Physiologically based pharmacokinetic pharmacodynamic processes

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

Exposures of newborns to PAHs depend on pharmacokinetic processes operating in the mother, and transfer through breast milk. Since it is difficult to characterize these pathways in humans, physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) models need to be developed using appropriate animal models, and incorporating key parameters such as dose, exposure duration, and developmental stage (Dorman et al, 2001). Thus, development of PBPK and PBPD models for PAHs is an immediate need that will help in not only characterizing the dose-response relationship, but also extrapolation of results from animal studies to humans. 

---