Abstract

Acceptable risk levels of compounds are primarily based on the toxicological characteristics of a single compound. In the real life situation, man is exposed to a wide variety of compounds. The joint action of these compounds can result in either addition, antagonism or potentiation. In case of potentiation, the resulting toxicity may be a potential hazard. In the risk assessment of non-genotoxic compounds, safety or uncertainty factors are used to correct for inter- and intraspecies variation and measurement errors. For genotoxic compounds the maximum tolerable dose and negligible dose have been set. It has become more and more practice to use the same safety factor for accouting for the interactions between compounds in a mixture. It is therefore necessary to gain insight in the joint action of compounds and in the chance that addition, antagonism or potentiation may occur. In the context of setting standards, interactions occurring at low doses (at the no-observed-adverse-effect level) are of special interest. Interactions between different compounds may influence the toxicokinetics or toxicodynamics of the compounds. It can be anticipated that at low doses, interaction is likely to occur at a fundamental biological level, i.e. at receptor level and/or enzyme level. This report provides an overview of the joint action of chemicals and forms a starting point for the subproject 'Combination-toxicology' which has been started on the laboratory of Toxicology, RIVM.