||Pharmacokinetics in Low Dose Extrapolation Using Animal Cancer Data.
Whittemore, A. S. ;
Crosser, S. ;
Silvers, A. ;
||Stanford Univ., CA. ;Electric Power Research Inst., Palo Alto, CA.;Health Effects Research Lab., Research Triangle Park, NC.
Laboratory animals ;
Computerized simulation ;
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Data on rodents exposed to carcinogens indicate that their tumor probabilities are proportional to effective concentrations of parent compound or metabolites at the target tissues. This proportionality suggests that observed nonlinear dose-response curves reflect dose-dependent kinetics between applied dose rate and effective concentrations. Therefore, low dose extrapolation procedures that include pharmacokinetic data could improve extrapolation accuracy. To test such procedures, bioassay and pharmacokinetic 'data' were simulated. Then, ignoring the mechanisms generating the data, four extrapolation procedures were used to estimate tumor probability at a low applied dose rate. Two of the procedures use a pharmacokinetic model and simulated pharmacokinetic data, and two do not. The pharmacokinetic model used for extrapolation was only an approximation to the one used to generate the pharmacokinetic data. (Copyright (c) 1986 by the Society of Toxicology.)