The majority of presentations at the workshop were associated with characterizing toxicity. Primary endpoints of interest included reproductive, developmental and cardiovascular effects, as highlighted by a series of presentations by Sharma, Hennig, Cassis, and Walker. Sharma opened the session and presented data characterizing mechanisms by which PCBs affect biological systems. The primary focus of this series of studies was the development and validation of experimental systems for evaluating gene-environment effects on female reproductive health. Using these experimental models, the authors reported a number of developmental outcomes (e.g., preterm birth, reduced litter size, diminished righting reflex) in Aroclor 1254-exposed mice. This was followed by results of an applied study evaluating the relationship between nutrition and lifestyle, exposure to environmental toxicants and disease (i.e., nutritional paradigm in environmental toxicology) (Hennig). Findings indicated that an increase in cellular oxidative stress and an imbalance in antioxidant status are critical events in PCB-mediated induction of inflammatory genes and endothelial cell dysfunction. The authors further demonstrated that diet-derived lipids and bioactive compounds can alter key events in PCB cytotoxicity, therefore demonstrating that nutrition can modulate environmental insults in the vasculature (which supports the theory that life-long exposures to PCBs is associated with vascular inflammation and atherosclerosis). Discussions about the (lack of a) margin of exposure between levels in the environment and levels used in experimental effects were focused on developmental effects, supported by measurements of follicular fluid levels of PCBs in humans (Foster).
Based on a series of in vivo and in vitro evaluations, Cassis reported that PCB 77 may contribute to the development of obesity and obesity-associated atherosclerosis based on findings that, in mice, PCB 77 exposure was associated with altered adipocyte differentiantion, adipocyte hypertorophy, proinflammatory cytokine levels, and body weight. Additional studies using TCDD further characterized the role of aryl hydrocarbon receptor (AhR) in alterations in blood pressure regulation (Walker). PCB associations with key events in cardiovascular disease were supported by findings presented by Choie et al. and Majkova et al. These groups further characterized proinflammatory responses associated with oxidative stress in vascular endothelial cells following exposures to dioxin-like PCBs and demonstrating that PCB-induced pro-inflammatory parameters are regulated through caveolae. And thus, inhibition of this step may be an important target for preventing PCB toxicity. Lastly, Shen et al. reported that PCBs can influence paraoxonase activity in rats, an antioxidant enzyme which may contribute to the risk of cardiovascular and other diseases.
Many other studies reported on mechanisms of action, genotoxicity, metabolic breakdown following exposure (and potential toxicity of metabolites). Several of these studies evaluated lower chlorinated congeners, particularly as they relate to toxicities associated with inhalation exposures and toxicity of metabolites. Genotoxicity was addressed in a number of presentations that collectively further characterized key events and/or dose-response relationships following exposure to PCBs in vivo and in vitro (Xie et al; Klingelhutz et al; Flor and Ludewig). There were several reports characterizing the association between PCB exposure and oxidative stress (Chaudhuri; Wagner et al; De et al; Kuppusamy et al.)
A fair number of studies reported on mechanisms or cellular interactions. Data on interactions of hydroxylated PCBs and PCB metabolites with sulfotransferases in rodents and humans were reported, aiding in further characterization of species differences (Ekuase et al; Liu et al). Interactions of PCBs with receptors other than AhR were reported by a number of authors and included pregnane X receptor (PXR) and altered thyroid hormone (TH) status, (Kopec et al; Zoeller). Active transport was also addressed, though Milanowski reported that PCBs were not substrates for the multi-drug resistance transporter under the conditions studied.
Dutta et al presented a series of assessments related to the identification of genomic biomarkers of PCB exposure in humans, highlighted by the identification of specific genes that could be used as potential diagnostic biomarkers for PCB-induced renal diseases. An interesting dataset was presented by Curran, characterizing genetic susceptibilities associated with PCB-induced developmental toxicity.
A series of findings presented by Seegal demonstrated that non-dioxin-like PCBs can alter central dopamine function in both humans and monkeys, and suggested that gender differences be further examined. Specifically, reductions in dopamine via inhibition of transport were observed (PCB 95 was more potent than 153, both of which were more potent than dioxin-like PCBs). The authors also reported that exposure to Aroclor mixtures (A1016 and A1260) decreased dopamine in primates. Pessah presented a detailed structure-activity relationship for PCBs and ryanodine receptor (RyR) and provided quantitative QSARs, thus supporting its involvement in PCB toxicity. Collectively, these data support that non-dioxin-like PCBs may also alter behavior and neurochemical function. The role of oxidative stress was also discussed as a mechanism associated with PCB 95, as data are suggestive that exposures lead to the formation of reactive oxygen species and subsequent neuronal cell death. The role of mitochondrial dysfunction was also discussed, as was the role of steady state levels versus the number of excursions over a threshold relative to PCB toxicities.
Several reports from epidemiological studies provided useful data characterizing effects in humans. As part of a longitudinal study of PCB exposures and child development in eastern Slovkia, Sovcikova et al. did not find an association between pre- and postnatal PCB concentrations and children's IQ at 45 months of age. Lack of effects were also reported by Turyk et al.; findings of a cross sectional, prospective study of adults from the Great lakes basin indicated that PCBs were not associated with diabetes. And using data from the EU 5thFP PCBRISK project, Trnovec et al. utilized benchmark dose calculations to evaluate human health outcomes after long-term and low-dose environmental exposures to PCBs. Results indicated that the proportion of the population considered at risk (i.e., serum concentrations below the BMDL) to neurobehavioral effects ranged from 2.1% for the least protective criteria to 23.7% for the most protective criteria.
Collectively, the toxicity data presented at the workshop suggested that PCB-induced inflammation is triggered through toll-like receptors. Data also indicated that PCBs inhibit angiogenic processes and appear to be associated with a number of endpoints related to cardiovascular effects. Key events may include disruption of endothelial barrier function, oxidative stress, and endothelial cell dysfunction, though further research to characterize these effects is needed. Evidence continues to build supporting an association between PCBs, obesity and disease; data were presented demonstrating a direct correlation between DL-PCBs and obesity (and subsequent inflammation, etc.) as well as PCB 77 induced events resulting in oxidative stress. Data also suggest that sustained AhR activation may be associated with hypertension and coronary heart disease in humans based on animal models of atherosclerosis, hypertension, and CV; associated with oxidative stress (contribute to hypertension). Additional evaluations are necessary to more fully characterize these effects at environmentally relevant exposure concentrations given that several studies suggest a very low (or no) margin of exposure.