• Androgen receptor
• Docking simulation
• Estrogen receptor
• Tert-butyl phenolic antioxidants
• Transcriptional activation

• Molecular Docking Simulation
• Humans
• Antioxidants/pharmacology
• Antioxidants/chemistry
• Antioxidants/toxicity
• Receptors, Androgen/metabolism
• Receptors, Androgen/genetics
• Receptors, Androgen/drug effects
• Transcriptional Activation/drug effects
• Phenols/pharmacology
• Phenols/toxicity
• Phenols/chemistry
• Cell Line, Tumor
• Estrogens/pharmacology
• Estrogens/chemistry
• Endocrine Disruptors/toxicity
• Endocrine Disruptors/pharmacology
• Androgens/pharmacology
• Estrogen Receptor alpha/genetics
• Estrogen Receptor alpha/agonists
• Estrogen Receptor alpha/metabolism
• Receptors, Estrogen/genetics
• Receptors, Estrogen/metabolism

• New Alternative Methods (NAMs)
• Next-generation risk assessment (NGRA)
• Pyrethroids
• Toxicodynamics
• Toxicokinetics

• Japan MPS initiative
• Microphysiological systems
• New approach methodologies
• OECD test guideline
• Regulatory science

• Japan
• Humans
• Drug Development/methods
• Drug Development/legislation & jurisprudence
• Animals
• Drug Industry
• Animal Testing Alternatives
• Risk Assessment
• Microphysiological Systems

• Androgen receptor
• Benzophenones
• Estrogen receptor
• IATA
• Transcriptional activity

• Receptors, Androgen/metabolism
• Receptors, Androgen/genetics
• Humans
• Benzophenones/toxicity
• Benzophenones/pharmacology
• Receptors, Estrogen/metabolism
• Receptors, Estrogen/genetics
• Animals
• Transcriptional Activation/drug effects
• Female
• Estrogens/toxicity
• Endocrine Disruptors/toxicity
• MCF-7 Cells
• Uterus/drug effects
• Uterus/metabolism

• bone marrow-derived dendritic cells
• chemical allergens
• in vitro assay
• potency
• sensitization

• Mice
• Animals
• Dermatitis, Allergic Contact/diagnosis
• Dermatitis, Allergic Contact/etiology
• Haptens
• Local Lymph Node Assay
• Flow Cytometry
• Allergens/adverse effects

• Defined Approaches
• Isothiazolinone
• Skin Sensitization

• NIER-2022-04-02-205 National Institute of Environmental Research
• Korea Environment Industry and Technology Institute
• RS-2023-00215856 Ministry of Environment

• Adverse outcome pathway
• Glutathione
• Male fertility toxicity
• Structure activity relationship

• cellular microenvironment
• disease modeling
• microfluidic platforms
• organs-on-chips
• personalized medicine
• tissue bioengineering

• 3Rs
• Complexity
• In toxicology
• Integrated approach
• Non-animal methods
• Replacement

• Animal Testing Alternatives
• Animals
• Artificial Intelligence
• Risk Assessment

• 681002 Horizon 2020
• 963845 Horizon 2020

• REACH
• Regulatory risk assessment
• cosmetics
• new approach methodologies
• non-animal methods

• alternative organisms
• animal experiments
• in silico
• in vitro
• in vivo

• Animals
• Drug Discovery

• Adverse outcome pathways
• Alkoxy alcohols
• Developmental toxicity
• Metabolism
• Zebrafish embryos

• developmental neurotoxicity
• microelectrode array
• neural network formation
• screening

• 21st century toxicology
• NAMs
• Q(SAR)
• TOX21
• TOX21c
• animal testing
• drug development
• high-throughput screening
• innovation
• new approach methodologies
• organ-on-a-chip
• pharmaceuticals
• read-across
• regulatory toxicology
• risk assessment
• toxicity testing
• toxicology

• Endocrine disruption
• Prioritization
• Steroidogenesis
• ToxCast

The pharmaceutical industry is in the midst of a productivity crisis and rates of translation from bench to bedside are dismal. Patients are being let down by the current system of drug discovery; of the several 1000 diseases that affect humans, only a minority have any approved treatments and many of these cause adverse reactions in humans. A predominant reason for the poor rate of translation from bench to bedside is generally held to be the failure of preclinical animal models to predict clinical efficacy and safety. Attempts to explain this failure have focused on problems of internal validity in preclinical animal studies (e.g. poor study design, lack of measures to control bias). However there has been less discussion of another key factor that influences translation, namely the external validity of preclinical animal models.

External validity is the extent to which research findings derived in one setting, population or species can be reliably applied to other settings, populations and species. This paper argues that the reliable translation of findings from animals to humans will only occur if preclinical animal studies are both internally and externally valid. We review several key aspects that impact external validity in preclinical animal research, including unrepresentative animal samples, the inability of animal models to mimic the complexity of human conditions, the poor applicability of animal models to clinical settings and animal–human species differences. We suggest that while some problems of external validity can be overcome by improving animal models, the problem of species differences can never be overcome and will always undermine external validity and the reliable translation of preclinical findings to humans.

We conclude that preclinical animal models can never be fully valid due to the uncertainties introduced by species differences. We suggest that even if the next several decades were spent improving the internal and external validity of animal models, the clinical relevance of those models would, in the end, only improve to some extent. This is because species differences would continue to make extrapolation from animals to humans unreliable. We suggest that to improve clinical translation and ultimately benefit patients, research should focus instead on human-relevant research methods and technologies.

• External validity
• Human-relevant methods
• Preclinical animal models
• Translation