Neurotoxicity modeling for risk assessment.

Abstract

The setting of acceptable exposure levels for neurotoxicants has followed the traditional approach of dividing experimental no-observed-adverse-effect-levels (NOAELs) by safety/uncertainty factors. NOAELs are believed by many toxicologists to represent levels having zero or negligible risk, while uncertainty factors are used to account for a number of sources of variation. Although the use of NOAELs in this manner has been criticized because of their imprecise quantitative definition, NOAELs for nonquantal neurotoxic effects have not been replaced by more precisely defined quantities (e.g., benchmark doses), partly due to the absence of a generally accepted methodology for attaching specific risk levels to low exposures. The present paper describes a quantitative approach to modeling nonquantal neurotoxic effects for risk assessment, which can be used to obtain results similar to the familiar results obtained in risk assessment for carcinogenicity and developmental toxicity. The steps involved in implementing the process are discussed, with particular attention being given to the critical step of defining an adverse neurologic effect. An experimental data set is used to illustrate the methodology.