title: Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment.
abstract: Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that report NMDR relationships with endocrine disruptors. Fifty-one experimental studies that investigated various effects associated with endocrine disruption elicited by many substances were selected. Scoring criteria were applied by adaptation of an approach previously used for identification of hormesis-type dose-response relationships. Out of the 148 NMDR relationships analyzed, 82 were categorized with this method as having a "moderate" to "high" level of plausibility for various effects. Numerous modes of action described in the literature can explain such phenomena. NMDR can arise from numerous molecular mechanisms such as opposing effects induced by multiple receptors differing by their affinity, receptor desensitization, negative feedback with increasing dose, or dose-dependent metabolism modulation. A stepwise decision tree was developed as a tool to standardize the analysis of NMDR relationships observed in the literature with the final aim to use these results in a Risk Assessment purpose. This decision tree was finally applied to studies focused on the effects of bisphenol A.
authors.affiliation: Risk Assessment Department, French Agency for Food, Environmental and Occupational Health & Safety (ANSES), 14 rue Pierre et Marie Curie, 94701, Maisons-Alfort Cedex, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lagarde
authors.affiliation: Risk Assessment Department, French Agency for Food, Environmental and Occupational Health & Safety (ANSES), 14 rue Pierre et Marie Curie, 94701, Maisons-Alfort Cedex, France. claire.beausoleil@anses.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Beausoleil
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Belcher
authors.affiliation: INRA, Laboratoire de Toxicologie Environnementale, UR 406 A&E, CS 40509, 84914, Avignon Cedex 9, France.
authors.forename: Luc P
authors.initials: LP
authors.lastname: Belzunces
authors.affiliation: BioSimulation Consulting Inc., Newark, DE, USA.
authors.forename: Claude
authors.initials: C
authors.lastname: Emond
authors.affiliation: Université de Rouen, UFR Médecine Pharmacie, Laboratoire de Toxicologie, UR 4651 ABTE, 76183, Rouen Cedex 1, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Guerbet
authors.affiliation: Risk Assessment Department, French Agency for Food, Environmental and Occupational Health & Safety (ANSES), 14 rue Pierre et Marie Curie, 94701, Maisons-Alfort Cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousselle
mesh_terms: D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004781:Environmental Exposure; D004784:Environmental Monitoring / Q000379:methods*; D004785:Environmental Pollutants / Q000633:toxicity*; D018570:Risk Assessment
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants