Dose-response assessment PBPK models

As shown previously, PBPK models allow the conversion of potential dose or exposure concentration to tissue dose, which can then be used for risk characterization purposes. The choice of an internal dose metric is based principally on an understanding of the mode of action of the chemical species of concern. The internal dose metric (sometimes called the biologically effective dose) is often used in place of the applied dose in quantitative dose-response assessments, in order to reduce the uncertainty inherent in using the applied dose to derive risk values. 

CHAPTER 21 PBPK MODELS IN CANCER RISK ASSESSMENT TABLE 21.4. Dose-Response Assessment for Angiosarcoma Induced by Vinyl Chloride... 

TABLE 21.5. Improvement of Cancer Dose-Response Assessment for Dichloromethane Using PBPK Models to Compute Relevant Dose Metrics... 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

Marino DJ, Clewell HJ, Gentry PR, Covington TR, Hack CE, David RM, Morgott DA. 2006. Revised assessment of cancer risk to dichloromethane. Part I. Bayesian PBPK and dose-response modeling in mice. Regul Toxicol Pharmacol 45 44-54. 

For all these reasons, PBPK models are and will continue to be increasingly used in toxicology. This is especially true in risk assessment studies since better definition of the internal tissue dose, may contribute to reduce the uncertainty associated with extrapolation to human beings of responses observed in animal toxicity studies in which animals usually receive high doses of xenobiotics by routes often different from the one(s) anticipated in human exposures. 

Physiologically Based Pharmacokinetic (PBPK) models and Biologically Based Dose-Response (BBDR) models are finding increasing use in risk assessment... 

By facilitating the simulation of the dose metrics for use in cancer dose-response analysis, the PBPK models address the uncertainty associated with interspecies, route-to-route, and high-dose to low-dose extrapolations (Andersen et al. 1993 Andersen and Krishnan 1994 Clewell et al. 2002a Clewell and Andersen 1987 Melnick and Kohn 2000). Since the first demonstration of the application of PBPK models in cancer risk assessment by Andersen and co-workers in 1987, there have been substantial efforts to evaluate the appropriate dose metrics and cancer risk associated with a number of other volatile organic chemicals using the PBPK modeling approach (Table 21.3). These risk assessments have been based on the PBPK model simulations of a variety of dose metrics that reflect the current state... 

The PBPK-based route-to-route extrapolation in cancer risk assessment frequently begins with the determination of a slope factor, associated with the response data for one exposure route, on the basis of the appropriate dose metrics (Dt), e.g., 2 X 10 pCT milligram metabofized per day per g of tissue. Then, the PBPK model, parametrized for other exposure route(s) of interest, is used to deter-nune the exposure dose that genrates the same Dt—that is, that corresponding to a predetermined risk level (e.g., 1 x 10 ) (Clewell et al. 2001). When linear extrapolation is appropriate, the following equation is used ... 

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