Dose-response analysis in risk assessment: evaluation of behavioral specificity.
Several methods of quantitative risk assessment that have been described recently are particularly applicable to neurotoxic end points. These methods can be broadly divided into two types of approaches based on their treatment of dose-response data to estimate risks. Benchmark approaches estimate risks using variability in response to a fixed dose level in comparison with background control variability. Probabilistic approaches estimate risks using the variability in the dose to produce a small effect in the sample population. The current report seeks to extend the development of probabilistic approaches for neurotoxic end points. Because behavioral data are often used to assess therapeutic efficacy as well as toxicity (unwanted effects), this analysis focused on the relative risks of producing these effects with the same agent. The therapeutic potential of GBR 12909 was determined by its ability to decrease cocaine-maintained responding in monkeys. The effects of this agent were also assessed in the same monkeys using food-maintained responding to provide an indication of behavioral toxicity. GBR 12909 decreased both behaviors, with complete decreases on drug-seeking behavior occurring at doses that had minimal effects on food-maintained responding. The difference in the estimates of doses to decrease drug-seeking and food-maintained behavior suggested that specific therapeutic effects could be obtained in the absence of unwanted side effects for a definable proportion of the population. These results also suggest that multiple behavioral end points can be useful for identifying specific effects of chemicals for the purposes' of risk assessment.
Glowa
J R
JR
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. G7W@cu.nih.gov
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008253:Macaca mulatta; D009498:Neurotoxins / Q000633:toxicity*; D010879:Piperazines / Q000627:therapeutic use; D011336:Probability; D018570:Risk Assessment
D009498:Neurotoxins; D010879:Piperazines; C043425:vanoxerine; D003042:Cocaine