Scientific Opinion on the hazard assessment of endocrine disruptors: Scientific criteria for identification of endocrine disruptors and appropriateness of existing test methods for assessing effects mediated by these substances on human health and the environment

Upon request of the European Commission, the Scientific Committee (SC) of the European Food Safety Authority reviewed existing information related to the testing and assessment of endocrine active substances (EASs) and endocrine disruptors (EDs). This work was conducted by a working group of experts in endocrinology, risk assessment and toxicology, together with observers from other EU agencies, namely EMA, ECHA and EEA. To distinguish between EDs and other groups of substances with different modes of action, it was concluded that an ED is defined by three criteria: the presence of i) an adverse effect in an intact organism or a (sub)population; ii) an endocrine activity; and iii) a plausible causal relationship between the two. As scientific criteria for adversity have not been generally defined, specific criteria for endocrine disrupting effects could not be identified. Hence, expert judgement is required to assess on a case-by-case basis the (eco)toxicological relevance of changes at the molecular to individual and/or (sub)population level following exposure to an EAS. The SC concluded that a reasonably complete suite of standardised assays for testing the effects of EASs is (or will soon be) available for the oestrogenic, androgenic, thyroid and steroidogenic modalities in mammals and fish, with fewer tests for birds and amphibians. Shortcomings in current tests and for other endocrine modalities and species were reviewed. Critical effect, severity, (ir)reversibility and potency aspects are part of the hazard characterisation of EDs. To inform on risk and level of concern for the purpose of risk management decisions, risk assessment (taking into account hazard and exposure data/predictions) makes best use of available information. Levels of concern are not determined exclusively by risk assessment but also by protection goals set by the risk management. © European Food Safety Authority, 2013

[1]  H. Holbech,et al.  Effects of exposure to 17α-ethinylestradiol during early development on sexual differentiation and induction of vitellogenin in zebrafish (Danio rerio) , 2003 .

[2]  J. Toppari,et al.  Genital anomalies in boys and the environment. , 2010, Best practice & research. Clinical endocrinology & metabolism.

[3]  S Coecke,et al.  The use of metabolising systems for in vitro testing of endocrine disruptors. , 2008, Current drug metabolism.

[4]  J. Haseman,et al.  Summary of the National Toxicology Program's report of the endocrine disruptors low-dose peer review. , 2002, Environmental health perspectives.

[5]  Fuart Gatnik Mojca,et al.  Review of QSAR Models and Software Tools for Predicting of Genotoxicity and Carcinogenicity , 2010 .

[6]  J. Heindel,et al.  Effects of endocrine disruptors on obesity. , 2008, International journal of andrology.

[7]  Karen A Kidd,et al.  Collapse of a fish population after exposure to a synthetic estrogen , 2007, Proceedings of the National Academy of Sciences.

[8]  Alan R. Boobis,et al.  IPCS Framework for Analyzing the Relevance of a Noncancer Mode of Action for Humans , 2008, Critical reviews in toxicology.

[9]  A. Vedani,et al.  VirtualToxLab - a platform for estimating the toxic potential of drugs, chemicals and natural products. , 2012, Toxicology and applied pharmacology.

[10]  M. Mizutani,et al.  Two-step models to predict binding affinity of chemicals to the human estrogen receptor α by three-dimensional quantitative structure–activity relationships (3D-QSARs) using receptor-ligand docking simulation , 2005, SAR and QSAR in environmental research.

[11]  T. Colborn,et al.  Chemically-induced alterations in sexual and functional development : the wildlife/human connection , 1992 .

[12]  France Mentré,et al.  Performance Comparison of Various Maximum Likelihood Nonlinear Mixed-Effects Estimation Methods for Dose–Response Models , 2012, The AAPS Journal.

[13]  Stig Johan Wiklund,et al.  Modelling and simulation in the pharmaceutical industry—some reflections , 2011, Pharmaceutical statistics.

[14]  Eva Bay Wedebye,et al.  Screening of 397 chemicals and development of a quantitative structure--activity relationship model for androgen receptor antagonism. , 2008, Chemical research in toxicology.

[15]  Melvin E Andersen,et al.  Toxicokinetic modeling and its applications in chemical risk assessment. , 2003, Toxicology letters.

[16]  Paul Mushak,et al.  Hormesis and Its Place in Nonmonotonic Dose–Response Relationships: Some Scientific Reality Checks , 2007, Environmental health perspectives.

[17]  E Mombelli,et al.  Evaluation of the OECD (Q)SAR Application Toolbox for the profiling of estrogen receptor binding affinities , 2012, SAR and QSAR in environmental research.

[18]  P. Foster.  Mode of Action: Impaired Fetal Leydig Cell Function—Effects on Male Reproductive Development Produced by Certain Phthalate Esters , 2005, Critical reviews in toxicology.

[19]  Patrick Bultinck,et al.  Computational medicinal chemistry for drug discovery , 2003 .

[20]  B. Blaauboer.  Biokinetic and Toxicodynamic Modelling and its Role in Toxicological Research and Risk Assessment , 2003, Alternatives to laboratory animals : ATLA.

[21]  Ursula Gundert-Remy,et al.  Physiologically-based Kinetic Modelling (PBK Modelling): Meeting the 3Rs Agenda , 2007, Alternatives to laboratory animals : ATLA.

[22]  R. Kruse,et al.  Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure , 2005, Environmental health perspectives.

[23]  Bert Brunekreef,et al.  Environmental exposure assessment in European birth cohorts: results from the ENRIECO project , 2013, Environmental Health.

[24]  E. B. Wedebye,et al.  QSAR model for human pregnane X receptor (PXR) binding: screening of environmental chemicals and correlations with genotoxicity, endocrine disruption and teratogenicity. , 2012, Toxicology and applied pharmacology.

[25]  A. Spanos,et al.  Risks to health and risks to science: the need for a responsible “bioevidential” scrutiny , 2008, Human & experimental toxicology.

[26]  A. B. Hill.  The Environment and Disease: Association or Causation? , 1965, Proceedings of the Royal Society of Medicine.

[27]  Julie E Goodman,et al.  Low-dose effects and nonmonotonic dose-responses of endocrine disrupting chemicals: has the case been made? , 2012, Regulatory toxicology and pharmacology : RTP.

[28]  Andrew P. Worth,et al.  Applicability of QSAR analysis in the evaluation of developmental and neurotoxicity effects for the assessment of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment , 2011 .

[29]  Daniel L Villeneuve,et al.  Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment , 2010, Environmental toxicology and chemistry.

[30]  Melanie Gross,et al.  Science based guidance for the assessment of endocrine disrupting properties of chemicals. , 2011, Regulatory toxicology and pharmacology : RTP.

[31]  Valérie Zuang,et al.  Alternative (non-animal) methods for cosmetics testing: current status and future prospects—2010 , 2011, Archives of Toxicology.

[32]  A G Renwick,et al.  Hazard characterisation of chemicals in food and diet. dose response, mechanisms and extrapolation issues. , 2002, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[33]  S. Swan,et al.  Lifestyle behaviors associated with exposures to endocrine disruptors. , 2012, Neurotoxicology.

[34]  Peter Matthiessen,et al.  Critical appraisal of the evidence for tributyltin‐mediated endocrine disruption in mollusks , 1998 .

[35]  E. Benfenati,et al.  In silico-aided prediction of biological properties of chemicals: oestrogen receptor-mediated effects. , 2008, Chemical Society reviews.

[36]  H. Bern,et al.  Altered mammary responsiveness to estradiol and progesterone in mice exposed neonatally to diethylstilbestrol. , 1992, Cancer letters.

[37]  M. Jacobs,et al.  In silico tools to aid risk assessment of endocrine disrupting chemicals. , 2004, Toxicology.

[38]  M. Kogevinas,et al.  European Birth Cohorts for Environmental Health Research , 2011, Environmental health perspectives.

[39]  Luciano Milanesi,et al.  Modelling the interaction of steroid receptors with endocrine disrupting chemicals , 2005, BMC Bioinformatics.

[40]  C. Tyler,et al.  Comparative responses of molluscs and fish to environmental estrogens and an estrogenic effluent. , 2003, Aquatic toxicology.

[41]  L Maslankiewicz,et al.  Can chemical structure predict reproductive toxicity , 2005 .

[42]  Bas J Blaauboer,et al.  Evaluation of research activities and research needs to increase the impact and applicability of alternative testing strategies in risk assessment practice. , 2011, Regulatory toxicology and pharmacology : RTP.

[43]  J. Toppari.  Environmental Endocrine Disrupters , 2008, Sexual Development.

[44]  A. Scott,et al.  Survey of estrogenic activity in United Kingdom estuarine and coastal waters and its effects on gonadal development of the flounder Platichthys flesus , 1999 .

[45]  Carolyn Vickers,et al.  IPCS framework for analysing the relevance of a cancer mode of action for humans , 2006 .