159 research outputs found

    Application of Physiologically Based Pharmacokinetic Models in Chemical Risk Assessment

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    Post-exposure risk assessment of chemical and environmental stressors is a public health challenge. Linking exposure to health outcomes is a 4-step process: exposure assessment, hazard identification, dose response assessment, and risk characterization. This process is increasingly adopting “in silico” tools such as physiologically based pharmacokinetic (PBPK) models to fine-tune exposure assessments and determine internal doses in target organs/tissues. Many excellent PBPK models have been developed. But most, because of their scientific sophistication, have found limited field application—health assessors rarely use them. Over the years, government agencies, stakeholders/partners, and the scientific community have attempted to use these models or their underlying principles in combination with other practical procedures. During the past two decades, through cooperative agreements and contracts at several research and higher education institutions, ATSDR funded translational research has encouraged the use of various types of models. Such collaborative efforts have led to the development and use of transparent and user-friendly models. The “human PBPK model toolkit” is one such project. While not necessarily state of the art, this toolkit is sufficiently accurate for screening purposes. Highlighted in this paper are some selected examples of environmental and occupational exposure assessments of chemicals and their mixtures

    Development of a Human Physiologically Based Pharmacokinetic (PBPK) Toolkit for Environmental Pollutants

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    Physiologically Based Pharmacokinetic (PBPK) models can be used to determine the internal dose and strengthen exposure assessment. Many PBPK models are available, but they are not easily accessible for field use. The Agency for Toxic Substances and Disease Registry (ATSDR) has conducted translational research to develop a human PBPK model toolkit by recoding published PBPK models. This toolkit, when fully developed, will provide a platform that consists of a series of priority PBPK models of environmental pollutants. Presented here is work on recoded PBPK models for volatile organic compounds (VOCs) and metals. Good agreement was generally obtained between the original and the recoded models. This toolkit will be available for ATSDR scientists and public health assessors to perform simulations of exposures from contaminated environmental media at sites of concern and to help interpret biomonitoring data. It can be used as screening tools that can provide useful information for the protection of the public

    Development of Screening Tools for the Interpretation of Chemical Biomonitoring Data

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    Evaluation of a larger number of chemicals in commerce from the perspective of potential human health risk has become a focus of attention in North America and Europe. Screening-level chemical risk assessment evaluations consider both exposure and hazard. Exposures are increasingly being evaluated through biomonitoring studies in humans. Interpreting human biomonitoring results requires comparison to toxicity guidance values. However, conventional chemical-specific risk assessments result in identification of toxicity-based exposure guidance values such as tolerable daily intakes (TDIs) as applied doses that cannot directly be used to evaluate exposure information provided by biomonitoring data in a health risk context. This paper describes a variety of approaches for development of screening-level exposure guidance values with translation from an external dose to a biomarker concentration framework for interpreting biomonitoring data in a risk context. Applications of tools and concepts including biomonitoring equivalents (BEs), the threshold of toxicologic concern (TTC), and generic toxicokinetic and physiologically based toxicokinetic models are described. These approaches employ varying levels of existing chemical-specific data, chemical class-specific assessments, and generic modeling tools in response to varying levels of available data in order to allow assessment and prioritization of chemical exposures for refined assessment in a risk management context

    Int J Mol Sci

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    Physiologically Based Pharmacokinetic (PBPK) models can be used to determine the internal dose and strengthen exposure assessment. Many PBPK models are available, but they are not easily accessible for field use. The Agency for Toxic Substances and Disease Registry (ATSDR) has conducted translational research to develop a human PBPK model toolkit by recoding published PBPK models. This toolkit, when fully developed, will provide a platform that consists of a series of priority PBPK models of environmental pollutants. Presented here is work on recoded PBPK models for volatile organic compounds (VOCs) and metals. Good agreement was generally obtained between the original and the recoded models. This toolkit will be available for ATSDR scientists and public health assessors to perform simulations of exposures from contaminated environmental media at sites of concern and to help interpret biomonitoring data. It can be used as screening tools that can provide useful information for the protection of the public

    Computational modeling of the pharmacokinetics and pharmacodynamics of selected xenobiotics

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    2016 Fall.Includes bibliographical references.The determination of important endpoints in toxicology and pharmacology continues to involve the acquisition of large amounts of data through resource-intensive experimental studies involving a large number of resources. Because of this, only a small fraction of chemicals in the environment and marketplace can reasonably be evaluated for safety, and many promising drug candidates must be eliminated from consideration based on inadequate evaluation. Promisingly, advances in biologically-based computational models are beginning to allow researchers to estimate these endpoints and make useful extrapolations using a limited set of experimental data. The work described in this dissertation examined how computational models can provide meaningful insight and quantitation of important pharmacological and toxicological endpoints related to toxicity and pharmacological efficacy. To this end, physiologically-based pharmacokinetic and pharmacodynamic models were developed and applied for several pharmaceutical agents and environmental toxicants to predict significant, and diverse, biological endpoints. First, physiologically-based modeling allowed for the evaluation of various dosing regimens of rifapentine, a drug that is showing great promise for the treatment of tuberculosis, by comparing lung-specific concentration predictions to experimentally-derived thresholds for antibacterial activity. Second, physiologically-based pharmacokinetic modeling, coupled with Bayesian inference, was used as part of a methodology to characterize genetic differences in acetaminophen pharmacokinetics and also to help clinicians predict an ingested dose of this drug under overdose conditions. Third, a methodology for using physiologically-based pharmacokinetic modeling to predict health-based cognitive endpoints was demonstrated for chronic exposure to chlorpyrifos, an organophosphorus insecticide. The environmental public health indicators derived from this work allowed for biomarkers of exposure to be used to predict neurobehavioral changes following long-term exposure to this chemical. Finally, computational modeling was used to develop a mechanistically-plausible pharmacodynamic model for hepatoprotective and pro-inflammatory events to relate trichloroethylene dosing conditions to observed pathologies associated with auto-immune hepatitis

    International Frameworks Dealing with Human Risk Assessment of Combined Exposure to Multiple Chemicals

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    The development of harmonised terminology and frameworks for the human risk assessment of combined exposure to multiple chemicals (“chemical mixtures”) is an important area for EFSA and a number of activities have already been undertaken, i.e. in the fields of pesticides and contaminants. The first step prior to a risk assessment of combined exposure to multiple chemicals is problem formulation defining the relevant exposure, hazard and population to be considered. In practice, risk assessment of multiple chemicals is conducted using a tiered approach for exposure assessment, hazard assessment and risk characterisation. Higher tiers require increasing knowledge about the group of chemicals under assessment and the tiers can range from tier 0 (default values, data poor situation) to tier 3 (full probabilistic models). This scientific report reviews the terminology, methodologies and frameworks developed by national and international agencies for the human risk assessment of combined exposure to multiple chemicals and provides recommendations for future activities at EFSA in this area

    EURL ECVAM Workshop on New Generation of Physiologically-Based Kinetic Models in Risk Assessment

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    The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) Strategy Document on Toxicokinetics (TK) outlines strategies to enable prediction of systemic toxicity by applying new approach methodologies (NAM). The central feature of the strategy focuses on using physiologically-based kinetic (PBK) modelling to integrate data generated by in vitro and in silico methods for absorption, distribution, metabolism, and excretion (ADME) in humans for predicting whole-body TK behaviour, for environmental chemicals, drugs, nano-materials, and mixtures. In order to facilitate acceptance and use of this new generation of PBK models, which do not rely on animal/human in vivo data in the regulatory domain, experts were invited by EURL ECVAM to (i) identify current challenges in the application of PBK modelling to support regulatory decision making; (ii) discuss challenges in constructing models with no in vivo kinetic data and opportunities for estimating parameter values using in vitro and in silico methods; (iii) present the challenges in assessing model credibility relying on non-animal data and address strengths, uncertainties and limitations in such an approach; (iv) establish a good kinetic modelling practice workflow to serve as the foundation for guidance on the generation and use of in vitro and in silico data to construct PBK models designed to support regulatory decision making. To gauge the current state of PBK applications, experts were asked upfront of the workshop to fill a short survey. In the workshop, using presentations and discussions, the experts elaborated on the importance of being transparent about the model construct, assumptions, and applications to support assessment of model credibility. The experts offered several recommendations to address commonly perceived limitations of parameterization and evaluation of PBK models developed using non-animal data and its use in risk assessment, these include: (i) develop a decision tree for model construction; (ii) set up a task force for independent model peer review; (iii) establish a scoring system for model evaluation; (iv) attract additional funding to develop accessible modelling software.; (v) improve and facilitate communication between scientists (model developers, data provider) and risk assessors/regulators; and (vi) organise specific training for end users. The experts also acknowledged the critical need for developing a guidance document on building, characterising, reporting and documenting PBK models using non-animal data. This document would also need to include guidance on interpreting the model analysis for various risk assessment purposes, such as incorporating PBK models in integrated strategy approaches and integrating them with in vitro toxicity testing and adverse outcome pathways. This proposed guidance document will promote the development of PBK models using in vitro and silico data and facilitate the regulatory acceptance of PBK models for assessing safety of chemicals

    Advancing human health risk assessment

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    Acknowledgements: The European Food Safety Authority (EFSA) and authors wish to thank the participants of the break‐out session ‘Advancing risk assessment science – Human health’ at EFSA's third Scientific Conference ‘Science, Food and Society’ (Parma, Italy, 18–21 September 2018) for their active and valuable contributions to the discussion. We also thank Hans Verhagen for carefully proofreading it.Peer reviewedPublisher PD

    Physiologically-Based Kinetics and Mechanistic Models to Assess Exposure to Chemicals

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    In our modern society we are exposed to a myriad of chemical substances. Before these substances can be brought onto the market for use and consumption, their safety – when used as intended – needs to be confirmed in a risk assessment. Typically, a risk assessment comprises a toxicological hazard assessment, the quantification of a dose-response relationship, an exposure assessment and a risk characterisation under the assessed conditions. Traditionally, a toxicological hazard assessment is performed in vivo in laboratory animals, and more recently, in targeted in vitro testing. However, due to calls for replacement, reduction and refinement of animal testing alternative methods such as in silico models are increasingly being used. Also, increasing emphasis is being placed on understanding mechanisms and pathways of toxicity as well as quantifying exposure which leads to an adverse effect in individuals. Physiologically-based kinetic and mechanistic models allow for a mathematical description of causal relationships between an exposure scenario and a toxicological outcome in a biological system. While much research has been focussed on investigating mechanisms of hepatotoxicity, little is known about adverse effects induced in the kidney and only limited computational models exist to investigate nephrotoxicity. However, the kidney is a major target for toxicity by pharmaceuticals and environmental pollutants. Accumulation is known to play an important role in certain nephrotoxicity pathways. Therefore, physiologically-based kinetic and mechanistic models are considered to offer valuable insights into mechanisms of nephrotoxicity. This thesis addresses the growing attention given to exposure-based and toxicokinetics-driven toxicity which has resulted in increasing recent application of PBK modelling. The overall aim of this thesis was to propose novel ways to use publicly available data for the quantitative assessment of adverse effects induced in the kidney following chemical exposure. The first part of this thesis examines the suitability of publicly available PBK models for the prediction of urine-level concentrations in the general population following oral doses of various chemicals. Human biomonitoring (HBM) data were used for validation of simulation results and a mixture risk assessment to illustrate how predictions may be used in a risk assessment context. The second part of this thesis shows the development of a mechanistic kidney model embedded in a full-body PBK model parameterised for aspirin (ASA) and salicylic acid (SA). The research presented herein demonstrates the generation of a novel kidney model which is set up for a young and healthy individual; this was amended to simulate kinetics of elderly individuals and tested for three exposure scenarios. Key challenges in this endeavour revolve around limited data available in the public literature and uncertainties related to scaling in vitro data to an in vivo setting
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