Thresholds in Toxicology and Risk Assessment

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Abstract
It is argued that dose-thresholds in a strict quantitative sense cannot exist in dose-response relationships that are studied by toxicologists. The biological, more qualitative, notion of thresholds can only be translated into quantitative terms by defining thresholds in the effect-size of continuous end-points: What size of an effect can the organism cope with and when is the effect adverse? These are key questions that toxicologists should address, for the various (continuous) end-points that may be observed in toxicological studies. Avoiding this question by resorting to a “formal” statistical test is deceptive and makes the outcome of a risk assessment fortuitous. There is no defendable rationale for different procedures of data analysis based upon assumed underlying mechanisms. The approach of data analysis should be determined by the nature and quality of the data. If the data allow for dose-response modelling, this should be done whatever the underlying biological mechanism. Quantal dose-response relationships (relating to noncancer end-points) are problematic, because their slopes are largely determined by the experimental noise. Therefore, the concept of “extra risk” is not well defined in this case. In the case of tumor incidence data, on the other hand, the definition and estimation of an extra risk level are defendable, if it can be assumed that the stochastic component of the carcinogenicity process itself is large compared to the interindividual variation and experimental noise.