MODELING FOR RISK ASSESSMENT OF NEUROTOXIC EFFECTS

The regulation of noncancer toxicants, including neurotoxicants, has u sually been based upon a reference dose (allowable daily intake). A re ference dose is obtained by dividing a no-observed-effect level by unc ertainty (safety) factors to account for intraspecies and interspecies sensitivities to a chemical. It is assumed that the risk at the refer ence dose is negligible, but no attempt generally is made to estimate the risk at the reference dose. A procedure is outlined that provides estimates of risk as a function of dose. The first step is to establis h a mathematical relationship between a biological effect and the dose of a chemical. Knowledge of biological mechanisms and/or pharmacokine tics can assist in the choice of plausible mathematical models. The ma thematical model provides estimates of average responses as a function of dose. Secondly, estimates of risk require selection of a distribut ion of individual responses about the average response given by the ma thematical model. In the case of a normal or lognormal distribution, o nly an estimate of the standard deviation is needed. The third step is to define an adverse level for a response so that the probability (ri sk) of exceeding that level can be estimated as a function of dose. Be cause a firm response level often cannot be established at which adver se biological effects occur, it may be necessary to at least establish an abnormal response level that only a small proportion of individual s would exceed in an unexposed group. That is, if a normal range of re sponses can be established, then the probability (risk) of abnormal re sponses can be estimated. In order to illustrate this process, measure s of the neurotransmitter serotonin and its metabolite 5-hydroxyindole acetic acid in specific areas of the brain of rats and monkeys are ana lyzed after exposure to the neurotoxicant methylene-dioxymethamphetami ne. These risk estimates are compared with risk estimates from the qua ntal approach in which animals are classified as either abnormal or no t depending upon abnormal serotonin levels.