Risk assessment pharmacokinetic approach

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... 

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. 

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... 

Clewell, H.J., M.E. Andersen, and H.A. Barton. 2002a. A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment. Environ. Health Perspect. 110 85-93. 

Yang, R.S., H.A. El-Masri, R.S. Thomas, A.A. Constan, and J.D. Tessari. 1995. The apphcation of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling for exploring risk assessment approaches for chemical mixtures. Toxicol. Lett. 79 193-200. 

These linear kinetic models and diffusion models of skin absorption kinetics have a number of features in common they are subject to similar constraints and have a similar theoretical basis. The kinetic models, however, are more versatile and are potentially powerful predictive tools used to simulate various aspects of percutaneous absorption. Techniques for simulating multiple-dose behavior evaporation, cutaneous metabolism, microbial degradation, and other surface-loss processes dermal risk assessment transdermal drug delivery and vehicle effects have all been described. Recently, more sophisticated approaches involving physiologically relevant perfusion-limited models for simulating skin absorption pharmacokinetics have been described. These advanced models provide the conceptual framework from which experiments may be designed to simultaneously assess the role of the cutaneous vasculature and cutaneous metabolism in percutaneous absorption. 

USEPA. Approaches for the application of physiologically based pharmacokinetic (PBPK) models and supporting data in risk assessment. Report number EPA/600/ R-05/043A. Washington, DC US Environmental Protection Agency, 2005. 

Leung, H. W., and Paustenbach, D. J. (1990). Cancer risk assessment for dioxane based upon a physiologically-based pharmacokinetic modeling approach. Toxicol Lett 51, 147—162. 

Over the past decade there has been a movement to harmonize cancer and noncancer risk assessment (Gaylor 1997 Bogdanffy et al. 2001) based on the premise that cancer and noncancer events share similar pharmacokinetic dependencies and overlapping MOAs and thus have similar dose-response relationships. The benchmark dose approach lends itself to the evaluation of both linear and nonlinear dose-response. In fact, one of the stated purposes of EPA s formalization of the benchmark dose process was to provide a standardized approach to chemical dose-response assessment, regardless of whether the chemical is a carcinogen. 

In summary, biologically based pharmacokinetic and pharmacodynamic models have tremendous potential to help solve problems in the skin. These models are especially useful for predicting pharmacokinetics and system responses that are nonUnear because they are based on first principles. They can also help design expraiments and develop and test hypotheses. Ultimately, these models can be used to improve risk assessments or develop prophylactic or therapentic approaches. 

Travis CC, White RK, Arms AD. 1989. A physiologically based pharmacokinetic approach for assessing the cancer risk of tetrachloroethylene. In Paustenbach DJ ed. The Risk Assessment of Environmental and Human Health Hazards A Textbook of Case Studies. John Wiley Sons, New York 769-796. 

FUN tool is a new integrated software based on a multimedia model, physiologically based pharmacokinetic (PBPK) models and associated databases. The tool is a dynamic integrated model and is capable of assessing the human exposure to chemical substances via multiple exposure pathways and the potential health risks (Fig. 9) [70]. 2-FUN tool has been developed in the framework of the European project called 2-FUN (Full-chain and UNcertainty Approaches for Assessing Health Risks in FUture ENvironmental Scenarios www.2-fun.org). 

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