Cancer risk assessment PBPK models

Sixth, and finally, the adequacy of model structure as well as parameter values should be evaluated based on comparison of mode predictions with experimental data that had not been used for calibration purpose. This process essentially evaluates whether the PBPK model is capable of providing reliable predictions of the various dose metrics of potential use in a cancer risk assessement. The model should not only reprodnce consistently the shape of the pharmacokinetic time-course curve (i.e., including bnmps and valleys) and not jnst provide satisfactory fit only to a portion of the cnrve. Evaluation or validation of PBPK models should be regarded... 

This study, like that of Fisher and Allen (1993), incorporated a linear multistage model. However, the mechanism of trichloroethylene carcinogenicity appears to be non-genotoxic, and a non-linear model (as opposed to the linearized multistage model) has been proposed for use along with PBPK modeling for cancer risk assessment. The use of this non-linear model has resulted in a 100-fold increase in the virtually safe lifetime exposure estimates (Clewell et al. 1995). 

The Corley model (Corley et al. 1990) was the first chloroform PBPK model to describe and ultimately predict the fate of chloroform in several species (including humans) under a variety of exposure conditions. Many subsequent PBPK models for chloroform (Chinery and Gleason 1993 McKone 1993) are based on the Corley model. The Corley model has been used for cancer risk assessment (Reitz et al. 1990). 

Sielken RL, Jr., Reitz RH, Hays SM. Using PBPK modeling and comprehensive realism methodology for the quantitative cancer risk assessment of butadiene. 

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS IN CANCER 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... 

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

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 ... 

Figure 21.6. PBPK model-based cancer risk assessment for lOppm of dichloromethane or 0.5 ppm of benzene alone or in mixture with lOppm each of toluene, m-xylene, and ethylbenzene (Mixture A) 5 ppm of toluene, 20 ppm of m-xylene and 40 ppm of ethylbenzene (Mixture B). Based on data from Haddad et al. (2001a).

Monte Carlo simulation, an iterative technique which derives a range of risk estimates, was incorporated into a trichloroethylene risk assessment using the PBPK model developed by Fisher and Allen (1993). The results of this study (Cronin et al. 1995), which used the kinetics of TCA production and trichloroethylene elimination as the dose metrics relevant to carcinogenic risk, indicated that concentrations of 0.09-1.0 pg/L (men) and 0.29-5.3 pg/L (women) in drinking water correspond to a cancer risk in humans of 1 in 1 million. For inhalation exposure, a similar risk was obtained from intermittent exposure to 0.07-13.3 ppb (men) and 0.16-6.3 ppb (women), or continuous exposure to 0.01-2.6 ppb (men) and 0.03-6.3 ppb (women) (Cronin et al. 1995). 

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. 

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