The use of surrogate endpoints to assess potential toxicity in humans

Data on toxic effects in humans may come from epidemiology studies, accidental poisonings, surveillance schemes or following intentional exposures. In many cases, a surrogate endpoint related to the adverse effect is investigated. Effects produced following intentional exposures are usually restricted to readily reversible, mild surrogate endpoints of the adverse effect of concern. Not all initial interactions within the target organ are related to the toxic effect, and many measurements are biomarkers of exposure not response. Biomarkers of response represent surrogate endpoints of response only if they are critical to the mode of action. The use of biomarkers and the possible problems with using surrogate endpoints are illustrated with data on aniline, cadmium, carbon monoxide, erythrosine, paracetamol (acetaminophen) and styrene. In vivo surrogate endpoints are normally used in risk assessment directly, whereas in vitro surrogate endpoints can be incorporated by the development of a biologically based dose-response model, or used to replace a default uncertainty factor by a chemical-specific adjustment factor.