Risk assessment for neurotoxic effects.
Regulation of neurotoxicants is generally based on setting allowable doses (exposures) by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that hopefully account for interspecies and intraspecies differences for extrapolations of experimental results obtained in animals to humans. This procedure makes no use of estimates of risk as a function of dose or does it acknowledge any risk at the NOAEL. The purpose of this paper is to illustrate how bioassay data can be used to estimate the risk of neurotoxic effects as a function of dose. In the absence of direct measurements of neurotoxic effects, biomarkers associated with neurotoxic effects can be used as measures of toxicity. In the absence of a definition of an adverse effect, an abnormal level for a measure of toxicity can be established which occurs only in a small fraction of a population which is not exposed to the substance under investigation. Risk is defined as the proportion of a population whose levels of a measure of toxicity equal or exceeds the abnormal level of the measure under study. The procedure is illustrated using data for neurochemical, neurohistological, and behavioral effects of methylenedioxymethamphetamine (MDMA) administered to rats or monkeys. This procedure is more versatile than the NOAEL/uncertainty factor approach since it provides estimates of risk as a function of dose of a potential neurotoxic substance.
National Center for Toxicological Research, Jefferson, Arkansas 72079.
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D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D001369:Axons / Q000187:drug effects; D015198:Designer Drugs / Q000633:toxicity; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009422:Nervous System Diseases / Q000139:chemically induced*; D051381:Rats; D011919:Rats, Inbred Strains; D012306:Risk; D012701:Serotonin / Q000378:metabolism
D015198:Designer Drugs; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine