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リスク評価における不確実係数の表現法 - NIHS

Hazard Identification Dose-response Assessment Exposure Assessment Risk Characterization 2 Problem Formulation Toxic effects with threshold Toxic response Dose 0 Threshold Toxic response Dose 0 Non-threshold carcinogenicity (DNA-direct acting chemicals) TDI/ADI approach (UF approach) Linear extrapolation or MOE approach (BMD method) 3 ( ) (UF) [ (SF) ] 100 ( ) 100 (100) 100 1mg 50kg 2 mg/kg/ 1/100 mg/kg/ 1mg 4

ADI: Acceptable Daily Intake ) 又は耐容一日摂取量( TDI: Tolerable Daily Intake )の算定。 ADI = NOAEL/SF (Safety factor: 安全係数) TDI = NOAEL/UF (Uncertainty factor : 不確実係数) 不確実性の要因

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  Acceptable, Daily, Intake, Acceptable daily intake, Daily intake

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Transcription of リスク評価における不確実係数の表現法 - NIHS

1 Hazard Identification Dose-response Assessment Exposure Assessment Risk Characterization 2 Problem Formulation Toxic effects with threshold Toxic response Dose 0 Threshold Toxic response Dose 0 Non-threshold carcinogenicity (DNA-direct acting chemicals) TDI/ADI approach (UF approach) Linear extrapolation or MOE approach (BMD method) 3 ( ) (UF) [ (SF) ] 100 ( ) 100 (100) 100 1mg 50kg 2 mg/kg/ 1/100 mg/kg/ 1mg 4 5 TDI UF UFh UF TDI(N) NOAEL (A) NOAEL (H)

2 UFa UFh UFa 7 1 10 1 10 NOAEL LOAEL 1 10 TDI 1 10 1 10 NOAEL no observed adverse effect level LOAEL: lowest observed adverse effect level ADI: acceptable daily intake TDI: Tolerable daily intake ADI = NOAEL/SF (Safety factor: ) TDI = NOAEL/UF (Uncertainty factor: ) 8 WHO WQGD IRIS : JMPR ATSDR ----------------------------------- Total 8112033133431143571527081701452705010015 0200250300350400135610202530506066901001 50200250300500100020003000500010000UF 115 151 26 122 27 LOAEL Short-term Carcinogenisity lack of data LOAEL 1 1 24 3 86 0 0 0 10 20 30 40 50 60 70 80 90 100 UF Short-term 0 0 23 0 128 0 0 0 50 100 150 200 UF 9 1 10* 1 10 NOAEL LOAEL 1 10 TDI 1 10 1 10 NOAEL no observed adverse effect level LOAEL: lowest observed adverse effect level ADI: acceptable daily intake TDI.

3 Tolerable daily intake ADI = NOAEL/SF (Safety factor: ) TDI = NOAEL/UF (Uncertainty factor: ) * Caloric demand CSAF UNCERTAINTY FACTOR 100 FOLD INTER - SPECIES DIFFERENCES 10 FOLD INTER - INDIVIDUAL DIFFERENCES 10 FOLD TOXICO - DYNAMIC AD UF 10 ( ) TOXICO - KINETIC AK UF 10 ( ) TOXICO - DYNAMIC HD UF 10 ( ) TOXICO - KINETIC HK UF 10 ( ) - INTER - SPECIES DIFFERENCES 10 FOLD INTER - INDIVIDUAL DIFFERENCES 10 FOLD TOXICO - DYNAMIC AD UF 10 ( ) TOXICO - KINETIC AK UF 10 ( ) TOXICO - DYNAMIC HD UF 10 ( ) TOXICO - KINETIC HK UF 10 ( ) A animal to human; H human variability; toxicodynamics ; K toxicokinetics A animal to human; H human variability; D toxicodynamics.

4 K toxicokinetics TOXICO - DYNAMIC AD AF - TOXICO - KINETIC AK AF - TOXICO - DYNAMIC HD AF - TOXICO - KINETIC HK AF - AF - the adjustment factor calculated from chemical-specific data AUC CL 10 TK WHO NOAEL mg/kg / 10 NOAEL GFR 145 23 mL/ 144 32 mL/ 95 2 GFR 144 mL/ 144 32 2=80 mL/ 6 60 10 6 TDI 60 mg/kg / LOAEL 100 200ng/kg 86ng/kg 86ng/kg LOAEL 1 pg/kg/ TDI 4 pg/kg/ AhR 10 1 )( )/(86 yearkgng UF 25000 CSAF AKAF 2500 13 1 10 1 10 NOAEL LOAEL 1 10 TDI 1 10 1 10 NOAEL no observed adverse effect level LOAEL: lowest observed adverse effect level ADI: acceptable daily intake TDI.

5 Tolerable daily intake ADI = NOAEL/SF (Safety factor: ) TDI = NOAEL/UF (Uncertainty factor: ) (UF) ADI/TDI ( ) ( ) ADI/TDI ( ) ( ) (UF) A A B B C (Ex. ) C TDI NOAEL TDI 16 NOAEL no observed adverse effect level LOAEL: lowest observed adverse effect level ADI: acceptable daily intake TDI: Tolerable daily intake ADI = NOAEL/SF (Safety factor: ) TDI = NOAEL/UF (Uncertainty factor.)

6 1 10 1 10 NOAEL LOAEL 1 10 TDI 1 10 1 10 F3 = A variable factor to account for toxicity studies of short-term exposure F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for cats,dogs and monkeys). F3 = 1 for reproductive studies in which the whole period of organogenesis is covered. F3 = 2 for a 6-month study in rodents, or a study in non-rodents. F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents. F3 = 10 for studies of a shorter duration. In all cases, the higher factor has been used for study durations between the time points, a factor of 2 for a 9-month rodent study.

7 ICH Q3C (R4) Solvents F3 90 .. 6 90 12 .. 2 12 .. 1 90 UF:10 (UF) 18 1 10 1 10 NOAEL LOAEL 1 10 TDI 1 10 1 10 NOAEL no observed adverse effect level LOAEL: lowest observed adverse effect level ADI: acceptable daily intake TDI: Tolerable daily intake ADI = NOAEL/SF (Safety factor: ) TDI = NOAEL/UF (Uncertainty factor: ) 19 Benchmark Dose BMD BMDL TDI 95% BMR BMDL BMD BMR 95% BMDL 5% 10% BMDL NOAEL NOAEL TDI Toxic effects with threshold Toxic response Dose 0 Threshold Toxic response Dose 0 Non-threshold carcinogenicity (DNA-direct acting chemicals) TDI/ADI approach (UF approach) Linear extrapolation or MOE approach (BMD method)

8 21 DNA VSD 100 mg/kg/day 0 20 1 BMDL10 10000 60 50 10 90 10 BMDL10 22 VSD DNA MOE 100 mg/kg/day 0 20 60 90 10 BMDL10 23 BMDL10 MOE 10,000 20 9 2 : 2009 21 6 11 NOAEL ADI/TDI ( ) 95% MOE UF (UF) MOE BMDL VSD(at 10-5 risk) ( ) 1/10,000 BMD 95% MOE MOE (2009 7 ) 2009 6 PVP 2013 5 6 P35-p37 PVP NOAEL BMDL10 (mg/kg / ) MOE / (NOAEL) 200 50 (BMDL10)

9 310 78 MOE (BMDL10) 180 45 MOE Margin of Exposure BMDL NOEL 72nd JECFA(2010) 1 g/kg bw/day 4 g/kg bw/day BMDL 1/10,000 BMD MOE? JECFA 2010 FFQ The different MOEs for genotoxic carcinogens from different origins Simplified MOE approaches bring different degrees of risk Contaminants in foods or drinking water: 10,000 (unintentionally intake , unavoidable risk) Byproducts in food additives: 100,000 (intentionally intake , avoidable risk?)

10 Foods components, chemicals generated during cooking: concern? or no concern? (unintentionally intake ?, unavoidable food intake ?) Risk communication and/or risk tradeoff analysis is required 31 95


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