U.S. EPA to eliminate all mammal testing by 2035

Grimm, David

doi:10.1126/science.aaz4593

Cited by 62 publications

(34 citation statements)

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“…Consequently, a validated physiological PBTK model can be re-used for any compound with relatively limited efforts and without testing in living animals and as such is in full accordance with the 3R principles (Russell and Burch 1959 ). PBTK models are therefore a very promising tool to help achieving the goal of U.S. EPA to eliminate all mammalian testing by 2035 (Grimm 2019 ).…”

Section: Introductionmentioning

confidence: 99%

A workflow to build PBTK models for novel species

et al. 2020

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Physiology-based pharmacokinetic and toxicokinetic (PBPK/TK) models allow us to simulate the concentration of xenobiotica in the plasma and different tissues of an organism. PBPK/TK models are therefore routinely used in many fields of life sciences to simulate the physiological concentration of exogenous compounds in plasma and tissues. The application of PBTK models in ecotoxicology, however, is currently hampered by the limited availability of models for focal species. Here, we present a best practice workflow that describes how to build PBTK models for novel species. To this end, we extrapolated eight previously established rabbit models for several drugs to six additional mammalian species (human, beagle, rat, monkey, mouse, and minipig). We used established PBTK models for these species to account for the species-specific physiology. The parameter sensitivity in the resulting 56 PBTK models was systematically assessed to rank the relevance of the parameters on overall model performance. Interestingly, more than 80% of the 609 considered model parameters showed a negligible sensitivity throughout all models. Only approximately 5% of all parameters had a high sensitivity in at least one of the PBTK models. This approach allowed us to rank the relevance of the various parameters on overall model performance. We used this information to formulate a best practice guideline for the efficient development of PBTK models for novel animal species. We believe that the workflow proposed in this study will significantly support the development of PBTK models for new animal species in the future.

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Section: Introductionmentioning

confidence: 99%

A workflow to build PBTK models for novel species

et al. 2020

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“…The considerations provided above are focused on the optimisation and improvement of in vivo fish behavioural testing to enhance its scientific and regulatory value. However, such an in vivo testing strategy would rapidly become incompatible with the recently announced ambition of the US Environmental Protection Agency and European Commission to phase out vertebrate in vivo testing in the next decade or so (i.e., by 2035 in the US) [ 62 ]. This political consideration highlights the urgency of supporting research initiatives aimed at understanding the mechanistic basis of chemical-induced behavioural perturbation in fish (and any other relevant vertebrate species).…”

Section: Discussionmentioning

confidence: 99%

Environmental Occurrence and Predicted Pharmacological Risk to Freshwater Fish of over 200 Neuroactive Pharmaceuticals in Widespread Use

Sumpter

Margiotta-Casaluci

2022

Toxics

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There is a growing concern that neuroactive chemicals released into the environment can perturb wildlife behaviour. Among these chemicals, pharmaceuticals such as antidepressants and anxiolytics have been receiving increasing attention, as they are specifically prescribed to modify behavioural responses. Many laboratory studies have demonstrated that some of these compounds can affect various aspects of the behaviour of a range of aquatic organisms; however, these investigations are focused on a very small set of neuroactive pharmaceuticals, and they often consider one compound at a time. In this study, to better understand the environmental and toxicological dimension of the problem, we considered all pharmaceuticals explicitly intended to modulate the central nervous system (CNS), and we hypothesised that these compounds have higher probability of perturbing animal behaviour. Based on this hypothesis, we used the classification of pharmaceuticals provided by the British National Formulary (based on their clinical applications) and identified 210 different CNS-acting pharmaceuticals prescribed in the UK to treat a variety of CNS-related conditions, including mental health and sleep disorders, dementia, epilepsy, nausea, and pain. The analysis of existing databases revealed that 84 of these compounds were already detected in surface waters worldwide. Using a biological read-across approach based on the extrapolation of clinical data, we predicted that the concentration of 32 of these neuroactive pharmaceuticals in surface waters in England may be high enough to elicit pharmacological effects in wild fish. The ecotoxicological effects of the vast majority of these compounds are currently uncharacterised. Overall, these results highlight the importance of addressing this environmental challenge from a mixture toxicology and systems perspective. The knowledge platform developed in the present study can guide future region-specific prioritisation efforts, inform the design of mixture studies, and foster interdisciplinary efforts aimed at identifying novel approaches to predict and interpret the ecological implications of chemical-induced behaviour disruption.

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“…This study provides an example of applying an in vitro metabolism method to a qHTS format, and it may be of use in exploring other newly developed in vitro metabolism methods to a qHTS format. Ultimately, these efforts may provide more robust in vitro testing options to help meet the stated goal of the U.S. EPA to eliminate all animal testing by the year 2035 (Grimm 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation

et al. 2022

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Currently, approximately 80,000 chemicals are used in commerce. Most have little-to-no toxicity information. The U.S. Toxicology in the 21st Century (Tox21) program has conducted a battery of in vitro assays using a quantitative high-throughput screening (qHTS) platform to gain toxicity information on environmental chemicals. Due to technical challenges, standard methods for providing xenobiotic metabolism could not be applied to qHTS assays. To address this limitation, we screened the Tox21 10,000-compound (10K) library, with concentrations ranging from 2.8 nM to 92 µM, using a p53 beta-lactamase reporter gene assay (p53-bla) alone or with rat liver microsomes (RLM) or human liver microsomes (HLM) supplemented with NADPH, to identify compounds that induce p53 signaling after biotransformation. Two hundred and seventy-eight compounds were identified as active under any of these three conditions. Of these 278 compounds, 73 gave more potent responses in the p53-bla assay with RLM, and 2 were more potent in the p53-bla assay with HLM compared with the responses they generated in the p53-bla assay without microsomes. To confirm the role of metabolism in the differential responses, we re-tested these 75 compounds in the absence of NADPH or with heat-attenuated microsomes. Forty-four compounds treated with RLM, but none with HLM, became less potent under these conditions, confirming the role of RLM in metabolic activation. Further evidence of biotransformation was obtained by measuring the half-life of the parent compounds in the presence of microsomes. Together, the data support the use of RLM in qHTS for identifying chemicals requiring biotransformation to induce biological responses.

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U.S. EPA to eliminate all mammal testing by 2035

Cited by 62 publications

References 0 publications

A workflow to build PBTK models for novel species

A workflow to build PBTK models for novel species

Environmental Occurrence and Predicted Pharmacological Risk to Freshwater Fish of over 200 Neuroactive Pharmaceuticals in Widespread Use

Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation

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