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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.
Highlights Perturbations in androgen signalling can cause adverse outcomes in humans. Chemical risk assessment should be protective for these adverse outcomes. We considered how to perform non-animal risk assessments for androgen signalling. Exposure data can and should be used to put in vitro mechanistic data into context. Several tools and knowledge gaps were highlighted.
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.
Highlights Perturbations in androgen signalling can cause adverse outcomes in humans. Chemical risk assessment should be protective for these adverse outcomes. We considered how to perform non-animal risk assessments for androgen signalling. Exposure data can and should be used to put in vitro mechanistic data into context. Several tools and knowledge gaps were highlighted.
Towards a non-animal risk assessment for anti-androgenic effects in humans
Dent, Matthew P. (author) / Carmichael, Paul L. (author) / Jones, Kevin C. (author) / Martin, Francis L. (author)
Environmental International ; 83 ; 94-106
2015-06-12
13 pages
Article (Journal)
Electronic Resource
English
5α-R , 5α-reductase type 2 , ADME , absorption, distribution, metabolism and excretion , AG , andrographolide , AGD , anogenital distance , AOP , adverse outcome pathway , AR , androgen receptor , BPAD , biological pathway altering dose , CHH , congenital hypogonadotrophic hypogonadism , DHT , dihydrotestosterone , ED , endocrine disrupter , EDSP , Endocrine Disrupter Screening Program , ER , oestrogen receptor , FSH(R) , follicle stimulating hormone (receptor) , GnRH(R) , gonadotropin releasing hormone (receptor) , hCG , human chorionic gonadotropin , HPT , hypothalamus–pituitary–testicular , IGD , isolated gonadotropin releasing hormone deficiency , IHD , isolated hypogonadism disease , IL-6 , interleukin-6 , LH(R) , luteinizing hormone (receptor) , LOEC , lowest observed effect concentration , MIE , molecular initiating event , MMTV , mouse mammary tumour virus , NRC , National Research Council , Oct1 , octamer-binding transcription factor-1 , OECD , Organization for Economic Cooperation and Development , PBPK , physiologically-based pharmacokinetic modelling , QIVIVE , quantitative <italic>in vitro</italic> to <italic>in vivo</italic> extrapolation , T , testosterone , TT21C , toxicity testing in the 21st Century , YAS , yeast androgen screen , Adverse outcome , Androgen receptor , Hypothalamus–pituitary–testicular (HPT) axis , Molecular initiating events (MIEs) , Toxicology testing
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