Toxicology of Industrial Compounds

176 EXTRAPOLATION OF TOXICITY DATA AND ASSESSMENT OF RISK
If the data base is sufficient, PBPK models provide scientific credibility to
interspecies extrapolation, extrapolation across routes of administration,
extrapolation from high-dose to low-dose and intraspecies extrapolation.
Recent concepts link the original tissue dose concept of PBPK models to
biologically based tissue response models, thus relating the delivered dose
via the mechanism of action to the toxic response and developing
integrated biological models (Conolly et al., 1988; Moolgavker et al.,
1988; Cohen and Ellwein, 1990; Conolly and Andersen, 1991). Such
approaches enable scientists to ask the right questions and to design new
mechanistic studies that will lead toward the goal of a scientifically-based
risk assessment.
Acknowledgement
The author thanks Richard A.Corley and the Glycol Ether Panel of the
Chemical Manufactures Association for providing data on 2butoxyethanol.
References
ANDERSEN, M.E. and KRISHNAN, K., 1994, Physiologically based
pharmacokinetics and cancer risk assessment, Environ. Health Perspect.
Suppl., 102 (Suppl. 1), 103–8.
ANDERSEN, M.E., CLEWELL, H.J., GARGAS, M.L., SMITH, F.A. and REITZ,
R.H., 1987, Physiologically based pharmacokinetics and the risk assessment
process, for methylene chloride, Toxicol. Appl. Pharmacol., 87, 185–205.
ARMS, A.D. and TRAVIS, C.C., 1988, Reference physiological parameters in
pharmacokinetic modeling, United States Evironmental Protection Agency,
EPA/600/6– 88/004, reproduced by US Department of Commerce, National
Technical Information Service, Springfield, VA.
BARTNIK, F.G., REDDY, A.K., KLECAK, G., ZIMMERMANN, V., HOSTYNEK,
J.J. and KUENSTLER, K., 1987, Percutaneous absorption, metabolism, and
hemolytic activity of n-butoxyethanol, Fundam. Appl. Toxicol., 8, 59–70.
CARFAGNA, M.A. and KEDDERIS, G.L., 1992, Isolated hepatocytes as in vitro
models for the biotransformation and toxicity of chemicals in vivo, CIIT
Activities, 12, 1–6.
COHEN, S.M. and ELLWEIN, L.B., 1990, Proliferative and genotoxic cellular
effects in 2-acetylaminofluorene bladder and liver carcinogenesis: biological
modeling of the ED01 study, Toxicol. Appl. Pharmacol, 104, 79–93.
CONOLLY, R.B. and ANDERSEN, M.E., 1991, Biologically based
pharmacodynamic models: tools for toxicological research and risk
assessment, Ann. Rev. Pharmacol. Toxicol., 31, 503–23.
CONOLLY, R.B., REITZ, R.H., CLEWELL, H.J., III and ANDERSEN, M.E.,
1988, Pharmacokinetics, biochemical mechanism and mutational