Polychlorinated Biphenyls In Humans Research Articles

Nutritional status and prey energy density govern reproductive success in a small cetacean

A variety of mammals suppress reproduction when they experience poor physical condition or environmental harshness. In many marine mammal species, reproductive impairment has been correlated to polychlorinated biphenyls (PCBs), the most frequently measured chemical pollutants, while the relative importance of other factors remains understudied. We investigate whether reproductively active females abandon investment in their foetus when conditions are poor, exemplified using an extensively studied cetacean species; the harbour porpoise (Phocoena phocoena). Data on disease, fat and muscle mass and diet obtained from necropsies in The Netherlands were used as proxies of health and nutritional status and related to pregnancy and foetal growth. This was combined with published life history parameters for 16 other areas to correlate to parameters reflecting environmental condition: mean energy density of prey constituting diets (MEDD), cumulative human impact and PCB contamination. Maternal nutritional status had significant effects on foetal size and females in poor health had lower probabilities of being pregnant and generally did not sustain pregnancy throughout gestation. Pregnancy rates across the Northern Hemisphere were best explained by MEDD. We demonstrate the importance of having undisturbed access to prey with high energy densities in determining reproductive success and ultimately population size for small cetaceans.

Developmental exposure to non-dioxin-like polychlorinated biphenyls promotes sensory deficits and disrupts dopaminergic and GABAergic signaling in zebrafish

The most abundant polychlorinated biphenyl (PCB) congeners found in the environment and in humans are neurotoxic. This is of particular concern for early life stages because the exposure of the more vulnerable developing nervous system to neurotoxic chemicals can result in neurobehavioral disorders. In this study, we uncover currently unknown links between PCB target mechanisms and neurobehavioral deficits using zebrafish as a vertebrate model. We investigated the effects of the abundant non-dioxin-like (NDL) congener PCB153 on neuronal morphology and synaptic transmission linked to the proper execution of a sensorimotor response. Zebrafish that were exposed during development to concentrations similar to those found in human cord blood and PCB contaminated sites showed a delay in startle response. Morphological and biochemical data demonstrate that even though PCB153-induced swelling of afferent sensory neurons, the disruption of dopaminergic and GABAergic signaling appears to contribute to PCB-induced motor deficits. A similar delay was observed for other NDL congeners but not for the potent dioxin-like congener PCB126. The effects on important and broadly conserved signaling mechanisms in vertebrates suggest that NDL PCBs may contribute to neurodevelopmental abnormalities in humans and increased selection pressures in vertebrate wildlife.

Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity.

Despite being banned from production for decades, polychlorinated biphenyls (PCBs) continue to pose a significant risk to human health. This is due to not only the continued release of legacy PCBs from PCB-containing equipment and materials manufactured prior to the ban on PCB production, but also the inadvertent production of PCBs as byproducts of contemporary pigment and dye production. Evidence from human and animal studies clearly identifies developmental neurotoxicity as a primary endpoint of concern associated with PCB exposures. However, the relative role(s) of specific PCB congeners in mediating the adverse effects of PCBs on the developing nervous system, and the mechanism(s) by which PCBs disrupt typical neurodevelopment remain outstanding questions. New questions are also emerging regarding the potential developmental neurotoxicity of lower chlorinated PCBs that were not present in the legacy commercial PCB mixtures, but constitute a significant proportion of contemporary human PCB exposures. Here, we review behavioral and mechanistic data obtained from experimental models as well as recent epidemiological studies that suggest the non-dioxin-like (NDL) PCBs are primarily responsible for the developmental neurotoxicity associated with PCBs. We also discuss emerging data demonstrating the potential for non-legacy, lower chlorinated PCBs to cause adverse neurodevelopmental outcomes. Molecular targets, the relevance of PCB interactions with these targets to neurodevelopmental disorders, and critical data gaps are addressed as well.

Dietary Habits and Cooking Methods Could Reduce Avoidable Exposure to PCBs in Maternal and Cord Sera

Polychlorinated biphenyls (PCBs), like other persistent organic pollutants, are accumulating throughout the food chain and pose health threats to humans, especially children and foetuses. There is no protocol for reducing the contamination levels of the PCBs in humans. This study identified food items and cooking methods that reduce serum PCB levels by analysing data collected from the Chiba Study of Mother and Child Health. The sample size was 194 subjects. Serum PCB levels were measured using gas chromatography–electron capture negative ionization quadrupole mass spectrometry. Information on dietary habits was obtained from a brief diet history questionnaire that included questions about food items and cooking methods. Food items were categorized into food groups, and nutrient levels were calculated based on food item consumption. Principal component analysis and lasso regression were used as statistical methods. The analyses of food items and nutrients suggested that food items rich in dietary fibre reduce avoidable exposure to PCBs, as could grilling and deep frying of food, which could reduce avoidable exposure to serum PCBs in mothers and foetuses. (174 words).

PCB 28 metabolites elimination kinetics in human plasma on a real case scenario: Study of hydroxylated polychlorinated biphenyl (OH-PCB) metabolites of PCB 28 in a highly exposed German Cohort

Polychlorinated biphenyls (PCBs) are suspected of carcinogenic, neurotoxic and immunotoxic effects in animals and humans. Although background levels of PCBs have been slowly decreased after their ban, they are still among the most persistent and ubiquitous pollutants in the environment, remaining the subject of great concern. PCB 28 is a trichlorinated PCB found in high concentrations not only in human plasma but also in indoor air in Europe, yet little is known about its metabolic pathway and potential metabolites in humans. The present study aims to elucidate the kinetics of metabolite formation and elimination by analyzing four hydroxylated PCBs (OH-PCBs) in human plasma as potential metabolites of the PCB 28 congener. For this purpose, the study was conducted in plasma samples of highly PCB-exposed individuals (N=268), collected from 2010 to 2014 as a representation of a real case scenario with longitudinal data. OH-PCBs have been predicted, synthesized in the course of this study and further identified and quantitated in human plasma. This is the first time that previously unknown PCB 28 metabolites have been measured in human plasma and half-lives have been estimated for PCB metabolites, which could then provide further understanding in the toxicological consequences of exposure to PCBs in humans.

Mechanistic polychlorinated biphenyl exposure modeling of mothers in the Canadian Arctic: the challenge of reliably establishing dietary composition

BackgroundTraditional food (TF) consumption represents the main route of persistent organic pollutant (POP) exposure for indigenous Arctic Canadians. Ongoing dietary transitions away from TFs and toward imported foods (IFs) may contribute to decreasing POP exposures observed in these groups. MethodsTo explore this issue, we combined the global fate and transport model GloboPOP and the human food chain bioaccumulation model ACC-Human Arctic to simulate polychlorinated biphenyl (PCB) exposure in two indigenous Arctic Canadian communities from the Inuvik region, Northwest Territories and Baffin region, Nunavut. Using dietary survey information from initial (1996–98) and follow-up (2005–07) biomonitoring campaigns in Inuvik and Baffin, we simulated PCB exposures (PCB-118, -138, -153, and -180) for each individual study participant and also whole study populations. ResultsTF intake rates, particularly of marine mammals (MMs), were the most important predictors of modeled PCB exposure, while TF consumption did not associate consistently with measured PCB exposures. Further, reported mean TF intake increased from baseline to follow-up in both Inuvik (from 8 to 183gd−1) and Baffin (from 60 to 134gd−1), opposing both the expected dietary transition direction and the observed decrease in human PCB exposures in these communities (ΣPCB Inuvik: from 43 to 29ngglipid−1, ΣPCB Baffin: from 213 to 82ngglipid−1). However dietary questionnaire data are frequently subject to numerous biases (e.g., recall, recency, confirmation), and thus casts doubt on the usefulness of these data. ConclusionsUltimately, our model's capability to reproduce historic PCB exposure data in these two groups was highly sensitive to TF intake, further underscoring the importance of accurate TF consumption reporting, and clarification of the role of dietary transitions in future POP biomonitoring of indigenous Arctic populations.

Elucidating the structural properties that influence the persistence of PCBs in humans using the National Health and Nutrition Examination Survey (NHANES) dataset

In human exposure studies involving Polychlorinated Biphenyls (PCBs), it is useful to establish when an individual was potentially exposed. Age dating PCB exposure is complex but assessments can be made because different PCB congeners have different residence times in the human body. The less chlorinated congeners generally tend to have shorter residence times because they are biotransformed and eliminated faster than more chlorinated congeners. Therefore, the presence of high proportions of less chlorinated congeners is often indicative of recent exposure. The 2003–04 National Health and Nutrition Examination Survey (NHANES) dataset contains results for the concentration of 37 PCBs in a sub-sample of the US population. Multivariate statistical analysis of the NHANES data showed that less chlorinated congeners are not always biotransformed faster than higher chlorinated compounds. For example, PCB 28 (a tri-chlorobiphenyl) appears to be more resistant to biotransformation than PCB 101 and 110 (penta-chlorobiphenyls). Using statistical analysis of the NHANES data in conjunction with previously published studies on PCB persistence in humans, it was possible to identify the structural relationships that determine if a PCB is likely to be from a recent exposure (termed ‘episodic’) or from steady state exposure. Congeners with chlorine atoms in the 2,5- and 2,3,6-positions appear to be more susceptible to biotransformation whereas congeners with chlorine bonds in the 2,3,4- 2,4,5- 3,4,5- and 2,3,4,5-positions appear to be more persistent. This work shows that future investigations to date PCB exposure would benefit from the analysis of a wide range of congeners, including the selection of key congeners based not only on the degree of chlorination but also on the positions of the chlorine atoms on the biphenyl.

Establishment of the cumulative margin of exposure for a group of polychlorinated biphenyl (PCB) congeners using an improved approach that accounts for both variability and uncertainty

In this study, the cumulative margin of exposure (MOE) was estimated for a group of polychlorinated biphenyls (PCBs) based on reduction of hepatic retinoids as a mode-of-action relevant toxicological endpoint. The MOE was defined as the ratio between a reference dose, derived using the benchmark dose (BMD) approach, and the estimated human dietary PCB exposure. A distribution for the cumulative MOE was established, taking into account inter- and intra-individual variability as well as uncertainty in data measurements. The cumulative MOE reflected mainly the MOE for PCB 126; other PCB congeners had little contribution to the cumulative exposure and MOE. The median of the 0.1st percentile for the cumulative MOE was about 20 for women; depending on the percentile, cumulative MOE was 2–4times higher for men compared to women. Furthermore, a relative potency factor (RPF) based approach was compared to an RPF-free approach for estimating the cumulative MOE. The RPF-free approach more completely accounts for variability and uncertainty but is more data intensive than the RPF-based approach, which can be more easily implemented in practice and allows for a use of historical data on RPFs. Consideration of the discussed approaches may contribute to improving cumulative health risk assessments.

Concentration-dependent half-lives of polychlorinated biphenyl in sera from an occupational cohort

Polychlorinated biphenyls (PCBs) are carcinogenic. Estimating PCB half-life in the body based on levels in sera from exposed workers is complicated by the fact that occupational exposure to PCBs was to commercial PCB products (such as Aroclors 1242 and 1254) comprised of varying mixtures of PCB congeners. Half-lives were estimated using sera donated by 191 capacitor manufacturing plant workers in 1976 during PCB use (1946–1977), and post-exposure (1979, 1983, and 1988). Our aims were to: (1) determine the role of covariates such as gender on the half-life estimates, and (2) compare our results with other published half-life estimates based on exposed workers. All serum PCB levels were adjusted for PCB background levels. A linear spline model with a single knot was used to estimate two separate linear equations for the first two serum draws (Equation A) and the latter two (Equation B). Equation A gave half-life estimates of 1.74years and 6.01years for Aroclor 1242 and Aroclor 1254, respectively. Estimates were 21.83years for Aroclor 1242 and 133.33years for Aroclor 1254 using Equation B. High initial body burden was associated with rapid PCB elimination in workers at or shortly after the time they were occupationally exposed and slowed down considerably when the dose reached background PCB levels. These concentration-dependent half-life estimates had a transition point of 138.57 and 34.78ppb for Aroclor 1242 and 1254, respectively. This result will help in understanding the toxicological and epidemiological impact of exposure to PCBs in humans.

Interpreting PCB levels in breast milk using a physiologically based pharmacokinetic model to reconstruct the dynamic exposure of Italian women

Polychlorinated biphenyls (PCBs) are persistent contaminants suspected to cause adverse health effects in humans. As PCBs levels in food have not been monitored frequently in the past, modeling approaches based on environmental data have been proposed to predict the human dietary intake. In this work, we propose to improve these approaches by taking into account internal levels of PCBs in humans. This methodology is based on the analysis of biomonitoring data using exposure and physiologically based pharmacokinetic (PBPK) modeling to determine the most probable scenario of exposure. Breast milk concentrations were measured in Italian women for PCB-138, PCB-153 and PCB-180. For each congener, three exposure scenarios were derived and a PBPK model was used to relate the lifetime exposure to the breast milk levels. For the three PCBs, we determined the most probable scenario of exposure. Our results support the adequacy of the exposure and the PBPK models for PCB-180 and PCB-153, whereas we observed discrepancies between the models and the biomonitoring data for PCB-138. Our intake estimates are in good agreement with previous exposure assessments based solely on food contamination demonstrating the relevance of our approach to reconstruct accurately the exposure and to fill in data gaps on exposure.

Metabolomic Analysis of the Effects of Polychlorinated Biphenyls in Nonalcoholic Fatty Liver Disease

Polychlorinated biphenyls (PCBs) are persistent organic pollutants and have been associated with abnormal liver enzymes and suspected nonalcoholic fatty liver disease (NAFLD), obesity, and the metabolic syndrome in epidemiological studies. In epidemiological surveys of human PCB exposure, PCB 153 has the highest serum levels among PCB congeners. To determine the hepatic effects of PCB 153 in mice, C57BL/6J mice were fed either a control diet (CD) or a high fat diet (HFD) for 12 weeks, with or without PCB 153 coexposure. The metabolite extracts from mouse livers were analyzed using linear trap quadrupole-Fourier transform ion cyclotron resonance mass spectrometer (LTQ-FTICR MS) via direct infusion nanoelectrospray ionization (DI-nESI) mass spectrometry. The metabolomics analysis indicated no difference in the metabolic profile between mice fed the control diet with PCB 153 exposure (CD+PCB 153) and mice fed the control diet (CD) without PCB 153 exposure. However, compared with CD group, levels of 10 metabolites were increased and 15 metabolites were reduced in mice fed HFD. Moreover, compared to CD+PCB 153 group, the abundances of 6 metabolites were increased and 18 metabolites were decreased in the mice fed high fat diet with PCB 153 exposure (HFD+PCB 153). Compared with HFD group, the abundances of 2 metabolites were increased and of 12 metabolites were reduced in HFD+PCB 153 group. These observations agree with the histological results and indicate that the metabolic effects of PCB 153 were highly dependent on macronutrient interactions with HFD. Antioxidant depletion is likely to be an important consequence of this interaction, as this metabolic disturbance has previously been implicated in obesity and NAFLD.

Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and neuropsychological status among older adults in New York

Polybrominated diphenyl ethers (PBDEs) are emerging environmental contaminants, but little is known about their possible human health effects. The objective of this study is to evaluate the association between exposure to PBDEs and neuropsychological function among older adults and the possibility of effect modification with polychlorinated biphenyls (PCBs). Serum samples were analyzed for concentrations of 9 PBDE and 30 PCB congeners and 34 tests of cognitive and motor function, affective state, and olfactory function were assessed among 144 men and women of 55–74 years of age. After adjustment for relevant confounders, no overall associations were observed between the sum of the PBDE congener concentrations in serum (∑ PBDE) and scores on the neuropsychological tests. However, statistically significant interactions were found between PBDEs and PCBs for some measures of verbal learning and memory. Among persons with ∑ PCB concentrations at or above the median of 467ppb (lipid basis), an increase in ∑ PBDE concentrations from the 25th to 75th percentile was associated with decreases between 7% and 12% on scores for certain subscales of the California Verbal Learning Test. In contrast, no statistically significant associations were observed for PBDEs among persons with ∑ PCB levels below the median. The results suggest that PBDEs and PCBs may interact to affect verbal memory and learning among persons 55–74 years old. This is the first study to evaluate the neuropsychological effects of PBDEs in adults and the possibility of synergy with PCBs in humans.

Determinants of serum concentrations of 1,1-dichloro-2,2-bis( p-chlorophenyl)ethylene and polychlorinated biphenyls among French women in the CECILE study

Background Dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) are persistent organochlorine compounds bioaccumulating in human tissues. Body burden of organochlorines may be influenced by individual characteristics such as age, weight variations, breastfeeding, dietary habits and place of residence. Objectives To assess the current serum concentrations of 1,1-dichloro-2,2-bis( p-chlorophenyl)ethylene ( p,p′-DDE), the main DDT breakdown product, and of PCBs in women from two French administrative areas (Ille-et-Vilaine and Côte d'Or). To identify determinants of the current serum levels among individual characteristics related to intake, metabolism, and excretion of organochlorines. Methods We measured serum p,p′-DDE and PCB levels in 1055 general population women who were recruited in 2005–2007 to serve as controls in a case-control study on breast cancer. Associations between organochlorine levels and age, current body mass index (BMI), BMI change during the last 10 years, dietary habits, breastfeeding history, residence area and education were assessed in multivariate analyses. Results Median concentrations of p,p′-DDE and total PCBs were 85 and 240 ng/g lipid, respectively. Based on multivariate analyses, the main predictors of high p,p′-DDE levels included age and frequent consumption of saltwater fish in women below 50 years, and high BMI in older women. Total PCB levels increased markedly with age. Among older women, other important predictors of high PCB levels included frequent consumption of saltwater fish and low BMI. Our results are also suggestive of an inverse association between PCB levels and BMI gain during the last ten years. Women in Côte d'Or had significantly higher PCB levels than women in Ille-et-Vilaine. Conclusion The patterns of associations between determinants and serum organochlorine concentrations suggest that human PCB contamination is still ongoing in France. The most important predictors of serum p,p′-DDE and PCB concentrations among French women include age, body mass index, dietary habits, and place of residence.

Passing Down Pollution: Calculating Intergenerational Exposure to PCBs

Countries around the world began phasing out production of polychlorinated biphenyls (PCBs) in the 1970s after adverse health and environmental effects of these chemicals came to light. A new study calculating intergenerational differences in human PCB exposure now suggests some of the highest exposures occurred well after the chemicals were phased out [EHP 119(5):641–646; Quinn et al.]. PCBs are manufactured organic chemicals that were used in numerous industrial applications starting in the 1920s. Although they have been phased out of production, PCBs are still being released into the environment from preexisting applications and improper disposal of products that contain them. Because of their chemical stability and transportability they bioaccumulate in the food chain, readily enter the human food supply, and pass from mother to infant in utero and during breastfeeding, with potentially harmful effects on the endocrine, immune, nervous, and reproductive systems. In 2010 three authors of the current study and another colleague developed and tested a mechanistic model called CoZMoMAN that accounts for PCBs’ emissions history and movement through the environment, the food chain, and the human body to predict concentrations in a population’s body fat. For the present study, the authors used CoZMoMAN to calculate how PCB concentrations in fat changed over the lifetimes of hypothetical Swedish women born each decade between 1920 and 2010. They also analyzed how such factors as the age at which a woman first gives birth, the number of children she bears (parity), and whether she breastfeeds her babies affect both her PCB body burden and that of her children. The model predicted that a woman’s PCB exposure was determined primarily by when she was born. Women born in the 1960s were predicted to have the highest cumulative lifetime exposure—PCBs were already in widespread use when these women were born, and emissions peaked as they were maturing in the 1970s. However, it was women born in the 1980s who experienced the highest prenatal exposure and the highest peak concentration at any given age. Prenatal exposure to PCBs can be associated with serious neurologic and reproductive consequences. Prenatal exposure was strongly influenced by children’s birth order, whereas postnatal exposure was influenced by whether children were fed breast milk or infant formula. A mother’s reproductive characteristics—specifically breastfeeding and parity—had a greater impact on her children’s PCB burden than on her own, but these characteristics only appeared to matter for infants born after the PCB phaseout. Because both pre- and postnatal PCB exposures have been associated with health complications, the results suggest the health effects of PCBs are likely to persist over several more generations.

Investigating Intergenerational Differences in Human PCB Exposure due to Variable Emissions and Reproductive Behaviors

BackgroundReproductive behaviors—such as age of childbearing, parity, and breast-feeding prevalence—have changed over the same historical time period as emissions of polychlorinated biphenyls (PCB) and may produce intergenerational differences in human PCB exposure.ObjectivesOur goal in this study was to estimate prenatal, postnatal, and lifetime PCB exposures for women at different ages according to year of birth, and to evaluate the impact of reproductive characteristics on intergenerational differences in exposure.MethodsWe used the time-variant mechanistic model CoZMoMAN to calculate human bioaccumulation of PCBs, assuming both hypothetical constant and realistic time-variant emissions.ResultsAlthough exposure primarily depends on when an individual was born relative to the emission history of PCBs, reproductive behaviors can have a significant impact. Our model suggests that a mother’s reproductive history has a greater influence on the prenatal and postnatal exposures of her children than it does on her own cumulative lifetime exposure. In particular, a child’s birth order appears to have a strong influence on their prenatal exposure, whereas postnatal exposure is determined by the type of milk (formula or breast milk) fed to the infant.ConclusionsPrenatal PCB exposure appears to be delayed relative to the time of PCB emissions, particularly among those born after the PCB production phaseout. Consequently, the health repercussions of environmental PCBs can be expected to persist for several decades, despite bans on their production for > 40 years.

Maternal plasma polychlorinated biphenyl levels in cynomolgus monkeys (Macaca fascicularis) affect infant social skills in mother–infant interaction

Polychlorinated biphenyls (PCBs) are endocrine disrupting chemicals that disturb normal development of embryonic brains. In the present study, we evaluated the relationship between maternal plasma PCB concentration and infant behavioral characteristics in mother-infant interactions. We grouped 20 pregnant cynomolgus monkeys (Macaca fascicularis) into higher and lower PCB exposure groups; monkeys in the higher PCB group had PCB concentrations above 15 pg/g, which is representative of natural exposure levels. Maternal PCB concentration correlated negatively with infant behaviors (approach, look, proximity, locomotion) at the age of 6 months (p < .05), when an increase in these behaviors should normally occur. These results suggest that maternal PCB exposure may affect the development of infant social behavior in cynomolgus monkeys. Furthermore, this study provides primate evidence to support observations of associations between behavioral and learning disabilities and prenatal exposure to PCBs in humans.

Multivariate models to predict human adipose tissue PCB concentrations in Southern Spain

The use of Polychlorinated biphenyls (PCBs) has been severely restricted due to their high toxicity and persistency in the environment. However, the presence of PCBs in human tissues nowadays is still been reported worldwide. Background exposure predictors of the human PCB body burden require more precise understanding. In the present study, PCB congeners 138, 153, and 180 were quantified in adult adipose tissue samples ( n = 387) from Granada Province (Southern Spain) and data on potential predictors of PCB concentrations were gathered by questionnaire. Chemical analysis of the selected congeners was done by gas chromatography and mass spectrometry, and multivariate analyses were performed stratifying by gender. PCB residues were quantified in 92% (PCB 153), 90% (PCB 180), and 86% (PCB 138) of the population. Geometric mean concentrations were 161.65 ± 4.41 ng/g lipid for PCB 153, 111.62 ± 6.27 ng/g lipid for PCB 180, and 38.41 ± 8.61 ng/g lipid for PCB 138. Multivariate models explained 30–36% of the variability in PCB concentrations. Age and body mass index (BMI) predicted exposure in both males and females and were positively correlated with the concentration of the three PCB congeners. Occupation and diet predicted exposure in the males, whereas only dietary predictors were observed in the females. Further in-depth studies are required to investigate the influence of dietary habits on the bioaccumulation of PCBs and to evaluate the impact of policies aimed at reducing human exposure.

Polychlorinated Biphenyls PCB 52, PCB 180, and PCB 138 Impair the Glutamate−Nitric Oxide−cGMP Pathway in Cerebellar Neurons in Culture by Different Mechanisms

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that accumulate in the food chain and are present in human blood and milk. Children born to mothers exposed to PCBs show cognitive deficits, which are reproduced in rats perinatally exposed to PCBs. It has been proposed that PCB-induced cognitive impairment is due to impairment of the glutamate-nitric oxide (NO)-cGMP pathway. The aim of the present work was to assess whether chronic exposure to the nondioxin-like PCB52, PCB138, or PCB180 alters the function of this pathway in primary cultures of rat cerebellar neurons and to assess whether different PCBs have similar or different mechanisms of action. PCB180 and PCB138 impair the function of the glutamate-NO-cGMP pathway at nanomolar concentrations, and PCB52 impairs the function of the glutamate-NO-cGMP pathway at micromolar concentrations. The mechanisms by which different PCBs impair the function of the glutamate-NO-cGMP pathway are different. Each PCB affects the pathway at more than one step but with different potency and, for some steps, in opposite ways. Exposure to the PCBs alters the basal concentrations of intracellular calcium, NO, and cGMP. The three PCBs increase NO; however, PCB52 and PCB138 increase basal cGMP, while PCB180 decreases it. PCB52 and PCB138 decrease the activation of soluble guanylate cyclase by NO, and PCB180 increases it. Long-term exposure to PCB52, PCB180, or PCB138 reduces the activation of NO synthase and the whole glutamate-NO-cGMP pathway in response to activation of N-methyl-d-aspartate receptors. The EC(50) was 300 nM for PCB52 and 2 nM for PCB138 or PCB180. These results show that chronic exposure to nondioxin like PCBs impairs the function of the glutamate-NO-cGMP pathway in cerebellar neurons by different mechanisms and with different potencies. Impaired function of this pathway would contribute to the cognitive alterations induced by perinatal exposure to PCBs in humans.

Estimating the half-lives of PCB congeners in former capacitor workers measured over a 28-year interval

To date, most estimates of the half-life of polychlorinated biphenyls (PCBs) in humans have been based on relatively short follow-up periods. To address this issue, we determined the half-lives of PCB congeners of occupational origin in the serum of former capacitor workers as part of a study conducted in 2003-2006--approximately 28 years after their last occupational exposure. A total of 241 persons from a source population of 6798 former capacitor workers were interviewed and asked to donate a blood sample for serum PCB congener analysis. A subgroup of 45 participants also had serum archived from 1976 and reanalyzed for the same 27 PCB congeners by the same laboratory. Our estimates of the half-lives of the congeners among these 45 persons were longer than those reported by Wolff et al. (1992), due primarily to the much longer interval between exposure and determination of serum PCB concentrations. Half-lives were significantly greater for the heavy versus light occupational congeners, for women versus men and for those with low versus high initial exposure. Current serum total PCB concentrations, expressed as the geometric mean of wet weight data, averaged 6.7 ng/g for the entire 241-person cohort, which represents a 10-fold decrease from values reported in the late 1970s, but is still nearly twice the average for persons of similar age residing in the same area, but without occupational exposure. In addition, current serum PCB concentrations remained significantly and positively associated with earlier occupational exposure, but were not associated with fresh water fish consumption. In general, the results support a consistent and long-duration trend of increased PCB body burden in this cohort of former capacitor workers compared with non-occupationally exposed individuals. The results may aid in further understanding the toxicological/epidemiological consequences of exposure to PCBs in humans.

The role of African American ethnicity and metabolism in sentinel polychlorinated biphenyl congener serum levels

Polychlorinated biphenyls (PCBs) are environmental contaminants found in the serum of human populations across the globe. A small set of sentinel PCB congeners (IUPAC# 101, 118, 138, 153, and 180) commonly sought in human serum are often used as markers of exposure. The Chicago Great Lakes cohort of pregnant African American women was developed to study organochlorine exposure through Great Lakes resources in a pregnant African American population and their children. Comparison of PCB serum concentrations in women reporting mixed race/ethnicity within the cohort shows significant elevations of serum PCB 101 and 118 in women reporting exclusive African American ancestry. Incubations were performed using pooled human liver microsomes followed by individual recombinant human CYP isoform microsomes to identify whether the other sentinel congeners are metabolized by human CYP 450. In human liver microsome metabolism experiments with the sentinel PCB congeners (IUPAC# 101, 118, 138, 153, and 180), only PCB 101 metabolism produced an identifiable metabolite. However, a significant loss of parent compound was observed for PCB 118 incubations with human liver microsomes. The loss of PCB 101 and PCB 118 in microsome experiments indicates they are likely metabolized in human liver. Therefore, CYP 450 mediated metabolic differences may contribute to differences in serum concentrations by race/ethnicity. PCB metabolism has an important impact on toxicity. PCB metabolites have been shown to differ significantly in toxicity profiles relative to parent compounds. Biomonitoring studies of PCB serum levels have correlated with toxicity for the metabolizable congeners such as PCB 101 and PCB 118. However, measurable amounts of metabolizable parent congeners such as PCB 101 may not be detectable in the serum of study participants. Because PCB 118 is metabolized, but is also readily found in human serum, it may be a better marker of metabolism related PCB toxicity. Human specific PCB metabolism is difficult to characterize but has important pathophysiological ramifications and deserves further study.