PCB, PCDD and PCDF congener profiles in two types of Aroclor 1254.

Monsanto produced two distinct variants of Aroclor 1254. The late-production variant resulted from a change in Monsanto's manufacturing process in the early 1970s. Previous literature had reported that the late-production variant was produced from 1974 to 1976, but subsequent work has identified a sample known to be obtained in 1972. In this paper, we present congener-specific PCB and PCDD/F data for this 1972 late-production sample, and a brief historical record of late-production Aroclor 1254.

Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1).

Ryanodine receptor isoforms are expressed in both excitable and nonexcitable tissues where they form microsomal Ca2+ release channels broadly involved in shaping cellular signaling. In this report, we provide a detailed structure-activity relationship (SAR) for polychlorinated biphenyl (PCB) congeners and metabolites necessary for enhancing ryanodine receptor type 1 (RyR1) activity using [3H]ryanodine ([3H]Ry) binding analysis. The 2,3,6-Cl PCB configuration is most important for optimal recognition by the RyR1 complex and/or critical for sensitizing its activation. Para substitution(s) diminishes the activity with para-chloro having a higher potency than the corresponding para-hydroxy derivative. The addition of a more bulky para-methyl-sulfonyl group eliminates the activity toward RyR1, supporting the importance of the para positions in binding RyR1. The requirement for an intact major T cell immunophilin FKBP12-RyR1 complex was observed with each of 12 active PCB congeners indicating a common mechanism requiring an immunophilin-regulated Ca2+ release channel. An excellent correlation between the relative potencies for doubling [3H]Ry binding and the corresponding initial rates of PCB-induced Ca2+ efflux indicates that [3H]Ry binding analysis provides a measure of dysregulation of microsomal Ca2+ transport. The SAR for activating RyR1 is consistent with those previously reported in several in vivo and in vitro studies, suggesting that a common mechanism may contribute to the toxicity of noncoplanar PCBs. A practical application of the receptor-based screen developed here with RyR1 is that it provides a quantitative SAR that may be useful in predicting biological activity and risk of mixtures containing noncoplanar PCB congeners that have low or a lack of aryl hydrocarbon receptor activity.

Serum PCB profiles in Native Americans from Wisconsin based on region, diet, age, and gender: Implications for epidemiology studies.

BACKGROUND: Different PCB congeners and different mixtures of congeners have been demonstrated to have different biological actions. More complete characterization of congener profiles in exposure sources may assist in predicting health outcomes. METHODS: Thirty-six (36) polychlorinated biphenyl (PCB) congeners were measured by gas chromatography isotope-dilution mass spectrometry (IDMS) in 314 serum samples from Native Americans in Wisconsin, Michigan and Minnesota. Five dietary groups were established based on the quantity and species of fish consumed and the waters from which the fish were caught. Multivariate statistical methods were able to resolve gender and dietary differences in PCB homologue and PCB congener patterns. RESULTS: Females had higher proportions of lower chlorinated homologues, including a consistently higher proportion of pentaCB 118. The relative presence of the very labile and volatile PCB 18, above 1% of the total PCB in females from the minimal fish consumption and "other" groups, suggests possible exposure to PCBs in the atmosphere. The dietary group consuming predatory fishes from Lakes Michigan and Superior had the highest serum concentrations of total PCB (mean of 3.1 ng/ml) and the most distinct congener profile. The two dietary groups least dependent on fishing or fishing mostly from inland lakes (non-Great Lakes) had the lowest total PCB concentrations, both with means of 1.4 ng/ml. CONCLUSIONS: These serum PCB concentrations were less than those found in earlier studies of fish consumers in the Great Lakes region and may reflect the decrease in PCBs in these lakes.

Formulation and characterization of an experimental PCB mixture designed to mimic human exposure from contaminated fish.

Each environmental exposure matrix contains a unique mixture of PCB congeners. Since several congener types have multiple and distinct biological actions, it is important to characterize congener profiles in exposure sources. The Fox River Environment and Diet Study (FRIENDS) is assessing the human health effects of consumption of PCB-contaminated fish from the Fox River in northeastern Wisconsin. Concurrent laboratory studies required the formulation of a dosing solution which closely mimicked the human PCB exposure from fish. PCB congener profiles from Fox River walleye were compared to profiles for various theoretical mixtures having different relative percentages of Aroclors by weight. The theoretical mixture which provided the best approximation of the Fox River fish PCB profile contained 35% 1242, 35% 1248, 15% 1254, and 15% 1260. A PCB mixture was formulated to match this theoretical construct, and the congener profile for the mixture of Aroclors was determined by capillary column gas chromatography with electron capture detection (GC/ECD). The relative percent of each congener was compared to the PCB congener profile of the theoretical Aroclor mixture and that for Fox River walleye. The specific congeners differed on average by 17% from the theoretical Aroclor mixture predicted values, and the specific congeners measured in the mixture were on average within 71% of those reported for Fox River fish. The mixture was found to have relatively low AhR activity but high RyR activity. Indirect comparisons suggest that in vivo toxicity was slightly greater than that for Aroclor 1254. This illustrates that Aroclor mixtures are useful for formulating dosing solutions which closely approximate actual environmental exposures.

Ortho-substituted polychlorinated biphenyl (PCB) congeners (95 or 101) decrease pituitary response to thyrotropin releasing hormone.

Polychlorinated biphenyl compounds (PCBs) are global environmental contaminants that cause disruption of the endocrine system in humans and wildlife. Recently, we reported that acute exposures to ortho-PCB congeners 95 (2,3,6-2',5') or 101 (2,4,5,-2',5') causes changes in the performance of the hypothalamo-pituitary-thyroid (HPT)-axis in developing rats through mechanism(s) not yet clear. The functionality of the HPT-axis was evaluated by using the thyrotropin releasing hormone (TRH) test following acute exposure to PCBs 95 or 101. Weanling female rats received PCBs 95 or 101 intraperitoneally (ip) at 32 mg/kg for 2 consecutive days and synthetic TRH was given 48 h after the last dose. Serum thyroxine (T4) levels decreased following exposure to both the congeners. In PCB 95-treated rats, serum thyroid stimulating hormone (TSH) levels were elevated in response to TRH, but were only 40% of the control response to TRH. No significant changes were seen in serum prolactin (PRL), hypothalamic dopamine (DA), thyroid gland morphology, or epithelial cell proliferation. It is suggested that these congeners, interfere with the HPT-axis by causing a subnormal response of the pituitary and thyroid to TRH stimulation.

Assessing human polychlorinated biphenyl contamination for epidemiologic studies: lessons from patterns of congener concentrations in Canadians in 1992.

Humans are always exposed to mixtures of polychlorinated biphenyls (PCBs), so assessment of their health effects is complicated. Because the original sources are relatively standard mixtures that change in predictable ways while traversing the environment, there is substantial uniformity in the congener mixtures people carry. To the extent that concentrations are highly correlated, measuring multiple congeners within correlated groups would be unnecessary and estimation of separate biologic effects would be impossible. We examined correlation patterns in previously collected data on 38 congeners (and 14 other organochlorines) from 497 human milk samples from Canada from 1992. Congeners 138, 153, 156, 157, 170, 183, 187, 194, 199, and 203 were highly intercorrelated; 180 had slightly lower correlations with this group. Congeners 74, 105, and 118 were highly intercorrelated and moderately to highly correlated with the first group. Congener 99 had moderate correlations with both these groups, and congener 66 had lesser correlations with the primary group. In contrast, congeners 28, 44, 49, 60, 90/101, 128, 137, and 193 showed little correlation with any other congeners. The remaining 14 congeners were uninformative; they were quantified in fewer than 30% of samples, and varying lipid concentrations meant that those quantified were not necessarily at higher concentrations than those not quantified. In study of human health effects of PCBs, the congener pattern present in the population under study should be examined when deciding which congeners to measure; instead of solely redundant or uninformative congeners, attention should be given to other congeners that may be more useful in addressing the question of interest.

Exposure to soil contaminated with an environmental PCB/PCDD/PCDF mixture modulates ultraviolet radiation-induced non-melanoma skin carcinogenesis in the Crl:SKH1-hrBR hairless mouse.

Chlorinated aromatic contaminants are active in carcinogenic processes within the skin and may have the potential to modulate ultraviolet radiation (UV)-induced skin carcinogenesis. Exposure to a complex environmental PCB/PCDD/PCDF mixture (polychlorinated biphenyls/polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans) during the irradiation phase of photocarcinogenesis was associated with significant (P < or = 0.001) reductions in papilloma incidence and squamous cell carcinoma multiplicity at irradiated skin sites. This protective effect was associated with significantly (P < 0.0001) reduced chronic epidermal thickening in UV and contaminant-exposed mice compared with mice exposed to UV only. Contaminant exposure was also associated with increased UV absorbance of skin methanol extracts implying a sunscreen-like effect.

The hypothalamo-pituitary-thyroid (HPT) axis: a target of nonpersistent ortho-substituted PCB congeners.

Coplanar polychlorinated biphenyls (PCBs) cause adverse effects in developing and adult animals. Less is known about the effects of nonplanar ortho-substituted PCBs. We investigated the effects of 2 nonplanar PCB congeners, 95 (2,3,6-2',5'-penta CB) or 101 (2,4,5-2',5'-penta CB), and estradiol on selected endocrine parameters. In Study 1, weanling female Sprague-Dawley (S-D) rats were given a single dose of PCB 95 ip at 4, 8, 16, and 32 mg/kg/day for 2 consecutive days and killed 24 h after the last dose. PCB 95 exposure caused a dose-dependent (p < 0.001) decrease in serum thyroxine (T4) levels. Serum thyroid stimulating hormone (TSH) concentrations did not change, but prolactin (PRL) levels increased in a nonlinear (with dose) manner. No significant changes were seen in thyroid gland morphology and pituitary lactotroph number. In Study 2, progression or regression of effects was assessed by lengthening the time and a second congener was tested. Weanling female S-D rats received a single dose of PCB 95 or PCB 101 ip at 16 and 32 mg/kg/day for 2 days and were killed 48 h after the last dose. PCB 95 and PCB 101 both decreased serum T4 (p < 0.001) and hypothalamic dopamine (DA; p < 0.05) levels. No changes were seen in serum triiodothyronine (T3), TSH, and PRL concentrations. Morphological analysis of the thyroid gland showed a decrease (p < 0.05) in colloid area in rats treated with PCB 95 or 101. However, the epithelial cell height increased only in PCB 95 treated rats. Thyroid epithelial cell proliferation increased (p < 0.05) following exposure to estradiol and PCB 95. The results suggest that the HPT axis appears to be a target of ortho-substituted PCBs. PCB 95 was more effective than PCB 101 in causing these changes.