Overdose toxicity studies versus threshold: elements of biology must be incorporated into risk assessment.

The estimation of risk and evaluation of risk/benefit are traditionally and by necessity oriented at the current state of science and technology to ensure contemporary rights of safety. This demands a careful development in the methodology of hazard identification and risk assessment and its continuous updating and involvement. Compounds, e.g. erythrosine, 2,4,5-T, TCDD, and antioxidants, have still to be judged case-by-case, taking into account all available information on dosage, effect, kinetics, and mechanism of action, i.e., matters of biology rather than of mathematics alone. Considerations of mechanism of action and kinetics, especially recognition of low-dose/high-affinity assumptions in vitro, are necessary. This might lead to a new view upon thresholds which appears to apply for promoters. As accepted in pharmacology the dose-dependent magnitude of response observed in vivo is often a composite effect. Composite effects in toxicology can be viewed as having similar characteristics in vivo as in vitro in terms of potency, slope, maximal efficay and variability. Composite vectors can be antagonistic, leading to toxic and carcinogenic results, but also to protection. A continuous updating of scientific expertise supported by own experimental work is required for the regulator.