Sources of uncertainty in pharmacokinetic prediction.
Assessment of the hazard associated with residues in food animals must be based on an accurate estimate of the residue levels present in the final food product, as well as animal toxicology studies to determine the potential untoward effects of these residues. Extrapolation of residue levels or toxic effects produced by the administration of a chemical in one species to predict residue levels or toxicology that may be produced by lower doses in the same species or by equivalent or lower doses in another species is associated inextricably with knowledge of the pharmacokinetics of the chemical. There are several factors that may influence the pharmacokinetics of xenobiotics which, if left unconsidered, may introduce uncertainty in the predictions of toxicity following any chemical exposure. Two of these factors are dose level and species differences. Because initial toxicity studies are designed to characterize the type of toxicity and to elucidate target organ effects the use of high doses is the accepted practice. However, because biotransformation and excretion of many chemicals are capacity-limited processes, extrapolation of toxicity to lower doses, without adequate pharmacokinetic information at those lower dose levels may result in overestimation of predicted toxicity. Furthermore, determination of tissue residue levels following administration of doses that saturate these processes may result in an overestimation of residues remaining following lower doses. Finally extrapolation of toxicity results across species may result in an over or underestimation of hazard without adequate information on the pharmacokinetics of the chemical in both species.
D000818:Animals; D000829:Animals, Domestic / Q000378:metabolism*; D002273:Carcinogens; D004146:Dioxanes / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005506:Food Contamination; D006801:Humans; D008954:Models, Biological; D010416:Pentachlorophenol / Q000378:metabolism; D010573:Pesticide Residues / Q000032:analysis; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution; D014116:Toxicology
D002273:Carcinogens; D004146:Dioxanes; D010573:Pesticide Residues; D004364:Pharmaceutical Preparations; D010416:Pentachlorophenol; C025223:1,4-dioxane