PBPK Modeling Characteristics and Approaches

the scope for the use of RBRK models in a particular risk assessment has to be clearly identified since it essentially determines the intended model complexity, model capability, and Ihe extent of model evaluation. Here, the goal is really to specify the purpose for which the RBRK model would be used in a cancer risk 

the equations employed in a PBPK model should be consistent with the state of knowledge or biologically plausible hypotheses of the mechanisms of ADME for the particular chemical. In this regard, the uptake of chemicals in systemic circulation is described as either a diffusion-limited or perfusion-limited process (Gerlowski and Jain 1983), and metabolic clearance in individual tissues or tissue groups is described using a maximal velocity and Michaelis constant, intrinsic clearance, or hepatic extraction ratio (Krishnan and Andersen 2007). The mass balance differential equations accounting for uptake clearance, efflux clearance, and metabolic clearance are formulated as a function of identifiable input parameters (Table 21.1). 

TABLE 21.1. Examples of Equations Used in PBPK Models of Lipophilic Volatile Organic Chemicals Metabolized Principally in Liver 

the PBPK model parameters should be estimated using valid in vivo, in vitro, or in silico methods. The current methods for estimation and analysis of chemical-specific parameters as well as biological input data for PBPK models can be found in Krishnan and Andersen (2007) as well as in Lipscomb and Ohanian 

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 

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