Cross-Species Extrapolation of Biological Data to Guide the Environmental Safety Assessment of Pharmaceuticals—The State of the Art and Future Priorities

Luigi Margiotta-Casaluci; Stewart F. Owen; Matthew J. Winter

doi:10.1002/etc.5634

Cross-Species Extrapolation of Biological Data to Guide the Environmental Safety Assessment of Pharmaceuticals—The State of the Art and Future Priorities

Luigi Margiotta-Casaluci^*, Stewart F. Owen, Matthew J. Winter

^*Corresponding author for this work

Analytical, Environmental & Forensic Sciences

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

The extrapolation of biological data across species is a key aspect of biomedical research and drug development. In this context, comparative biology considerations are applied with the goal of understanding human disease and guiding the development of effective and safe medicines. However, the widespread occurrence of pharmaceuticals in the environment and the need to assess the risk posed to wildlife have prompted a renewed interest in the extrapolation of pharmacological and toxicological data across the entire tree of life. To address this challenge, a biological “read-across” approach, based on the use of mammalian data to inform toxicity predictions in wildlife species, has been proposed as an effective way to streamline the environmental safety assessment of pharmaceuticals. Yet, how effective has this approach been, and are we any closer to being able to accurately predict environmental risk based on known human risk? We discuss the main theoretical and experimental advancements achieved in the last 10 years of research in this field. We propose that a better understanding of the functional conservation of drug targets across species and of the quantitative relationship between target modulation and adverse effects should be considered as future research priorities. This pharmacodynamic focus should be complemented with the application of higher-throughput experimental and computational approaches to accelerate the prediction of internal exposure dynamics. The translation of comparative (eco)toxicology research into real-world applications, however, relies on the (limited) availability of experts with the skill set needed to navigate the complexity of the problem; hence, we also call for synergistic multistakeholder efforts to support and strengthen comparative toxicology research and education at a global level. Environ Toxicol Chem 2023;00:1–13.

Original language	English
Journal	ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY
DOIs	https://doi.org/10.1002/etc.5634
Publication status	Accepted/In press - 2023

Keywords

Computational toxicology
Pharmaceuticals
Species extrapolation
Toxicodynamics
Toxicokinetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/etc.5634

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@article{f76b952966384bb6991d8106e24fac6e,

title = "Cross-Species Extrapolation of Biological Data to Guide the Environmental Safety Assessment of Pharmaceuticals—The State of the Art and Future Priorities",

abstract = "The extrapolation of biological data across species is a key aspect of biomedical research and drug development. In this context, comparative biology considerations are applied with the goal of understanding human disease and guiding the development of effective and safe medicines. However, the widespread occurrence of pharmaceuticals in the environment and the need to assess the risk posed to wildlife have prompted a renewed interest in the extrapolation of pharmacological and toxicological data across the entire tree of life. To address this challenge, a biological “read-across” approach, based on the use of mammalian data to inform toxicity predictions in wildlife species, has been proposed as an effective way to streamline the environmental safety assessment of pharmaceuticals. Yet, how effective has this approach been, and are we any closer to being able to accurately predict environmental risk based on known human risk? We discuss the main theoretical and experimental advancements achieved in the last 10 years of research in this field. We propose that a better understanding of the functional conservation of drug targets across species and of the quantitative relationship between target modulation and adverse effects should be considered as future research priorities. This pharmacodynamic focus should be complemented with the application of higher-throughput experimental and computational approaches to accelerate the prediction of internal exposure dynamics. The translation of comparative (eco)toxicology research into real-world applications, however, relies on the (limited) availability of experts with the skill set needed to navigate the complexity of the problem; hence, we also call for synergistic multistakeholder efforts to support and strengthen comparative toxicology research and education at a global level. Environ Toxicol Chem 2023;00:1–13.",

keywords = "Computational toxicology, Pharmaceuticals, Species extrapolation, Toxicodynamics, Toxicokinetics",

author = "Luigi Margiotta-Casaluci and Owen, {Stewart F.} and Winter, {Matthew J.}",

note = "Funding Information: The present study was supported by a CRACK IT Phase 1 grant (NC/C021102/1) awarded by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) to Luigi Margiotta‐Casaluci. Additional support to Luigi Margiotta‐Casaluci is provided by King's College London, School of Cancer and Pharmaceutical Science. Matthew J. Winter is supported by funding from The Royal Society, the NC3Rs, the Biotechnology and Biological Sciences Research Council, AstraZeneca and the University of Exeter, Faculty of Health and Life Sciences. Funding Information: One of the most important observations that can be made concerning the last 10 years of research in the cross‐species extrapolation field—applied to the ecotoxicology of pharmaceuticals—is that the tremendous advancements achieved to date have emerged thanks to the synergistic partnership between industry, government agencies, and academia. We propose that this synergy should be expanded further if we want to achieve our ambitious global protection goals for all species and not just a few. In line with our position, LaLone et al. ( 2021 ) have called for the formation of a global cross‐sector collaborative consortium aimed to advance the development and implementation of cross‐species extrapolation methods in regulatory toxicology. The authors have led the formation and launch of a new International Consortium to Advance Cross‐Species Extrapolation in Regulation (ICACSER; https://www.setac.org/page/scixspecies ). We welcome and support this initiative, and we encourage any interested reader to join the ICACSER consortium. Cross‐species extrapolation is also at the heart of a new large research project, funded by the European Commission, called . This project, started in 2021, will explore the concept of “phylotoxicology,” which aims at replacing traditional animal testing with an “evolutionarily diverse model suite of organisms from multiple branches of the tree of life” (Colbourne et al., 2022 ). Although many research questions remain open, the progress obtained in the last 10 or so years and the rejuvenated global interest and initiatives in comparative toxicology suggest that cross‐species extrapolation research will remain at the center of future ecotoxicological research. Implementing this vision in regulatory toxicology would enable us to achieve the true global protection of human and environmental health. Precision Toxicology Publisher Copyright: {\textcopyright} 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.",

year = "2023",

doi = "10.1002/etc.5634",

language = "English",

journal = "ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY",

issn = "0730-7268",

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T1 - Cross-Species Extrapolation of Biological Data to Guide the Environmental Safety Assessment of Pharmaceuticals—The State of the Art and Future Priorities

AU - Margiotta-Casaluci, Luigi

AU - Owen, Stewart F.

AU - Winter, Matthew J.

N1 - Funding Information: The present study was supported by a CRACK IT Phase 1 grant (NC/C021102/1) awarded by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) to Luigi Margiotta‐Casaluci. Additional support to Luigi Margiotta‐Casaluci is provided by King's College London, School of Cancer and Pharmaceutical Science. Matthew J. Winter is supported by funding from The Royal Society, the NC3Rs, the Biotechnology and Biological Sciences Research Council, AstraZeneca and the University of Exeter, Faculty of Health and Life Sciences. Funding Information: One of the most important observations that can be made concerning the last 10 years of research in the cross‐species extrapolation field—applied to the ecotoxicology of pharmaceuticals—is that the tremendous advancements achieved to date have emerged thanks to the synergistic partnership between industry, government agencies, and academia. We propose that this synergy should be expanded further if we want to achieve our ambitious global protection goals for all species and not just a few. In line with our position, LaLone et al. ( 2021 ) have called for the formation of a global cross‐sector collaborative consortium aimed to advance the development and implementation of cross‐species extrapolation methods in regulatory toxicology. The authors have led the formation and launch of a new International Consortium to Advance Cross‐Species Extrapolation in Regulation (ICACSER; https://www.setac.org/page/scixspecies ). We welcome and support this initiative, and we encourage any interested reader to join the ICACSER consortium. Cross‐species extrapolation is also at the heart of a new large research project, funded by the European Commission, called . This project, started in 2021, will explore the concept of “phylotoxicology,” which aims at replacing traditional animal testing with an “evolutionarily diverse model suite of organisms from multiple branches of the tree of life” (Colbourne et al., 2022 ). Although many research questions remain open, the progress obtained in the last 10 or so years and the rejuvenated global interest and initiatives in comparative toxicology suggest that cross‐species extrapolation research will remain at the center of future ecotoxicological research. Implementing this vision in regulatory toxicology would enable us to achieve the true global protection of human and environmental health. Precision Toxicology Publisher Copyright: © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

PY - 2023

Y1 - 2023

N2 - The extrapolation of biological data across species is a key aspect of biomedical research and drug development. In this context, comparative biology considerations are applied with the goal of understanding human disease and guiding the development of effective and safe medicines. However, the widespread occurrence of pharmaceuticals in the environment and the need to assess the risk posed to wildlife have prompted a renewed interest in the extrapolation of pharmacological and toxicological data across the entire tree of life. To address this challenge, a biological “read-across” approach, based on the use of mammalian data to inform toxicity predictions in wildlife species, has been proposed as an effective way to streamline the environmental safety assessment of pharmaceuticals. Yet, how effective has this approach been, and are we any closer to being able to accurately predict environmental risk based on known human risk? We discuss the main theoretical and experimental advancements achieved in the last 10 years of research in this field. We propose that a better understanding of the functional conservation of drug targets across species and of the quantitative relationship between target modulation and adverse effects should be considered as future research priorities. This pharmacodynamic focus should be complemented with the application of higher-throughput experimental and computational approaches to accelerate the prediction of internal exposure dynamics. The translation of comparative (eco)toxicology research into real-world applications, however, relies on the (limited) availability of experts with the skill set needed to navigate the complexity of the problem; hence, we also call for synergistic multistakeholder efforts to support and strengthen comparative toxicology research and education at a global level. Environ Toxicol Chem 2023;00:1–13.

AB - The extrapolation of biological data across species is a key aspect of biomedical research and drug development. In this context, comparative biology considerations are applied with the goal of understanding human disease and guiding the development of effective and safe medicines. However, the widespread occurrence of pharmaceuticals in the environment and the need to assess the risk posed to wildlife have prompted a renewed interest in the extrapolation of pharmacological and toxicological data across the entire tree of life. To address this challenge, a biological “read-across” approach, based on the use of mammalian data to inform toxicity predictions in wildlife species, has been proposed as an effective way to streamline the environmental safety assessment of pharmaceuticals. Yet, how effective has this approach been, and are we any closer to being able to accurately predict environmental risk based on known human risk? We discuss the main theoretical and experimental advancements achieved in the last 10 years of research in this field. We propose that a better understanding of the functional conservation of drug targets across species and of the quantitative relationship between target modulation and adverse effects should be considered as future research priorities. This pharmacodynamic focus should be complemented with the application of higher-throughput experimental and computational approaches to accelerate the prediction of internal exposure dynamics. The translation of comparative (eco)toxicology research into real-world applications, however, relies on the (limited) availability of experts with the skill set needed to navigate the complexity of the problem; hence, we also call for synergistic multistakeholder efforts to support and strengthen comparative toxicology research and education at a global level. Environ Toxicol Chem 2023;00:1–13.

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KW - Pharmaceuticals

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ER -

Cross-Species Extrapolation of Biological Data to Guide the Environmental Safety Assessment of Pharmaceuticals—The State of the Art and Future Priorities

Abstract

Keywords

UN SDGs

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