Neurotoxicology dose/response assessment for several cholinesterase inhibitors: use of uncertainty factors

Dose/response assessment for non-carcinogenic endpoints typically uses the Acceptable Daily Intake (ADI) or Reference Dose (RfD) approach, in which a dose believed to cause no toxic effect is divided by a number of safety or uncertainty factors (e.g., to control for variability and cross-species extrapolation), in order to estimate a dose presumed to have no adverse effects in humans. With the establishment of neurotoxicology testing guidelines, routine use of uncertainty factors to undertake neurotoxicity dose/response assessment procedures is likely. This approach to dose/response assessment has not yet been widely applied to neurotoxicity data. The purpose of this study was to assess the use of uncertainty factors and the assumptions underlying the use of the uncertainty factor method in assessing risk for several known human neurotoxicants. Because of the availability of a large neurotoxicity data base which included human exposure data, parathion, diisopropylfluorophosphate, physostigmine and acrylamide were chosen for this analysis. Literature searches were conducted for both human and animal data. The resulting data were assigned to one of five end point categories: Neurochemistry/neuropathology, physiology/consummatory behavior, sensory/motor, electrophysiology, and learning/memory behavior. No-observed-adverse-effect levels (NOAELs) and/or lowest-observed-adverse-effect levels (LOAELs) were determined when possible for each end point and for several species. Reference doses (RfDs) were calculated and compared across species. A number of issues and critical assumptions were identified.