a Synthetic Chemicals PlantEnvironmental Health Perspectives, 1981