Relevance of experimental studies to human risk.
Confidence in the extrapolation of animal toxicity data to humans can be enhanced by the application of pharmacokinetic concepts integrated with chronic toxicity data and knowledge of a chemical's mechanism(s) of toxicity. Basic pharmacokinetic concepts (including dose-dependent or Michaelis-Menten kinetics) and their relationship to the risk estimation process are discussed using vinyl chloride and styrene as specific examples. Species differences in metabolic rates must be considered in order to arrive at realistic estimates of human risk to vinyl chloride-induced liver angiosarcomas utilizing vinyl chloride toxicity data observed in rats. Because small animal species generally metabolize chemicals more rapidly than larger species on a body surface area basis, small animals should be more sensitive to chemicals (such as vinyl chloride) that exert their toxicities via the metabolic formation of toxic products. Inhaled styrene is a chemical whose clearance from the blood at low exposure levels in both rats and humans follows first-order kinetics. However, at higher exposure levels, the pharmacokinetic fate of styrene in rats is dose-dependent, suggesting a saturation of styrene metabolism. These data indicate that any extrapolation of observable toxicity at elevated exposure levels in rats to anticipated responses at lower levels in either rats or humans may be invalid. An integration of the foregoing concepts provides a sound scientific basis for the use of experimental animal data to predict the risk to humans from chemical exposure.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D051379:Mice; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012306:Risk; D013045:Species Specificity; D020058:Styrene; D013343:Styrenes / Q000378:metabolism / Q000633:toxicity; D014116:Toxicology / Q000379:methods*; D014752:Vinyl Chloride / Q000378:metabolism / Q000633:toxicity
D002273:Carcinogens; D004364:Pharmaceutical Preparations; D013343:Styrenes; D020058:Styrene; D014752:Vinyl Chloride