Risk assessment pharmacokinetics

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 3-4 shows a conceptualized representation of a PBPK model. 

Andersen ME, Clewell HJ 3rd, Gargas ME, et al. 1987. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol Appl Pharmacol 87 185-205. 

Notice Approaches for the Application of Physiologically-Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment E-Docket ID No. ORD-2005-0022. Fed Reg July 28, 2005 70 (144) 43692-43693. 

Clewell HJ 3rd, Gentry PR, Covington TR, Gearhart JM. Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment. Environ Health Perspect 2000 May 108 Suppl 2 283-305. 

Air Force. 1990. Development and validation of methods for applying pharmacokinetic data in risk assessment Volume n. Trichloroethylene. Wright-Patterson Air Force Base, OH U.S. Air Force, Air Force Systems Command, Harry G. Armstrong Medical Research Laboratory, Human Systems Division. NTIS No. AD-A237 366. 

Clewell HJ, Gentry PR, Gearhart JM, et al. 1995. Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants Examples with vinyl chloride and trichloroethylene. Chemosphere 31 2561-2578. 

Cronin WJ, Oswald EJ, Shelley ML, et al. 1995. A trichloroethylene risk assessment using a Monte Carlo analysis of parameter uncertainty in conjunction with physiologically-based pharmacokinetic modeling. Risk Anal 15 555-565. 

Absorbed lead is distributed in various tissue compartments. Several models of lead pharmacokinetics have been proposed to characterize such parameters as intercompartmental lead exchange rates, retention of lead in various pools, and relative rates of distribution among the tissue groups. See Section 2.3.5 for a discussion of the classical compartmental models and physiologically based pharmacokinetic models (PBPK) developed for lead risk assessments. 

PBPK and classical pharmacokinetic models both have valid applications in lead risk assessment. Both approaches can incorporate capacity-limited or nonlinear kinetic behavior in parameter estimates. An advantage of classical pharmacokinetic models is that, because the kinetic characteristics of the compartments of which they are composed are not constrained, a best possible fit to empirical data can be arrived at by varying the values of the parameters (O Flaherty 1987). However, such models are not readily extrapolated to other species because the parameters do not have precise physiological correlates. Compartmental models developed to date also do not simulate changes in bone metabolism, tissue volumes, blood flow rates, and enzyme activities associated with pregnancy, adverse nutritional states, aging, or osteoporotic diseases. Therefore, extrapolation of classical compartmental model simulations... 

O Flaherty EJ. 1987. Modeling An introduction. In Pharmacokinetics in risk assessment Drinking water and health, vol 8. National Academy of Sciences, Washington, D.C. National Academy Press, 27-3. 

Selection of target pharmaceuticals (see Table 1) was based on the following criteria (1) the sales and practices in Spain (according to National Health system), (2) compound pharmacokinetics (the percentage of excretion as nonmetabolized substance), (3) their occurrence in the aquatic media (data taken from other similar studies), and (4) on data provided by environmental risk assessment approaches, which link the calculation of predicted environmental concentrations (PEC) with toxicity data in order to evaluate which compounds are more liable to pose an environmental risk for aquatic organisms [20-22], In the current European... 

Andersen, M.E., J.J. Mills, M.L. Gargas, L. Kedderis, L.S. Bimbaum, D. Neubert, and W.F. Greenlee. 1993. Modeling receptor-mediated processes with dioxin implications for pharmacokinetics and risk assessment. Risk Analysis 13 25-36. 

Andersen ME (1995) Development of physiologically based pharmacokinetic and physiologically based pharmacodynamic models for applications in toxicology and risk assessment. Toxicol Lett 79 35-44... 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

Connally, R. and Anderson, M. (1991). Biologically based pharmacokinetic models Tools for toxicological research risk assessment. Annu. Rev. Pharmacol. Toxicol. 31 503-523. 

Nevertheless, there are many scientists engaged in the adventure of finding ways to improve the conduct of risk assessment. This chapter is devoted to highlighting some of their achievements. The full basis for each of the many examples discussed is not presented, because this requires a far more complete explanation of, for example, pharmacokinetics or mechanisms of toxicity than we have offered in the earlier... 

If it is possible to acquire an adequate understanding of pharmacokinetics, it may be possible in specific cases to document (1) changing pharmacokinetic patterns with changing dose or (2) pharmacokinetic patterns in the animal species used to develop toxicity data that are substantially different from those seen or expected in humans. Such differences would document that the usual defaults do not hold in those specific cases. The effects of using pharmacokinetic data in the risk assessment process instead of the usual defaults would depend upon what those data actually revealed. 

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