Dose-response and threshold-mediated mechanisms in mutagenesis: statistical models and study design.
The objective of this paper is to review the use, in mutagenesis, of various mathematical models to describe the dose-response relationship and to try to identify thresholds. It is often taken as axiomatic that genotoxic carcinogens could damage DNA at any level of exposure, leading to a mutation, and that this could ultimately result in tumour development. This has led to the assumption that for genotoxic chemicals, there is no discernible threshold. This assumption is increasingly being challenged in the case of aneugens. The distinction between 'absolute' and 'pragmatic' thresholds is made and the difficulties in determining 'absolute' thresholds using hypothesis testing approaches are described. The potential of approaches, based upon estimation rather than statistical significance for the characterization of dose-response relationships, is stressed. The achievement of a good fit of a mathematical model to experimental data is not proof that the mechanism supposedly underlying this model is operating. It has been argued, in the case of genotoxic chemicals, that any effects produced by a genotoxic chemical which augments that producing a background incidence in unexposed individuals will lead to a dose-response relationship that is non-thresholded and is linear at low doses. The assumptions underlying this presumption are explored in the context of the increasing knowledge of the mechanistic basis of mutagenicity and carcinogenicity. The possibility that exposure to low levels of genotoxic chemicals may induce and enhance defence and repair mechanisms is not easily incorporated into many of the existing mathematical models and should be an objective in the development of the next generation of biologically based dose-response (BB-DR) models. Studies aimed at detecting or characterizing non-linearities in the dose-response relationship need appropriate experimental designs with careful attention to the choice of biomarker, number and selection of dose levels, optimum allocation of experimental units and appropriate levels of replication within and repetition of experiments. The characterization of dose-response relationships with appropriate measures of uncertainty can help to identify 'pragmatic' thresholds based upon biologically relevant criteria which can help in the regulatory process.
Lovell
D P
DP
BIBRA International, Woodmansterne Road, Carshalton, Surrey, UK. david_lovell@sandwich.pfizer.com
D000782:Aneuploidy; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D015233:Models, Statistical; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity*; D012107:Research Design
D009153:Mutagens