RESUMO
The growth in drug development over the past years reflects significant advancements in basic sciences and a greater understanding of molecular pathways of disease. Benchmarking industry practices has been important to enable a critical reflection on the path to evolve pharmaceutical testing, and the outcome of past industry surveys has had some impact on best practices in testing. A survey was provided to members of SPS, ACT, and STP. The survey consisted of 37 questions and was provided to 2550 participants with a response rate of 24%. Most respondents (â¼75%) came from the US and Europe. The survey encompassed multiple topics encountered in nonclinical testing of pharmaceuticals. The most frequent target indications were oncology (69%), inflammation (55%), neurology/psychiatry/pain (46%), cardiovascular (44%), and metabolic diseases (39%). The most frequent drug-induced toxicology issues confronted were hepatic, hematopoietic, and gastrointestinal. Toxicological effects that impacted the no observed adverse effect level (NOAEL) were most frequently based on histopathology findings. The survey comprised topics encountered in the use of biomarkers in nonclinical safety assessment, most commonly those used to assess inflammation, cardiac/vascular, renal, and hepatic toxicity as well as common practices related to the assessment of endocrine effects, carcinogenicity, genotoxicity, juvenile and male-mediated developmental and female reproductive toxicity. The survey explored the impact of regulatory meetings on program design, application of the 3 Rs, and reasons for program delays. Overall, the survey results provide a broad perspective of current practices based on the experience of the scientific community engaged in nonclinical safety assessment.
Assuntos
Avaliação Pré-Clínica de Medicamentos/normas , Indústria Farmacêutica/normas , Indústria Farmacêutica/tendências , Guias como Assunto , Preparações Farmacêuticas/normas , Testes de Toxicidade/normas , Testes de Toxicidade/tendências , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/métodos , Previsões , Humanos , Inquéritos e Questionários , Testes de Toxicidade/métodos , Estados UnidosRESUMO
The liver is among the most frequently targeted organs by noxious chemicals of diverse nature. Liver toxicity testing using laboratory animals not only raises serious ethical questions, but is also rather poorly predictive of human safety towards chemicals. Increasing attention is, therefore, being paid to the development of non-animal and human-based testing schemes, which rely to a great extent on in vitro methodology. The present paper proposes a rationalized tiered in vitro testing strategy to detect liver toxicity triggered by chemicals, in which the first tier is focused on assessing general cytotoxicity, while the second tier is aimed at identifying liver-specific toxicity as such. A state-of-the-art overview is provided of the most commonly used in vitro assays that can be used in both tiers. Advantages and disadvantages of each assay as well as overall practical considerations are discussed.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Técnicas In Vitro/tendências , Fígado/efeitos dos fármacos , Testes de Toxicidade/tendências , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Humanos , Modelos Animais , Medição de RiscoRESUMO
In 1997, the first in vivo bisphenol A (BPA) study by endocrinologists reported that feeding BPA to pregnant mice induced adverse reproductive effects in male offspring at the low dose of 2 µg/kg/day. Since then, thousands of studies have reported adverse effects in animals administered low doses of BPA. Despite more than 100 epidemiological studies suggesting associations between BPA and disease/dysfunction also reported in animal studies, regulatory agencies continue to assert that BPA exposures are safe. To address this disagreement, the CLARITY-BPA study was designed to evaluate traditional endpoints of toxicity and modern hypothesis-driven, disease-relevant outcomes in the same set of animals. A wide range of adverse effects was reported in both the toxicity and the mechanistic endpoints at the lowest dose tested (2.5 µg/kg/day), leading independent experts to call for the lowest observed adverse effect level (LOAEL) to be dropped 20 000-fold from the current outdated LOAEL of 50 000 µg/kg/day. Despite criticism by members of the Endocrine Society that the Food and Drug Administration (FDA)'s assumptions violate basic principles of endocrinology, the FDA rejected all low-dose data as not biologically plausible. Their decisions rely on 4 incorrect assumptions: dose responses must be monotonic, there exists a threshold below which there are no effects, both sexes must respond similarly, and only toxicological guideline studies are valid. This review details more than 20 years of BPA studies and addresses the divide that exists between regulatory approaches and endocrine science. Ultimately, CLARITY-BPA has shed light on why traditional methods of evaluating toxicity are insufficient to evaluate endocrine disrupting chemicals.
Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Testes de Toxicidade/métodos , Testes de Toxicidade/normas , Testes de Toxicidade/tendênciasRESUMO
The 90-day toxicity study is one of the studies used in the safety assessment of food ingredients, medicines or other chemical substances. This paper reviews the current role of the 90-day oral toxicity study in European regulatory dossiers of chemicals by reviewing EU legislation and EU and OECD guidance documents. Regulatory provisions with regard to necessity, objectives and design of such 90-day toxicity studies vary between the different sectors addressed in this review. Most often the 90-day study is expected to be part of the standard test battery used for chemical risk assessment, without necessarily being a legal requirement and its objectives may vary between regulatory domains. Exceptions, when a 90-day study is not required are spelled out in the chemicals legislation and for food contact materials. The sectorial study design requirements of the 90-day toxicity study are very often embedded in the OECD TG 408 protocol. Differences in study objectives are not necessarily reflected in specific study designs. Considering the call for the reduction of using experimental animals for scientific purposes and the fact that a 90-day study may serve different purposes, consistency between the necessity to conduct such a study, its objectives and the study design to achieve these objectives may improve judicious use of laboratory animals. Thus there may be an opportunity to reflect and further optimise the design of in vivo toxicology studies, such as the 90-day study. This should be based on a systematic analysis of past studies and risk assessments.
Assuntos
Alternativas aos Testes com Animais/legislação & jurisprudência , Alternativas aos Testes com Animais/normas , União Europeia , Organização para a Cooperação e Desenvolvimento Econômico/legislação & jurisprudência , Organização para a Cooperação e Desenvolvimento Econômico/normas , Testes de Toxicidade/normas , Administração Oral , Alternativas aos Testes com Animais/tendências , Animais , Humanos , Organização para a Cooperação e Desenvolvimento Econômico/tendências , Medição de Risco , Roedores , Fatores de Tempo , Testes de Toxicidade/tendênciasRESUMO
Although the need for non-animal alternatives has been well recognised for the human health hazard assessment of chemicals in general, it has become especially pressing for cosmetic ingredients due to the full implementation of testing and marketing bans on animal testing under the European Cosmetics Regulation. This means that for the safety assessment of cosmetics, the necessary safety data for both the ingredients and the finished product can be drawn from validated (or scientifically-valid), so-called "Replacement methods". In view of the challenges for safety assessment without recourse to animal test data, the Methodology Working Group of the Scientific Committee on Consumer Safety organised a workshop in February 2019 to discuss the key issues in regard to the use of animal-free alternative methods for the safety evaluation of cosmetic ingredients. This perspective article summarises the outcomes of this workshop and reflects on the state-of-the-art and possible way forward for the safety assessment of cosmetic ingredients for which no experimental animal data exist. The use and optimisation of "New Approach Methodology" that could be useful tools in the context of the "Next Generation Risk Assessment" and the strategic framework for safety assessment of cosmetics were discussed in depth.
Assuntos
Alternativas aos Testes com Animais/tendências , Cosméticos/efeitos adversos , Testes de Toxicidade/tendências , Animais , Simulação por Computador , Qualidade de Produtos para o Consumidor , Cosméticos/classificação , Cosméticos/farmacocinética , Difusão de Inovações , União Europeia , Previsões , Humanos , Modelos Biológicos , Medição de Risco , Relação Estrutura-AtividadeRESUMO
Advances in the biological sciences have led to an ongoing paradigm shift in toxicity testing based on expanded application of high-throughput in vitro screening and in silico methods to assess potential health risks of environmental agents. This review examines progress on the vision for toxicity testing elaborated by the US National Research Council (NRC) during the decade that has passed since the 2007 NRC report on Toxicity Testing in the 21st Century (TT21C). Concomitant advances in exposure assessment, including computational approaches and high-throughput exposomics, are also documented. A vision for the next generation of risk science, incorporating risk assessment methodologies suitable for the analysis of new toxicological and exposure data, resulting in human exposure guidelines is described. Case study prototypes indicating how these new approaches to toxicity testing, exposure measurement, and risk assessment are beginning to be applied in practice are presented. Overall, progress on the 20-year transition plan laid out by the US NRC in 2007 has been substantial. Importantly, government agencies within the United States and internationally are beginning to incorporate the new approach methodologies envisaged in the original TT21C vision into regulatory practice. Future perspectives on the continued evolution of toxicity testing to strengthen regulatory risk assessment are provided.
Assuntos
Rotas de Resultados Adversos , Medição de Risco/métodos , Testes de Toxicidade/métodos , Animais , Carcinógenos/química , Carcinógenos/toxicidade , Biologia Computacional/métodos , Mineração de Dados , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Ensaios de Triagem em Larga Escala , Humanos , National Academy of Sciences, U.S. , Relação Estrutura-Atividade , Testes de Toxicidade/tendências , Toxicogenética/métodos , Toxicologia/métodos , Estados UnidosRESUMO
Digoxin is a cardiac glycoside derived from the common foxglove digitalis purpurea and has been available for several centuries as a medicinal agent. Despite extensive patient experience over many years, there remains some controversy regarding the possibility that digoxin might have a deleterious effect on survival. This study was constructed to assess trends in digoxin toxicity research using well-established qualitative and quantitative bibliometric indicators. The current study is based on publications that have been indexed in Scopus. Articles referring to the subject of digoxin toxicity between 1849 and 2015 were assessed according to the document type, publication language, countries/territories, institutions, journal, impact factors, total number of citations, h-index, average number of citations per publication, and international collaborations. There were 2900 publications that included 2542 (87.7%) original research articles, while 5.3% were reviews and 4.6% letters. The country of origin was the USA in 849 publications, Germany in 241, the UK in 150, and France in 143. The USA and the UK had the highest number of international collaborations. The average number of citations per publications related to digoxin toxicity was 8.1, and the h-index was 59. The USA and Canada had the highest h-indices by country at 46 and 22, respectively. This study presents the first bibliometric analysis on digoxin toxicity publications. The USA was the most important contributors to digoxin toxicity literature with the greatest international collaboration, largest number of articles and highest h-index, followed by Germany and the UK. There has been a trend towards reduced publication numbers related to digoxin toxicity at global level, although it is still an important issue and we present the current research themes related to digoxin toxicity that were identified.
Assuntos
Pesquisa Biomédica/tendências , Fármacos Cardiovasculares/toxicidade , Digitoxina/toxicidade , Internacionalidade , Toxicologia/tendências , Animais , Bibliometria , Humanos , Medição de Risco , Testes de Toxicidade/tendênciasRESUMO
In the past 10 years, the public, private, and non-profit sectors have found agreement that hazard identification and risk assessment should capitalize on the explosion of knowledge in the biological sciences, moving away from in life animal testing toward more human-relevant in vitro and in silico methods, collectively referred to as new approach methodologies (NAMs). The goals for implementation of NAMs are to efficiently identify possible chemical hazards and to gather dose-response data to inform more human-relevant safety assessment. While work proceeds to develop NAMs, there has been less emphasis on creating decision criteria or showing how risk context should guide selection and use of NAMs. Here, we outline application scenarios for NAMs in different risk contexts and place different NAMs and conventional testing approaches into four broad levels. Level 1 relies solely on computational screening; Level 2 consists of high throughput in vitro screening with human cells intended to provide broad coverage of possible responses; Level 3 focuses on fit-for-purpose assays selected based on presumptive modes of action (MOA) and designed to provide more quantitative estimates of relevant dose responses; Level 4 has a variety of more complex multi-dimensional or multi-cellular assays and might include targeted in vivo studies to further define MOA. Each level also includes decision-appropriate exposure assessment tools. Our aims here are to (1) foster discussion about context-dependent applications of NAMs in relation to risk assessment needs and (2) describe a functional roadmap to identify where NAMs are expected to be adequate for chemical safety decision-making.
Assuntos
Alternativas aos Testes com Animais/tendências , Testes de Toxicidade/tendências , Animais , Biologia Computacional/métodos , Química Computacional/métodos , Ensaios de Triagem em Larga Escala , Humanos , Técnicas In Vitro , MamíferosRESUMO
Since a few decades, a new invertebrate animal model has emerged in toxicology studies: the planarian. This non-parasitic flatworm, from phylum Platyhelminthes, has an amazing regenerative capacity and has been described as "immortal under the edge of the knife" in 1814 by Dalyell. This formidable capacity is due to the abundance of stem cells called neoblasts, allowing for a tiny fragment equivalent to 1/279th of the size of the planarian to generate a whole animal. The planarian has also a human-like nervous system with several neurotransmitters and has been used to evaluate developmental perturbations and neurotoxicity. This review summarizes the main planarian toxicology studies and highlights the potential of this original animal model for research.
Assuntos
Modelos Animais , Planárias , Testes de Toxicidade/tendências , Toxicologia/métodos , Animais , Modelos Animais de Doenças , Inseticidas/toxicidade , Metais/toxicidade , Síndromes Neurotóxicas/patologia , Compostos Organometálicos/toxicidade , Planárias/fisiologia , Testes de Toxicidade/métodos , Toxicologia/tendênciasRESUMO
Nowadays, nanoproducts have found numerous applications, allowing them to enter the human body in different ways. Skin is a major body organ that acts as the first-line barrier between the internal organs and external environment. Although the inhalation and ingestion of nanoparticles is more dangerous compared with skin exposure, there are noteworthy information gaps in skin exposure to nanoparticles that need much attention. Despite the few reviews in the literature on the cytotoxic effects of nanoparticles, no research has reviewed the clinical side effects of nanoparticles following topical admonition, including skin inflammation, skin cancer and genetic toxicity.
Assuntos
Dermatite de Contato/etiologia , Modelos Biológicos , Nanopartículas/toxicidade , Pele/metabolismo , Testes de Toxicidade/métodos , Administração Cutânea , Animais , Simulação por Computador , Dermatite de Contato/patologia , Relação Dose-Resposta a Droga , Humanos , Modelos Animais , Nanopartículas/administração & dosagem , Tamanho da Partícula , Permeabilidade , Pele/efeitos dos fármacos , Pele/patologia , Absorção Cutânea , Testes de Toxicidade/tendênciasRESUMO
Five years ago, an ambitious collaboration, the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA; henceforth CLARITY), was launched by three US agencies. The goal was to provide a definitive evaluation of bisphenol A (BPA) and explain disparities between traditional regulatory studies and findings from independent investigators. BPA or vehicle-treated rats from an FDA facility were used in a guideline study and animals and/or tissues were provided to academic researchers for analysis. An interim summary released in February 2018 by the FDA concluded that currently authorized uses of BPA continue to be safe. We disagree. In this Perspectives, we summarize the goals, design and problems of CLARITY. We conclude that, despite its flaws, CLARITY provides important insight and, taken together, the data provide compelling evidence that low-dose BPA exposure induces marked adverse effects. Indeed, the greatest number of effects were observed at doses 20,000 times lower than the current 'safe' dose of BPA for humans.
Assuntos
Disruptores Endócrinos/toxicidade , Testes de Toxicidade/métodos , United States Food and Drug Administration/legislação & jurisprudência , Animais , Compostos Benzidrílicos/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/tendências , Humanos , Fenóis/toxicidade , Testes de Toxicidade/tendências , Estados Unidos , United States Food and Drug Administration/tendênciasAssuntos
Diferenciação Celular/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Testes de Toxicidade , Animais , Técnicas de Cultura de Células , Humanos , Modelos Biológicos , Sistema Nervoso/embriologia , Sistema Nervoso/crescimento & desenvolvimento , Testes de Toxicidade/métodos , Testes de Toxicidade/tendênciasRESUMO
Pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other possible drug-related problems.1 While current models of pharmacovigilance, with their tools and methodologies, were developed for prescription drugs, safety surveillance is just as important for over-the-counter health products such as dietary supplements. The practice of pharmacovigilance is challenging in itself; however, there are unique challenges associated with dietary supplements.2.
Assuntos
Qualidade de Produtos para o Consumidor , Suplementos Nutricionais/efeitos adversos , Segurança do Paciente , Farmacovigilância , Fitoterapia/efeitos adversos , Preparações de Plantas/efeitos adversos , Controle de Qualidade , Testes de Toxicidade , Animais , Qualidade de Produtos para o Consumidor/normas , Suplementos Nutricionais/normas , Previsões , Humanos , Segurança do Paciente/normas , Fitoterapia/normas , Fitoterapia/tendências , Preparações de Plantas/normas , Melhoria de Qualidade , Medição de Risco , Testes de Toxicidade/normas , Testes de Toxicidade/tendênciasRESUMO
For a long time, the discussion about animal testing vs its alternatives centered on animal welfare. This was a static warfare, or at least a gridlock, where life scientists had to take a position and make their value choices and hardly anyone changed sides. Technical advances have changed the frontline somewhat, with in vitro and in silico methods gaining more ground. Only more recently has the economic view begun to have an impact: Many animal tests are simply too costly, take too long, and give misleading results. As an extension and update to previous articles in this series written a decade ago, we reanalyze the economic landscape of especially regulatory use of animal testing and this time also consider respective alternative tests. Despite some ambiguity and data gaps, which we have filled with crude estimates, a picture emerges of globally regulated industries that are subject to stark geographic and sectorial differences in regulation, which determine their corresponding animal use. Both animal testing and its alternatives are industries in their own right, offering remarkable business opportunities for biotech and IT companies as well as contract research organizations. In light of recent revelations as to the reproducibility and relevance issues of many animal tests, the economic consequences of incorrect results and the reasons for still maintaining often outdated animal test approaches are discussed.
Assuntos
Alternativas aos Testes com Animais/economia , Bem-Estar do Animal , Testes de Toxicidade/economia , Testes de Toxicidade/tendências , Alternativas aos Testes com Animais/métodos , Animais , Humanos , Modelos Animais , Reprodutibilidade dos Testes , Pesquisa/economiaRESUMO
Immune-based childhood diseases and conditions, including allergic diseases and asthma, recurrent otitis media, pediatric celiac disease, and type 1 diabetes have been on the rise over the past decades. As a result, the use of developmental immunotoxicity (DIT) testing to identify potential environmental risk factors contributing to these and other diseases has become a priority for scientists across sectors. This chapter serves to provide insight into the scientific basis for DIT and determining the necessity of DIT testing and offers recommendations for DIT testing parameters to optimize sensitivity, power, and concordance among DIT assays.
Assuntos
Sistema Imunitário/embriologia , Testes de Toxicidade/métodos , Testes de Toxicidade/tendências , HumanosRESUMO
Assay systems using in vitro cultured cells are increasingly applied for evaluation of the efficacy, safety, and toxicity of drug candidates. In vitro cell-based assays have two main applications in the drug discovery process: searching for a compound that is effective against the target disease (seed investigation) and confirmation of safety during use of the identified compounds (safety assessment). Currently available in vitro cell-based assays have been designed to evaluate the efficacy and toxicity in single organs, but the in vivo pharmacokinetics and pharmacodynamics of the administered drug candidates have not been considered. Thus, an evaluation system that interconnects cell culture units, one of which has appropriate drug metabolism activities and the other assesses the efficacy and toxicity of compounds, is needed. Accordingly, the in vitro ADME-Tox culture system known as organs-on-a-chip has been proposed. In this review, after introducing the organs-on-a-chip system, the evaluation of enterohepatic circulation and the gut-liver axis relationship will be presented as an example of the application of the organs-on-a-chip system for ADME studies based on inter-organ network. Additionally, the functions required for the organs-on-a-chip system and the necessity of standardization of cells mounted on the chip system will be discussed.
Assuntos
Dispositivos Lab-On-A-Chip/tendências , Taxa de Depuração Metabólica/efeitos dos fármacos , Preparações Farmacêuticas/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Taxa de Depuração Metabólica/fisiologia , Preparações Farmacêuticas/administração & dosagem , Testes de Toxicidade/métodos , Testes de Toxicidade/tendênciasRESUMO
Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).
Assuntos
Alternativas aos Testes com Animais , Guias como Assunto , Síndromes Neurotóxicas/etiologia , Testes de Toxicidade/métodos , Animais , Educação , Humanos , Medição de Risco , Testes de Toxicidade/tendênciasRESUMO
The liver is a vital organ fulfilling a central role in over 500 major metabolic functions, including serving as the most essential site for drug biotransformation. Dysfunction of the drug biotransformation processes may result in the exposure of the liver (and other organs) to hepatotoxins, potentially interacting with cellular constituents and causing toxicity and various lesions. Hepatotoxicity can be investigated on a tissue, cellular and molecular level by employing various in vivo and in vitro techniques, including novel three-dimensional (3 D) cell culturing methods. This paper reflects on the liver and its myriad of functions and the influence of drug biotransformation on liver dysfunction. Current in vivo and in vitro models used to study liver function and dysfunction is outlined, emphasizing their advantages and disadvantages. The advantages of novel in vitro 3 D cell culture models are discussed and the possibility of novel models to bridge the gap between in vitro and in vivo models is explained. Progression made in the field of cell culturing methods such as 3 D cell culturing techniques over the last decade promises to reduce the use of in vivo animal models in biotransformation and toxicological studies of the liver.
Assuntos
Técnicas de Cultura de Células/tendências , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Descoberta de Drogas/tendências , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Testes de Toxicidade/tendências , Alternativas aos Testes com Animais/tendências , Animais , Biotransformação , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Difusão de Inovações , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Medição de Risco , Especificidade da EspécieRESUMO
In vitro chemical safety testing methods offer the potential for efficient and economical tools to provide relevant assessments of human health risk. To realize this potential, methods are needed to relate in vitro effects to in vivo responses, i.e., in vitro to in vivo extrapolation (IVIVE). Currently available IVIVE approaches need to be refined before they can be utilized for regulatory decision-making. To explore the capabilities and limitations of IVIVE within this context, the U.S. Environmental Protection Agency Office of Research and Development and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods co-organized a workshop and webinar series. Here, we integrate content from the webinars and workshop to discuss activities and resources that would promote inclusion of IVIVE in regulatory decision-making. We discuss properties of models that successfully generate predictions of in vivo doses from effective in vitro concentration, including the experimental systems that provide input parameters for these models, areas of success, and areas for improvement to reduce model uncertainty. Finally, we provide case studies on the uses of IVIVE in safety assessments, which highlight the respective differences, information requirements, and outcomes across various approaches when applied for decision-making.