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Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation

In vitro methods offer opportunities to provide mechanistic insight into bioactivity as well as human-relevant toxicological assessments compared to animal testing. One of the challenges for this task is putting in vitro bioactivity data in an in vivo exposure context, for which in vitro to in vivo...

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Autores principales: Zhang, Jingjie, Chang, Xiaoqing, Holland, Tessa L., Hines, David E., Karmaus, Agnes L., Bell, Shannon, Lee, K. Monica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915826/
https://www.ncbi.nlm.nih.gov/pubmed/35295123
http://dx.doi.org/10.3389/ftox.2021.787756
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author Zhang, Jingjie
Chang, Xiaoqing
Holland, Tessa L.
Hines, David E.
Karmaus, Agnes L.
Bell, Shannon
Lee, K. Monica
author_facet Zhang, Jingjie
Chang, Xiaoqing
Holland, Tessa L.
Hines, David E.
Karmaus, Agnes L.
Bell, Shannon
Lee, K. Monica
author_sort Zhang, Jingjie
collection PubMed
description In vitro methods offer opportunities to provide mechanistic insight into bioactivity as well as human-relevant toxicological assessments compared to animal testing. One of the challenges for this task is putting in vitro bioactivity data in an in vivo exposure context, for which in vitro to in vivo extrapolation (IVIVE) translates in vitro bioactivity to clinically relevant exposure metrics using reverse dosimetry. This study applies an IVIVE approach to the toxicity assessment of ingredients and their mixtures in e-cigarette (EC) aerosols as a case study. Reported in vitro cytotoxicity data of EC aerosols, as well as in vitro high-throughput screening (HTS) data for individual ingredients in EC liquids (e-liquids) are used. Open-source physiologically based pharmacokinetic (PBPK) models are used to calculate the plasma concentrations of individual ingredients, followed by reverse dosimetry to estimate the human equivalent administered doses (EADs) needed to obtain these plasma concentrations for the total e-liquids. Three approaches (single actor approach, additive effect approach, and outcome-oriented ingredient integration approach) are used to predict EADs of e-liquids considering differential contributions to the bioactivity from the ingredients (humectant carriers [propylene glycol and glycerol], flavors, benzoic acid, and nicotine). The results identified critical factors for the EAD estimation, including the ingredients of the mixture considered to be bioactive, in vitro assay selection, and the data integration approach for mixtures. Further, we introduced the outcome-oriented ingredient integration approach to consider e-liquid ingredients that may lead to a common toxicity outcome (e.g., cytotoxicity), facilitating a quantitative evaluation of in vitro toxicity data in support of human risk assessment.
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spelling pubmed-89158262022-03-15 Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation Zhang, Jingjie Chang, Xiaoqing Holland, Tessa L. Hines, David E. Karmaus, Agnes L. Bell, Shannon Lee, K. Monica Front Toxicol Toxicology In vitro methods offer opportunities to provide mechanistic insight into bioactivity as well as human-relevant toxicological assessments compared to animal testing. One of the challenges for this task is putting in vitro bioactivity data in an in vivo exposure context, for which in vitro to in vivo extrapolation (IVIVE) translates in vitro bioactivity to clinically relevant exposure metrics using reverse dosimetry. This study applies an IVIVE approach to the toxicity assessment of ingredients and their mixtures in e-cigarette (EC) aerosols as a case study. Reported in vitro cytotoxicity data of EC aerosols, as well as in vitro high-throughput screening (HTS) data for individual ingredients in EC liquids (e-liquids) are used. Open-source physiologically based pharmacokinetic (PBPK) models are used to calculate the plasma concentrations of individual ingredients, followed by reverse dosimetry to estimate the human equivalent administered doses (EADs) needed to obtain these plasma concentrations for the total e-liquids. Three approaches (single actor approach, additive effect approach, and outcome-oriented ingredient integration approach) are used to predict EADs of e-liquids considering differential contributions to the bioactivity from the ingredients (humectant carriers [propylene glycol and glycerol], flavors, benzoic acid, and nicotine). The results identified critical factors for the EAD estimation, including the ingredients of the mixture considered to be bioactive, in vitro assay selection, and the data integration approach for mixtures. Further, we introduced the outcome-oriented ingredient integration approach to consider e-liquid ingredients that may lead to a common toxicity outcome (e.g., cytotoxicity), facilitating a quantitative evaluation of in vitro toxicity data in support of human risk assessment. Frontiers Media S.A. 2022-02-02 /pmc/articles/PMC8915826/ /pubmed/35295123 http://dx.doi.org/10.3389/ftox.2021.787756 Text en Copyright © 2022 Zhang, Chang, Holland, Hines, Karmaus, Bell and Lee. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Toxicology
Zhang, Jingjie
Chang, Xiaoqing
Holland, Tessa L.
Hines, David E.
Karmaus, Agnes L.
Bell, Shannon
Lee, K. Monica
Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation
title Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation
title_full Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation
title_fullStr Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation
title_full_unstemmed Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation
title_short Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation
title_sort evaluation of inhalation exposures and potential health impacts of ingredient mixtures using in vitro to in vivo extrapolation
topic Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915826/
https://www.ncbi.nlm.nih.gov/pubmed/35295123
http://dx.doi.org/10.3389/ftox.2021.787756
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