Attached Sheet Original: Japanese Provisional translation Fundamental Concepts in the Safety Assessment of Foods Containing Soy Isoflavones for the purpose of Specified Health Use May 2006 Food Safety Commission Novel Foods Expert Committee Notes Note 1: In this report “Soy isoflavones,” unless specified otherwise, indicates total isoflavone, including glycoside/glycosides and aglycone/aglycones, and where expressed as “soy isoflavone glycoside” or “soy isoflavone aglycone” indicates soy isoflavone glycoside or soy isoflavone aglycone respectively. Note 2: In this report, when converting soy isoflavone glycoside to soy isoflavone aglycone, in the event that the composition ratio is not clearly defined, the ratio of the molecular weight of genistein (270.24) to that of its glycoside, genistin (432.38), i.e. (0.625), is used as the coefficient. The reason for using the value of genistein is that it has the greatest binding capacity to estrogen receptor of the soy isoflavone aglycones. 1 Contents Notes............................................................................................................................................. 1 Progress of evaluation ................................................................................................................. 5 Food Safety Commission Members............................................................................................. 6 Food Safety Commission Novel Foods Expert Committee Members ........................................ 6 1 Introduction.......................................................................................................................... 7 2 Overview of soy isoflavone ................................................................................................. 10 2.1 Properties of soy isoflavone ......................................................................................... 10 2.2 Internal metabolism of soy isoflavones (kinetics) ...................................................... 10 2.3 Currently known biological effects of soy isoflavones ................................................ 11 2.3.1 Biological effects via estrogen receptor ................................................................ 11 2.3.2 Topoisomerase inhibition effect ............................................................................ 11 2.3.3 Other...................................................................................................................... 12 2.3.3.1 Animal testing ................................................................................................ 12 2.3.3.2 Human tests etc.............................................................................................. 12 2.4 Diagnostic markers used in soy isoflavones safety assessment ................................ 13 3 Dietary intake of soy isoflavone from soy food products................................................... 13 3.1 Content of soy isoflavones in various soy food products ............................................ 13 3.2 Dietary intake of soy isoflavones from soy food products based on 2002 National Nutrition Survey (provisional calculation)................................................................. 14 3.3 Others........................................................................................................................... 15 4 Test reports on soy isoflavones........................................................................................... 16 4.1 Reports on pharmacokinetics ...................................................................................... 16 4.1.1 Animal testing ....................................................................................................... 16 4.1.2 Human tests and observational studies etc. ........................................................ 17 4.2 Test reports regarding safety ...................................................................................... 19 4.2.1 Animal tests........................................................................................................... 19 4.2.2 Observational studies in human........................................................................... 22 4.2.2.1 Premenopausal females.................................................................................. 22 4.2.2.2 Postmenopausal females ................................................................................ 25 4.2.2.3 Males ............................................................................................................... 29 4.2.2.4 Pregnant females (including potentially pregnant), fetuses, infants and small children.................................................................................................. 30 4.2.2.5 Other human tests.......................................................................................... 31 4.2.3 Others .................................................................................................................... 32 4.2.3.1 Reports on risk of cancer etc. ......................................................................... 32 4.2.3.2 Relativity to cancer with high sensitivity to estrogen................................... 32 4.2.3.3 Points of concern regarding intake of hormonal agents (pharmaceuticals) etc..................................................................................................................... 33 5 Situation of investigations in other countries................................................................... 34 2 5.1 Situation of Food Standard Agency (FSA) investigations.......................................... 34 5.2 Situation of Food and Drug Administration (FDA) and Agency for Healthcare Research and Quality (AHRQ) investigations ........................................................... 35 5.3 Situation of Agence Française de Sécurité Sanitaire des Aliments (AFSSA) investigations............................................................................................................... 36 5.4 Situation of investigations in other countries ............................................................ 36 6 Concept regarding safety assessment ............................................................................... 36 6.1 Establishing a safe upper limit for standard intakes of soy isoflavone..................... 37 6.1.1 Establishing an upper limit for standard daily intakes of soy isoflavone based on dietary experience ............................................................................................ 37 6.1.2 Establishing an upper limit for standard daily intakes of soy isoflavone based on human clinical research ................................................................................... 37 6.1.3 Establishing the upper limit for daily extra dietary intake of soy isoflavone as a food for specified health use based on human clinical research....................... 38 6.1.4 Summary of establishment of upper limit for standard intakes of soy isoflavone ............................................................................................................... 40 6.1.4.1 Upper limit for standard daily intakes of soy isoflavone .............................. 40 6.1.4.2 Upper limit for daily extra dietary intake of soy isoflavone as a food for specified health use......................................................................................... 41 6.2 Validation of established safe dietary intake standards for soy isoflavone............... 41 6.2.1 Premenopausal females, postmenopausal females, and males........................... 41 6.2.2 Pregnant females (including potentially pregnant), fetuses, infants and small children .................................................................................................................. 42 6.2.2.1 Pregnant females (including potentially pregnant) and fetuses .................. 42 6.2.2.2 Infants and small children ............................................................................. 42 6.2.3 Regarding equol production capacity ................................................................... 43 7 Results of safety assessment.............................................................................................. 43 7.1 Premenopausal females, postmenopausal females, and males ................................. 43 7.2 Pregnant females (including potentially pregnant), fetuses, infants and small children ........................................................................................................................ 43 7.2.1 Pregnant females (including potentially pregnant) and fetuses......................... 43 7.2.2 Infants and small children.................................................................................... 44 8 Summary ............................................................................................................................ 44 8.1 Premenopausal females, postmenopausal females, and males ................................. 44 8.1.1 Expected upper limit for safe standard daily intakes of soy isoflavone.............. 44 8.1.2 Expected upper limit for safe daily extra dietary intake of soy isoflavone as a food for specified health use.................................................................................. 45 8.2 Regarding pregnant females, fetuses, infants and small children ............................ 45 9 Conclusions........................................................................................................................