STATE OF THE ART ASSESSMENT OF ENDOCRINE DISRUPTERS Final Report Project Contract Number 070307/2009/550687/SER/D3 Authors: Andreas Kortenkamp, Olwenn Martin, Michael Faust, Richard Evans, Rebecca McKinlay, Frances Orton and Erika Rosivatz 23.12.2011 TABLE OF CONTENTS TABLE OF CONTENTS 0 EXECUTIVE SUMMARY ......................................................................................................................... 7 1 INTRODUCTION .................................................................................................................................... 9 1.1 TERMS OF REFERENCE, SCOPE OF THE REPORT ........................................................................... 9 1.2 STRUCTURE OF THE REPORT ....................................................................................................... 11 2 DEFINITION OF ENDOCRINE DISRUPTING CHEMICALS ...................................................................... 13 2.1 THE ENDOCRINE SYSTEM ............................................................................................................ 13 2.2 ADVERSITY ................................................................................................................................... 15 2.2.1 DEFINITION........................................................................................................................... 15 2.2.2 ASSAY REQUIREMENTS ........................................................................................................ 16 2.2.3 ECOTOXICOLOGICAL EFFECTS .............................................................................................. 16 2.3 MODE OF ACTION ....................................................................................................................... 17 2.4 PROOF OF CAUSALITY ................................................................................................................. 17 2.5 DEFINITIONS OF POTENTIAL AND POSSIBLE ENDOCRINE DISRUPTERS ...................................... 19 2.6 ENDOCRINE MODULATION, ENDOCRINE ACTIVITY, ENDOCRINE MODULATORY ACTIVITY ....... 19 3 FRAMEWORKS FOR REGULATORY TESTING AND SCREENING ........................................................... 21 3.1 THE OECD CONCEPTUAL FRAMEWORK ...................................................................................... 21 3.1.1 CONCEPTUAL FRAMEWORK GUIDANCE DOCUMENT .......................................................... 24 3.1.2 DETAILED REVIEW PAPER ON NOVEL TESTS AND ENDPOINTS ............................................ 26 3.1.3 CORRELATIONS BETWEEN TEST OUTCOMES AT LOWER LEVELS WITH THOSE AT HIGHER LEVELS ........................................................................................................................................... 28 3.2 TIERED TESTING STRATEGIES ...................................................................................................... 30 4 SCIENTIFIC RESULTS OF REGULATORY RELEVANCE ........................................................................... 32 4.1 WEIGHT-OF-EVIDENCE APPROACHES ......................................................................................... 32 4.1.1 EPIDEMIOLOGICAL CRITERIA OF CAUSAL INFERENCE ......................................................... 32 4.1.2 QUALITY CRITERIA FOR TOXICOLOGICAL STUDIES ............................................................... 34 4.1.3 ECHA GUIDANCE ON WEIGHT OF EVIDENCE EVALUATION ................................................. 35 4.1.4 EXAMPLES OF WOE APPROACHES FOR ENDOCRINE DISRUPTERS ...................................... 36 4.1.4.1 WHO/IPCS Global assessment of the state-of-the-science of endocrine disrupters .... 36 4.1.4.2 RPS-BKH Endocrine Disrupters database ...................................................................... 37 4.1.5 IMPLICATIONS FOR THE REGULATION OF ENDOCRINE DISRUPTERS .................................. 38 4.2 CONCEPTUAL FRAMEWORKS FOR EVALUATING EVIDENCE OF MODE OF ACTION(S) ............... 39 4.2.1 MECHANISM, MODE OF ACTION AND KEY EVENTS ............................................................. 39 Page 2 of 135 TABLE OF CONTENTS 4.2.2 MODE OF ACTION ANALYSIS METHODOLOGY ..................................................................... 40 4.3 LOW DOSE EFFECTS AND THRESHOLDS ...................................................................................... 42 4.3.1 CATEGORIES OF MODE OF ACTION THAT CAN INFORM LOW DOSE EXTRAPOLATIONS ..... 43 4.3.2 ABSENCE OF THRESHOLDS AT THE HUMAN POPULATION LEVEL AND IMPORTANCE OF PRE-EXISTING EXPOSURES ............................................................................................................ 44 4.4 CRITICAL WINDOWS OF SENSITIVITY AND IRREVERSIBLE EFFECTS ............................................ 44 4.4.1 IMPLICATIONS FOR TESTING AND REGULATION ................................................................. 45 4.5 MIXTURES .................................................................................................................................... 46 4.6 THRESHOLDS OF TOXICOLOGICAL CONCERN ............................................................................. 46 4.7 ENDPOINTS, MODES-OF-ACTION AND ASSAYS ........................................................................... 47 4.7.1 HUMAN HEALTH .................................................................................................................. 48 4.7.1.1 Reproductive health ...................................................................................................... 48 4.7.1.1.1 Male Reproductive Health ..................................................................................... 48 4.7.1.1.2 Female Reproductive Health ................................................................................. 48 4.7.1.2 Hormonal cancers ......................................................................................................... 49 4.7.1.3 Metabolism and development ...................................................................................... 50 4.7.2 WILDLIFE .............................................................................................................................. 50 4.7.2.1 Invertebrates ................................................................................................................. 50 4.7.2.2 Fish ................................................................................................................................ 52 4.7.2.3 Amphibians ................................................................................................................... 53 4.7.2.4 Reptiles.......................................................................................................................... 54 4.7.2.5 Birds .............................................................................................................................. 55 4.7.2.6 Mammals ...................................................................................................................... 55 4.8 CHEMICALS OF CONCERN AND EXPOSURE ................................................................................. 56 4.8.1 POLYCHLORINATED BIPHENYLS (PCBS) ................................................................................ 59 4.8.2 POLYCHLORINATED DIBENZODIOXINS (PCDDS) AND POLYCHLORINATED DIBENZOFURANS (PCDFS) .......................................................................................................................................... 59 4.8.3 POLYBROMINATED BIPHENYLETHERS (PBDES) .................................................................... 60 4.8.4 PERFLUORINATED COMPOUNDS (PFCS) .............................................................................. 61 4.8.5 PESTICIDES ........................................................................................................................... 61 4.8.5.1 Dicarboxamides ............................................................................................................. 61 4.8.5.2 Azole fungicides ............................................................................................................ 62 4.8.5.3 Triazines ........................................................................................................................ 63 4.8.6 HEAVY METALS ..................................................................................................................... 64 Page 3 of 135 TABLE OF CONTENTS 4.8.7 BISPHENOL A ........................................................................................................................ 65 4.8.8 PHTHALATES......................................................................................................................... 65 4.8.9 PARABENS ............................................................................................................................ 66 4.8.10 OTHER CHEMICALS............................................................................................................. 67 5 EUROPEAN REGULATORY FRAMEWORK ............................................................................................ 69 5.1 CLASSIFICATION AND LABELLING ................................................................................................ 69 5.1.1 CARCINOGENS ...................................................................................................................... 69 5.1.1.1 Definition and categorisation ......................................................................................