Empirically Observed Distributions of Pharmacokinetic and 经验观察到的分布的药代动力学和.docVIP

Empirically Observed Distributions of Pharmacokinetic and Pharmacodynamic Variability in Humans—Implications for the Derivation of Single Point Component Uncertainty Factors Providing Equivalent Protection as Existing RfDs Dale Hattisa and Meghan Keaney Lynchb aGeorge Perkins Marsh Institute, Clark University, Worcester MA bBoston University School of Public Health, Boston, MA Hattis, D. and Lynch, M. K. “Empirically Observed Distributions of Pharmacokinetic and Pharmacodynamic Variability in Humans—Implications for the Derivation of Single Point Component Uncertainty Factors Providing Equivalent Protection as Existing RfDs.” In Toxicokinetics in Risk Assessment, J. C. Lipscomb and E. V. Ohanian, eds., Informa Healthcare USA, Inc., 2007, pp. 69-93. Introduction/Abstract The IPCS framework for development of data-derived uncertainty factors1 that is described and used extensively in other chapters of this volume is a welcome effort to open up the traditional system of risk assessment for noncancer effects. It provides guidance for modification of the traditional adjustment factors on a case-by-case basis where more information is present than usual on either human interindividual variability or interspecies dose projections for the parent chemical or metabolite responsible for the toxicity of a particular environmental chemical. Welcome as this goal is, however, the derivation of the IPCS guidance does not draw on as extensive a database of pharmacokinetic and pharmacodynamic variability observations as is now available (Hattis et al., 1999b 2002 also see our web site [/faculty/dhattis] documenting much of the data). Nor does it derive the specific guidance for modifying the existing uncertainty factors on a quantitative analysis of the “baseline “uncertainties in human pharmacokinetic and pharmacodynamic variabilities for individual chemicals. (By the “baseline” uncertainty, we mean, the uncertainty one should have in the absence of chemical-specific informatio