Modeling for risk assessment of neurotoxic effects.
The regulation of noncancer toxicants, including neurotoxicants, has usually been based upon a reference dose (allowable daily intake). A reference dose is obtained by dividing a no-observed-effect level by uncertainty (safety) factors to account for intraspecies and interspecies sensitivities to a chemical. It is assumed that the risk at the reference 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 establish a mathematical relationship between a biological effect and the dose of a chemical. Knowledge of biological mechanisms and/or pharmacokinetics can assist in the choice of plausible mathematical models. The mathematical model provides estimates of average responses as a function of dose. Secondly, estimates of risk require selection of a distribution of individual responses about the average response given by the mathematical model. In the case of a normal or lognormal distribution, only an estimate of the standard deviation is needed. The third step is to define an adverse level for a response so that the probability (risk) of exceeding that level can be estimated as a function of dose. Because a firm response level often cannot be established at which adverse biological effects occur, it may be necessary to at least establish an abnormal response level that only a small proportion of individuals would exceed in an unexposed group. That is, if a normal range of responses can be established, then the probability (risk) of abnormal responses can be estimated.(ABSTRACT TRUNCATED AT 250 WORDS)
Gaylor
D W
DW
U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Slikker
W
W
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016001:Confidence Intervals; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005260:Female; D000882:Haplorhini; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism*; D008297:Male; D008452:Maximum Allowable Concentration; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D051381:Rats; D012016:Reference Values; D012307:Risk Factors; D012701:Serotonin / Q000378:metabolism*; D013045:Species Specificity
D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine