Abstract
This publication summarizes discussions that were held during an international expert hearing organized by the German Federal Institute for Risk Assessment (BfR) in Berlin, Germany, in October 2017. The expert hearing was dedicated to providing practical guidance for the measurement of circulating hormones in regulatory toxicology studies. Adequate measurements of circulating hormones have become more important given the regulatory requirement to assess the potential for endocrine disrupting properties for all substances covered by the plant protection products and biocidal products regulations in the European Union (EU). The main focus was the hypothalamus–pituitary–thyroid axis (HPT) and the hypothalamus–pituitary–gonadal axis (HPG). Insulin, insulin-like growth factor 1 (IGF-1), parathyroid hormone (PTH) and vitamins A and D were also discussed. During the hearing, the experts agreed on specific recommendations for design, conduct and evaluation of acceptability of studies measuring thyroid hormones, thyroid stimulating hormone and reproductive hormones as well as provided some recommendations for insulin and IGF-1. Experts concluded that hormonal measurements as part of the test guidelines (TGs) of the Organisation for Economic Co-operation and Development (OECD) were necessary on the condition that quality criteria to guarantee reliability and reproducibility of measurements are adhered to. Inclusion of the female reproductive hormones in OECD TGs was not recommended unless the design of the study was modified to appropriately measure hormone concentrations. The current report aims at promoting standardization of the experimental designs of hormonal assays to allow their integration in OECD TGs and highlights research needs for better identification of endocrine disruptors using hormone measurements.
Highlights
According to the definition proposed by World Health Organization/International Programme on Chemical Safety in 2002, endocrine disruptor (ED) is an “an exogenous substance or mixture that alters function(s) of theOlena Kucheryavenko, Glenn Lurman and Anja Lehmann are equal contributors.Extended author information available on the last page of the article endocrine system and causes adverse health effects in an intact organism, or its progeny, orpopulations” (WHO/IPCS 2002)
Considering the importance of hormonal measurements as in vivo mechanistic parameters for the assessment of EDs, the question of incorporating hormone measurements in the OECD test guidelines (TGs) was addressed during the expert hearing
The experts agreed that currently technical feasibility does not prevent the inclusion of hypothalamus–pituitary–thyroid axis (HPT) and hypothalamus– pituitary–gonadal axis (HPG) hormones in the OECD test guidelines
Summary
According to the definition proposed by World Health Organization/International Programme on Chemical Safety in 2002, endocrine disruptor (ED) is an “an exogenous substance or mixture that alters function(s) of theOlena Kucheryavenko, Glenn Lurman and Anja Lehmann are equal contributors.Extended author information available on the last page of the article endocrine system and causes adverse health effects in an intact organism, or its progeny, or (sub)populations” (WHO/IPCS 2002). Archives of Toxicology (2019) 93:1157–1167 disrupting properties during registration and re-approval of an active substance, the European Commission (EC) has endorsed scientific criteria for the identification of EDs in the context of BP and for active substances, safeners and synergists in PPPs (EC 2017, 2018). It is designed to implement a hazard-based evaluation principle of the relevant endocrine disrupting properties of a substance and to advise applicants and regulatory authorities on how to assess available data using a weight of evidence approach. Changes in hormone concentrations gain particular weight in the assessment of possible endocrine disrupting properties of the substance during the pre-approval process. Significant changes in concentrations of oestradiol, testosterone and thyroid hormones may be indicative of an endocrine activity of an active substance on the experimental organism, and this should be contextualized in the MoA framework (i.e. dose and temporal concordance of the observed effects). Because hormone concentrations fluctuate in response to the influence of internal and external factors (e.g. oestrous cycle, stress, circadian rhythm), a detailed description of the experimental conditions of the hormonal assays need to be provided to facilitate generation of meaningful and reliable results that can efficiently contribute to the MoA analysis
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