General view of Oak Park Area: 43 hectars
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1 General view of Oak Park 1987 Area: 43 hectars
2 TCDD LEVELS 1987: CDC measures dioxin in Vietnam veterans blood 1988: CDC begins to analyze Seveso samples About 30,000 serum samples ( ml) kept frozen since July 1976 at Desio Hospital Exposure levels have been determined in many subjects and show low, medium and high contamination
3 TCDD VALUES IN SEVESO POPULATION Serum TCDD (ppt) Nd Nd Nd Nd Nd non ABR Zone Zone A without chloracne Chloracne Type 2 Type Zone A with chloracne Mocarelli et al. J Toxicol Environ Health 1991; 32:357-66
4 Median TCDD value in A, B, R zones N=302 2,965 ppt N=264 A Zone A Zone 6-7 B Zone R Zone Age in ppt 140 ppt 52 ppt Female <13 yrs 1,840 ppt 455 ppt 261 ppt 95 ppt Male <13 yrs
5 1976 Lab Tests and TCDD: Females 2-10 ys U/L n= ppt AST ALT GGT TCDD
6 CLINICAL BIOCHEMISTRY AND TCDD EXPOSURE GGT IN FEMALES ( YEAR OLD IN AND IN 1994) : Serum TCDD levels G G T U/L R.L. R.L.
7 METABOLISM: MICROSOMAL INDUCTION µmol/g of creatinine Urinary D-Glucaric acid excretion in 1976 (median values) Controls ppt >1000 ppt Ideo G et al, EHP 1985 ; 60:
8 METABOLISM: MICROSOMAL INDUCTION D-Glucaric acid excretion in urine was significantly elevated in a group of adults tested in D-Glucaric levels were higher in children with chloracne than in children without it. Values decreased yearly and by 1981 they returned within the normal range Ideo G et al, EHP 1985 ; 60:
9 TCDD HALF-LIFE IN ADULTS FEMALES about 9 years MALES about 7 years CHILDREN much shorter
10 SEX RATIO at BIRTH males / 206 total births = or 51.4%
11
12 Characteristics of Seveso study population 452 families 130 men with measured TCDD concentration married to females living outside zones A, B and R 156 females with measured TCDD concentration married to males living outside zones A, B and R 168 couples with both partners living in zones A, B and R in 1976 With measured TCDD: 142 mothers and 109 fathers With estimated TCDD: 27 mothers and 59 fathers Children: 88 boys 103 girls Children: 127 boys 106 girls Children: 113 boys 137 girls Mocarelli et al., Lancet 2000; 355:
13 TCDD AND SEX RATIO GOALS OF THE STUDY 1. Is the sex ratio change dependent on TCDD serum level in fathers, mothers or both? 2. Is there a possible TCDD dose-effect (sex ratio) correlation?
14 TCDD AND SEX RATIO GOALS OF THE STUDY 3. Is any sex ratio dependent on a different sensitivity to TCDD of the reproductive system at different ages? 4. How long is the effect lasting?
15 SEX RATIO IN THE STUDY POPULATION COMPARED TO THE EXPOSURE STATUS OF PARENTS Father s Mother s Children Total Sex TCDD TCDD ratio (ppt) (ppt) M F Unexposed Unexposed >15 > >15 Unexposed Unexposed > Total Different from expected sex ratio value of at p= 0.03 Mocarelli P et al., Lancet 2000; 355:
16 TCDD and SEX RATIO Exposure of men to TCDD is linked to a lowered sex ratio Females do not contribute to this phenomenon
17 FATHER S TCDD SERUM CONCENTRATION IN 1976 AND SEX RATIO OF OFFSPRING 160 Number of Children * p=0.04 and p=0.02 compared to the expected sex ratio of χ 2 for trend = 7.08 p= * Unexpos ,400 TCDD serum concentration (ppt)
18 TCDD and SEX RATIO Initial TCDD concentrations lower than 80 ppt in fathers (lower than 16 ng/kg body weight) were predictor of reduced probability of a male birth
19 AGE AND EXPOSURE STATUS OF FATHER IN 1976 AND SEX RATIO OF OFFSPRING Number of Children p=0.002 (in respect to sex ratio of 0.514) p<0.05 (in respect to unexposed) Unexposed 3-45 y Exposed < 19 y Exposed > 19 y
20 TCDD and SEX RATIO Our data support a permanent effect from pre- and puberty years and an immediate effect in adults
21 SEX RATIO AT BIRTH BY QUARTILE OF FATHER S TCDD SERUM CONCENTRATION AT TIME OF CONCEPTION TCDD at Mean (SD) Number Sex ratio Father s conception age (years) of children (95% CI) age at (ppt) at exposure M F conception (2.89) (3.4) (2.7) (3.1) It includes 92 men younger than 19 years of age in 1976 exposed to TCDD concentrations higher than 15 ppt Mocarelli P et al., Lancet 2000; 355:
22 TCDD and SEX RATIO Experimental data and our observations support the hypothesis that dioxin permanently affects the reproductive system
23 HUMAN ICSI F M χ 2 p Spermatozoa Testis ns Epididymus ns CryoEmbrio ns Ejaculated Bonduelle et al. Hum Repr 1998; 13 (Suppl 1): and personal communication
24 TCDD and SEX RATIO TCDD mean concentration in fathers is similar to doses inducing epididymal impairments in rats (exposed in utero or during lactation) and is only about 20 times the average level currently found in humans in industrialized countries
25 SEX RATIO ( ) FROM 198 WORKERS IN UFA EXPOSURE F M (2,4,5-T; TCP) P < father and mother P < father (150) ns mother (48) Ryan et al. Organohal. Comp. 2001; 53: Yucheng change in sex ratio after PCBs PCDFs ingestion in 1979 in Taiwan Age at Fathers p exposure Exposed Unexposed Del Rio Gomez et al. Lancet 2002; 360: ys 286 (45.8%) 705 (54.2%) 0.02 > 19 ys 183 (54.1%) 345 (54.9%) n.s.
26 Cl O Cl TCDD Cl O Cl The International Agency for Research on Cancer (IARC) classified TCDD as a known human carcinogen, primarily based on occupational studies of increased mortality from all cancers combined. TCDD is also an endocrine disruptor. IARC Monogr. Eval. Carcinog. Risk. Hum. 1997
27 CANCER MORTALITY IN SEVESO Men Men and Women A (804 inhabitants) and B (5.941 inhabitants) Zone Rectal cancer (RR=2.4) Lung cancer (RR=1.3) Lymphoempoietic neoplasms (RR=1.7) Hodgkin s disease (RR=4.9) Non-Hodgkin s Lymphoma (RR=2.8) Myeloid leukemia (RR=3.8) Bertazzi PA et al. Am. J Epidemiol 2001; 153:
28 Breast Cancer risk in Seveso and Serum dioxin concentration Cohort: 981 women 1-40 y in 1976 studied in (average 40.8 y) 15 breast cancer cases y at explosion (average 30.1 y) y at diagnosis (average 45.2 y) M.Warner, B. Eskenazi, P.Mocarelli et al. EHP 2002;110:
29 Breast Cancer risk in Seveso and Serum dioxin concentration At diagnosis: 9 women were premenopausal 6 women were postmenopausal Estrogen receptor 87% positive Progesterone receptor 100% positive M.Warner, B.Eskenazi, P.Mocarelli et al. EHP 2002;110:
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