Diabetes in Native Americans: elevated risk as a result of exposure to polychlorinated biphenyls (PCBs).

We have studied rates of diabetes in 601 members of the Mohawk Nation at Akwesasne, ages 18-84 years, in relation to serum concentrations of 101 polychlorinated biphenyl (PCB) congeners and three chlorinated pesticides [dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and mirex]. Diabetes was determined from either a diagnosis by a physician or by having a fasting glucose concentration of >125 mg/dL. Rates of diabetes are high in this community. Three models were used. In the first model rate ratios (RR) were determined for quartiles of total PCBs after adjustment for age, sex, body mass index (BMI) and total serum lipids. For total PCBs RR=2.21 (1.2-4.2), while for total pesticides RR=3.75 (1.3-10.7). When the total PCB results were also adjusted for total pesticides and the total pesticide results were also adjusted for total PCBs (Model 2) the RRs were somewhat reduced. In Model 3 we considered subgroups of PCBs based on numbers of chlorines on the molecule (tri-/tetra, penta-/hexa, hepta plus) and numbers of ortho chlorines (non-/mono; di-, tri-/tetra-), and considered each of the pesticides individually after adjustment for all other contaminants as well as age, sex, BMI and serum lipids. We found a highly significant association between diabetes and PCBs with only three or four chlorines (RR=5.02), but no significant association with those with greater chlorination. When evaluating PCBs based on numbers of ortho chlorines only, those with no or one ortho chlorine showed significant associations. As mono-ortho PCBs include some with dioxin-like activity, we compared those with and without a TEF, and found that the association with diabetes was exclusively with the non-dioxin-like congeners. Of the pesticides only hexachlorobenzene showed a small but significant association with diabetes. Because lower chlorinated PCBs are more volatile and do not greatly accumulate in fish, these results suggest that inhalation is the major route of exposure to those PCBs that increase risk of diabetes.

Prenatal exposure to organochlorine pesticides and infant birth weight in China.

In utero exposure to organochlorine pesticides (OCPs) is thought to be potentially harmful to fetal development. We aimed to investigate the associations of maternal and cord serum OCPs levels with infant birth weight in China. In this study, we measured serum levels of 18 OCPs in 81 mother-infant pairs, including DDT, hexachlorocyclohexanes (BHC), hexachlorobenzene (HCB), heptachlors, chlordanes, endosulfan-I, and mirex using a high-resolution-gas-chromatography with high-resolution-mass-spectrometry method. We found that p,p'-DDE and ß-BHC had the highest detection rate in both maternal and cord blood serum (97.2% and 96.7%, respectively), followed by HCB (93.0%, 51.7%), p,p'-DDT (88.7%, 36.7%), and p,p'-DDD (83.1%, 60.0%). Among all OCPs, the concentration of p,p'-DDE was the highest (mothers geometric mean (GM): 203.54ngg(-1), newborns GM: 116.14ngg(-1)), followed by HCB (70.62ngg(-1), 65.16ngg(-1)), and ß-BHC (67.67ngg(-1), 33.39ngg(-1)). Multiple linear regression analyses showed that each 1ngg(-1) increment of cord serum p,p'-DDE, total DDT, and ß-BHC was associated with a 0.10g, 0.10g, and 0.92g decrease in infant birth weight, respectively, and as the cord serum concentrations of p,p'-DDT, p,p'-DDD, HCB and mirex increased, the infant birth weight was also decreased, although the associations were not statistically significant due to the relatively small sample size. These results suggest that p,p'-DDE, ß-BHC, and HCB were the predominant OCPs in the serum of Chinese pregnant women and cord blood of their newborns. Prenatal exposure to DDT, ß-BHC, HCB, and mirex were associated with a decrease in birth weight, but these results need validation in larger sample-sized studies.

Organochlorine pesticides and risk of endometriosis: findings from a population-based case-control study.

BACKGROUND: Endometriosis is considered an estrogen-dependent disease. Persistent environmental chemicals that exhibit hormonal properties, such as organochlorine pesticides (OCPs), may affect endometriosis risk. OBJECTIVE: We investigated endometriosis risk in relation to environmental exposure to OCPs. METHODS: We conducted the present analyses using data from the Women's Risk of Endometriosis (WREN) study, a population-based case-control study of endometriosis conducted among 18- to 49-year-old female enrollees of a large health care system in western Washington State. OCP concentrations were measured in sera from surgically confirmed endometriosis cases (n = 248) first diagnosed between 1996 and 2001 and from population-based controls (n = 538). We estimated odds ratios (OR) and 95% CIs using unconditional logistic regression, adjusting for age, reference date year, serum lipids, education, race/ethnicity, smoking, and alcohol intake. RESULTS: Our data suggested increased endometriosis risk associated with serum concentrations of ß-hexachlorocyclohexane (HCH) (third vs. lowest quartile: OR = 1.7; 95% CI: 1.0, 2.8; highest vs. lowest quartile OR = 1.3; 95% CI: 0.8, 2.4) and mirex (highest vs. lowest category: OR = 1.5; 95% CI: 1.0, 2.2). The association between serum ß-HCH concentrations and endometriosis was stronger in analyses restricting cases to those with ovarian endometriosis (third vs. lowest quartile: OR = 2.5; 95% CI: 1.5, 5.2; highest vs. lowest quartile: OR = 2.5; 95% CI: 1.1, 5.3). CONCLUSIONS: In our case-control study of women enrolled in a large health care system in the U.S. Pacific Northwest, serum concentrations of ß-HCH and mirex were positively associated with endometriosis. Extensive past use of environmentally persistent OCPs in the United States or present use in other countries may affect the health of reproductive-age women.

Relationships of putative endocrine disruptors to human sexual maturation and thyroid activity in youth.

Endocrine disruption has become a significant human health concern, but is difficult to study outside of the laboratory for several reasons including the multiplicity of exposures, the difficulty in assessing each exposure, and the variety of possible outcomes among human populations. This review summarizes our studies of the relationships of measured persistent organic pollutants (PCBs, p,p'-DDE, HCB and mirex), and heavy metals (lead and mercury), to outcomes directly related to thyroid function and sexual maturation. These studies were conducted in a sample of Native American youth from the Akwesasne Mohawk community. The participants were first studied during puberty (10-16.9 years of age) and then at approximately 18 years of age. Results from these studies show that PCB levels are positively related to TSH and negatively to free T4. Further, these effects are conditioned by breastfeeding history. Anti-thyroid peroxidase antibody levels also are related to PCB levels suggesting elevated risk of autoimmune disease among the exposed. Earlier age at menarche is associated with higher PCB levels while risk of delay is associated with higher lead levels. Some evidence that the timing of exposure produces different effects is presented, and the level of exposure in the participants suggests that effects observed may be relevant to a considerable proportion of the US population. Further investigations are warranted to determine effect thresholds and mechanisms.

Diabetes in relation to serum levels of polychlorinated biphenyls and chlorinated pesticides in adult Native Americans.

BACKGROUND: Recent research suggests that diabetes, a condition whose incidence is increasing, is associated with exposure to polychlorinated biphenyls (PCBs) and chlorinated pesticides. OBJECTIVES: We investigated the potential association between diabetes and serum levels of PCBs, dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB), and mirex in a cross-sectional study of an adult Native-American (Mohawk) population. METHODS: Through a standardized questionnaire we collected demographic, medical, and lifestyle information from 352 adults, > or =30 years of age. We collected fasting serum samples that were analyzed for 101 PCB congeners, DDE, HCB, and mirex along with fasting glucose, triglycerides, and cholesterol. Participants who had fasting-glucose values > 125 mg/dL and/or who were taking antidiabetic medication were defined as persons with diabetes. We conducted logistic regression to assess the potential association between organochlorine serum levels and diabetes, while controlling for the potential confounding variables of age, body mass index (BMI), smoking, sex, and serum lipid levels. Organochlorine serum levels were categorized in tertiles, and the lowest tertile was used as the reference category. RESULTS: The prevalence of diabetes was 20.2%. The odds ratio (OR) of having diabetes for participants in the highest tertile of total PCB concentration compared with the lowest tertile was 3.9 (95% confidence interval, 1.5-10.6). The corresponding ORs for DDE and HCB were even higher. Elevated serum mirex was not associated with diabetes. After adjustment for other analytes, the OR for HCB remained significant, whereas ORs for PCBs and DDE remained elevated but not statistically significant. In contrast, after adjustment for other analytes, the OR for mirex became statistically significant and indicated an inverse association. CONCLUSIONS: In this study of adult Native Americans, elevated serum PCBs, DDE, and HCB were positively associated with diabetes after controlling for potential confounders, whereas a negative association was observed for mirex.

Relationship of lead, mercury, mirex, dichlorodiphenyldichloroethylene, hexachlorobenzene, and polychlorinated biphenyls to timing of menarche among Akwesasne Mohawk girls.

BACKGROUND: Children are commonly exposed at background levels to several ubiquitous environmental pollutants, such as lead and persistent organic pollutants, that have been linked to neurologic and endocrine effects. These effects have prompted concern about alterations in human reproductive development. Few studies have examined the effects of these toxicants on human sexual maturation at levels commonly found in the general population, and none has been able to examine multiple toxicant exposures. The aim of the current investigation was to examine the relationship between attainment of menarche and levels of 6 environmental pollutants to which children are commonly exposed at low levels, ie, dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), polychlorinated biphenyls (PCBs), mirex, lead, and mercury. METHODS: This study was conducted with residents of the Akwesasne Mohawk Nation, a sovereign territory that spans the St Lawrence River and the boundaries of New York State and Ontario and Quebec, Canada. Since the 1950s, the St Lawrence River has been a site of substantial industrial development, and the Nation is currently adjacent to a US National Priority Superfund site. PCB, p,p'-DDE, HCB, and mirex levels exceeding the US Food and Drug Administration recommended tolerance limits for human consumption have been found in local animal species. The present analysis included 138 Akwesasne Mohawk Nation girls 10 to 16.9 years of age. Blood samples and sociodemographic data were collected by Akwesasne community members, without prior knowledge of participants' exposure status. Attainment of menses (menarche) was assessed as present or absent at the time of the interview. Congener-specific PCB analysis was available, and all 16 PCB congeners detected in >50% of the sample were included in analyses (International Union of Pure and Applied Chemistry numbers 52, 70, 74, 84, 87, 95, 99, 101 [+90], 105, 110, 118, 138 [+163 and 164], 149 [+123], 153, 180, and 187). Probit analysis was used to determine the median age at menarche for the sample. Binary logistic regression analysis was used to determine predictors of menarcheal status. Six toxicants (p,p'-DDE, HCB, PCBs, mirex, lead, and mercury) were entered into the logistic regression model. Age, socioeconomic status (SES), and BMI were tested as potential cofounders and were included in the model at P < .05. Interactions among toxicants were also evaluated. RESULTS: Toxicant levels were measured in blood for this sample and were consistent with long-term exposure to a variety of toxicants in multiple media. Mercury levels were at or below background levels, all lead levels were well below the Centers for Disease Control and Prevention action limit of 10 microg/dL, and PCB levels were consistent with a cumulative, continuing exposure pattern. The median age at menarche for the total sample was 12.2 years. The predicted age at menarche for girls with lead levels above the median (1.2 microg/dL) was 10.5 months later than that for girls with lead levels below the median. In the logistic regression analysis, age was the strongest predictor of menarcheal status and SES was also a significant predictor but BMI was not. The logistic regression analysis that corrected for age, SES, and other pollutants (p,p'-DDE, HCB, mirex, and mercury) indicated that, at their respective geometric means, lead (geometric mean: 0.49 microg/dL) was associated with a significantly lower probability of having reached menarche (beta = -1.29) and a group of 4 potentially estrogenic PCB congeners (E-PCB) (geometric mean: 0.12 ppb; International Union of Pure and Applied Chemistry numbers 52, 70, 101 [+90], and 187) was associated with a significantly greater probability of having reached menarche (beta = 2.13). Predicted probabilities at different levels of lead and PCBs were calculated on the basis of the logistic regression model. At the respective means of all toxicants and SES, 69% of 12-year-old girls were predicted to have reached menarche. However, at the 75th percentile of lead levels, only 10% of 12-year-old Mohawk girls were predicted to have reached menarche; at the 75th percentile of E-PCB levels, 86% of 12-year-old Mohawk girls were predicted to have reached menarche. No association was observed between mirex, p,p'-DDE, or HCB and menarcheal status. Although BMI was not a significant predictor, we tested BMI in the logistic regression model; it had little effect on the relationships between menarcheal status and either lead or E-PCB. In models testing toxicant interactions, age, SES, lead levels, and PCB levels continued to be significant predictors of menarcheal status. When each toxicant was tested in a logistic regression model correcting only for age and SES, we observed little change in the effects of lead or E-PCB on menarcheal status. CONCLUSIONS: The analysis of multichemical exposure among Akwesasne Mohawk Nation adolescent girls suggests that the attainment of menarche may be sensitive to relatively low levels of lead and certain PCB congeners. This study is distinguished by the ability to test many toxicants simultaneously and thus to exclude effects from unmeasured but coexisting exposures. By testing several PCB congener groupings, we were able to determine that specifically a group of potentially estrogenic PCB congeners affected the odds of reaching menarche. The lead and PCB findings are consistent with the literature and are biologically plausible. The sample size, cross-sectional study design, and possible occurrence of confounders beyond those tested suggest that results should be interpreted cautiously. Additional investigation to determine whether such low toxicant levels may affect reproduction and disorders of the reproductive system is warranted.

Profiles of ortho-polychlorinated biphenyl congeners, dichlorodiphenyldichloroethylene, hexachlorobenzene, and Mirex among male Lake Ontario sportfish consumers: the New York State Angler cohort study.

Great Lakes sportfish consumption is a recognized human exposure source to environmental organochlorine compounds. Using data collected as part of the New York State Angler Cohort Study, 203 males were considered with regard to history of Lake Ontario sportfish consumption and sera levels of 57 ortho-substituted polychlorinated biphenyl (PCB) congeners, dichlorodiphenyldichloroethylene, hexachlorobenzene, and Mirex. Consumption of six species of highly contaminated Lake Ontario sportfish during the years 1980 to 1990 was considered. Exposure was weighted by average annual frequency of consumption, whole-fish PCB estimates, and meal size to determine a continuous index of exposure. This index was dichotomized to compare "consumers" to "nonconsumers" in several procedures. Recovery and lipid-adjusted serum values for PCB congener IUPAC Nos. 138+163 (rsp=0.3), 183 (rsp=0.3), 187 (rsp=0.4), and 188 (rsp=0.3) and Mirex (rsp=0.4) were significantly correlated with the index of fish consumption (P<0.001). A logistic regression model, using forward stepwise selection procedures (alpha in/out=0.002/0.004), was employed to account for high intercorrelations among organochlorine predictor variables. Mirex was the sole statistically significant predictor variable of "consumer/nonconsumer." A one-unit increase in log Mirex was associated with a 92.0% increase in the odds of having reported sportfish consumption (OR=1.92, 95%CI=1.43, 2.58). Age, body mass index, cigarette smoking, water/wildfowl consumption, and year of sampling were considered covariates. The results of this study support the premise that long-term dietary consumption of Lake Ontario sportfish, even at comparatively low levels, contributes significantly to the body burden of organochlorine compounds in western New York anglers and sportsmen.

Quantitative determination of endocrine- disrupting polychlorinated biphenyls and organochlorinated pesticides in human serum using gas chromatography with electron-capture detection and tandem mass spectrometry.

A sensitive, selective and reliable procedure was developed and validated to determine organochlorinated compounds, which have endocrine-disrupting effects, in human serum. Target compounds were selected between polychlorinated biphenyls and organochlorinated pesticides. Sample workup consisted of (1) extraction of serum with organic solvents, (2) clean-up of the organic extract using acid treatment with H(2)SO(4), (3) elution of the cleaned-up extract through a liquid column chromatographic system and (4) analysis of the fraction eluted by gas chromatography with electron capture detection (ECD) and tandem mass spectrometry (MS/MS) detection. Performance characteristics, such as linearity, sensitivity, precision, accuracy and recovery, of both chromatographic methods were studied. The proposed analytical methodology was applied to determine the target compounds in serum samples from women living in agricultural areas of Almería (Spain). The results show the advantage of MS/MS over ECD in the analysis of real human serum samples where matrix interferences can be confused with target pesticides.

Blood PCB, p,p'-DDE, and mirex levels in Great Lakes fish and waterfowl consumers in two Ontario communities.

PCB, p,p'-DDE, and mirex levels were examined in blood plasma samples of 232 anglers from Cornwall and Mississauga, Ontario, in a pilot study to establish the feasibility and suitability of using a cohort of Ontario fish license holders for large-scale health studies. Great Lakes fish, waterfowl, and ocean fish consumption were examined as predictors of contaminant levels using regression analysis, with adjustment for age, gender, and community. Levels of Great Lakes fish and waterfowl consumption and contaminant levels were generally low in comparison with those observed in other Great Lakes studies. However, even within these low levels, Great Lakes fish consumption was associated with increased blood plasma PCB levels in men and mirex levels in both men and women. Waterfowl consumption was associated with higher plasma PCB (men and women), DDE (men only), and mirex levels (men and Cornwall women), and requires further exploration. We conclude that other study designs are required (to identify high consumers) for carrying out studies of health effects associated with high levels of Great Lakes fish and waterfowl consumption.

Determination of Mirex in human blood serum containing polychlorinated biphenyls by using packed column gas chromatography.

An analytical method has been developed that uses electron capture/gas-liquid chromatography to determine Mirex in serum containing polychlorinated biphenyls (PCBs) (Aroclor 1260). With this method, 0.2 ppb Mirex can be determined in 4 mL serum that also contains 10 ppb PCBs. The method provides approximately 70% recovery of Mirex at 1.0 and 3.5 ppb. The coefficients of variation are 4.5 and 4.6% at 1.0 and 3.5 ppb, respectively. In a cooperative study with the Ohio Department of Health, the Centers for Disease Control used this method to determine the extent of exposure of Salem, OH, residents to Mirex. Confirmation of Mirex was obtained by using high resolution gas chromatography and high resolution mass spectrometry.

Determination of extractable mirex in whole blood.

A method for the determination of free mirex in blood has been developed in which whole blood is extracted with acetone-hexane (9+91), passed through Na2SO4, concentrated, and analyzed by electron capture gas-liquid chromatograpohy (GLC). Results were highest for fresh blood. Recoveries were verified by determining 14C-labeled mirex before and after extraction. Little mirex was detected in the samples after extraction. Hydrolysis of residual blood indicates that a metabolite of mirex is released. The possible metabolite has a GLC retention time and mass spectrum which resemble hydroxy metabolites of mirex.

Tissue distribution and elimination of 2,8-dihydromirex in the rat.

The tissue distribution and elimination kinetics of 14C-labeled dihydromirex were investigated in the rat. Dihydromirex was distributed in all tissues examined after iv or oral administration; the highest concentrations were found in the fat, liver, and skin. The pattern of distribution was similar to that of photomirex and mirex. Elimination of dihydromirex from the blood after an iv dose was expressed by a four-compartment model, whereas fecal excretion was represented by a biphasic curve. Excretion of dihydromirex occurred predominantly in the feces; only minute amounts were found in the urine and bile. Dihydromirex constituted 90-100% of the total radioactivity in tissues and feces. No metabolite was detected.

Mirex kinetics in chickens.

Mirex kinetics were determined in chickens after a single dose of 30 mg/kg iv or 300 mg/kg orally. The decline in blood concentrations was biphasic and suggested uptake of mirex by "fast" and "slow" tissue compartments, with the greatest accumulation in fat and skin 2 wk after administration. Less than 1% of the dose was excreted in 2 wk. Mirex depletion rates in skin and fat were determined in growing chicks fed 1 or 10 ppm mirex in the diet for 1 wk. Calculated disappearance half-times for mirex were 24.8 in skin and 31.5 d in fat. The decrease in tissue concentrations was attributed to dilution in tissue mass accompanying the rapid growth rate rather than to excretion of mirex. The results do not indicate that avian species eliminate mirex more efficently than mammals.

Mirex kinetics in the rhesus monkey. I. Disposition and excretion.

Three female rhesus monkeys were given 14C-Mirex (5.23 mCi/mmol) iv (two animals) or po (one animal) in a dose of about 1 mg/kg for the purpose of determining the distribution and excretion of this polycyclic perchlorinated insecticide. Blood, plasma, urine, feces, and tissue samples were analyzed for 14C content. Monkeys were autopsied 23, 106, and 388 days after receiving 14C-Mirex. Following iv administration, plasma 14C showed a rapid decrease over the first few hours from the initial high levels. In the monkey given the compound orally, 14C first appeared in the plasma at 2 hr and reached a maximum at 5 hr. Thereafter, the decline in plasma radioactivity paralleled that found in the animals dosed i.v. After 2 weeks, the rate of decline in all animals was very slow. Excretion and tissue distribution of Mirex were essentially the same whether the compound was given po or iv. Less than 0.6% of the dose was found in the urine. 14C was excreted in the feces for the duration of the experiment with a maximum cumulative excretion of 7% after 388 days. At autopsy all tissues analyzed contained 14C. The highest concentration of 14C was found in the fat (estimated to contain at least 80% of the dose), followed by adrenal, peripheral nerve, thyroid, and skin. Chemical analysis of the nature of the radioactivity in fat and feces showed that at least 95% and was present as unchanged Mirex. There was a small amount of a compound more polar than Mirex in the feces, containing less than 3% of the fecal radioactivity.

Mirex kinetics in the rhesus monkey. II. Pharmacokinetic model.

14C-Mirex was given iv and po to female rhesus monkeys (Macaca mulatta) and radioactivity was measured in plasma, urine, and feces at intervals after dosing and in tissues when animals were killed. Graphical analysis of plots of the logarithm of plasma concentration vs. time was used to provide estimates of the values of the first-order rate constants required by the proposed pharmacokinetic models. A BASIC-language program, FITKIN, was used to obtain numerical solutions to the differential equations for each model and to adjust the estimates to obtain a normalized, least squares fit. Of several models postulated, a mammillary, four-compartment, open-system model, providing for the urinary excretion of Mirex from a "central" compartment and for the fecal excretion of Mirex from a "fast" tissue compartment, yielded theoretical data in agreement with observed values. This model predicted that the accumulation of Mirex into fat would be retarded by the presence of a "slow" tissue compartment so that distribution equilibrium would take about half a year. From that time to the end of a 5-year projection, little decline in the quantities of Mirex was predicted for any compartment. Sequestration in fat and a lack of metabolism were responsible for the long biological half-life of Mirex in the rhesus monkey.