Developmental toxicity of polychlorinated biphenyls (PCBs): a systematic review of experimental data

Experimental reproductive and developmental toxicity studies with polychlorinated biphenyls (PCBs) are reviewed in brief to determine their relevance for current environmental exposure of humans during the prenatal and postnatal developmental periods. Additional material is published in electronic form only, which contains graphic overviews on individual PCBs and various mixtures that are linked with the relevant citations. In this comprehensive article we focus on interactions of PCBs with biological substrates that could mediate adverse effects observed in experimental animals and in children, and the shortcomings of many of the animal studies available. A main point of criticism involves the relative lack of animal data on several of those persistent congeners, either as individual compounds or as environmentally relevant mixtures, which are currently used as a measure of human exposure. Experimental studies in animals are frequently conducted with commercial PCB mixtures, a test design that does not reflect the exposure situation in humans. Important improvements of animal experiments could be achieved by more complete reporting of litter data (pre- and post-natal losses, toxic signs in the dam and the offspring, birth weights and postnatal growth data), the inclusion of endpoints that have been found previously to be affected by PCBs, and measurements of internal exposure data.An erratum to this article can be found at     

Airborne polychlorinated biphenyls (PCBs) reduce telomerase activity and shorten telomere length in immortal human skin keratinocytes (HaCat)

PCBs, a group of 209 individual congeners, are ubiquitous environmental pollutants and classified as probable human carcinogens. One major route of exposure is by inhalation of these industrial compounds, possibly daily from inner city air and/or indoor air in contaminated buildings. Hallmarks of aging and carcinogenesis are changes in telomere length and telomerase activity. We hypothesize that semi-volatile PCBs, like those found in inner city air, are capable of disrupting telomerase activity and altering telomere length. To explore this possibility, we exposed human skin keratinocytes to a synthetic Chicago Airborne Mixture (CAM) of PCBs, or the prominent airborne PCB congeners, PCB28 or PCB52 for up to 48 days and determined telomerase activity, telomere length, cell proliferation, and cell cycle distribution. PCBs 28, 52 and CAM significantly reduced telomerase activity from days 18-48. Telomere length was shortened by PCB 52 from day 18 and PCB 28 and CAM from days 30 on. All PCBs decreased cell proliferation from day 18; only PCB 52 produced a small increase of cells in G0/G1 of the cell cycle. This significant inhibition of telomerase activity and reduction of telomere length by PCB congeners suggest a potential mechanism by which these compounds could lead to accelerated aging and cancer.     

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.     

Dioxin-Like and Non-Dioxin-Like Toxic Effects of Polychlorinated Biphenyls (PCBs): Implications For Risk Assessment

Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative, and toxic contaminants in the environment. Individual PCB congeners exhibit different phy sicochemical properties and biological activities that result in different environmental distributions and toxicity profiles. The variable composition of PCB residues in environmental matrices and their different mechanisms of toxicity complicate the development of scientifically based regulations for the risk assessment. In this article various approaches for the assessment of risks of PCBs have been critically examined. Recent developments in the toxic equivalency factor (TEF) approach for the assessment of toxic effects due to dioxin-like PCBs have been examined. PCB exposure studies that describe non-dioxin-like toxic effects, particularly neurobehavioral effects and their effective doses in animals were compiled. A comparative assessment of effective doses for dioxin-like and non-dioxin-like effects by PCBs has been made to evaluate the relative significance of non-ortho-and ortho-substituted PCBs in risk assessment. Using mink as an example, relative merits and implications of using TEF and total PCB approaches for assessing the potential for toxic effects in wildlife was examined. There are several advantages and limitations associated with each method used for PCB risk assessment. Toxic effects due to coplanar PCBs occur at relatively smaller concentrations than those due to non-dioxin-like PCBs and therefore the TEF approach derives the risk assessment of PCBs, in the environment. The need for the refinement of TEF approach for more accurate assessment of risks is discussed.     

Pharmacokinetics and blood levels of polychlorinated biphenyls

Despite the enormous number of reports on polychlorinated biphenyl (PCB) toxicology, both the causal interpretation of epidemiological studies and the risk assessment of human exposures have been hampered by the lack of information on the pharmacokinetics of various PCB isomers and congeners. Thus, the assessment of exposure by means of measuring either total PCBs or individual congeners in the blood has so far been unsatisfactory. For example, the concentration and the pattern of congeners in the blood did not correlate with that at site(s) of action. In fact, the same levels of blood PCBs correlated with either toxic effects or no effects (both in clinical and epidemiological studies). In addition, when toxicity caused by PCBs was observed, the severity of the signs did not correlate with blood levels.Reasons for such a qualified failure are manifold and include different ways of reporting blood measurements, the different toxicological characteristics of each PCB, and different timing of sampling the blood, etc. Therefore, only limited conclusions can be drawn concerning what blood PCB measurements mean.     

ORAL ADMINISTRATION OF PCBs INDUCES PROINFLAMMATORY AND PROMETASTATIC RESPONSES

Exposure to specific congeners of polychlorinated biphenyls (PCBs) can induce proinflammatory alterations, which may contribute to the formation of blood-borne tumor metastasis. The main aim of the present study was to establish an experimental model of PCB exposure in which PCBs are administered by oral gavage, which resembles the human exposure through the food chain. To determine structure-function relationship, we studied induction of inflammatory responses in the livers, lungs and brains of mice treated with PCB77 (a major coplanar PCB), PCB104 (a non-coplanar PCB with multiple ortho-chlorine substituents), and PCB153 (a major non-coplanar PCB) after a single gavage dose (150 μmol/kg body weight). The strongest expression of proinflammatory proteins occurred 24 h following the PCB administration independent of the class of PCB congeners. These data indicate that food-chain exposure to PCBs can induce proinflammatory mediators in organs that are potential targets for PCB-induced toxicity.     

Biological monitoring of indoor-exposure to dioxin-like and non-dioxin-like polychlorinated biphenyls (PCB) in a public building

The release of PCBs from sealant material in public buildings and the resulting indoor air levels have raised growing concerns about possible human health effects connected with this exposure. Ambient monitoring of PCBs in a public building has revealed a contamination with the more volatile lower chlorinated PCB 28, PCB 52 and PCB 101. This gave reason for a large biological monitoring study in order to examine the internal exposure to PCBs in persons working in that building. Blood samples from 209 persons employed in the PCB-contaminated building were drawn. 98 persons matched for age and gender working in non-contaminated buildings served as control group. Plasma samples were analysed for the six indicator PCBs (PCB 28, 52, 101, 138, 153, 180) and 12 dioxin-like PCBs using GC/MS (LOD: 0.01 μg/L). Significant differences between both collectives were only found for the plasma levels of the lower chlorinated PCB 28, PCB 52 and PCB 101 and for the dioxin-like congeners PCB 105 and PCB 118, which are due to inhalative exposure to these congeners via indoor air. Median plasma levels of PCB 28, PCB 52 and PCB 101 in the employees of the contaminated building were 0.087 μg/L, 0.024 μg/L and 0.012 μg/L, respectively. The concentrations of the higher chlorinated PCBs and all other dioxin-like congeners investigated were within the normal range of the general population. There was no relationship between indoor air measurements and internal exposure of the employees in the corresponding office, but estimated lifetime exposure of the employees turned out to be a significant factor for plasma levels of PCB 28. Our biomonitoring results served as a basis for individual risk communication and successful risk management.     

Carcinogenicity of “Non-Dioxinlike” Polychlorinated Biphenyls

Complex technical mixtures of polychlorinated biphenyls (PCBs) cause liver and thyroid neoplasms in rodents, whereas very few data are available on the carcinogenic potency of single non-dioxinlike (NDL) PCB congeners. In most genotoxicity assays technical PCB mixtures and individual congeners were inactive, suggesting that PCBs act as indirect, nongenotoxic carcinogens. Various mechanisms, including suppression of apoptosis in preneoplastic cells or inhibition of intercellular communication, have been suggested to be active in liver tumor promotion by PCBs. A decrease in thyroid hormone levels after PCB treatment has been suggested to play a role in the development of thyroid neoplasms in rats; however, other mechanisms may also be involved. Results from a chronic carcinogenicity study in rats indicate that not the dose of total PCBs but the total TCDD or toxic equivalents (TEQs) associated with “dioxinlike” (DL) constituents within a technical mixture are mainly if not exclusively responsible for the development of liver neoplasms in female rats. Quantitative comparison reveals almost identical dose-response curves for the total TEQs in various technical PCB mixtures and for TCDD as inducers of hepatic neoplasms in female rats. Tumor promotion experiments have shown, however, that, after initiation with a genotoxic carcinogen, technical PCB mixtures and individual DL-and NDL-PCBs act as liver tumor promoters in rodents. Based on these data, a weak carcinogenic potency of individual NDL-PCB congeners cannot be excluded. In epidemiological studies, increased mortality from cancers of the liver, gallbladder, biliary tract, gastrointestinal tract, and from brain cancer and malignant melanoma were observed in workers exposed to a series of technical PCB mixtures. A significant association between PCB concentrations in adipose tissue and non-Hodgkins lymphoma was found in another study. While in all human studies mixed exposure to DL-and NDL-PCBs occurred, no comprehensive data are available on the relative contribution of NDL-PCBs to the overall external and/or internal PCB exposure in those cohorts.     

Morphological alterations of Vero cell exposed to coplanar PCB 126 and noncoplanar PCB 153

Polychlorinated biphenyls (PCBs) are widespread, persistent environmental contaminants that display a complex spectrum of toxicological properties. Exposure to PCBs has been associated with morphological anomalies in cell cultures. However, most mechanistic studies of PCBs' toxic activity have been focused on coplanar congeners. It is of importance to determine whether PCB treatment would influence cell configuration and whether these changes would depend on the structural characteristics of PCBs. In this study, we investigated cell morphological alteration in Vero cell cultures after exposure to coplanar PCB 126 and noncoplanar PCB 153. The survival of Vero cells was measured through the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) test. Cytotoxicity results suggested that PCB congeners had a toxic, antiproliferative effect on Vero cells. Morphological studies described structural modifications and provided evidence that apoptosis might be the main cell death pathway in PCB 153‐treated cells. The comparison between PCB 126 and PCB 153 indicated that the cell death mechanisms involved in coplanar or noncoplanar PCB congener exposure were different in Vero cells. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

Polychlorinated biphenyl (PCB) exposure in mothers and time to pregnancy in daughters

Developmental exposure to polychlorinated biphenyls (PCBs) disrupts reproduction in animals. Human data are lacking. We measured PCBs in preserved mothers' serum samples collected during 1960-1963, 1-3 days after their daughters' birth. We recorded time to pregnancy (TTP) in 289 daughters 28-31 years later. PCB congeners 187, 156, and 99 in mother's serum were associated with longer TTP in their daughters while PCB congeners 105, 138 and 183 were associated shorter TTP. Probability of pregnancy fell by 38% (95% CI 17-53%) and infertility was higher (30% not pregnant after 13 cycles versus 11% not pregnant after 13 cycles) among women whose mothers had a higher proportion of PCB congeners associated with longer TTP (75th percentile versus 25th percentile). This study demonstrates, for the first time, that developmental exposure to PCBs may disrupt pregnancy in humans.     

Carcinogenicity of "non-dioxinlike" polychlorinated biphenyls

Complex technical mixtures of polychlorinated biphenyls (PCBs) cause liver and thyroid neoplasms in rodents, whereas very few data are available on the carcinogenic potency of single non-dioxinlike (NDL) PCB congeners. In most genotoxicity assays technical PCB mixtures and individual congeners were inactive, suggesting that PCBs act as indirect, nongenotoxic carcinogens. Various mechanisms, including suppression of apoptosis in preneoplastic cells or inhibition of intercellular communication, have been suggested to be active in liver tumor promotion by PCBs. A decrease in thyroid hormone levels after PCB treatment has been suggested to play a role in the development of thyroid neoplasms in rats; however, other mechanisms may also be involved. Results from a chronic carcinogenicity study in rats indicate that not the dose of total PCBs but the total TCDD or toxic equivalents (TEQs) associated with "dioxinlike" (DL) constituents within a technical mixture are mainly if not exclusively responsible for the development of liver neoplasms in female rats. Quantitative comparison reveals almost identical dose-response curves for the total TEQs in various technical PCB mixtures and for TCDD as inducers of hepatic neoplasms in female rats. Tumor promotion experiments have shown, however, that, after initiation with a genotoxic carcinogen, technical PCB mixtures and individual DL-and NDL-PCBs act as liver tumor promoters in rodents. Based on these data, a weak carcinogenic potency of individual NDL-PCB congeners cannot be excluded. In epidemiological studies, increased mortality from cancers of the liver, gallbladder, biliary tract, gastrointestinal tract, and from brain cancer and malignant melanoma were observed in workers exposed to a series of technical PCB mixtures. A significant association between PCB concentrations in adipose tissue and non-Hodgkins lymphoma was found in another study. While in all human studies mixed exposure to DL-and NDL-PCBs occurred, no comprehensive data are available on the relative contribution of NDL-PCBs to the overall external and/or internal PCB exposure in those cohorts.     

Neurotoxicity of polychlorinated biphenyls: structure-activity relationship of individual congeners

Neurotoxicity of Polychlorinated Biphenyls: Structure-Activity Relationship of Individual Congeners, Shain, W., Bush, B., Seegal, R. (1991). Toxicol. Appl. Pharmacol. 111, 33-42. Experimental and epidemiological data indicate that polychlorinated biphenyls (PCBs) may function as neurotoxicants. The mechanism(s) of action of PCBs in the brain is not well understood. One reason for our lack of understanding of PCB action in the central nervous system is that, in general, commercial mixtures of PCBs have been used for these experiments. We used a homogeneous cell line, PC12 cells, to investigate the relative potency of 43 individual PCB congeners. The neurotoxicant action of PCB congeners was measured as a decrease in cell dopamine content. We first described the potency of individual congeners; 2,2'-dichlorobiphenyl was the most potent congener (EC50 = 65 microM). The structure-activity relationships described in these experiments indicated that (i) congeners with ortho- or ortho-, para-chlorine substitutions were most potent; (ii) chlorination in a meta position decreased cell dopamine content in ortho-substituted congeners, but had little effect in ortho-, para-substituted congeners; and (iii) increasing congener chlorination did not correlate with a decrease in potency, though total chlorination of a ring appeared to reduce potency. Second, we determined that potency did not correlate with either cellular PCB content or gas chromatographic retention time. Finally, experiments with 2,2'-dichlorobiphenyl indicated that PCBs and not their metabolites were the toxicants. Thus, PCB congeners decrease cell dopamine content by interaction at specific sites that have preference for ortho- or ortho-, para-substituted congeners. The neurotoxic action of PCBs may occur by a different mechanism than PCB hepato- and immunotoxicity since these effects are most sensitive to non-ortho-substituted, dioxin-like, congeners.     

Ecotoxicology of polychlorinated biphenyls in fish—a critical review

Polychlorinated biphenyls (PCBs) are widespread persistent anthropogenic contaminants that can accumulate in tissues of fish. The toxicity of PCBs and their transformation products has been investigated for nearly 50 years, but there is a lack of consensus regarding the effects of these environmental contaminants on wild fish populations. The objective of this review is to critically examine these investigations and evaluate publicly available databases for evidence of effects of PCBs in wild fish. Biological activity of PCBs is limited to a small proportion of PCB congeners [e.g., dioxin-like PCBs (DL-PCBs)] and occurs at concentrations that are typically orders of magnitude higher than PCB levels detected in wild fish. Induction of biomarkers consistent with PCB exposure (e.g., induction of cytochrome P450 monooxygenase system) has been evaluated frequently and shown to be induced in fish from some environments, but there does not appear to be consistent reports of damage (i.e., biomarkers of effect) to biomolecules (i.e., oxidative injury) in these fish. Numerous investigations of endocrine system dysfunction or effects on other organ systems have been conducted in wild fish, but collectively there is no consistent evidence of PCB effects on these systems in wild fish. Early life stage toxicity of DL-PCBs does not appear to occur at concentrations reported in wild fish embryos, and results do not support an association between PCBs and decreased survival of early life stages of wild fish. Overall, there appears to be little evidence that PCBs have had any widespread effect on the health or survival of wild fish.     

Apoptosis-mediated neurotoxic potential of a planar (PCB 77) and a nonplanar (PCB 153) polychlorinated biphenyl congeners in neuronal cell cultures

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants, some of which may be neurotoxic depending on the chemical structure of the congeners. This study investigated the neurotoxic potential of 3,3',4,4'-tetrachlorobiphenyl (TCB) (PCB 77, a non-ortho-substituted planar congener) and 2,2',4,4',5,5'-hexachlorobiphenyl (HCB) (PCB 153, a di-ortho-substituted nonplanar congener) by assessing cell viability and apoptotic cell death in neuronal cell cultures. We have combined morphological and biochemical techniques to establish the relevance of apoptosis in neuronal cell death induced by the two selected PCB congeners. Treatment with both planar and nonplanar congeners caused the loss of cell viability and accelerated apoptosis in a time- and concentration-dependent manner. However, the extent of apoptosis generated was greater for the non-ortho-substituted planar congener (PCB 77) than for the di-ortho-substituted nonplanar congener (PCB 153). This was correlated with the loss of cell viability since the planar congener was more cytotoxic. Based on our findings, the apoptosis induced by PCBs involves the increase of caspase-3 activity in neuronal cell cultures. It is reasonable to assume that PCB-induced apoptosis may be linked to the neurotoxic effect of these toxicants and that different molecular mechanisms may operate in the induction of apoptosis depending on the planarity or nonplanarity of the PCB congeners.     

Routine analysis of 101 polychlorinated biphenyl congeners in human serum by parallel dual-column gas chromatography with electron capture detection

Polychlorinated biphenyl (PCB) exposure has been linked to a variety of toxic effects in animal experiments and in certain human case reports and epidemiologic studies. A total of 209 individual PCB congeners are possible, based on chlorination level and ring substitution pattern. Commercial PCBs are a complex mixture of congeners, and over 75 of these have been reported to be present in human tissues at widely varying levels. Because the biologic activity of individual PCBs is a function of extent and pattern of chlorine substitution, "congener-specific" PCB analysis of human tissue has gained increasing importance in assessing possible links between PCB exposure and toxic effects. A high-sensitivity analytical method using dual-column gas chromatography (GC) with electron capture detection (ECD) for determining 101 PCB congeners (83 individual, 18 as pairs/triplets) plus 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), hexachlorobenzene (HCB), and mirex, in human serum is described. Separation is performed concurrently on parallel-configured DB-5 and Apiezon-L capillary columns. The current method is a modification of previously reported dual-column GC-ECD systems with improvements to the extraction and analytical protocols and the implementation of a comprehensive QA/QC program. The method employs two surrogate standards (PCBs IUPAC 125 and 192) and internal standard (IUPAC 104)-based quantitation, in addition to per-batch check standards and method blanks. Although optimized for serum, the method is applicable to all human, experimental animal, and environmental biota samples. The accuracy, precision, and reliability of the method were assessed using a variety of QA/QC endpoints. Finally, the use of the method in determining level and prevalence of PCB congeners in a cohort of adult Native-American individuals with historical environmental PCB exposure is reported.     

Transcriptomics identifies differences between ultrapure non-dioxin-like polychlorinated biphenyls (PCBs) and dioxin-like PCB126 in cultured peripheral blood mononuclear cells

Polychlorinated biphenyls (PCBs) remain ubiquitously present in human lipids despite the ban on their production and use. Their presence can be chemically monitored in peripheral blood samples of the general population. We tested whether in vitro exposure to different PCB congeners induced different gene expression profiles in peripheral blood cells. We have isolated peripheral blood mononuclear cells (PBMC) from whole blood of 8 healthy individuals and exposed these cells in vitro to individual non-dioxin-like (NDL)-PCB congeners (PCB52, 138 or 180; 10μM) or dioxin-like (DL)-PCB congener PCB126 (1μM) during 18h. Differential gene expression response was measured using Agilent whole-human genome microarrays. Two-way ANOVA analysis of the data showed that both gender and PCB exposure are important factors influencing gene expression responses in blood cells. Hierarchical cluster analysis of genes influenced by PCB exposure, revealed that DL-PCB126 induced a different gene expression response compared to the NDL-PCBs. Biological interpretation of the results revealed that exposure to PCB126 induced the AhR signaling pathway, whereas the induction of nuclear receptor pathways by the NDL-PCBs was limited in blood cells. Nevertheless, molecular responses of blood cells to individual PCB congeners revealed significantly expressed genes that play a role in biological functions and processes known to be affected by PCB exposure in vivo. Observed gene expression changes in this in vitro model were found to be related to hepatotoxicity, immune and inflammatory response and disturbance of lipid and cholesterol homeostasis.     

Biotransformation of polychlorinated biphenyls (PCBs) and bioformation of hydroxylated PCBs in fish

Hydroxylated PCBs (OH-PCBs) are a class of organic contaminants that have been found recently in the plasma of Great Lakes fish, the source of which is either bioformation from PCBs or accumulation from the environment. To address the potential for fish to biotransform PCBs and bioform OH-PCBs juvenile rainbow trout (Oncorhynchus mykiss; approximately 80 g) were exposed to dietary concentrations of an environmentally relevant mixture of PCBs. Eight OH-PCBs were found in the plasma of rainbow trout after 30 days of exposure to the PCBs, the relative pattern of which was similar to those observed in wild lake trout (Salvelinus namaycush) from Lake Ontario. Hydroxylated-PCBs were not found (detection limit 0.02 pg/g) in the food or control (not PCB-exposed) fish. A curvilinear logt(1/2)-logK(ow) relationship for recalcitrant PCBs was found, similar to previously reported relationships, although t(1/2) values were longer and shorter than studies using smaller fish or cooler temperatures, respectively. A number of PCB congeners fell below the logt(1/2)-logK(ow) relationship providing the first estimates of non-chiral PCB biotransformation rates in fish. Enantioselective degradation of the chiral congeners PCBs 91 and 136, also indicated biotransformation. Biotransformation of PCBs was structure-dependent with greater biotransformation of PCBs with vicinal hydrogen atoms in the meta/para positions, suggesting CYP 2B-like biotransformation. Other chiral congeners with a meta/para substitution pattern showed no enantioselective degradation but were biotransformed based on the logt(1/2)-logK(ow) relationship. The results of this study demonstrate that laboratory held rainbow trout can biotransform a number of PCB congeners and that bioformation is likely an important source of OH-PCBs in wild salmonids of the Great Lakes.     

Prenatal PCB exposure and neonatal behavioral assessment scale (NBAS) performance

We examined the relationship between prenatal (cord blood) polychlorinated biphenyls (PCBs) and Neonatal Behavioral Assessment Scale (NBAS) performance in babies born to women who consumed contaminated Lake Ontario fish. Cord blood PCBs, DDE, HCB, Mirex, lead, and hair mercury levels were determined for 152 women who reported never consuming Lake Ontario fish and 141 women who reported consuming at least 40 PCB-equivalent lbs. of Lake Ontario fish over their lifetime. Earlier work demonstrated that the newborns of fish eaters are exposed to a more heavily chlorinated distribution of PCB congeners, and that highly chlorinated PCBs (hepta-, octa-, and nonachlorinated biphenyls) are most strongly correlated with breast milk levels, perhaps providing the best index of PCB exposure in the Oswego cohort. Given the above, one would predict that these PCBs would be related to impaired performance on those NBAS clusters associated with fish consumption: namely Habituation, Autonomic, and Reflex clusters of the NBAS. Excepting the Relex cluster, these predictions were confirmed. Results revealed significant linear relationships between the most heavily chlorinated PCBs and performance impairments on the Habituation and Autonomic clusters of the NBAS at 25-48 h after birth. Additionally, higher prenatal PCB exposure was associated with a nonspecific performance impairment on the NBAS as evidenced by a significantly greater proportion of NBAS scales in which poor performance was exhibited (more than 1 standard deviation below the mean) in the most highly exposed neonates. Moreover, PCBs of lighter chlorination were unrelated to NBAS performance, as were DDE, Mirex, HCB, lead, and mercury. These results corroborate our earlier findings linking Lake Ontario fish consumption to the most heavily chlorinated PCB congeners, and suggest that the chlorination and persistence of PCBs may be an important factor both for exposure assessment and for determining relationships with neurobehavioral functions.     

Induction of hepatic cytochromes P450 in dogs exposed to a chronic low dose of polychlorinated biphenyls.

Induction of cytochrome P450 isoforms, specifically CYP1A1, and their catalytic activities are potential biomarkers of environmental contamination by polychlorinated biphenyls (PCBs). In this study, dogs were exposed to 25 ppm or 5 ppm Aroclor 1248 (PCB mixture) daily in their diet for 10 or 20 weeks, respectively. Relative to controls, hepatic microsomes from dogs dosed with PCBs had higher levels of CYP1A1 detected in immunoblots and higher levels of EROD activity, but low levels of induction for CYP2B and PROD activity. Concentrations of 96 PCB congeners in serum and liver were evaluated using capillary chromatography. Results showed that all dogs exposed to PCB mixtures had higher levels of PCB in serum and liver. Dogs preferentially sequestered highly chlorinated PCB congeners in liver relative to serum. With these experiments, we demonstrated that EROD activity was a potentially sensitive marker of PCB exposure at 5 and 25 ppm. Furthermore, CYP1A1 and EROD activity were maximally induced in dogs consuming dietary concentrations only 2.5 times the maximal permissible level for human food (FDA). The value of CYP1A1 induction as a biomarker of PCB exposure was tenuous because neither CYP1A1 levels nor EROD activity correlated with total PCB body burden. However, a small subset of congeners were identified in liver that may strongly influence EROD and PROD induction. Finally, two dogs in the 25 ppm dose group were fasted for 48 h. After 24 h of fasting, several new congeners appeared in the serum and remained in the serum for the remainder of the fast. The fast caused a 293% increase in PCB concentration in serum. This increase has strong implications regarding mobilization of toxic PCBs in wildlife during fasting (e.g., migration, hibernation).     

Reproductive abnormalities, teratogenicity, and developmental problems in American kestrels (Falco sparverius) exposed to polychlorinated biphenyls

This study found abnormalities in multiple reproductive stages in captive American kestrels (Falco sparverius) when exposed to polychlorinated biphenyls (PCBs) through dietary and in ovo exposure. American kestrels laid eggs with environmentally relevant total PCB levels (34.1 micrograms/g whole egg wet weight) when consuming PCB-spiked (Aroclor 1248:1254:1260) food (5-7 micrograms/g body weight per day) for 100 d only in 1998. In 1999, the same adults laid eggs with estimated total PCBs of 23 micrograms/g. Effects of maternal (only female exposed) and paternal (only male exposed) in ovo PCB exposure were investigated. Maternal F1 eggs contained predicted total PCB concentrations of 0.34 microgram/g. Specific abnormalities occurred more frequently during dietary F0 exposure, particularly aggressive courtship interactions, clutch abandonment, occurrences of cracked eggs, and developmental effects. Multiple developmental effects were more pronounced during than after dietary PCB exposure of adults, and although these effects were limited, nevertheless they occurred in the F1 maternal and F1 paternal pairs. However, the incidence of multiple deformities throughout the breeding season increased dramatically from 1998 (13%) to 1999 (56%) in F0 PCB-exposed pairs. Developmental abnormalities were unlikely to be attributed to the extrinsic factors of disease, genetics, or nutritional (vitamin D3) deficiencies, but rather to adverse changes in parental behavior and intrinsic factors involving altered genetic material and PCB exposure. Readily cleared PCB congeners may induce specific types of behavioral and developmental abnormalities, but persistent congeners and metabolites are likely producing (1) odd laying patterns, (2) odd laying patterns, (2) developmental effects including embryonic underdevelopment and edema, and (3) increased incidences of multiple deformities within a clutch.