Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment

Pletz, Julia; Blakeman, Samantha; Paini, Alicia; Parissis, Nikolaos; Worth, Andrew; Andersson, Anna‐Maria; Frederiksen, Hanne; Sakhi, Amrit Kaur; Thomsen, Cathrine; Bopp, Stephanie K.

doi:10.1016/j.envint.2020.105978

Cited by 29 publications

(26 citation statements)

References 73 publications

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“…These two issues present differently in the context of environmental toxicology for two reasons. First, the mixture approach is not necessarily a limit with regard to environmental exposure to a mixture of contaminants, now the subject of recent methodological developments (Pletz et al 2020). Indeed, our eight hazardous substances assessed simultaneously in rabbits were selected because they represent major classes of compounds ubiquitous in the environment and human samples.…”

Section: Discussionmentioning

confidence: 99%

Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data

Gayrard

Moreau

Picard‐Hagen

et al. 2021

Environ Health Perspect

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Section: Discussionmentioning

confidence: 99%

Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data

Gayrard

Moreau

Picard‐Hagen

et al. 2021

Environ Health Perspect

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“…• The exposure estimation to pyrethroid pesticides during nervous system development in HOS should be improved by using reliable methods (i.e. measuring the active substance or its specific metabolite/s in blood or biomarkers in urine at several times of development during pre and postnatal periods, and application of PBPK models to biomonitoring data (Pletz et al, 2020)) to decrease the uncertainty on the current exposure levels and on the causal association with the DNT outcomes.…”

Section: Recommendationsmentioning

confidence: 99%

“…In doing this, the PPR Panel recommends that the uncertainties identified in the postulated AOP network should be further explored and possibly resolved by including additional KEs based on biological knowledge of the pathway. A transparent approach should be applied in developing IATA using an evidence‐based approach and a quantitative estimation of the WoE through a probabilistic expression of the uncertainties. The exposure estimation to pyrethroid pesticides during nervous system development in HOS should be improved by using reliable methods (i.e. measuring the active substance or its specific metabolite/s in blood or biomarkers in urine at several times of development during pre and postnatal periods, and application of PBPK models to biomonitoring data (Pletz et al., 2020)) to decrease the uncertainty on the current exposure levels and on the causal association with the DNT outcomes. The AOP‐informed IATA was considered a valuable approach for the DNT hazard characterisation. Paucity of available AOPs is a limitation and development of DNT‐related AOPs is recommended.…”

Section: Recommendationsmentioning

confidence: 99%

Development of Integrated Approaches to Testing and Assessment (IATA) case studies on developmental neurotoxicity (DNT) risk assessment

Hernandez-Jerez¹,

Adriaanse²,

Aldrich³

et al. 2021

EFS2

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The EFSA Panel on Plant Protection Products and their Residues (PPR) has developed, as a self-task mandate (EFSA-Q-2019-00100), two adverse outcome pathway (AOP)-informed integrated approach to testing and assessment (IATA) case studies to answer a developmental neurotoxicity (DNT) hazard identification and characterisation problem formulation that could support the regulatory decisions for the pesticide active substances deltamethrin and flufenacet. The IATA were developed to assess the applicability of the DNT in vitro testing battery (IVB), designed to explore fundamental neurodevelopmental processes, in the regulatory risk assessment of pesticides. For this purpose, an evidence-based-approach methodology was applied: 1) systematic literature review and critical appraisal of all the evidence i.e. human observational studies, in vivo data from rodent models and new approach methodologies (NAMs, i.e. in vitro studies including high-throughput testing from IVB and zebrafish studies from the literature) for both case studies; 2) a quantitative uncertainty analysis of all the evidence using expert knowledge elicitation (EKE) and a probabilistic approach; 3) integration of all the evidence using the AOP conceptual framework. This stepwise approach resulted in the postulation of an evidencebased AOP network for one of the case studies. A probabilistic quantification of the weight of evidence (WoE) using Bayesian network analysis allowed the assessment and the quantification of the uncertainty in the postulated AOP. The approach taken allowed conclusions to be drawn with an acceptable level of certainty in DNT hazard identification and characterisation of deltamethrin and that flufenacet is not a developmental neurotoxicant, supporting the relevance of the mechanistic understanding. The case studies show the applicability of the DNT-IVB for hazard identification and characterisation and illustrate the usefulness of an AOP-informed IATA for regulatory decision making. The overall activity led to improved interpretation of human data by providing a plausible mechanistic link to adverse outcomes, which would support their contextualisation in the risk assessment process. This Scientific Opinion allows the PPR Panel to draft several recommendations for the implementation of the AOP-informed IATA methodology and of the DNT-IVB in the regulatory risk assessment of pesticides.

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“…In vitro toxicity data improve the relevance of testing for predicting human responses and provide information for evaluating toxicity pathway perturbations [ 39 ]. The physiologically based toxicokinetic (PBTK) model is an essential tool for the IVIVE process, describing the human body as a group of connected compartments [ 40 , 43 , 44 ]. It can combine an in vitro dose with an in vivo dose.…”

Section: Introductionmentioning

confidence: 99%

Liver-Based Probabilistic Risk Assessment of Exposure to Organophosphate Esters via Dust Ingestion Using a Physiologically Based Toxicokinetic (PBTK) Model

Ding

Liu

Zhang

et al. 2021

IJERPH

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Organophosphate esters (OPEs) are widely used and harmful to organisms and human health. Dust ingestion is an important exposure route for OPEs to humans. In this study, by integrating ToxCast high-throughput in vitro assays with in vitro to in vivo extrapolation (IVIVE) via physiologically based Toxicokinetic (PBTK) modeling, we assessed the hepatocyte-based health risk for humans around the world due to exposure to two typical OPEs (TPHP and TDCPP) through the dust ingestion exposure route. Results showed that the health guidance value of TPHP and TCDPP obtained in this study was lower than the value obtained through animal experiments. In addition, probabilistic risk assessment results indicate that populations worldwide are at low risk of exposure to TPHP and TDCPP through dust ingestion due to low estimated daily intakes (EDIs) which are much lower than the reference dose (RfDs) published by the US EPA, except in some regional cases. Most margin of exposure (MOE) ranges of TDCPP for children are less than 100, which indicates a moderately high risk. Researchers should be concerned about exposure to TDCPP in this area. The method proposed in this study is expected to be applied to the health risk assessment of other chemicals.

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Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment

Cited by 29 publications

References 73 publications

Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data

Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data

Development of Integrated Approaches to Testing and Assessment (IATA) case studies on developmental neurotoxicity (DNT) risk assessment

Liver-Based Probabilistic Risk Assessment of Exposure to Organophosphate Esters via Dust Ingestion Using a Physiologically Based Toxicokinetic (PBTK) Model

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