title: Towards a non-animal risk assessment for anti-androgenic effects in humans.
abstract: Toxicology testing is undergoing a transformation from a system based on high-dose studies in laboratory animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. We review the tools and approaches that could be used to develop a non-animal safety assessment for anti-androgenic effects in humans, with a focus on the molecular initiating events (MIEs) that human disorders indicate critical for normal functioning of the hypothalamus-pituitary-testicular (HPT) axis. In vitro test systems exist which can be used to characterize the effects of test chemicals on some MIEs such as androgen receptor antagonism, inhibition of steroidogenic enzymes or 5α-reductase inhibition. When used alongside information describing the pharmacokinetics of a specific chemical exposure, these could be used to inform a pathways-based safety assessment. However, some parts of the HPT axis such as events occurring in the hypothalamus or pituitary are not well represented by accepted in vitro methods. In vitro tools to characterize perturbations in these events need to be developed before a fully integrated model of the HPT axis can be described. Knowledge gaps also exist which prevent us from using in vitro data to predict the type and severity of in vivo effect(s) that could arise from a given level of in vitro anti-androgenic activity. This means that more work is needed to reliably link an MIE with an adverse outcome. However, especially for chemicals with low anti-androgenic activity, human exposure data can be used to put in vitro mode of action data into context for risk-based safety decision-making.
authors.affiliation: Safety and Environmental Assurance Centre, Unilever Colworth Science Park, Bedfordshire MK44 1LQ, UK. Electronic address: matthew.dent@unilever.com.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Dent
authors.affiliation: Safety and Environmental Assurance Centre, Unilever Colworth Science Park, Bedfordshire MK44 1LQ, UK.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Carmichael
authors.affiliation: Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4YQ, UK.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Jones
authors.affiliation: Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4YQ, UK. Electronic address: f.martin@lancaster.ac.uk.
authors.forename: Francis L
authors.initials: FL
authors.lastname: Martin
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity*; D000826:Animal Testing Alternatives / Q000379:methods*; D052244:Endocrine Disruptors / Q000633:toxicity*; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D008297:Male; D018570:Risk Assessment / Q000379:methods
chemical_list: D000726:Androgen Antagonists; D052244:Endocrine Disruptors
keywords: Adverse outcome; Androgen receptor; Hypothalamus–pituitary–testicular (HPT) axis; Molecular initiating events (MIEs); TT21C; Toxicology testing