... 4...5...6...7...10...11... 12...12...12...13...14...15...15...16...16...17...17...18...18...19...19...19 Hill...20...20...21...21...22...23...24...25... 34...34...35...38-2 -
...41...49...51...51...51...52...53...56...56...57...60...60-3 -
In silico (ERα, ERβ, AR, TR, AhR, In vitro (ERα, ERβ, AR, TR, AhR, ) In vivo (ER, AR, TR, AhR, ) Hold - 4 -
- 5 -
74.Thiophenol 93.Hexabromocyclododecane 88.Bumetrizole UV - 6 -
α Helix No. 12 100 80 60 40 20 0 11 10 9 8 7 6 Log [ (M)] 5-7 -
- 8 - Ligand / Receptor Complex Coated Antigen Secondary Antibody Chromogenesis Ligand 100 90 80 70 60 50 40 30 7 8 9 10 11 12 13 14 Log [Receptor (M)] 100 90 80 70 60 50 40 30 7 8 9 10 11 12 13 14 100 90 80 70 60 50 40 30 7 8 9 10 11 12 13 14 Log [Receptor (M)] Log [Receptor (M)] 100 90 80 70 60 50 40 30 7 8 9 10 11 12 13 14 Log [Receptor (M)] 100 90 80 70 60 50 40 30 7 8 9 10 11 12 13 14 100 90 80 70 60 50 40 30 7 8 9 10 11 12 13 14 Receptor Receptor Antibody Antibody Coated Antigen Secondary Antibody Chromogenesis DAX SHP GCNF1 LRH1 SF1 NOR1 NURR1 NGFIB AR PR MR ERRγ ERRβ ERRα ERβ ERα GR EAR2 COUPβ COUPα PNR TLL TR4 TR2 RXRγ RXRβ RXRα HNF4γ HNF4α CAR PXR VDR FXRβ FXR LXRβ LXRα RORγ RORβ RORα Rev-erb β Rev-erb α PPARγ PPARβ PPARα RARβ RARα TRβ TRα DAX SHP GCNF1 LRH1 SF1 NOR1 NURR1 NGFIB AR PR MR ERRγ ERRβ ERRα ERβ ERα GR EAR2 COUPβ COUPα PNR TLL TR4 TR2 RXRγ RXRβ RXRα HNF4γ HNF4α CAR PXR VDR FXRβ FXR LXRβ LXRα RORγ RORβ RORα Rev-erb β Rev-erb α PPARγ PPARβ PPARα RARβ RARα TRβ TRα
- 9 -. α β β β α α α β αβ β α α β β
in silico (RBA) ERER in vitro ERERARTR ER Cell free ERE SPRHTPS ERER - 10 -
0 10 20 30 40 50 60 70 80 * F1 * * F2 * * * 0 10 20 30 40 50 60 70 * * * In silico (ERα, ERβ, AR, TR, AhR, In vitro (ERα, ERβ, AR, TR, AhR, ) Hold In vivo (ER, AR, TR, AhR, ) - 11 -
(incidence) mortalityprevalence person-years 10 10 10 10 160 160 10 10 160 10 160 1.6-12 -
10 10 10 10-13 -
risk (relative risk, RR)(odds ratio, OR)correlation coefficient 400 10 100 400/100 10,000 10,000 10 10,000 400 40010 10,000 100 10010 300 100 300/100 100 100 80 50 100 100 100 100 80 50 20 50 80/20=4 50/50=1 4/1=4 100 100-14 -
80/(80+50k)k 20/(20+50k) {80/(80+50k)}/{20/(20+50k)} 80+50k 20+50k 50k (80/50)/(20/50)(80/20)/(50/50) () study design 1) randomized controlled trial 2) (cohort study) 3) retrospective cohort study 4) (case-control study) 5) (nested case-control study) 6) (cross-sectional study) 7) (ecological study) intervention study observational study random allocation supplement placebo - 15 -
cohort O/E observed to expected ratiostandardized mortality ratio, SMRstandardized incidence ratio, SIR O/E observed O/E expected O/E - 16 -
O/E 100 100 (case) (control) population controlhospital control matching individual matchingfrequency matching - 17 -
PCB PCB PCB - 18 -
chance (bias) (confounding) (causality) alternative explanations - 19 -
causal inference Hill Hill 1964 U.S. Surgeon General's Advisory Committee on Smoking and Health, 1964 Hill, 1965 1965 1 14 association (causation) 9 (viewpoints) criteria 1991 10 1994 1996 1998 2000 2002 2002-20 -
Department of Health and Human Services1980 The Report on Carcinogens2000 218 Known to be human carcinogen Reasonably anticipated to be human carcinogen sufficient evidence limited evidence International Agency for Cancer Research1972 IARC IARC Monographs on the Evaluation of Carcinogenic Risks to Humans (a) (b) (c) (a) - 21 -
(a) (c) sufficient evidencea probably limited evidence sufficient evidenceb possibly limited evidence less than sufficient evidence inadequate inadequatelimited probably evidence suggesting lack of carcinogenicity 1964 2004 5 28 The Health Consequence of Smoking: A Report of the Surgeon General 1964 1 941 Introduction and approach to causal inference 1964-22 -
associated with a significant increase1969 a likely risk factor1971 (a major risk factor)(1973) (strong associations)(1974) a major, independent risk factor(1980) the most powerful risk factor1983 a cause and the most powerful risk factor1989 A D Hill Hill evidence against competing noncausal explanations (evidence supporting causal ones [explanations]) Hill Hill - 23 -
Hill - 24 -
Hill AB. The environment and disease: association or causation? Proc Roy Soc Med 1965;58:295-300. National Academy of Sciences. Veterans and Agent Orange, Update 2002, Executive Summary. Washington DC: National Academy Press, 2003 National Toxicology Program. Report on Carcinogens. Ninth edition. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, 2000. International Agency for Research on Cancer. Some Internally Deposited Radionuclides. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 78. Lyon: International Agency for Research on Cancer, 2001. U.S. Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. - 25 -