US EPA SAB Evaluation of Dioxin Assessment 1995

US EPA SAB Evaluation of Dioxin Assessment (1995) ¢ Substantive changes were needed to the chapter on dose–response modeling and risk characterization. ¢ EPA should develop a new chapter on toxicity equivalence factors (TEFs). ¢ The health and exposure sections did not require significant changes. ¢ The revised chapters on dose–response modeling and risk characterization should undergo external peer review prior to the SAB rereview of these issues.

US EPA SAB Evaluation (2001) of Dioxin Reassessment (2000) ¢ Human Carcinogen Designation TCDD : 인체발암물질 (HUMAN CARCINOGEN) DIOXIN : 유력한 인체발암물질 (LIKELY HUMAN CARCINOGEN) l the lack of a consistent carcinogenic response across the various epidemiological studies l the small relative risks observed in each study over a wide range of exposures l the possible impact of confounders l the lack of understanding of the mechanism of action l the fact that the primary increase demonstrated by EPA is in total number of tumors Source : Paustenbach, Regul. Toxicol. & Pharma. , 2002 : 36 ; 211 -219

Epidemiology Data : Linear Dose-Response? Source : Paustenbach, Regul. Toxicol. & Pharma. , 2002 : 36 ; 211 -219

US NAS Evaluation (2003) of Dioxin Reassessment (2000) ¢ Definition of Dioxin-like compounds l PCDDs : polychlorinated dibenzo-p-dioxins l PCDFs : polychlorinated dibenzofurans l PCBs : polychlorinated biphenyls l PBDDs : polybrominated dibenzo-p-dioxins l PBDFs : polybrominated dibenzofurans Source : NAS Review Draft report, 2003

독일 산업 근로자의 다이옥신 노출에 의한 암 사망률 비교 IHD : ischaemic heart disease SMR : standardized mortality ratio

NAS 2003 Review draft Dose-Response assessment : cancer slope factor - 2 ¢ Summary of the combined cohort and selected industrial cohort studies with high exposure levels Reference All cancers Lung cancer Observed SMR 95% CI 394 1. 2 1. 1 – 1. 3 127 1. 2 1. 0 – 1. 4 International cohort Kogevinas et al. (1997) Industrial populations (high-exposure subcohorts) Fingerhut et al. (1991 a) (USA) 114 1. 5 1. 2 – 1. 8 40 1. 4 1. 0 – 1. 9 Becher et al. (1996) (Germany) 105 1. 3 1. 0 – 1. 5 33 1. 4 1. 0 – 2. 0 51 1. 5 1. 1 – 1. 9 14 1 0. 5 – 1. 7 18 1. 9 1. 1 – 3. 0 7 2. 4 1. 0 – 5. 0 288 1. 4 1. 2 – 1. 6 94 1. 1 – 1. 7 Hooiveld et al. (1996) (Netherlands) Ott and Zober (1996 b) (BASH accident) Total P value < 0. 001 < 0. 01

NAS 2003 Review draft Dose-Response assessment : cancer slope factor - 3 ¢ Summary of all site cancer ED 01 and slope factor Study ED 01 (LED 01) (ng/kg) Model Cancer slope factor (pg/kg-day)-1 Epidemiological data Hamburg cohort, Becher at al. (1998) Power 6 5. 1 x 10 -3 Hamburg cohort, Becher at al. (1998) Additive 18. 2 1. 6 x 10 -3 Hamburg cohort, Becher at al. (1998) multiplicative 32. 2 8. 9 x 10 -4 NIOSH cohort, Steenland et al. (2001) Linear 18. 6 (11. 5) 1. 5 x 10 -3 BASF cohort, from Ott and Zober (1996) multiplicative 50. 9 (25. 0) 5. 7 x 10 -4 Linear Dose : 32 (22) Adipose : 38(28) 9. 7 x 10 -4 8. 0 x 10 -4 Animal study data Sprague-Dawely rats, Kociba et al. (1978) Goodman and Sauer (1992), pathology Total 미국 EPA 제안 (1988) 미국 EPA 제안 (1994) 미국 EPA 최근 제안 (2000/03) (Geo-mean) 1. 0 x 10 -5 1. 0 x 10 -4 1. 0 x 10 -3

NAS 2003 Review draft Dose-Response assessment : non-cancer effect - POD ¢ ¢ Non-cancer ED 01 ¢ 1 – 100 ng/kg-day ¢ 10 – 1000 ng/kg body burden Point of departure ¢ Middle range : – 500 ng/kg 100 ¢ Safety factor = 10 ¢ POD : 10 – 50 ng/kg

NAS 2003 Review draft Exposure assessment - 2 ¢ Adult contact rates and background intakes of dioxins Exposure route Contact rate Dioxins and Furans Dioxin-like PCBs Total Levels Intake (TEQ-WHO 98) (pg TEQWHO 98/kg-d) Soil ingestion 50 mg/d 9. 3 pg/g 0. 0066 2. 3 fg/g 0. 0016 0. 0082 Soil dermal 12 g/d 9. 3 pg/g 0. 0016 2. 3 fg/g 0. 00039 0. 002 Freshwater fish & shellfish 5. 9 g/d 1. 0 pg/g 0. 084 1. 2 pg/g 0. 18 Marine fish & shellfish 9. 6 g/d 0. 26 pg/g 0. 036 0. 25 pg/g 0. 034 0. 07 Inhalation 13. 3 m 3/d 0. 12 pg/m 3 0. 023 NA 0. 023 Milk 175 g/d 0. 018 pg/g 0. 045 0. 088 pg/g 0. 022 0. 067 Dairy 55 g/d 0. 12 pg/g 0. 094 0. 058 pg/g 0. 046 0. 14 Eggs 0. 24 g/kg-d 0. 081 pg/g 0. 019 0. 101 pg/g 0. 024 0. 043 Beef 0. 67 g/kg-d 0. 18 pg/g 0. 13 0. 084 pg/g 0. 06 0. 19 Pork 0. 22 g/kg-d 0. 28 pg/g 0. 062 0. 012 pg/g 0. 0026 0. 065 Poultry 0. 50 g/kg-d 0. 068 pg/g 0034 0. 026 pg/g 0. 013 0. 047 Other meats 0. 35 g/kg-d 0. 18 fg/g 0. 062 0. 041 pg/g 0. 014 0. 076 Vegetable fat 17 g/d 0. 056 pg/g 0. 014 0. 037 pg/g 0. 009 0. 023 Water 1. 4 L/d 0. 0005 pg/L 0. 000011 NA 0. 000011 0. 33 0. 94 Total 0. 61 NA NA

NAS 2003 Review draft Exposure assessment - 3 ¢ Variability in average daily toxic equivalent (TEQ) intake as a function of age Age range Intake, mass basis (pg TEQ-WHO 98/d) Intake, body weight basis (pg TEQ-WHO 98/kg-d) 1 – 5 years 50 3. 3 6 -11 years 54 1. 8 12 – 19 years 61 1. 1 Adult 66 0. 9

NAS 2003 Review draft Exposure assessment - 4 ¢ Predicted distributions and average levels within an adult population for four years

NAS 2003 Review draft Exposure assessment - 5 ¢ ¢ ¢ Peak dioxin body burden levels in background populations and epidemiological cohort Mean background level of USA ¢ 47. 6 ppt lipid ¢ 11. 9 ng/kg BB Occupational exposure ¢ 10 – 1000 times of background exposure

NAS 2003 Review draft Exposure assessment : Special population ¢ Sensitive subpopulations l l l Nursing infants Women of childbearing age Individual unique diets Occupationally exposed individuals Cigarette smokers Individuals who may live near significant sources

NAS 2003 Review draft Exposure assessment : Age-specific exposure - 1 ¢ Fetuses l l ¢ Reflect the body burden of the mother Greatest impact on the mother’s body burden is form of her lifetime exposure history Nursing infants l l Special cases Depend on breast feeding periods A limited portion of their lives Short-term increased intake levels will have limited additional impact on risk as compared with overall lifetime exposure

NAS 2003 Review draft Exposure assessment : Age-specific exposure - 2 ¢ Nursing scenarios l l (a) Lipid levels Formula only, 6 week, 6 month, 1 year, 2 years In all four scenarios, the lipid concentrations merged at about 10 years of age at a concentration of about 13 ppt lipid level (2 ppt BB). (b) Body burden

NAS 2003 Review draft Risk characterization ¢ Background exposure l l l ¢ Dose-response assessment l l ¢ Daily intake : 1 pg-TEQ/kg-day Tissue level : 25 pg-TEQ/g lipid Body burden : 5 ng-TEQ/kg Cancer slope factor : 1 x 10 -3 (pg/kg-day)-1 POD for non-cancer effects : 10 -50 ng/kg Risk characterization l l Excess cancer risk : 1/1000 – 1/100 MOE : 10 or less

Exposure and risk assessment by EU Commission (2000) ¢ Effect assessment l l l ¢ Neurodevelopmental effect Reproductive effect Endocrine effects Dose-response assessment l l l PTMI : 70 pg/kg-month TWI : 14 pg/kg-week TDI : 2. 3 – 2. 0 pg/kg-day Source : NAS Review Draft report, 2003

Exposure and risk assessment by EU Commission (2000) ¢ Exposure assessment l l ¢ Bioaccumulation is continuing along the trophic chain Average dietary intake : 1. 2 – 3. 0 pg/kg-day Risk characterization l l European population would still exceed the TWI or TDI The sharp decrease of ‘background levels’ on the environment in the last 20 years Necessary to develop a Community strategy for dioxins and PCBs

CONTENTS ¢ ¢ Human Exposure : Trends in Worldwide Exposure l Human exposure : 구두발표(26편), 포스터발표(29편) l Body burden : 구두발표(10편), 포스터(45편) Human Poisonings and epidemiology l Poisoning : 구두발표(9편), 포스터발표(2편) l Epidemiology : 구두발표(4편), 포스터(3편)

HUMAN EXPOSURE – 1 Trends in Worldwide Exposure ¢ Various POPs l l l PCDDs/Fs, Dioxin-like PCBs Hydroxylated PCBs PCNs (polychlorinated naphthalenes) PC-Paraffins (polychlorinated Paraffins) Polychlorinated musk components as well as the PBDEs ¢ Analysis of human samples and various foods, mainly of animal origin ¢ Focused on exposure of different populations

HUMAN EXPOSURE – 2 Trends in Worldwide Exposure ¢ Human levels of Dioxins and PCBs in Russian l l ¢ PCNs levels of New Yorker by Jiang et al. l l ¢ Detection range : 49 – 275 ng/g lipid Nonylphenol levels of Taiwan by Chen et al. l l ¢ Detection range : <900 – 19, 000 pg/g lipid Octa-CN was the predominant congener CPs in human milk of Germany by Reth et al. l ¢ Declining between 1988/89 and 2002/03 by more than 50% PBDEs in blood is very low (0. 1 – 0. 2 ng/g lipid) Maternal blood : 268 ng/g fat Umbilical cord blood : 50% lower of maternal blood EDI of PBDEs in Canadian by Daimond et al l EDI (Estimated daily intake) for adults : 155 ng/day, 2 ng/kg-day EDI for breast-fed infants : 1, 965 ng/day, 280 ng/kg-day For toddlers dust accounts for 90% of their EDI

HUMAN EXPOSURE – 3 Trends in Worldwide Exposure ¢ PBDEs levels of Kuwait by Gevaod et al. l l l ¢ 17 homes measured over six week (2004) Concentration range : 2. 4 – 385 pg/㎥ PBDE 47 : predominant congener (51% of total PBDEs) Median non-dietary PBDEs = 238 pg/day (adults) & 1041 pg/day (children) Dust ingestion pathway : 59% (adults) & 94% (children) Dust inhalation pathway : 41% (adults) & 6% (children) POPs levels in blood of Russian by Konoplev et al. l l HCBs, DDT, HCH, PCBs, PCDD/Fs, PBDEs POPs levels are increased only in the Easternmost and Westernmost areas of Russian Arctic

HUMAN EXPOSURE – 4 Body burden ¢ German l l l ¢ Acceptable weekly intake : 14 pg/kg-week Feeds for Dairy cow : not exceed 0. 1 ng/kg of dry matter 2002 feedstuffs survey : 1. 6% exceeding 2003 feedstuffs survey : 4. 7% exceeding 2004 feedstuffs survey : on going… North American (NA; Canada + USA) l l l 2002 Survey of body burden for PBDES, PCBs, DDT PBDEs : 75 – 150 ng/g lipid PCBs or DDTs : 100 – 300 ng/g lipid PCBs 1250 ng/g lipid BB : neurodevelopment effects in monkey PCBs 1650 ng/g lipid BB : behavioral impairment in monkey PBDEs 99 th, PCBs 98 th, DDT 95 th : concerning levels

HUMAN EXPOSURE – 5 ¢ Trend in Human exposure l Background exposure of populations to many organic compounds is of growing importance worldwide l Significant increase in reports describing the distribution of POPs among various tissues and the contribution of dietary and non-dietary intake of PBDEs l Many newer compounds such as BFRs, polycyclic musk components, hydroxy-metabolites of well studied POPs are now being investigated

Human Poisoning - 1 ¢ Yushchenko case by Ryan l l l ¢ First symptom : 3 hrs later symptoms of severe headache after Dinner Culminating with the expression of chloracne some weeks later The relatively long leg time of more than three months between appearance of the acute symptoms Bioassay of Yushchenko case by Abraham et al. l l l Blood sampling : 2004. 11 Bioassay : Dr CALUX High TEQ levels (about 100, 000 pg/g fat = 0. 1 ppm fat) in the serum PCBs : little or no 2, 3, 7, 8 -TCDD : 100 ng/g fat (100 ppb) in blood by GC-HRMS Total body burden : 1 - 2 mg or 20 ug/kg

Human Poisoning - 2 ¢ 2, 3, 7, 8 -TCDD poisoning by Alexandra et al. l l l ¢ Two young female patients (Vienna, 1997) Concentration : 144, 000 ng/g and 26, 000 pg/g Cytochrome P 450 1 A 2 activity : 8 -10 times higher than non smoker controls Seveso, Italy accidents study by Mocarelli at al. l l l A 10 -fold increase in serun TCDD level was associated with a lengthening of the menstrual cycle by 0. 93 days A reduction in the chronic in the chance for low menstrual flow Skewing of the sex ratio : males << females (p<0. 001) human male reproductive system is very sensitive to dioxin

Human Poisoning - 2 ¢ Yusho(Japan, 1968) & Yucheng(Taiwan) accident l l l Total PCBs (75㎍/g lipid) and TEQ (40 ng/g lipid) Decreased 2. 3 ㎍/g lipid and 0. 6 ng/g lipid Half lives : 4. 2 and 2. 5 years (first 15 years) 9. 1 and 7. 7 years (next 15 years) High level poisonings (10 -20 ㎍/kg) usually result in pain and poor health

Epidemiology - 1 ¢ Herbicide spraying in Veterans by Pavuk et al. l l Air Force Health Study – Ranch Hand veterians For Ranch Hands (1967 -1968년 사이에 30일 이상 작업 근무자) l Increase the risk of All SEER site cancer and prostate cancer

Epidemiology - 2 ¢ Effect of POPs in relation to weight and height of children by Rylander l investigate whether intrauterine exposure for POP may have negative impact on children's weight and height at 4 and 7 years of age l PCB-153 levels (ng/g lipid) : LBW – 295, NBW-243 l Although not statistically significant, the association between the estimated plasma concentrations of PCB-153 during year of childbirth and the outcomes were in the hypothesized

Epidemiology - 3 ¢ Sex ration of offspring and occupational exposure to fly ash in Japan by Mori l l l the workers still have strong concern because of the lack of clear epidemiological evidence a cohort study focusing on risk assessment for cancer mortality and changes in the sex ratio of offspring among the municipal solid waste incinerator workers Cohort was established 2002. 9 – 2004. 12 Questionnaire study, duration of exposure(DOE), job experience to fly ash(FA), age of first exposure(AFA), year at first exposure(YFE) 등을 조사 DOE shows a trend which can support a speculation that longer exposure to fly ash may lower the sex ratio the results may suggest possible association between DOE and changes in sex ratio