EUROPEAN COMMISSION XXIV/B3/SC4 DIRECTORATE-GENERAL XXIV CONSUMER POLICY AND CONSUMER HEALTH PROTECTION Directorate B - Scientific Health Opinions Unit B3 - Management of scientific committees II OPINION OF THE SCIENTIFIC COMMITTEE ON VETERINARY MEASURES RELATING TO PUBLIC HEALTH ASSESSMENT OF POTENTIAL RISKS TO HUMAN HEALTH FROM HORMONE RESIDUES IN BOVINE MEAT AND MEAT PRODUCTS _________________________ 30 APRIL 1999 (references completed) INDEX 1. INTRODUCTION...................................................................................................1 1.1. Mandate.........................................................................................................1 1.2. Background....................................................................................................1 1.3. General considerations and introduction to the report: ....................................2 2. EMERGING CONCERNS RELATED TO HORMONALLY ACTIVE SUBSTANCES .......................................................................................................4 2.1. Definitions......................................................................................................4 2.2. Effects of hormones at different stages of life..................................................5 2.2.1. Effects of sex hormones during the intrauterine and perinatal periods on development ....................................................................5 2.2.2. Endocrine effects of sex hormones on growth and puberty in humans ........................................................................................... 11 2.2.3. Effects of sex hormones on reproduction......................................... 15 2.3. Human exposure to oestrogens and its relationship to cancer........................ 16 2.3.1. Descriptive epidemiology................................................................ 16 2.3.2. Etiologic epidemiology ................................................................... 17 2.3.3. Other hormonal effects relevant to cancer ....................................... 21 2.4. Sexual hormones and the immune system...................................................... 22 2.4.1. Sexual hormones and autoimmunity ................................................ 22 2.4.2. Sexual hormones and tolerance to the foetus in pregnancy; orientation of the immune response and allergic diseases ................. 23 2.5. OESTROGEN METABOLITES AS DNA-REACTIVE AND GENOTOXIC SUBSTANCES .................................................................... 24 2.5.1. DNA damage by oestrogen-3,4-quinones ........................................ 24 2.5.2. Properties of 4-Catechol-Oestrogens: Formation of Depurinating Adducts and Tumor Initiation..................................... 25 2.5.3. Redox Cycling of Catechol-Oestrogens, Their Semiquinones and Quinones.................................................................................. 26 2.5.4. Testing the genotoxicity of oestrogens ............................................ 27 I 3. GENERAL CONSIDERATIONS RELATING TO EXPOSURE ASSESSMENT ..................................................................................................... 27 3.1. Quantification of hormones in edible tissues.................................................. 27 3.2. Exposure in relation to endogenous hormone production in humans at different stages of life ................................................................................... 28 3.3. Exposure considerations upon misuse........................................................... 30 3.3.1. Misplaced implants.......................................................................... 30 3.3.2. Off-label use ................................................................................... 31 3.3.3. Black-market drugs......................................................................... 31 3.3.4. Secondary risks............................................................................... 32 4. CHARACTERISTICS OF THE INDIVIDUAL COMPOUNDS UNDER CONSIDERATION............................................................................................... 33 4.1. 17 β-oestradiol............................................................................................. 33 4.1.1. Pharmacokinetics and biotransformation of 17β-oestradiol in animals............................................................................................ 33 4.1.2. Oestradiol disposition in the target animal ....................................... 34 4.1.3. Interactions..................................................................................... 35 4.1.4. Pharmacokinetics and biotransformation of 17β-oestradiol in humans. .......................................................................................... 36 4.1.5. Assessment of excess exposure to oestrogens from consumption of hormone-treated beef ............................................. 36 4.1.6. Genotoxicity................................................................................... 39 4.1.7. DNA adducts and DNA damage ..................................................... 41 4.1.8. Carcinogenicity............................................................................... 42 4.1.9. Effects on growth and reproduction ................................................ 43 4.1.10. Effects on the immune system ......................................................... 44 4.2. Testosterone................................................................................................. 45 4.2.1. Pharmacokinetics and Biotransformation of Testosterone in animals............................................................................................ 46 4.2.2. Testosterone disposition in the target animal ................................... 46 II 4.2.3. Pharmacokinetics and Biotransformation (in humans)...................... 47 4.2.4. Assessment of Excess Exposure to testosterone from Consumption of Hormone-treated Beef........................................... 47 4.2.5. Mutagenicity and genotoxicity of testosterone................................. 49 4.2.6. DNA adducts and DNA damage ..................................................... 49 4.2.7. Carcinogenicity............................................................................... 49 4.2.8. Effects of testosterone on growth and reproduction ........................ 50 4.2.9. Effects of testosterone on the immune system ................................. 50 4.3. Progesterone ................................................................................................ 51 4.3.1. Pharmacokinetics and biotransformation of progesterone in animals............................................................................................ 51 4.3.2. Progesterone disposition in the target animal................................... 52 4.3.3. Pharmacokinetics and biotransformation of progesterone in humans ........................................................................................... 52 4.3.4. Assessment of excess exposure to progesterone from consumption of hormone-treated beef ............................................. 52 4.3.5. Mutagenicity and genotoxicity of progesterone ............................... 54 4.3.6. DNA adducts and DNA damage ..................................................... 54 4.3.7. Carcinogenicity............................................................................... 54 4.3.8. Effect of progesterone on growth and reproduction......................... 54 4.3.9. Effects of progesterone on the immune system................................ 55 4.4. Trenbolone................................................................................................... 55 4.4.1. Pharmacokinetics and biotransformation of trenbolone in animals............................................................................................ 55 4.4.2. Trenbolone disposition in the target animal...................................... 56 4.4.3. Pharmacokinetics and biotransformation of trenbolone in humans ........................................................................................... 56 4.4.4. Assessment of exposure to trenbolone from consumption of hormone-treated beef...................................................................... 57 4.4.5. Mutagenicity and genotoxicity ........................................................ 57 III 4.4.6. DNA adducts and DNA damage ..................................................... 59 4.4.7. Carcinogenicity............................................................................... 59 4.4.8. Effect of trenbolone on growth and reproduction ............................ 59 4.4.9. Effects of trenbolone on the immune system.................................... 60 4.5. Zeranol......................................................................................................... 60 4.5.1. Pharmacokinetics and biotransformation of zeranol in animals......... 60 4.5.2. Zeranol disposition in the target animal ........................................... 61 4.5.3. Pharmacokinetics and biotransformation of zeranol in humans......... 63 4.5.4. Assessment of exposure to zeranol from consumption of hormone-treated beef...................................................................... 63 4.5.5. Mutagenicity and genotoxicity of zeranol........................................ 64 4.5.6. DNA adducts and DNA damage ..................................................... 64 4.5.7. Carcinogenicity..............................................................................