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ToxSci Advance Access published online on May 24, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh178
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received April 14, 2004
Accepted April 30, 2004

Forum

How to Assess Human Carcinogenic Risk of Chemicals? Contributions of the EUROTOX Specialty Section Carcinogenesis

Hermann M. Bolt 1* Gisela H. Degen 1

1 Institut für Arbeitsphysiologie an der Universität Dortmund Leibniz Research Centre for Working Environment and Human Factors Ardeystr. 67, D-44139 Dortmund, Germany

* To whom correspondence should be addressed. E-mail: bolt{at}ifado.de.


  Abstract

There is growing recognition that carcinogenic risk extrapolation to low doses (and standard setting) should consider the mode of action of a given chemical. So far, there is agreement to distinguish between genotoxic and non-genotoxic chemicals, yet further differentiations seem appropriate. For genotoxic carcinogens, case studies of chemicals point to a whole array of possibilities. There is a number of apparently genotoxic carcinogens where practical thresholds are a matter of discussion. For instance, positive data of chromosomal effects only, in the absence of mutagenicity, may support the characterization of a compound that produces carcinogenic effects only at high, toxic doses. There is a wide consensus that for non-DNA reactive genotoxicants such as aneugens thresholds should be defined. Specific mechanisms of clastogenicity have been repeatedly addressed as also having thresholds, such as toposisomerase II poisons or mechanisms based on reactive oxygen. These and other arguments, when taken together, lead to distinctions of groups of carcinogens, which have been introduced by Streffer et al. (2004): (A) Non-threshold genotoxic carcinogens; for risk low-dose assessment the linear non-threshold (LNT) model appears appropriate. (B) Genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported. In these cases the LNT model is used as a default assumption, based on the scientific uncertainty, and backed by the precautionary principle. (C) Genotoxic carcinogens for which a practical threshold is supported. (D) Non-genotoxic carcinogens and non DNA-reactive carcinogens; for these compounds a true ("perfect") threshold is associated with a clearly founded NOAEL.


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