Toxicological Modes Of Action PDF Download

Generally, the assessment of hazard and risk to humans that might arise from exposure to chemical substances is based on the extrapolation from data generated in studies with experimental animals. The assumption is made that the effects observed in the animals would also be expressed in humans and, to account for uncertainties including intra- and interspecies variability, and more recently susceptible human subpopulations, assessment factors are applied in deriving 'safe' exposures for humans. This is usually done without testing the hypothesis in humans, as the default approach allows for humans to be more sensitive than the most susceptible animal species. However, for those substances where humans are not sensitive to the effects seen in the animal studies, this approach is conservative and may result in risk management measures being taken that are totally unwarranted. An alternative approach is proposed in this report for the evaluation of such substances. The view has been expressed by many leading researchers and regulatory organisations that an understanding of the molecular and cellular processes underlying toxicity and carcinogenicity allows a more scientifically-based risk assessment and, where such information is available and adequate, this should replace default approaches in assessing human risk. All mechanisms of toxicity can be described in terms of a sequence of events, each of which is critical to the manifestation of the toxic endpoint. To elucidate such a mechanism requires rigorous investigation to obtain a complete and detailed understanding of the process leading to a toxic effect. However, the complete elucidation of all the events leading to the effect is not essential for evaluating the species differences in sensitivity to a toxicant. To achieve this we can restrict our understanding to selected key events within the complete sequence of events. This concept, termed the 'mode of action' can be used for the evaluation of species specificity including human susceptibility. If it could be shown that one or more of the key events could not occur in humans, or could only occur to a much lesser extent, it could be assumed that the mode of action of the substance in question was not relevant to the assessment of human risk. In such cases departure from the default approach would be justified. This philosophy is illustrated by a number of well-studied examples for which the modes of action and corresponding key events have been established for effects that are not relevant to humans. A structured two-step 'mode of action' approach was developed to guide the evaluation of substances expressing toxicity suspected as being species-specific and of questionable relevance to humans. Advice is given on how to identify the key events in the mode of action of the toxicological effect, how to test the strength of the data on which the mode of action hypothesis is based and how to establish its relevance to humans. The extent to which new data will be required to associate a substance with an established mechanism of toxicity or mode of action will vary, depending on the existing knowledge of the role of toxicokinetics and toxicodynamics and of the understanding already available within that class of chemicals. The use of this approach to identify those substances which express toxicity in experimental animals via a mode of action that is not relevant to humans will enable a more scientifically objective assessment of risk in humans. Furthermore, adopting a 'mode of action' approach should considerably speed up the risk assessment process and avoid unnecessary animal experimentation. [Editor]