Dent, Matthew and Martin, Frank and Halsall, Crispin and Carmichael, Paul (2019) Towards a non-animal risk assessment for anti-androgenic effects in humans. PhD thesis, Lancaster University.
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Abstract
In recent years, concern has been raised over the possibility that substances in foods, consumer products and the environment are causing health effects in humans and the environment due to their ability to perturb endocrine signalling. Toxicological risk assessments therefore need to be protective for these modes of action. The accepted approach for assessing potential ‘endocrine disrupting chemicals’ (EDCs) involves the generation of laboratory animal data. The growing dissatisfaction of many scientists with the relevance of animal studies to the assessment of human risk and increasing societal demand for an end to animal testing presents challenges and opportunities in the safety evaluation of these substances. This thesis examines the opportunities to apply non-animal approaches to the risk assessment of anti-androgenic substances in consumer products. Gaps were identified that are currently preventing the adoption of such an approach, which broadly cover three areas. Firstly, under the current paradigm, in vitro alerts for anti-androgenicity invariably trigger animal testing, so an approach to allow risk-based decision making using only in vitro and exposure data is needed. Secondly, there is a lack of in vitro tools able to characterise the effects of substances affecting the hypothalamic and pituitary control of gonadotropin secretion; a search was conducted for cells that could address this. Thirdly, there are currently no in vitro models capable of distinguishing between exposures that cause adaptive changes to endocrine signalling and those that cause adverse health effects. The use of 3D prostate microtissues was therefore investigated to assess whether these would provide biomarkers to identify tipping points between adaptive and adverse responses. A tiered, exposure-led, and human-relevant risk assessment approach was developed that can be applied to safety decision making and prevent unnecessary animal use. Further developments in some of the higher-tier tools investigated will further reduce and ultimately replace the use of animals in risk assessment of anti-androgens.