Incorporation of Pharmacokinetic and Pharmacodynamic Data into Risk Assessments

Lipscomb, John C.; Meek, M.E.; Krishnan, Kannan; Kedderis, Gregory L.; Clewell, Harvey J.; Haber, Lynne T.

doi:10.1080/15376520490429382

Cited by 16 publications

(6 citation statements)

References 37 publications

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“…PBPK-based models can provide chemical-specific estimates of interspecies and interindividual differences in toxicokinetics (vs. UF of 4 extrapolating from animals to humans or UF of 3.3 within a human population). ( 30 , 141 , 142 ) For example, the default interspecies UF was reduced to 3 in the U.S. EPA methods due to the use of the DAF. ( 4 ) This factor may be reduced further when using more chemical-specific models.…”

Section: Other Dosimetry Considerationsmentioning

confidence: 99%

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Kuempel

Sweeney

Morris

et al. 2015

Journal of Occupational and Environmental Hygiene

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The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates.

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Section: Other Dosimetry Considerationsmentioning

confidence: 99%

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Kuempel

Sweeney

Morris

et al. 2015

Journal of Occupational and Environmental Hygiene

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“…The consideration of hepatic metabolic clearance data, either on their own or in combination with complementary information on absorption, distribution, metabolism and excretion (ADME) can support different aspects of chemical safety assessment including the development of Integrated Approaches to Testing and Assessment (IATA), informing toxicity study design and enhancing the interpretation of toxicological endpoint data (Bessems and Geraets, 2013). Chemical-specific in vitro hepatic metabolic clearance data can also be used to refine the extrapolation of toxicological results from animals to humans (Lipscomb et al, 2004). For example, when extrapolating from rat to human, understanding the qualitative and quantitative differences in clearance between species provides the basis for the derivation of chemical-specific adjustment factors as an informed alternative to using the usual default factor of 4 (the kinetics contribution to the value of 10 used for interspecies variability) (Dorne and Renwick, 2005;Bhat et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Gouliarmou¹,

Lostia²,

Coecke³

et al. 2018

Toxicology in Vitro

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Hepatic metabolic clearance is one of the most important factors driving the overall kinetics of chemicals including substances used in various product categories such as pesticides, biocides, pharmaceuticals, and cosmetics. A large number of in vitro systems from purified isozymes and subcellular organelles to hepatocytes in simple cultures and in complex scaffold setups are available for measuring hepatic metabolic clearance for different applications. However, there is currently no approach for systematically characterising and comparing these in vitro methods in terms of their design, applicability and performance. To address this, existing knowledge in the field of in vitro human hepatic metabolic clearance methods was gathered and analysed in order to establish a framework to systematically characterise methods based on a set of relevant components. An analogous framework would be also applicable for non-human in vitro systems. The components are associated with the biological test systems used (e.g. subcellular or cells), the in vitro method (e.g. number of cells, test item solubility), related analytical techniques, data interpretation methods (based on substrate depletion/metabolite formation), and performance assessments (precision and accuracy of clearance measurements). To facilitate the regulatory acceptance of this class of methods, it is intended that the framework provide the basis of harmonisation work within the OECD.

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“…For example, the magnitude of the factor for human variability in toxicokinetics (HK AF ) may be calculated based on an evaluation of human variability in the area under the tissue concentration-time curve (AUC) or clearance. A PBPK model provides an excellent basis for performing such an evaluation (Lipscomb et al, 2004;Pelekis et al, 2001). This paper describes the initial development of a generic PBPK model that can be used to estimate age-specific CSAFs for any chemical, exposure route, and life stage, dependent only on the availability of adequate chemicalspecific partitioning and metabolism information.…”

mentioning

confidence: 99%

Review and Evaluation of the Potential Impact of Age- and Gender-Specific Pharmacokinetic Differences on Tissue Dosimetry

Clewell¹,

Teeguarden²,

McDonald³

et al. 2002

Critical Reviews in Toxicology

130

118

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In standard risk assessment methods for carcinogenic or noncarcinogenic chemicals, quantitative methods for evaluating interindividual variability are not explicitly considered. These differences are currently considered by the use of statistical confidence limits or default uncertainty factors. This investigation consisted of multiple tasks aimed at making quantitative predictions of interindividual differences in susceptibility by using physiologically based pharmacokinetic (PBPK) models. Initially, a systematic, comprehensive review of the literature was conducted to identify any quantitative information related to gender- or age-specific physiological and biochemical factors that could influence susceptibility to chemical exposure. These data were then organized from a pharmacokinetic perspective by process and by chemical class to identify key factors likely to have a significant impact on susceptibility as it relates to internal target tissue dose. Overall, a large number of age- and gender-specific quantitative differences in pharmacokinetic parameters were identified. The majority of these differences were identified between neonates/children and adults, with fewer differences identified between young adults and the elderly. The next phase of this work consists of using PBPK models to develop examples of approaches through the development of case studies. The goal of the case studies is to continue to develop a methodology that incorporates PBPK modeling to assess the likelihood that a chemical or class of chemicals may present an age- or gender-specific risk. The case studies should also demonstrate practical methods for quantitatively incorporating information on age- and gender-specific pharmacokinetic differences in risk assessments for chemicals.

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Incorporation of Pharmacokinetic and Pharmacodynamic Data into Risk Assessments

Cited by 16 publications

References 37 publications

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Review and Evaluation of the Potential Impact of Age- and Gender-Specific Pharmacokinetic Differences on Tissue Dosimetry

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