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.

Proposed Key Characteristics of Male Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Evidence in Human Health Hazard Assessments

“…The prostate gland and seminal vesicles produce seminal plasma for sperm transport and capacitation. Normal accessory reproductive organ functions can be altered by exposure to reproductive toxicants such as vinclozolin and flutamide (Dent et al. 2015).…”

“…Gonadotropins, sex steroids, and thyroid hormones produced by the hypothalamic–pituitary–gonadal (HPG) axis, the hypothalamic–pituitary–adrenal axis, and the hypothalamic–pituitary–thyroid axis play an important role in the normal development and function of the male reproductive system (Dent et al. 2015).…”

Rational Selection of the 3D Structure of Biomacromolecules for Molecular Docking Studies on the Mechanism of Endocrine Disruptor Action

“…43,44 Deciphering the mechanism between xenobiotics and biomacromolecules will be conducive to develop the endocrine-based adverse outcome pathway. 45−47 Molecular modeling methods were widely used to reveal the interaction mechanism.…”

Employing Dietary Comparators to Perform Risk Assessments for Anti-Androgens Without Using Animal Data

“…One example of a receptor-mediated MIE is androgen receptor (AR) antagonism. We have previously described how a non-animal risk assessment for anti-androgenic effects could be developed and the central importance of the AR to this strategy (Dent et al , 2015).…”