Associations of exposure to dioxins and polychlorinated biphenyls with diabetes: based on epidemiological findings

Persistent organic pollutants (POPs) are a group of chemical substances that have the common properties of resistance to biodegradation, wide-range transportation, high lipophilicity, bioaccumulation in fat, and biomagnification in the food chain. POPs are persistent in the environment worldwide and have potential adverse impacts on human health and the environment. Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) are well known chemicals that are considered as POPs. The association between high-level exposure to dioxins and type 2 diabetes among U.S. Air Force veterans who had been exposed to Agent Orange contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during the Vietnam War was reported in the late 1990s. This association has been supported by similar epidemiologic studies, whose subjects were exposed to high doses of dioxins in their places of work involving phenoxyacid herbicide production and spraying, and in the industrial accident in Seveso, Italy. Recently, low-level exposure to dioxins and PCBs has been reported to be linked to type 2 diabetes. Cross-sectional studies in the U.S. general population and Japanese general population showed that body burden levels of some dioxins and PCBs were strongly associated with the prevalence of type 2 diabetes. Very recently, following these cross-sectional studies, several prospective studies have suggested that low-level exposure to some PCBs predicted the future risk of type 2 diabetes in the general population. Environmental exposure to some dioxins and PCBs, which mainly accumulate in adipose tissue, may play a role in the development of type 2 diabetes.     

Effects of polychlorinated biphenyls on the nervous system.

The neurological effects of polychlorinated biphenyls (PCBs) have been extensively investigated in humans and in animals. The main focus in human studies has been on the effects in neonates and young children, although studies of adults have also been conducted. A great deal of concern exists that even low levels of PCBs transferred to the fetus across the placenta may induce long-lasting neurological damage. Because PCBs are lipophilic substances, there is also concem that significant amounts might be transferred to nursing infants via breast milk. Studies in humans who consumed large amounts of Great Lakes fish contaminated with environmentally persistent chemicals, including PCBs. have provided evidence that PCBs are important contributors to subtle neurobehavioral alterations observed in newborn children and that some of these alterations persist during childhood. Some consistent observations at birth have been motor immaturity and hyporeflexia and lower psychomotor scores between 6 months and 2 years old. There is preliminary evidence that highly chlorinated PCB congeners, which accumulate in certain fish, are associated with neurobehavioral alterations seen in some newbom children. Subtle neurobehavioral alterations have also been observed in children bom to mothers in the general population with the highest PCB body burdens. Because of the limitations of epidemiological studies, these effects cannot be attributed entirely to PCB exposure. In one general population study, there was strong evidence that dioxins, as well as PCBs, were contributors to the neurobehavioral effects seen in exposed children. Children born to women who accidentally consumed rice oil contaminated with relatively high amounts of PCBs and chlorinated dibenzofurans (CDFs) during pregnancy also had neurodevelopmental changes. Studies in animals support the human data. Neurobehavioral alterations have been also observed in rats and monkeys following prenatal and/or postnatal exposure to commercial Aroclor mixtures, defined experimental congener mixtures, single PCB congeners, and Great Lakes contaminated fish. In addition, monkeys exposed postnatally to PCB mixtures of congeneric composition and concentration similar to that found in human breast milk showed learning deficits long after exposure had ceased. A few other generalizations can be made from the data in animals. It appears that ortho-substituted PCB congeners are more active than coplanar PCBs in modifying cognitive processes. In addition, one effect observed in both rats and monkeys--deficits on delayed spatial alternation--has been known to be induced by exposure to ortho-substituted PCBs, defined experimental mixtures, and commercial Aroclors. Both dioxin-like and non-dioxin-like PCB congeners have been shown to induce neurobehavioral alterations in animals. Changes in levels of neurotransmitters in various brain areas have also been observed in monkeys, rats, and mice. Of all the observed changes, the most consistent has been a decrease in dopamine content in basal ganglia and prefrontal cortex, but further research is needed before specific neurobehavioral deficits can be correlated with PCB-induced changes in specific neurotransmitters in specific brain areas.     

2007年北京市居民母乳中二噁英类化合物负荷水平调查

目的 调查北京地区居民母乳中多氯代苯并二噁英和多氯代苯并呋喃(PCDD/Fs)和二噁英样多氯联苯(dl-PCBs)的污染水平,评价一般人群PCDD/Fs和dl-PCBs的机体负荷状况.方法 2007年在北京市11个区、县中采集母乳样品110份,制成11个混合样品后,采用同位素稀释技术以高分辨气相色谱-高分辨质谱(HRGC-HRMS)测定母乳样品中的PCDD/Fs和dl-PCBs.结果 北京市母乳样品中二噁英类化合物含量最高的组分为八氯代二苯并二噁英(OCDD)和多氯联苯(PCB)-118、PCB-105,其含量中位数分别为20.6 pg/g脂肪、4.07和1.63 ng/g脂肪.按毒性当量(TEQ)计,北京市11个母乳混合样品中总二噁英类化合物含量中位数为7.4 pg TEQ/g脂肪;最高的为通州区,含量中位数为13.5 pg TEQ/g脂肪;最低的为平谷区,为4.3 pg TEQ/g脂肪.结论 目前北京市母乳中PCDD/Fs和dl-PCBs处于较低水平,但随着我国的快速工业化,人群此类物质的机体负荷水平有可能会上升,因此有必要持续跟踪监测.     

Relationship between insulin sensitivity and exposure to dioxins and polychlorinated biphenyls in pregnant women

The aim of this study was to examine the relationship between insulin sensitivity and polychlorinated biphenyls (PCBs) exposure in non-diabetic pregnant women. Forty gravidas, 21-39 years of age and residing within the study area, were recruited. Seventeen 2,3,7,8-substituted dichloro-p-dioxin, dibenzofurans and 12 PCBs were measured using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Serum insulin and glucose were also measured. Insulin sensitivity and the quantitative insulin sensitivity check index (QUICKI) were calculated based on fasting glucose and insulin levels. Three specific congeners of PCBs (123, 126, and 169) were significantly associated with insulin activity (r=−0.34∼−0.36, p<0.05). Statistical analyses revealed that insulin sensitivity was significantly associated with age- and pre-pregnancy body mass indices (BMI)-adjusted for decreasing toxic equivalents (TEQ) of PCBs (p=0.02 for age- and BMI-adjusted). We also performed an insulin correlation for total TEQ and the TEQ of PCBs, and determined that insulin sensitivity was predicted by the TEQ of PCBs by a regression coefficient of −0.189 after adjustment for age and pre-pregnancy BMI. These findings suggest that PCBs may be associated with decreasing insulin sensitivity in non-diabetic pregnant women; however, the mechanism remains to be ascertained.     

Relationships of thyroid hormones with polychlorinated biphenyls, dioxins, furans, and DDE in adults

BACKGROUND: Thyroid hormone homeostasis can be disrupted by exposure to ubiquitous and bioaccumulative organochlorines such as polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDDs). Whereas investigations of health effects have generally focused on human populations with relatively high exposures through occupation, accident, or high fish consumption, general population exposures may also carry risk. METHODS: We studied associations of total thyroxine (T(4)) and thyroid-stimulating hormone (TSH) with PCBs, dioxin-like toxic equivalents (TEQs), and p,p'-diphenyldichloroethene (DDE) in adult participants without thyroid disease who participated in the 1999-2002 National Health and Nutrition Examination Survey, a cross-sectional survey examining a random sample representative of the U.S. population. RESULTS: We found inverse associations of total T(4) with exposure to TEQs in both sexes, with stronger associations in females. In women, mean T(4) was 8.2 microg/dL, and levels were on average 0.75 microg/dL lower (95% confidence interval, 0.04-1.46) in women in the highest quintile of TEQ exposure compared with the lowest two quintiles. Effects were stronger in people > 60 years of age, with negative associations of T(4) with PCBs and TEQs, and positive associations of TSH with PCBs and TEQs in older women, and a negative association of TSH with PCBs in older men. CONCLUSIONS: The data show a dose-dependent decrease in total T(4) with exposure to TEQs at levels similar to those found in the general U.S. population. The effects were stronger in women. The results suggest that older adults, who have a high risk of thyroid disease, may be more at risk for disruption of thyroid hormone homeostasis by dioxin-like organochlorines than younger adults.     

Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children

Prenatal exposure to polychlorinated biphenyls (PCBs) and dioxins is associated with changes in the T-cell lymphocyte population in healthy Dutch infants. We investigated whether these changes persist into later childhood and whether background exposure to PCBs and dioxins is associated with the prevalence of infectious or allergic diseases and humoral immunity at preschool age. The total study group consisted of 207 healthy mother-infant pairs. We estimated prenatal exposure to PCBs and dioxins by the sum of PCBs 118, 138, 153, and 180 (sigmaPCB) in maternal and cord plasma and in breast-fed infants by the dioxin, planar, and mono-ortho PCB toxic equivalent (TEQ) levels in human milk. At 42 months of age, current body burden was estimated by the PCB in plasma. We assessed the prevalence of infectious and allergic diseases by parent questionnaire, and measured humoral immunity by antibody levels for mumps, measles, and rubella after primary vaccination. We performed immunologic marker analyses of lymphocytes in a subgroup of 85 children. Prenatal PCB exposure was associated with an increased number of lymphocytes, T-cells, and CD3CD8(+) (cytotoxic), CD4(+)CD45RO(+) (memory), T-cell receptor (TcR) [alpha]ss(+), and CD3(+)HLA-DR(+) (activated) T cells and lower antibody levels to mumps and measles at preschool age. Adjusted for confounders, prenatal PCB exposure was associated with less shortness of breath with wheeze, and current PCB body burden was associated with a higher prevalence of recurrent middle-ear infections and of chicken pox and a lower prevalence of allergic reactions. A higher dioxin TEQ was associated with a higher prevalence of coughing, chest congestion, and phlegm. We conclude that in Dutch preschool children the effects of perinatal background exposure to PCBs and dioxins persist into childhood and might be associated with a greater susceptibility to infectious diseases. Common infections acquired early in life may prevent the development of allergy, so PCB exposure might be associated with a lower prevalence of allergic diseases.     

Effects of polychlorinated biphenyls on development and reproduction

As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals found at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) sites that have the greatest public health impact. These profiles comprehensively summarize toxicological and environmental information. This article, which constitutes the release of an important section of the Toxicological Profile for Polychlorinated Biphenyls (ATSDR 2000) into the scientific literature, focuses on the developmental and reproductive effects of this group of synthetic organic chemicals (PCBs) in humans and animals. Information on other health effects, toxicokinetics, mechanisms of toxicity, biomarkers, interactions, chemical and physical properties, potential for human exposure, and regulations and advisories is detailed in the profile. Interested readers are encouraged to consult the original toxicological profile for more information. Profiles can be requested from ATSDR's Information Center by telephone (1-888-42-ATSDR [1-888-422-8737] or E-mail: (atsdric@cdc.gov).     

Impact of polychlorinated biphenyls contamination on estrogenic activity in human male serum

Polychlorinated biphenyls (PCBs) are thought to cause numerous adverse health effects, but their impact on estrogen signaling is still not fully understood. In the present study, we used the ER-CALUX bioassay to determine estrogenic/antiestrogenic activities of the prevalent PCB congeners and PCB mixtures isolated from human male serum. The samples were collected from residents of an area with an extensive environmental contamination from a former PCB production site as well as from a neighboring background region in eastern Slovakia. We found that the lower-chlorinated PCBs were estrogenic, whereas the prevalent higher-chlorinated PCB congeners 138, 153, 170, 180, 187, 194, 199, and 203, as well as major PCB metabolites, behaved as antiestrogens. Coplanar PCBs had no direct effect on estrogen receptor (ER) activation in this in vitro model. In human male serum samples, high levels of PCBs were associated with a decreased ER-mediated activity and an increased dioxin-like activity, as determined by the DR-CALUX assay. 17beta-Estradiol (E2) was responsible for a major part of estrogenic activity identified in total serum extracts. Significant negative correlations were found between dioxin-like activity, as well as mRNA levels of cytochromes P450 1A1 and 1B1 in lymphocytes, and total estrogenic activity. For sample fractions containing only persistent organic pollutants (POPs), the increased frequency of antiestrogenic samples was associated with a higher sum of PCBs. This suggests that the prevalent non-dioxin-like PCBs were responsible for the weak antiestrogenic activity of some POPs fractions. Our data also suggest that it might be important to pay attention to direct effects of PCBs on steroid hormone levels in heavily exposed subjects.     

Body burden of polychlorinated biphenyls among persons employed in capacitor manufacturing

Summary In an effort to assess exposure among workers engaged in capitor manufacture, PCB concentration was determined in plasma (290) and adipose tissue (61). In general, males had higher concentrations of PCBs than females.The correlation of plasma concentration (1–546 ppb) of the more highly chlorinated PCBs, which had been used in the past, with total duration of employment suggested accumulation over time. The gc-ec pattern of these PCB peaks was, in most cases, characteristic of exposure to a PCB mixture with 54% chlorine.The less highly chlorinated PCBs, di-, tri-, and tetrachlorobiphenyls, were the source of current exposure, and were observed in concentrations of 6–2530 ppb in plasma. Higher exposure occurred among persons with direct contact with PCBs, in jobs such as capacitor filling.Adipose tissue concentrations, for both the more highly chlorinated PCBs (1–165 ppm) and lower chlorinated PCBs (0.6-414 ppm), were proportional to those in plasma.Abbreviations PCB polychlorinated biphenyl - p,p-DDE 2,2-bis-(4-chlorophenyl)-1,1-dich-loroethylene - DDT dichlorodiphenyltrichloroethane Presented in part, at the XIX. International Congress on Occupational Health, Dubrovnik, September, 1978     

Effects of prenatal exposure to polychlorinated biphenyls and dioxins on mental and motor development in Japanese children at 6 months of age

Several studies have shown that prenatal and/or postnatal background-level exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs) and dioxins, induces adverse effects on the neurodevelopment of children. However, other studies have not detected any harmful influences on neurodevelopment. Furthermore, except in western countries, no developmental tests have been carried out in relation to detailed assessment of exposure to PCBs and dioxins. In this study (the Hokkaido Study on Environment and Children's Health), the effect of prenatal exposure to background levels of PCBs and dioxins on infant neurodevelopment in Japan/Sapporo was elucidated. The associations between the total or individual isomer level of PCBs and dioxins in 134 Japanese pregnant women's peripheral blood and the mental or motor development of their 6-month-old infants were evaluated using the second edition of the Bayley Scales of Infant Development. The mean level of total toxicity equivalency quantity (TEQ) was 18.8 (4.0-51.2) pg/g lipid in blood of 134 mothers. After adjustment for potential confounding variables, the total TEQ value was shown not to be significantly associated with mental developmental index (MDI) or psychomotor developmental index (PDI). However, the levels of one polychlorinated dibenzo-p-dioxin (PCDD) isomer, total PCDDs, and total PCDDs/polychlorinated dibenzofurans (PCDFs) were significantly negatively associated with MDI, and the levels of two PCDD isomers and three PCDF isomers were significantly negatively associated with the PDI. In conclusion, the background-level exposure of several isomers of dioxins during the prenatal period probably affects the motor development of 6-month-old infants more than it does their mental development.     

Occupational exposure to polychlorinated biphenyls in electrical workers. I. Environmental and blood polychlorinated biphenyls concentrations.

Industrial exposure to polychlorinated biphenyls (PCBs) and internal dose were investigated in 80 worker exposed for many years to PCB mixtures with a 42% chlorine content (Pyralene 3010 and Apirolio). PCBs were determined by liquid gas chromatography on samples taken from workroom air, workroom surfaces and tools, the palms of the hand, and the blood of the workers. In the workroom air samples, PCB concentrations ranged from 48 to 275 micrograms/m3. All tested surfaces and tools were heavily contaminated, with a range from 0.2 to 159 micrograms PCBs per cm2 of surface. Considerable amounts of PCBs were detected on the palms of the hands of the workers (2-28 microgram/cm2 of skin surface). In blood, total PCB concentrations from 88 to 1319 micrograms/kg were observed: comparing the blood concentrations of low and high chlorine content biphenyls, a significant difference was found for the low-chlorinated biphenyl concentrations between workers currently exposed and workers exposed only in the past. In groups of workers who were homogeneous as regards work area and job, the PCB concentrations in the blood were closely correlated with the length of actual occupational exposure to these compounds. These findings led to the conclusion that absorption of PCBs in these workers had occurred mainly through the skin, therefore industrial preventive surveillance must take this route of exposure into account. Since blood PCB concentrations appear to be correlated with the length of exposure, PCB determination on whole blood may be used to monitor industrial and environmental exposure to PCBs.     

Effects of dietary polychlorinated biphenyls on cholesterol catabolism in rats

Dietary polychlorinated biphenyls (PCBs) caused hypercholesterolaemia in rats. The concentration and output of biliary cholesterol was significantly lower than that of the control group. Biliary output of total bile acids was significantly decreased in rats given the PCB-supplemented diet. Faecal excretion of total steroids (sum of neutral steroids and acidic steroids) was not significantly changed in rats given the PCB-supplemented diet. The present results indicate that dietary PCBs cause hypercholesterolaemia without modifying the faecal total steroids excretion. These results suggest that PCBs produce hypercholesterolaemia accompanied by changes in biliary or faecal excretion of bile acids and neutral steroids in addition to an increase in hepatic cholesterol synthesis.     

Polybrominated biphenyls, polychlorinated biphenyls, body weight, and incidence of adult-onset diabetes mellitus

BACKGROUND: Prior studies have reported an increased risk of diabetes related to polychlorinated biphenyl (PCB) exposure. No study has yet investigated whether polybrominated biphenyls (PBBs), which are similar in chemical structure, increase the incidence of diabetes. METHODS: The Michigan PBB cohort was established in 1976 and surveyed again in 1991-1993 and in 2001. PBB and PCB serum levels were measured from blood collected at enrollment. To determine the incidence of adult-onset diabetes, we analyzed cohort members without diabetes at enrollment, ages 20 years and older, with known PBB and PCB levels, who participated in at least 1 follow-up survey (n = 1384). Using Poisson regression, we determined the incidence density ratio (IDR) of diabetes for different serum levels of PBB and PCB, controlling for age, body mass index, smoking, and alcohol consumption at enrollment. RESULTS: Analyzing 25 years of follow-up data, we did not find that higher PBB serum levels were a risk factor for the incidence of diabetes mellitus. However, in women, but not in men, higher PCB serum levels were associated with increased incidence of diabetes (IDR = 2.33; 95% confidence interval = 1.25-4.34 in the highest PCB group compared with the lowest). In both men and women, overweight and obesity increased the diabetes incidence. CONCLUSIONS: We found no association between PBB serum levels and diabetes incidence. In women, there was a positive linear association of diabetes incidence with PCB serum levels at enrollment. This finding is in agreement with 2 prior studies indicating a higher relative risk of diabetes in PCB-exposed women.     

Interactive effects of environmentally relevant polychlorinated biphenyls and dioxins on [3H]phorbol ester binding in rat cerebellar granule cells.

Polychlorinated biphenyls (PCBs) are persistent contaminants that exist as complex mixtures in the environment. One problem faced by risk assessors is that the possible interactive effects of specific PCB congeners and related chemicals found in environmental and biological samples have not been systematically investigated. Some PCBs perturb Ca2+ homeostasis and cause protein kinase C (PKC) translocation in neuronal cell cultures and in brain homogenate preparations at concentrations where no cytotoxicity is observed, and these systems are necessary for the growth and normal functioning of neurons. The changes in second messenger systems appear to be associated with the extent of noncoplanarity of the PCB molecule. We studied the interactive effects of selected PCB congeners, a PCB metabolite, and a dioxin on PKC translocation, as determined by [3H]phorbol ester binding in cerebellar granule cells. The binary combinations included coplanar and noncoplanar PCB congeners or PCB congeners with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/PCB metabolite. In addition, we tested the interactive effects of several PCB congeners (three or more) found in environmental samples such as human milk and blood, contaminated fish, and brain samples from PCB-treated animals. The results indicated that 1) the coplanar congener [3,3',4, 4'-tetrachlorobiphenyl (TeCB)] did not alter the in vitro activity of the noncoplanar (2,2',5,5'-TeCB) or coplanar [4, 4'-dichlorobiphenyl (DCB)] congeners; 2) binary mixtures of active PCB congeners (2,2',4,4'-TeCB and 2,2'-DCB; 2,2'-DCB and 3,5-DCB; 2,2',3,5',6-PeCB and 2,2',4,4',5-PeCB) interact in a dose-additive manner; 3) TCDD did not alter the activity of either coplanar (3,3', 4,4'-TeCB) or noncoplanar (2,2',5,5'-TeCB) congeners; 4) the interaction between the parent PCB congener and hydroxy metabolite of PCB is additive; 5) PCB congener mixtures at the ratios found in environmental samples are biologically active; and 6) there was no indication of synergism in any of the combinations studied. These results suggest that the biological effects of binary mixtures of PCB congeners fit a dose-additive model, indicating that there is a specific site of action for these PCB congeners which is independent of the aryl hydrocarbon receptor. Environmental mixtures contain mostly noncoplanar PCB congeners, and because they appear to be biologically active, the potential human health risk by this group of chemicals should be considered in the risk assessment of PCBs.     

Fate and complex pathogenic effects of dioxins and polychlorinated biphenyls in obese subjects before and after drastic weight loss

Background

In humans, persistent organic pollutants (POPs) are stored primarily in adipose tissue. Their total body burden and their contribution to obesity-associated diseases remain unclear.

Objectives

We characterized POP total body burden and their redistribution in obese individuals before and after drastic weight loss and compared these values with a variety of molecular, biological, and clinical parameters.

Methods

Seventy-one obese subjects were enrolled and underwent bariatric surgery. Blood and adipose tissue samples were obtained at different times from these individuals as well as from 18 lean women.

Results

POP content (17 dioxins/furans and 18 polychlorinated biphenyl congeners) in different adipose tissue territories was similar, allowing us to assess total POP body burden from a single biopsy. Total POP body burden was 2 to 3 times higher in obese than in lean individuals. We also found increased expression of some POP target genes in obese adipose tissue. Drastic weight loss led to increased serum POPs and, within 6–12 months, to a significant 15% decrease in total polychlorinated biphenyl body burden. Importantly, serum POP levels were positively correlated with liver toxicity markers and lipid parameters, independently of age and body mass index.

Conclusions

POP content in adipose tissue and serum correlate with biological markers of obesity-related dysfunctions. Drastic weight loss leads to a redistribution of POPs and to a moderate decrease of their total body burden.