Serum dioxin concentrations and endometriosis: a cohort study in Seveso, Italy.

Dioxin, a ubiquitous contaminant of industrial combustion processes including medical waste incineration, has been implicated in the etiology of endometriosis in animals. We sought to determine whether dioxin exposure is associated with endometriosis in humans. We conducted a population-based historical cohort study 20 years after the 1976 factory explosion in Seveso, Italy, which resulted in the highest known population exposure to 2,3,7,8-tetrachlorodibenzo-(italic)p(/italic)-dioxin (TCDD). Participants were 601 female residents of the Seveso area who were (3/4) 30 years old in 1976 and had adequate stored sera. Endometriosis disease status was defined by pelvic surgery, current transvaginal ultrasound, pelvic examination, and interview (for history of infertility and pelvic pain). "Cases" were women who had surgically confirmed disease or an ultrasound consistent with endometriosis. "Nondiseased" women had surgery with no evidence of endometriosis or no signs or symptoms. Other women had uncertain status. To assess TCDD exposure, individual levels of TCDD were measured in stored sera collected soon after the accident. We identified 19 women with endometriosis and 277 nondiseased women. The relative risk ratios (RRRs) for women with serum TCDD levels of 20.1-100 ppt and >100 ppt were 1.2 [90% confidence interval (CI) = 0.3-4.5] and 2.1 (90% CI = 0.5-8.0), respectively, relative to women with TCDD levels (3/4) 20 ppt. Tests for trend using the above exposure categories and continuous log TCDD were nonsignificant. In conclusion, we report a doubled, nonsignificant risk for endometriosis among women with serum TCDD levels of 100 ppt or higher, but no clear dose response. Unavoidable disease misclassification in a population-based study may have led to an underestimate of the true risk of endometriosis

Serum Dioxin Concentrations and Quality of Ovarian Function in Women of Seveso

BACKGROUND: Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been associated with alterations in ovarian function and hormones in animals, it has not been studied in humans. On 10 July 1976, an explosion exposed residents of Seveso, Italy, to the highest levels of TCDD in a population. Twenty years later, we initiated the Seveso Women’s Health Study to study reproductive health. OBJECTIVE: We related TCDD levels measured in sera collected near the time of explosion and ovarian function (ovarian cysts, ovarian follicles, ovulation rate, serum hormones) at follow-up. METHODS: We included 363 women who were 20–40 years of age and nonusers of oral contraceptives. We examined the relationship of 1976 serum TCDD levels with ultrasound-detected ovarian follicles among 96 women in the menstrual follicular phase and serum hormone levels (estradiol, progesterone) among 129 women in the menstrual luteal phase at follow-up. Ovulation was defined by serum progesterone levels > 3 ng/mL. RESULTS: The median serum TCDD level was 77.3 ppt, lipid-adjusted. Serum TCDD was not associated with number or size of ovarian follicles. Of women in the luteal phase, 87 (67%) ovulated. Serum log(10)TCDD was not associated with odds of ovulation [adjusted odds ratio = 0.99; 95% confidence interval (CI), 0.5 to 1.9]. Among those who had ovulated, serum log(10)TCDD was not associated with serum progesterone [adjusted beta (adj-β ) = −0.70; 95% CI, −2.4 to 1.0] or estradiol (adj-β = −1.81; 95% CI, −10.4 to 6.8). CONCLUSIONS: We found no clear evidence that 1976 TCDD exposure was associated with ovarian function 20 years later in women exposed to relatively high levels in Seveso, Italy

Serum Dioxin Concentrations and Age at Menopause

2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD), a halogenated compound that binds the aryl hydrocarbon receptor, is a by-product of numerous industrial processes including waste incineration. Studies in rats and monkeys suggest that TCDD may affect ovarian function. We examined the relationship of TCDD and age at menopause in a population of women residing near Seveso, Italy, in 1976, at the time of a chemical plant explosion. We included 616 of the women who participated 20 years later in the Seveso Women’s Health Study. All women were premenopausal at the time of the explosion, had TCDD levels measured in serum collected soon after the explosion, and were ≥ 35 years of age at interview. Using proportional hazards modeling, we found a 6% nonsignificant increase in risk of early menopause with a 10-fold increase in serum TCDD. When TCDD levels were categorized, compared with women in the lowest quintile (< 20.4 ppt), women in quintile 2 (20.4–34.2 ppt) had a hazard ratio (HR) of 1.1 (p = 0.77), quintile 3 (34.3–54.1 ppt) had an HR of 1.4 (p = 0.14), quintile 4 (54.2–118 ppt) had an HR of 1.6 (p = 0.10), and quintile 5 (> 118 ppt) had an HR of 1.1 (p = 0.82) for risk of earlier menopause. The trend toward earlier menopause across the first four quintiles is statistically significant (p = 0.04). These results suggest a nonmonotonic dose-related association with increasing risk of earlier menopause up to about 100 ppt TCDD, but not above

2,3,7,8-Tetrachlorodibenzo-p-dioxin plasma levels in Seveso 20 years after the accident.

In 1976, near Seveso, Italy, an industrial accident caused the release of large quantities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into the atmosphere, resulting in the highest levels of the toxicant ever recorded in humans. The contaminated area was divided into three zones (A, B, R) corresponding to decreasing TCDD levels in soil, and cohort including all residents was enumerated. The population of the surrounding noncontaminated area (non-ABR) was chosen as referent population. Two decades after the accident. plasma TCDD levels were measured in 62 subjects randomly sampled from the highest exposed zones (A and B) and 59 subjects from non-ABR, frequency matched for age, gender, and cigarette smoking status. Subjects living in the exposed areas have persistently elevated plasma TCDD levels (range = 1.2-89.9 ppt; geometric mean = 53.2 and 11.0 ppt for Zone A and Zone B, respectively). Levels significantly decrease by distance from the accident site (p = 0.0001), down to general population values (4.9 ppt) in non-ABR, thus validating the original zone classification based on environmental measurements. Women have higher TCDD levels than men in the entire study area (p = 0.0003 in Zone B; p = 0.007 in non-ABR). This gender difference persists after adjustment for location within the zone, consumption of meat derived from locally raised animals, age, body mass index, and smoking. There is no evidence for a gender difference in exposure, so variation in metabolism or elimination due to body fat or hormone-related factors may explain this finding. Elevated TCDD levels in women may contribute to adverse reproductive, developmental, and cancer outcomes

Increasing Efficiency and Quality by Consolidation of Clinical Chemistry and Immunochemistry Systems with MODULAR ANALYTICS SWA

MODULAR ANALYTICS Serum Work Area (in USA Integrated MODULAR ANALYTICS, MODULAR ANALYTICS is a trademark of a member of the Roche Group) represents a further approach to automation in the laboratory medicine. This instrument combines previously introduced modular systems for the clinical chemistry and immunochemistry laboratory and allows customised combinations for various laboratory workloads. Functionality, practicability, and workflow behaviour of MODULAR ANALYTICS Serum Work Area were evaluated in an international multicenter study at six laboratories. Across all experiments, 236000 results from 32400 samples were generated using 93 methods. Simulated routine testing which included provocation incidents and anomalous situations demonstrated good performance and full functionality. Heterogeneous immunoassays, performed on the E-module with the electrochemiluminescence technology, showed reproducibility at the same level of the general chemistry tests, which was well within the clinical demands. Sample carryover cannot occur due to intelligent sample processing. Workflow experiments for the various module combinations, with menus of about 50 assays, yielded mean sample processing times of <38 minutes for combined clinical chemistry and immunochemistry requests; <50 minutes including automatically repeated samples. MODULAR ANALYTICS Serum Work Area offered simplified workflow by combining various laboratory segments. It increased efficiency while maintaining or even improving quality of laboratory processes

Developmental Dental Aberrations After the Dioxin Accident in Seveso

Children’s developing teeth may be sensitive to environmental dioxins, and in animal studies developing teeth are one of the most sensitive targets of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Twenty-five years after the dioxin accident in Seveso, Italy, 48 subjects from the contaminated areas (zones A and B) and in patches lightly contaminated (zone R) were recruited for the examination of dental and oral aberrations. Subjects were randomly invited from those exposed in their childhood and for whom frozen serum samples were available. The subjects were frequency matched with 65 subjects from the surrounding non-ABR zone for age, sex, and education. Concentrations of TCDD in previously analyzed plasma samples (zone ABR subjects only) ranged from 23 to 26,000 ng/kg in serum lipid. Ninety-three percent (25 of 27) of the subjects who had developmental enamel defects had been < 5 years of age at the time of the accident. The prevalence of defects in this age group was 42% (15 of 36) in zone ABR subjects and 26% (10 of 39) in zone non-ABR subjects, correlating with serum TCDD levels (p = 0.016). Hypodontia was seen in 12.5% (6 of 48) and 4.6% (3 of 65) of the zone ABR and non-ABR subjects, respectively, also correlating with serum TCDD level (p = 0.05). In conclusion, developmental dental aberrations were associated with childhood exposure to TCDD. In contrast, dental caries and periodontal disease, both infectious in nature, and oral pigmentation and salivary flow rate were not related to the exposure. The results support our hypothesis that dioxins can interfere with human organogenesis

Age- and Concentration-Dependent Elimination Half-Life of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Seveso Children

OBJECTIVE: Pharmacokinetic and statistical analyses are reported to elucidate key variables affecting 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in children and adolescents. DESIGN: We used blood concentrations to calculate TCDD elimination half-life. Variables examined by statistical analysis include age, latency from exposure, sex, TCDD concentration and quantity in the body, severity of chloracne response, body mass index, and body fat mass. PARTICIPANTS: Blood was collected from 1976 to 1993 from residents of Seveso, Italy, who were < 18 years of age at the time of a nearby trichlorophenol reactor explosion in July 1976. RESULTS: TCDD half-life in persons < 18 years of age averaged 1.6 years while those ≥18 years of age averaged 3.2 years. Half-life is strongly associated with age, showing a cohort average increase of 0.12 year half-life per year of age or time since exposure. A significant concentration-dependency is also identified, showing shorter half-lives for TCDD concentrations > 400 ppt for children < 12 years of age and 700 ppt when including adults. Moderate correlations are also observed between half-life and body mass index, body fat mass, TCDD mass, and chloracne response. CONCLUSIONS: Children and adolescents have shorter TCDD half-lives and a slower rate of increase in half-life than adults, and this effect is augmented at higher body burdens. RELEVANCE: Modeling of TCDD blood concentrations or body burden in humans should take into account the markedly shorter elimination half-life observed in children and adolescents and concentration-dependent effects observed in persons > 400–700 ppt

Dioxin Exposure, from Infancy through Puberty, Produces Endocrine Disruption and Affects Human Semen Quality

BACKGROUND: Environmental toxicants are allegedly involved in decreasing semen quality in recent decades; however, definitive proof is not yet available. In 1976 an accident exposed residents in Seveso, Italy, to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). OBJECTIVE: The purpose of this study was to investigate reproductive hormones and sperm quality in exposed males. METHODS: We studied 135 males exposed to TCDD at three age groups, infancy/prepuberty (1-9 years), puberty (10-17 years), and adulthood (18-26 years), and 184 healthy male comparisons using 1976 serum TCDD levels and semen quality and reproductive hormones from samples collected 22 years later. RESULTS: Relative to comparisons, 71 men (mean age at exposure, 6.2 years; median serum TCDD, 210 ppt) at 22-31 years of age showed reductions in sperm concentration (53.6 vs. 72.5 million/mL; p = 0.025); percent progressive motility (33.2% vs. 40.8%; p < 0.001); total motile sperm count (44.2 vs. 77.5 x 10(6); p = 0.018); estradiol (76.2 vs. 95.9 pmol/L; p = 0.001); and an increase in follicle-stimulating hormone (FSH; 3.58 vs. 2.98 IU/L; p = 0.055). Forty-four men (mean age at exposure, 13.2 years; median serum TCDD, 164 ppt) at 32-39 years of age showed increased total sperm count (272 vs. 191.9 x 10(6); p = 0.042), total motile sperm count (105 vs. 64.9 x10(6); p = 0.036), FSH (4.1 vs. 3.2 UI/L; p = 0.038), and reduced estradiol (74.4 vs. 92.9 pmol/L; p < 0.001). No effects were observed in 20 men, 40-47 years of age, who were exposed to TCDD (median, 123 ppt) as adults (mean age at exposure, 21.5 years). CONCLUSIONS: Exposure to TCDD in infancy reduces sperm concentration and motility, and an opposite effect is seen with exposure during puberty. Exposure in either period leads to permanent reduction of estradiol and increased FSH. These effects are permanent and occur at TCDD concentrations < 68 ppt, which is within one order of magnitude of those in the industrialized world in the 1970s and 1980s and may be responsible at least in part for the reported decrease in sperm quality, especially in younger men