Grantee Research Project Results
Final Report: Immunotoxicity of Both Nondegraded and Biodegraded Polychlorinated Biphenyls (PCBs)
EPA Grant Number: R826687Title: Immunotoxicity of Both Nondegraded and Biodegraded Polychlorinated Biphenyls (PCBs)
Investigators: London, Lucille , Smithwick, Laura Ashley , Quensen, John , Morris, Pamela
Institution: Medical University of South Carolina
EPA Project Officer: Aja, Hayley
Project Period: September 15, 1998 through September 14, 2001
Project Amount: $379,176
RFA: Exploratory Research - Human Health (1998) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The objective of this research project was to understand the biological process by which complex mixtures of contaminants can be degraded in the environment, and to apply that knowledge to better understand potential human health effects associated with exposure. We focused on the biodegradation of complex mixtures of polychlorinated biphenyls (PCBs) and their subsequent immunotoxicological effects.
PCBs are widespread environmental contaminants and available evidence suggests that the immune system is a target for PCB toxicity. The persistence of PCBs in the environment along with their bioaccumulation in living organisms raise concerns regarding their immunotoxic potential and subsequent effects on health. We examined the immunotoxicity of PCBs and their biodegraded products using a well-defined immunologic parameter as an indicator of immunotoxicity. We assessed both nondegraded and biodegraded (anaerobic dechlorination) PCBs on their ability to modulate the murine B cell proliferative response to the mitogen, lipopolysaccaride (LPS). We also investigated the ability of PCBs and their dechlorinated products to modulate immunoglobulin secretion in vitro after LPS stimulation.
In initial studies, four commercial PCB mixtures (Aroclors) or six individual PCB congeners were evaluated for their effect on splenocyte viability and lipopolysaccharide (LPS)-induced splenocyte proliferation in vitro in two strains of mice, C57Bl/6 (high affinity aromatic hydrocarbon receptor (AhR) complex) and DBA/J (low affinity AhR complex) (Stack, et al., 1999). All four Aroclors, the selected individual noncoplanar congeners, or two tertiary mixtures containing one congener from each class, significantly decreased the in vitro LPS-induced proliferation of murine splenocytes in either strain of mice without inducing a significant decrease in viability. In contrast, selected individual coplanar or mono-ortho-coplanar congeners did not inhibit splenocyte proliferation or viability at any concentration. These results suggest that mixtures of PCBs and/or congener class (specifically, noncoplanar congeners) may be more highly immunotoxic than individual planar or mono-ortho-coplanar congeners alone. This is significant since PCB mixtures, not individual congeners, were used industrially, and now contaminate the environment. In addition, with respect to human toxicity, only those congeners that bioaccumulate have the potential to influence human health. Our results implicating noncoplanar congeners as potentially immunotoxic are significant because these congeners selectively bioaccumulate, and traditional means of assessing toxicity based on TEQ values may underestimate their importance.
Summary/Accomplishments (Outputs/Outcomes):
Our results demonstrate that: (1) inhibition of LPS-induced splenocyte proliferation is dependent on ortho- chlorine substitutions, and congeners without these ortho- substitutions inhibit proliferation to a lesser extent; (2) removal of the non-ortho- (and some mono-ortho-) substituted congeners from an Aroclor mixture by an activated charcoal column does not reduce the observed toxicity as measured by LPS-induced splenocyte proliferation; and (3) anaerobic dechlorination preferentially removes meta- and para- chlorines from PCB congeners, resulting in a mixture with an accumulation of ortho- substituted congeners. Anaerobically dechlorinated Aroclor 1242 mixtures (ortho- enriched) inhibit LPS-induced splenocyte proliferation to a similar extent as parent Aroclor. Our results suggest that mixtures of PCBs and/or congener classes (specifically, noncoplanar congeners) may be more highly immunotoxic than individual planar and mono-ortho-coplanar congeners alone. These results have important practical significance, because mixtures of PCB congeners were used industrially and now contaminate the environment. In addition, noncoplanar congeners that exhibit toxic effects in our immunoassay, tend to bioaccumulate. Once in the environment, PCBs may be degraded by multiple processes that alter the congener profiles and percent chlorination of the parent mixtures. One such process that has been shown to modify PCB congener profiles in anaerobic sediments, reductive dechlorination, generally involves the removal of meta- and para- chlorines from more highly chlorinated congeners, resulting in the accumulation of less chlorinated, ortho-substituted congeners. For example, 2-CB, 2,2'-CB, 2,6-CB, 2,2', 6-CB, and 2,3',6-CB have been shown to accumulate following dechlorination of Aroclor 1242 by process C, a dechlorination process that removes meta- and para- chlorines. Evidence for anaerobic degradation in the environment has been presented from the Hudson River, Woods Pond, the Housatonic River, Baltimore Harbor, as well as many other PCB-contaminated areas, suggesting that this is a common occurrence.
A parent PCB mixture in the environment may be anaerobically dechlorinated to produce a mixture with decreased coplanar, dioxin-like congeners and thus decreased Ah receptor-mediated activity; however, increasing evidence of the toxicity of ortho-substituted congeners suggests the toxicity of remaining ortho- substituted congeners must be considered as well. The purpose of this investigation was to evaluate the toxicity of these ortho- substituted congeners that accumulate following reductive dechlorination. The immunotoxic potential of individual congeners as well as PCB mixtures were measured using a model immunotoxicity assay in which lymphocyte viability, proliferation, and antibody secretion following PCB exposure were assessed. The toxicity of Aroclor 1242, dechlorinated Aroclor 1242, individual congeners that accumulate following dechlorination of Aroclor 1242, as well as ortho- and non-ortho fractions of Aroclor 1242 were assessed to determine changes in toxicity that occur with changes in Aroclor composition. Predominately, only the noncoplanar congeners, regardless of their chlorine content, exhibited a toxic effect on the ability of splenocytes to proliferate in response to LPS. These results are consistent with the toxic effects observed with noncoplanar congeners in a variety of biological systems, including effects on neurotoxicity, neutrophil function, and insulin release, among others. In addition to evaluating the ability of murine splenocytes to proliferate in response to LPS in the presence of various PCBs, we also evaluated whether these same PCB mixtures also effect LPS-induced immunoglobulin secretion. A similar predominate effect of noncoplanar congeners on immunoglobulin secretion also was observed, although to a lesser extent than the inhibition observed on proliferation. Our results implicating noncoplanar congeners as potentially immunotoxic are significant because these congeners selectively bioaccumulate and the traditional means of assessing toxicity based on TEQ values may underestimate their importance.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
| Other project views: | All 14 publications | 3 publications in selected types | All 2 journal articles |
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Smithwick LA, Smith A, Quensen JF 3rd, Stack A, London L, Morris PJ. Inhibition of LPS-induced splenocyte proliferation by ortho-substituted polychlorinated biphenyl congeners. Toxicology. 2003 Jun 30;188(2-3):319-333. |
R826687 (Final) |
not available |
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Stack A, Altman-Hamamdzic S, Morris PJ, London L. Polychlorinated biphenyl mixtures (Aroclors) inhibit LPS-induced murine splenocyte proliferation in vitro. Toxicology, Volume 139, Issue 1-2, November 29, 1999, Pages 137-154. |
R826687 (2000) R826687 (Final) |
not available |
Supplemental Keywords:
polychlorinated biphenyls, PCBs, sediments, bioremediation, cleanup., Health, RFA, Scientific Discipline, PHYSICAL ASPECTS, Waste, Health Risk Assessment, Physical Processes, Risk Assessments, chemical mixtures, Environmental Chemistry, Analytical Chemistry, Biochemistry, Bioremediation, environmental mutagens, detoxification, ecological risk assessment, aerobic degradation, immune response, human exposure, immune systems, PCB, in situ bioremediation, bioaccumulation, biodegradation, complex mixtures, exposure, bioacummulation, aroclor, lipopolysaccarid, human health riskProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.