Serum To 2,3,7,8-tetrachlorodibenzo-p-dioxin Research Articles

Prenatal dioxin exposure and thyroid hormone levels in the Seveso second generation study

BackgroundIn animal studies, perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters thyroid homoeostasis and thyroid hormone concentrations; epidemiologic evidence is limited. ObjectivesWe aimed to determine the association of prenatal exposure to TCDD with thyroid hormone concentrations in the Seveso Second Generation Study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 chemical factory explosion in Seveso, Italy. MethodsWe included 570 children (288 female, 282 male) with complete follow-up data, including a fasting blood draw. Serum levels of total and free thyroxine (T4), free triiodothyronine (T3), and thyroid stimulating hormone (TSH) were measured using immunoassays. We defined prenatal TCDD exposure as: 1) maternal initial TCDD concentration measured in serum collected soon after the explosion and 2) maternal TCDD estimated at pregnancy. ResultsCompared to the lowest quartile (Q1), maternal initial serum TCDD was associated with lower free T3 (Q2: adj-β = −0.13, 95%CI -0.26, 0.00; Q3: adj-β = −0.22, 95%CI -0.35, −0.09; Q4: adj-β = −0.14, 95%CI -0.28, 0.00; p-trend = 0.02). In participants with high thyroid antibody status, inverse associations between maternal initial serum TCDD and free T3 were significantly stronger than in participants with normal antibody status (p-interaction = 0.02). We also observed a positive association between maternal initial serum TCDD and TSH concentrations in participants with high thyroid antibody status (Q2: adj-β = 11.4%, 95%CI -25.2, 66.1; Q3: adj-β = 49.0%, 95%CI 3.0, 115.5; Q4: adj-β = 105.5, 95%CI 36.6, 209.2; p-trend < 0.01) but not in those participants with normal antibody status (p-interaction < 0.01). Similar results were found for TCDD estimated at pregnancy. DiscussionOur results suggest prenatal exposure to TCDD, a potent endocrine-disrupting compound, may alter thyroid function later in life. Populations with additional thyroid stress may be particularly susceptible to in utero exposure of thyroid disrupting chemicals.

Gene-Dioxin Interactions and Time to Pregnancy in the Seveso Women’s Health Study

TPS 634: Health effects of pops, voc and other chemicals, Johan Friso Foyer, Floor 1, August 27, 2019, 3:00 PM - 4:30 PM Background/Aim: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, has been associated with reduced fertility in multiple animal species. TCDD is proposed to impact fertility via altered activity of the aryl hydrocarbon receptor (AhR) pathway, which regulates diverse biological and developmental processes, including xenobiotic metabolism. The Seveso Women’s Health Study (SWHS) followed up 981 women exposed to TCDD in a chemical factory explosion in 1976. Twenty years later, we reported longer time to pregnancy (TTP) associated with individual 1976 serum TCDD levels, but the youngest women had not yet attempted pregnancy. Now, 40 years after the explosion, when most women will have completed their families, we aim to re-examine the relationship of TCDD exposure with TTP and assess whether variations in AhR pathway genes modify this relationship. Methods: Of 617 women who had attempted pregnancy after the explosion, 367 delivered a live birth not associated with contraceptive failure. We examined the relationship of 1976 serum TCDD levels to TTP (parameterized as the monthly probability of conception within the first 12 months of trying) using discrete-time Cox proportional hazards regression. We also utilized genotype data (87 SNPs across 7 AhR pathway genes) to examine gene-environment interactions between AhR pathway variants and TCDD levels on TTP. Results: Women averaged 26.7 (±4.3) years at the time of attempting pregnancy. Median TTP was 2 months, with 17.2% taking 12 or more months to conceive. Consistent with our previous findings, a 10-fold increase in serum TCDD was associated with longer TTP (adjusted fecundability odds ratio = 0.80; 95%CI: 0.66, 0.98). In preliminary analyses, we found one SNP in AHRR which adversely modified the association between TCDD levels and TTP, implicating gene-environment interaction. Conclusions: These results suggest that TCDD exposure is associated with reduced fertility in the Seveso cohort; gene-environment interaction may play a role.

In Utero Dioxin Exposure and Age at Menarche in the Seveso Second Generation

Introduction: In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant and potent endocrine disrupting compound, is associated with delayed pubertal development in animal studies. On July 10, 1976, an explosion at a chemical plant near Seveso, Italy exposed nearby residents to high levels of TCDD. The Seveso Women&amp;#8217;s Health Study (SWHS), initiated in 1996, is the only study to date of TCDD&amp;#8217;s health effects in a female population with the unique benefit of individual TCDD measured in blood collected near the time of the explosion. In 2014, we enrolled SWHS offspring (those exposed in utero to TCDD) in the Seveso Second Generation study. We examined the relationship of in utero TCDD exposure with reported age at onset of menarche among SWHS daughters.Methods: Age at onset of menarche (in years) was collected by maternal or self-report at interview in 341 SWHS daughters. We defined in utero TCDD exposure as initial (1976) maternal serum TCDD level and TCDD extrapolated to pregnancy. Data were analyzed using Cox proportional hazards models.Results: At interview, 287 daughters were postmenarche, averaging 25.6 (&amp;#177;8.0) years of age. The mean reported age at menarche was 12.1 (&amp;#177;1.3) years. Overall, we found no change in risk of menarche onset with a 10-fold increase in initial maternal TCDD (Hazard Ratio (HR) &amp;#61; 0.91, 95% CI 0.79, 1.06) or TCDD estimated at pregnancy (HR &amp;#61; 0.86, 95% CI 0.72, 1.03). When we considered maternal menarche status at explosion as a potentially sensitive developmental exposure window, TCDD estimated at pregnancy (log10) was associated with later age at menarche among daughters whose mothers were premenarche at explosion (HR &amp;#61; 0.71, 95% CI 0.50, 1.00) but not postmenarche at explosion (HR &amp;#61; 0.87, 95% CI 0.71, 1.07).Conclusions: These results suggest in utero exposure to TCDD may alter pubertal timing among daughters of women who were prepubescent at the time of the Seveso accident.

In Utero Dioxin Exposure and Fertility of the Seveso Second Generation

Background/Aim: In animal studies, maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with decreased fertility in offspring. The Seveso Women’s Health Study (SWHS) of women exposed to TCDD in 1976 is unique in that we measured TCDD blood levels near the time of the explosion. In 2014, we initiated the Seveso Second Generation Health Study. We aim to examine the relationship of in utero TCDD exposure with time to pregnancy (TTP) and infertility among SWHS daughters. Methods: We asked SWHS children ≥ 18 years about their pregnancy history, including time to pregnancy and infertility. Of 225 daughters, 80 had attempted pregnancy. Of these, 66 had delivered a livebirth not associated with contraceptive failure and 4 reported still trying unsuccessfully after 12 or more months. We defined in utero TCDD exposure as: 1) initial maternal serum TCDD concentration and 2) TCDD estimated at pregnancy. We examined the relation of in utero TCDD to TTP (parameterized as the monthly probability of conception within the first 12 months of trying) and to infertility (defined as conception after at least 12 months of trying). We modelled fecundability with discrete-time Cox proportional hazards regression and fertility with logistic regression. Results: Women averaged 30.0 (±3.5) years at the time of attempting pregnancy. Median TTP was 2 months and 15.7% reported taking 12 or more months to conceive. A 10-fold increase in initial maternal TCDD was non-significantly associated with longer TTP (adjusted fecundability odds ratio = 0.61; 95%CI: 0.32, 1.18) and increased odds of infertility (adjusted odds ratio= 1.38; 95%CI: 0.36, 5.36). Results for TCDD estimated at pregnancy will be presented. Conclusions: These results are consistent with animal studies and suggest in utero TCDD exposure may alter fertility in female offspring. However, sample size of pregnancies is lower than expected given the age of the female population.

Morbidity in New Zealand pesticide producers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

ObjectivesTo conduct a cross-sectional morbidity survey among 245 former employees of a pesticide production plant exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in New Zealand. MethodsDemographic factors and health information were collected in face-to-face interviews. TCDD, lipids, thyroid hormones, glucose and immunoglobulin G (IgG) were determined in non-fasting blood. For 111 participants, a neurological examination was conducted. Associations between health outcomes and working in a TCDD exposed job (prevalence 49%) and serum TCDD concentration≥10pg/g lipid (18%) were assessed using logistic regression whilst controlling for age, gender, smoking, body mass index and ethnicity. ResultsDiabetes was more common in those who had worked in TCDD exposed jobs (OR 4.0, 95%CI 1.0–15.4) and in those with serum TCDD ≥10pg/g (OR 3.1, 95%CI 0.9–10.7). Non-fasting glucose levels >6.6mmol/l were more common in those with TCDD exposed jobs (OR 3.6, 95%CI 1.0–12.9), as were serum free thyroxine 4<12.8pmol/l (OR 4.5, 95%CI 1.4–14.4), triglycerides >1.7mmol/l (OR 2.5, 95%CI 1.1–5.7) and high density lipoprotein cholesterol (HDL) <1mmol/l (OR 4.0, 95%CI 1.2–13.2). IgG was negatively associated with TCDD (linear regression p=0.05). The neurological examination revealed a higher frequency of abnormal reflexes in those with serum TCDD ≥10pg/g (OR 4.8, 95%CI 1.1–21.0). ConclusionsIn this occupationally exposed population, TCDD was associated with an increased risk of diabetes and a range of subclinical responses in multiple systems (peripheral nervous system, immune system, thyroid hormones and lipid metabolism), several decades after last exposure. These results need to be interpreted with caution due to the small study size and the cross-sectional nature of the study.

Sex ratio of the offspring of New Zealand phenoxy herbicide producers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

ObjectivesExposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has inconsistently been associated with a decreased sex ratio of the offspring (number of male births divided by total births). We conducted a study among men...

Maternal dioxin exposure and pregnancy outcomes over 30 years of follow-up in Seveso

Animal evidence suggests an association between exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and adverse pregnancy outcomes. Epidemiologic studies report inconsistent results, but are limited by narrow range of exposure, small sample size, and lack of a biologic measure of highest lifetime exposure. On July 10, 1976, a chemical explosion in Seveso, Italy resulted in the highest known residential exposure to TCDD. In 1996, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort of TCDD exposure and reproductive health. Individual-level TCDD was measured in serum collected soon after the explosion. After 20years of follow-up, we found no association between maternal TCDD in 1976 serum or estimated at pregnancy and spontaneous abortion (SAB), fetal growth, or gestational length. Here, we present an updated analysis of TCDD exposure and adverse pregnancy outcomes from a subsequent follow-up of the SWHS cohort in 2008–2009.SWHS women had 1211 post-explosion pregnancies through the 2008–2009 follow-up. We found no association between TCDD estimated at pregnancy and SAB, fetal growth, or gestational length. However, we found a non-significant inverse association between maternal 1976 serum TCDD and birthweight (adjusted β=−22.8, 95% CI: −80.1, 34.6). The association was stronger among first post-explosion births, but remained non-significant (adjusted β=−47.7, 95% CI: −107.3, 11.9). SWHS is the first study to be able to consider two potentially relevant measures of TCDD exposure: highest lifetime dose and in utero. Our results, although non-significant, suggest that highest dose may be more relevant in epidemiologic studies of TCDD and pregnancy outcomes.

Serum TCDD and TEQ concentrations among Seveso women, 20 years after the explosion.

The Seveso Women's Health Study (SWHS) is a historical cohort study of the female population residing near Seveso, Italy, on 10 July 1976, when a chemical explosion resulted in the highest known residential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Individual TCDD concentration was measured in serum collected near the time of the explosion, and in 1996, we collected adequate blood for TCDD and total dioxin toxic equivalent (TEQ) measurement. Polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls were measured in 1996 serum for a sample (n=225, 23%) of the SWHS cohort and WHO 2005 TEQs were calculated. We examined characteristics that predict 1996 TCDD concentrations and estimated TCDD elimination half-life over the 20-year period since the explosion. Median lipid-adjusted TCDD and total TEQ concentrations in 1996 serum were 7.3 and 26.2 p.p.t., respectively. Initial 1976 TCDD and age at explosion were the strongest predictors of 1996 TCDD. The TCDD elimination half-life was 7.1 years for women older than 10 years in 1976, but was shorter in those who were younger. Twenty years after the explosion, TCDD concentrations in this SWHS sample, the majority of who were children in 1976, remain elevated relative to background. These data add to the limited data available on TCDD elimination half-life in children.

TCDD exposure estimation for workers at a New Zealand 2,4,5-T manufacturing facility based on serum sampling data

Employment in the manufacture of the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) is associated with potential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and elevated serum lipid TCDD concentrations can be measured in workers for decades after terminated occupational exposure. As part of an epidemiological study of 1599 workers employed at a facility in New Plymouth, New Zealand that manufactured 2,4,5-T, serum TCDD concentrations measured in blood samples from 346 workers were used with work history records and a simple pharmacokinetic model in a linear regression to estimate dose rates associated with specific job exposure groups at the facility. The model was used to estimate serum TCDD concentration profiles over time for each individual in the full study group and accounted for 30% of the observed variance in TCDD concentrations in the serum donor subgroup. The model underestimated measured concentrations substantially for eleven individuals in the study group; examination of questionnaire data revealed a variety of activities apart from routine employment at the facility that may have contributed to the measured serum TCDD concentrations. Estimated serum TCDD concentrations were below 300 p.p.t. for all individuals in the cohort over the entire study time period, lower than estimates for other 2,4,5-T worker populations. This finding is consistent with occupational medicine records, which indicated that no cases of chloracne were ever diagnosed among workers employed on the site. The modeled exposures will be used in an evaluation of mortality patterns of workers at this facility.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) plasma concentrations in residents of Paritutu, New Zealand: Evidence of historical exposure

An assessment of community exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was undertaken in Paritutu, New Zealand. The suburb lies adjacent to an agrichemical facility that produced 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), between 1962 and 1987. Soil TCDD measurements from 73 nearby addresses demonstrated a pattern of TCDD deposition consistent with an aerial plume following the prevailing local wind patterns and the agrichemical plant as the point source. Blood samples were taken from 52 volunteers having lived for three or more years in Paritutu between 1962 and 1987. Candidate selection focused primarily on individuals who were most likely to show elevated TCDD blood lipid levels when compared to age and gender stratified national average blood concentrations, and secondarily on individuals that provided additional information about specific exposure periods, potential exposures of younger age groups, and specific dietary patterns. A multipathway exposure model was used to estimate serum TCDD levels in each participant. Age and gender-specific TCDD elimination kinetics were also considered. Historical TCDD environmental concentrations were back-calculated from soil concentrations at each residence assuming TCDD releases occurred pre-dominantly between 1962 and 1975. Serum was analysed for chlorinated dibenzodioxins and dibenzofurans, and a subset was analysed for dioxin-like polychlorinated biphenyls. TCDD in serum lipid exceeded two standard deviations above national background levels for 14 participants, and 3 standard deviations for 10 participants. The highest TCDD lipid concentration was 33.3 ng/kg-lipid, or 11 times higher than the comparative 1997 national average. Elevated TCDD concentrations were observed primarily, but not exclusively, in the older study participants who had been in residence in Paritutu before 1968. The study demonstrated TCDD exposure in this community, occurring most likely through the aerial route, and most probably from fugitive emissions during manufacture.

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

BackgroundEnvironmental 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).ObjectiveThe purpose of this study was to investigate reproductive hormones and sperm quality in exposed males.MethodsWe 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.ResultsRelative 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 × 106; 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 × 106; p = 0.042), total motile sperm count (105 vs. 64.9 ×106; 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).ConclusionsExposure 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.

Dioxin Exposure and Time to Pregnancy in Seveso

ISEE-687 Objective: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, has been associated with reduced fertility in multiple animal species at doses below toxic levels. To date, no epidemiologic studies have examined the association of TCDD exposure with infertility in women. On July 10, 1976, as a result of a chemical explosion, residents of Seveso, Italy, experienced the highest levels of TCDD in a human population. Twenty years later, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort study of the reproductive health of the women. We examined the association between TCDD exposure and fertility as measured by time to pregnancy (TTP). Materials and Methods: The SWHS cohort comprises 981 women who were 0 to 40 years in 1976, resided in the most contaminated areas, and had adequate archived sera collected soon after the explosion. Individual serum TCDD exposure was measured by high-resolution mass spectrometry. We examined the relation of serum TCDD with TTP or the number of months to become pregnant, using a discrete-time analogue of the Cox proportional hazards model. TTP (months) was treated as a continuous variable and censored at 13 months if women had reported attempting to conceive for a period of 12 months or longer. Results: Of 475 women who reported a post-explosion pregnancy, 340 had a planned or noncontracepted pregnancy resulting in a live birth. The median TTP was 3.0 months. Preliminary results suggest that women with higher serum TCDD levels took longer to become pregnant. Adjusting for parity, and parental smoking and age, a 10-fold increase in TCDD was associated with a 32% reduced odds of achieving pregnancy (adj-fOR = 0.76, 95% CI: 0.61, 0.94). Conclusions: These results suggest TCDD exposure may be associated with reduced fertility in the Seveso cohort. The results will be interpreted in light of study advantages and limitations.

TCDD and Puberty in Girls

We would like to comment on the article by Warner et al. (2004), in which the authors reported no significant associations between age at menarche and exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an extremely potent antiestrogenic xenobiotic. The exposure of girls to TCDD at Seveso, Italy, resulted in very high serum TCDD levels (> 100 pg/g lipid), 10–100 times levels usually seen today. Warner et al. noted that the literature is mixed regarding the agonist/ antagonist effects in humans of persistent exposures of this type. First, polybrominated biphenyl exposures have been associated with earlier menarche in girls, whereas experimental models show delayed puberty, a discordance that may be due to timing of exposure (Blanck et al. 2000). Second, as Warner et al. (2004) noted, the experimental data show that TCDD and other estrogen antagonists delay vaginal opening (VO) and disrupt cyclicity in rodents treated pre-natally (Gray et al. 1997; Levy et al. 1995). However, hormonal activity depends on both timing and level of dose, such that phytoestrogens, for example, may be estrogenic—hastening VO—at high doses given after birth (Lamartiniere et al. 1995; Whitten et al. 1995). Epidemiologic data regarding hormonally dependent female cancer are equivocal, such that there have been suggestions of a protective (i.e., antiestrogenic) effect of TCDD for breast and uterine cancer in TCDD-exposed women from Seveso (Bertazzi et al. 2001), whereas a carcinogenic effect has been observed in cohorts exposed for longer times (Manz et al. 1991; Warner et al. 2002). The findings of Warner et al. (2004), albeit not statistically significant, suggest earlier menarche with higher TCDD level among women who were younger than 8 years of age at the time of exposure [hazard ratio, 1.08 for 10-fold increase in TCDD levels; 95% confidence interval (CI), 0.89–1.30) but not among all women regardless of age. The study population appears to have the usual patterns of risk for menarche as indicated by associations that occur in the expected directions [e.g., for Seveso zone, body mass index (BMI), physical activity, alcohol intake]. Also, TCDD levels were higher among younger girls (median, 205 ppt) than in all girls (median, 140 ppt), an effect that may reflect lower BMI among younger girls and dilution of body burden by greater body size in older girls, but also a significantly higher target-organ dose. Warner et al. (2004) examined associations in premenarcheal girls who were a younger subset (0–8 years of age) during the exposure window in 1976. This age stratum should capture any strong underlying associations among girls exposed early in life. However, it is known that pubertal transition occurs around 5–7 years of age and that age at menarche is strongly correlated with age at first signs of development (de Ridder et al. 1992; Nicolson and Hanley 1953). Therefore, hormonal exposures before 5 years of age might alter the milestones of female development, including menarche, either more potently or in a different direction than peripubertal exposures. Therefore, the youngest girls in this population (Warner et al. 2004) may have been more susceptible to hormonal effects of environmental toxicants. Recognizing the limitation of small numbers available for further age stratification, it would be interesting to know whether risk of earlier (or later) puberty was raised among girls exposed at earlier ages, such as 0–4 years.

Relationship of serum TCDD concentrations and age at exposure of female residents of Seveso, Italy.

In 1976, a chemical plant explosion near Seveso, Italy, resulted in the highest known exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in residential populations. In 1996, we initiated the Seveso Women's Health Study (SWHS), a historical cohort study of females who were 40 years old at the time of explosion and residents of the most heavily contaminated areas, zones A and B. Serum samples collected near the time of the explosion were analyzed for TCDD. We also analyzed pooled serum samples collected in 1976 from females who resided in zone non-ABR, the "unexposed" zone, to assess concurrent background exposures to other dioxins, furans, and coplanar polychlorinated biphenyls (PCBs). The median lipid-adjusted TCDD level for residents of zones A and B combined was 56 ppt (range = 2.5-56,000 ppt). Zone A residents had 5-fold higher TCDD levels (n = 67, median = 272 ppt) than did zone B residents (n = 814, median = 47 ppt). The youngest children had the highest TCDD levels, which decreased with age at explosion until approximately 13 years of age and were constant thereafter. Therefore, children living in zones A and B received a disproportionately higher exposure to TCDD as a result of the explosion. Zone of residence and age were the strongest predictors of TCDD level. Chloracne, nearby animal mortality, location (outdoors vs. indoors) at the time of explosion, and consumption of homegrown food were also related to serum TCDD levels. The serum pools from zone non-ABR residents had an average TCDD concentration of 20.2 ppt, and average total toxic equivalent (TEQ) concentration of 100.4 ppt. Therefore, background exposure to dioxins, furans, and PCBs unrelated to the explosion may have been substantial. As a consequence, previous SWHS studies that considered only TCDD exposure may have underestimated health effects due to total TEQ concentrations.

The potential role of exposure to environmental toxicants in the pathophysiology of endometriosis.

Humans and animals are exposed daily to a complex mixture of polyhalogenated aromatic hydrocarbons (PHAHs). Previous work has shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with a dose-dependent increase in the incidence and severity of endometriosis in the rhesus monkey. Dioxin-like chemicals can also exert effects in combination with TCDD via the aryl hydrocarbon receptor. Using a rhesus model of chronic TCDD exposure and endometriosis, serum concentrations of TCDD and 19 dioxin-like PHAHs were quantified 13 years after termination of exposure to TCDD. In additional studies, the immune status of TCDD-exposed monkeys was evaluated. For TCDD-exposed and unexposed animals, TCDD exposure correlated with an increased serum TCDD concentration. Furthermore, TCDD exposure and an elevated serum TCDD concentration were associated with increased serum levels of triglycerides, 1,2,3,6,7,8-hexachlorodibenzofuran (HxCDF), PCB77, and PCB126. Importantly, the animals with elevated serum levels of PCB77 and PCB126 and increased total serum TCDD equivalents (TEQs) had a high prevalence of endometriosis, and the severity of disease correlated with the serum concentration of PCB77. In immune studies, TCDD exposure correlated with increased tumor necrosis factor alpha (TNFalpha) production by peripheral blood mononuclear cells (PBMC) in response to stimulation by T cell mitogen and decreased NK cytolytic activity. Elevated serum concentrations of TCDD, 1,2,3,6,7,8-HxCDF, and PCB126 correlated with increased numbers of CD3+/CD25- and CD3-/CD25+ leukocytes and enhanced secretion of TNFalpha by mitogen-stimulated PBMC. This evidence suggests that TCDD exposure and endometriosis in the rhesus monkey may be associated with increased serum concentrations of specific coplanar PCB compounds and long-term alterations in systemic immunity. Furthermore, the data suggest a potential involvement of an increased body burden of PCB compounds in the etiology of endometriosis in the rhesus. Recent advances in the detection and assay of individual PHAH congeners in biological samples have made it possible to assess total PHAH body burden in humans and animals. Future studies are expected to exploit this advance to assess the health impact of PHAH body burdens in both exposed individuals and the general population. Serum PHAH concentrations and TEQs in TCDD-exposed monkeys with endometriosis are similar to or lower than blood levels in the general human population; thus, it is important to consider the implications of these findings for human health and the prevalence of endometriosis in humans. Additional studies are warranted, particularly in human subjects, to explore the potential implications of these data.

Relation of serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) level to hematological examination results in veterans of Operation Ranch Hand.

The authors studied indices of hematologic function and exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Vietnam War veterans of Operation Ranch Hand--the Air Force unit responsible for the aerial spraying of Agent Orange and other herbicides in Vietnam. The herbicides were contaminated with TCDD. The authors measured TCDD serum levels in 1987 or later and extrapolated the result to the time of service in Vietnam. The authors studied serum TCDD level in relation to red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, white blood cell count, platelet count, and erythrocyte sedimentation rate at each of 4 physical examinations. Compared with veterans not involved in Operation Ranch Hand, those with the highest TCDD levels in Operation Ranch Hand had mean corpuscular volumes that were about 1% higher and platelet counts that were about 4% higher. These small increases were unlikely to be of clinical significance and may not have been caused by TCDD.

Serum levels of TCDD and dioxin-like chemicals in Rhesus monkeys chronically exposed to dioxin: correlation of increased serum PCB levels with endometriosis.

Humans and animals are exposed daily to a complex mixture of polyhalogenated aromatic hydrocarbons (PHAHs). Previous work has shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with a dose-dependent increase in the incidence and severity of endometriosis in the rhesus monkey. Dioxin-like chemicals can also exert effects in combination with TCDD via the aryl hydrocarbon receptor. This study demonstrates that the serum levels of TCDD and specific dioxin-like PHAH congeners were increased in TCDD-treated animals with endometriosis 13 years after the TCDD exposure. Nine TCDD-exposed and 6 unexposed female rhesus monkeys were evaluated for serum content of relevant compounds and for endometriosis by surgical laparoscopy. Additional studies were done on 4 animals that died 7 to 11 years after exposure to TCDD and 4 lead-treated animals with no history of PHAH treatment. For TCDD-exposed and unexposed animals, TCDD exposure correlated with an increased serum TCDD concentration. Furthermore, TCDD exposure and an elevated serum TCDD concentration were associated with increased serum levels of triglycerides, 1,2,3,6,7,8-hexachlorodibenzofuran, 3,3',4,4'-tetrachlorobiphenyl (TCB) and 3,3'4,4',5-pentachlorobiphenyl (PnCB). Importantly, the animals with elevated serum levels of 3,3',4,4'-TCB, 3,3',4,4',5-PnCB and an increased total serum TEQ had a high prevalence of endometriosis, and the severity of disease correlated with the serum concentration of 3,3,',4,4'-TCB. Increased serum concentrations of coplanar PCBs were also present in lead-treated animals. Implications of these findings for human health and the prevalence of endometriosis in humans will be discussed.

Evaluation of diabetes mellitus, serum glucose, and thyroid function among United States workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

OBJECTIVE: Some studies suggest that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may affect glucose metabolism and thyroid function. To further assess the relation between exposure to TCDD and endocrine function, data from...

Estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin using a minimal physiologic toxicokinetic model.

In this study we investigated estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on a minimal physiologic toxicokinetic model in humans. Our purpose was to obtain a mathematical tool for dose-response studies based on human data. We first simplified an existing model of TCDD kinetics in humans and estimated its parameters (i.e., liver elimination and background input of TCDD) using repeated measures of serum dioxin taken in Vietnam veterans (Ranch Hand data and data from an unexposed reference group). We carried out computer simulation and estimation of the model parameters both under a nonlinear weighted least-squares model (naive pooled data approach) and under a nonlinear mixed-effects model. The best parameter estimates were obtained with log-transformed data under a mixed-effects model: liver elimination parameter kf = 0.022 days-1 (95% confidence interval [CI] = 0.020, 0.024), and background input rate input = 0.1251 pg/kg/day (95% CI = 0.071, 0.179). The dioxin kinetic model and its estimated parameters were then used to provide dose estimates for a cohort of workers with exposure to TCDD at chemical plants in the United States. First, the model was used to estimate the rate of occupational intake of TCDD in a subset of the cohort consisting of 253 subjects for whom one measure of serum TCDD was available. A model of change in body-mass index over time was also identified for this subsample. The occupational exposure rate was estimated by linear regression using the above values of kinetic parameters and assuming an initial condition for serum TCDD of 7 ppt, i.e., the average level found in unexposed workers. The estimate of the occupational exposure parameter was 232.7 pg/kg/day (95% CI 192, 273). This value can be applied to the full cohort to obtain for each cohort member the time course of serum dioxin concentration from which exposure indices can be derived. Sensitivity coefficients to model parameters (background input, kf, occupational exposure, and the assumed TCDD concentration at hire) allow for a convenient recalculation of the serum TCDD curve and of the derived exposure indices for different assumed values of the model parameters.

Evaluation of cardiovascular outcomes among U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Some animal studies and some human studies suggest that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may be associated with adverse effects on the cardiovascular system. As part of a cross-sectional medical study comparing workers employed 15 years earlier in the manufacture of 2,4,5-trichlorophenol or one of its derivatives at two U.S. chemical plants with an unexposed comparison group, we examined the association between TCDD exposure and various cardiovascular outcomes. A total of 281 workers and 260 unexposed referents participated. The workers had substantial exposure to TCDD, as demonstrated by significantly elevated mean serum TCDD concentration of 220 pg/g of lipid, compared with 7 pg/g of lipid among the referents. No significant association was found between TCDD exposure and any of the cardiovascular outcomes including myocardial infarction, angina, cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow. Although our study had sufficient statistical power to detect an elevated risk for cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow, it had low power (approximately 50%) to detect an elevated risk for myocardial infarction and angina. Our review of the literature suggests that our negative findings are consistent with those from other cross-sectional medical studies. Although several mortality studies of TCDD-exposed cohorts found significantly increased risks for cardiovascular disease mortality, similar increased risks were not observed in other mortality studies. The data available do not provide definitive conclusions but indicate that further examination of the association between TCDD exposure and cardiovascular disease should be pursued.