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TGA Review of Hgps

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TGA Review of Hgps A REVIEW TO UPDATE AUSTRALIA’S POSITION ON THE HUMAN SAFETY OF RESIDUES OF HORMONE GROWTH PROMOTANTS (HGPs) USED IN CATTLE Prepared by Chemical Review and International Harmonisation Section Office of Chemical Safety Therapeutic Goods Administration of the Department of Health and Ageing Canberra July 2003 A draft of this report was tabled at the 25th Meeting of the Advisory Committee on Pesticides and Health (ACPH), held in Canberra on the 1st May 2003. The report was subsequently endorsed out-of-session by the ACPH. Hormone Growth Promotants TABLE OF CONTENTS ABBREVIATIONS ................................................................................................................................................................4 EXECUTIVE SUMMARY ..................................................................................................................................................7 INTRODUCTION..................................................................................................................................................................9 HEALTH CONCERNS ASSOCIATED WITH HGP S................................................................................................................9 DIFFICULTIES ASSOCIAT ED WITH ASSESSING THE SAFETY OF HGPS.........................................................................10 RISK ASSESSMENTS OF HGP S .........................................................................................................................................10 PURPOSE OF THE CURRENT REVIEW................................................................................................................................11 INTERNATIONAL SCIENTIFIC ASSESSMENTS OF HGPS ............................................................................ 12 THE EUROPEAN COMMISSION (EC)................................................................................................................................12 WHO/FAO JOINT EXPERT COMMITTEE ON FOOD ADDITIVES (JECFA) .................................................................15 INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC)................................................................................21 UNITED STATES FOOD AND DRUG ADMINISTRATION (FDA).....................................................................................26 THE AUSTRALIAN POSITION.............................................................................................................................................28 DISCUSSION ....................................................................................................................................................................... 32 CONCLUSIONS .................................................................................................................................................................. 42 ANNEX 1: EVALUATION OF STUDIES COMMISSIO NED OR CITED BY THE EC .............................. 43 SUMMARIES OF 17 EC-COMMISSIONED STUDIES .........................................................................................46 SUMMARIES OF RECENT STUDIES CITED BY THE EC ................................................................................55 EVALUATION OF 17 EC-COMMISSIONED STUDIES ......................................................................................61 STUDY 1: PRESENCE OF OESTROGENS IN MEAT...........................................................................................................61 STUDY 2: HORMONES AS GROWTH PROMOTERS: GENOTOXICITY AND MUTAGENICITY OF ZERANOL AND TRENBOLONE...................................................................................................................................................61 STUDY 3: METABOLIC PATHWAYS OF OESTROGENS AS STEROIDAL GROWTH PROMOTING AGENTS...................63 STUDY 4: METABOLITES OF MELENGESTROL ACETATE, TRENBOLONE ACETATE AND ZERANOL IN BOVINE AND HUMANS...........................................................................................................................................................64 STUDY 5: APPLICATION OF ANABOLIC AGENTS TO FOOD PRODUCING ANIMALS – HEALTH RISKS THROUGH DISREGARD OF REQUIRE MENTS OF GOOD VETERINARY PRACTICE ..........................................................65 STUDY 6: ANALYSIS OF 500 SAMPLES FOR THE PRESENCE OF GROWTH PROMOTERS............................................81 STUDY 7: ANALYSIS OF 500 SAMPLES FOR THE PRESENCE OF GROWTH PROMOTERS............................................82 STUDY 8: COMPARISON OF ASSAY METHODS..............................................................................................................84 STUDY 9: BIOASSAY OF OESTROGENIC/ANTI-OESTROGENIC COMPOUNDS..............................................................93 STUDY 10: INTERACTION OF XENOBIOTICS WITH SEX HORMONE BINDING GLOBULIN; IMPACT ON ENDOGENOUS STEROID TRANSPORT , BIOAVAILABILITY AND MECHANISM OF ACTION.................................................95 STUDY 11: REPRODUCTIVE SEQUELAE OF DEVELOPMENTAL EXPOSURE OF RABBITS T O TRENBOLONE, ZERANOL AND MELENGESTROL ACETATE; EMPHASIS ON DIFFERENTIAL AND NEOPLASTIC TRANSFORMATION OF GERM CELLS...............................................................................................................................................96 STUDY 12: LONG TERM EFFECTS IN CHILDREN TO OESTROGENISED MEAT ..............................................................98 STUDY 13: ANDROGEN EXPOSURES IN UTERO, RISK OF BREAST CANCER.................................................................99 STUDY 14: ENDOCRINE DISRUPTING ACTIVITY OF ANABOLIC STEROIDS USED IN CATTLE ..................................101 STUDY 15: SCREENING WATER SAMPLES FOR OESTROGENIC AND ANDROGENIC ANABOLIC CHEMICALS.........104 STUDY 16: ENDOCRINE DISRUPTING EFFECTS OF CATTLE FARM EFFLUENT ON ENVIRONMENTAL SENTINEL SPECIES..........................................................................................................................................................106 STUDY 17: HUMAN CELLS EXPOSED TO THE OESTROGENIC COMPOUND ZERANOL..............................................107 EVALUATION OF RECENT STUDIES CITED BY THE EC............................................................................110 METABOLISM OF 17b-OESTRADIOL AND QUANTITATIVE ANALYSIS OF OESTROGEN RESIDUES IN EDIBLE TISSUES FROM TREATED STEERS...............................................................................................................................110 OESTROGENIC POTENCY OF RESIDUES.........................................................................................................................112 RECENT FINDINGS ON THE MUTAGENICITY AND GENOTOXICITY OF 17b-OESTRADIOL ........................................118 MUTAGENICITY AND GENOTOXICITY OF MGA ..........................................................................................................133 ANNEX 2: LIST OF JECFA EVALUATIONS ........................................................................................................134 ___________________________________________________________________________ - 2 - Australian Pesticides and Veterinary Medicines Authority ANNEX 3: PUBLIC HEALTH CONSIDERATIONS OF HGPS BY REGULATORY COMMITTEES IN AUSTRALIA ................................................................................................................................................136 ANNEX 4: MINUTES OF THE ADVISORY COMMITTEE ON PESTICIDES AND HEALTH RELATING TO THE HEALTH ASSESSMENT OF HGPS ..........................................................145 ANNEX 5: HGP POSITION PAPER...........................................................................................................................159 REFERENCES ...................................................................................................................................................................167 SECONDARY CITATIONS ..........................................................................................................................................171 ___________________________________________________________________________ - 3 - Hormone Growth Promotants ABBREVIATIONS Time Weight d Day bw Body weight h Hour g Gram min Minute kg Kilogram mo Month mg Milligram wk Week mg Microgram s Second ng Nanogram yr Year wt Weight Length Dosing cm Centimetre id Intradermal m Metre im Intramuscular µm Micrometre inh Inhalation mm Millimetre ip Intraperitoneal nm Nanometre iv Intravenous po Oral sc Subcutaneous mg/kg bw/d mg/kg bodyweight/day Volume Concentration L Litre M Molar mL Millilitre ppb Parts per billion µL Microlitre ppm Parts per million Chemistry bPR bovine uterine progestin receptor BSO L-buthionine(S,R)sulfoximine COMT catechol-O-methyltransferase CYP1A1 oestrogen-2-hydroxylase CYP1b1 17b-oestradiol-4-hydroxylase dA deoxyadenosine dG deoxyguanosine DMSO dimethylsulphoxide DNA deoxyribonucleic acid EIA enzyme immunoassay ER oestrogen receptor ERa oestrogen receptor alpha ERb oestrogen receptor beta hER human oestrogen receptor GC-MS gas chromatography-mass spectrometry hprt hypoxanthine-guanine phosphoribosyltransferase hER human oestrogen receptor hSHBG human sex-hormone binding globulin HPLC high performance liquid chromatography LC-DAD liquid chromatography with diode array detection LC-MS liquid chromatography-mass spectrometry mRNA messenger ribonucleic acid MNNG N-methyl-N-nitro-N-nitroso-guanidine 8-oxo -dG 8-hydroxy -2’-deoxyguanosine
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