The metabolism of polychlorinated biphenyls (PCBs) is complex and has an impact on toxicity, and thereby on the assessment of PCB risks. A large number of reactive and stable metabolites are formed in the processes of biotransformation in biota in general, and in humans in particular. The aim of this document is to provide an overview of PCB metabolism, and to identify the metabolites of concern and their occurrence. Emphasis is given to mammalian metabolism of PCBs and their hydroxyl, methylsulfonyl, and sulfated metabolites, especially those that persist in human blood. Potential intracellular targets and health risks are also discussed.

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Metabolism and metabolites of polychlorinated biphenyls

In vitro genotoxicity testing needs to include tests in both bacterial and mammalian cells, and be able to detect gene mutations, chromosomal damage and aneuploidy. This may be achieved by a combination of the Ames test (detects gene mutations) and the in vitro micronucleus test (MNvit), since the latter detects both chromosomal aberrations and aneuploidy. In this paper we therefore present an analysis of an existing database of rodent carcinogens and a new database of in vivo genotoxins in terms of the in vitro genotoxicity tests needed to detect their in vivo activity. Published in vitro data from at least one test system (most were from the Ames test) were available for 557 carcinogens and 405 in vivo genotoxins. Because there are fewer publications on the MNvit than for other mammalian cell tests, and because the concordance between the MNvit and the in vitro chromosomal aberration (CAvit) test is so high for clastogenic activity, positive results in the CAvit test were taken as indicative of a positive result in the MNvit where there were no, or only inadequate data for the latter. Also, because Hprt and Tk loci both detect gene-mutation activity, a positive Hprt test was taken as indicative of a mouse-lymphoma Tk assay (MLA)-positive, where there were no data for the latter. Almost all of the 962 rodent carcinogens and in vivo genotoxins were detected by an in vitro battery comprising Ames+MNvit. An additional 11 carcinogens and six in vivo genotoxins would apparently be detected by the MLA, but many of these had not been tested in the MNvit or CAvit tests. Only four chemicals emerge as potentially being more readily detected in MLA than in Ames+MNvit--benzyl acetate, toluene, morphine and thiabendazole--and none of these are convincing cases to argue for the inclusion of the MLA in addition to Ames+MNvit. Thus, there is no convincing evidence that any genotoxic rodent carcinogens or in vivo genotoxins would remain undetected in an in vitro test battery consisting of Ames+MNvit.

A core in vitro genotoxicity battery comprising the Ames test plus the in vitro micronucleus test is sufficient to detect rodent carcinogens and in vivo genotoxins.

Air samples were collected in Chicago, Illinois in 2007, and 3,3′-dichlorobiphenyl (PCB11, CAS 2050-67-1) was detected and quantified using GC/MS/MS in 91% of 184 samples. To the best of our knowledge, this is the first published report of PCB11 in ambient air. This compound is ubiquitous in air throughout the city of Chicago. The annual mean concentration in air samples collected from November 2006 to November 2007 is 24 pg m−3 (±24 pg m−3 SD), although the seasonal variation is significant. The concentration of PCB11 is up to 15% of measured polychlorinated biphenyls (PCBs) in air but only up to 0.16% of commercial Aroclor mixtures that were banned from production in the 1970s. PCB11 is associated with pigments, paints, and resins and has been reported to be a dominant congener among PCBs detected in the wastewater effluent from paint production. The wide distribution of PCB11 in Chicago air is consistent with volatilization of this compound from painted surfaces although the actual source of PCB11 is u...

https://pubs.acs.org/doi/pdf/10.1021/es801823r

Discovery of non-aroclor PCB (3,3'-dichlorobiphenyl) in Chicago air.

Concentrations of polybrominated diphenyl ethers (PBDEs) and other brominated flame retardants (BFRs) have been rapidly increasing in fish, birds, sediments, indoor environments, and humans, but emission sources and exposure pathways of these pollutants remain poorly understood. The many BFR-containing materials in buildings constitute a large reservoir of these compounds, and in-use releases from this reservoir may be a significant environmental source. To estimate in-use releases from building materials and contents in residences, we monitored 12 houses and garages in two seasons and combined measurements of BFRs in air and settled dust, air exchange rates, and other information in an approach that utilized the building as a “natural” test chamber. Results were scaled to provide a first estimate of aggregate emission rates from U.S. houses. PBDE releases total about 4 μg h−1 per house or 20 ng m−2 h−1, and U.S. houses and garages collectively release about 4100 kg y−1. Most of these releases are settled...

Concentrations and Emissions of Polybrominated Diphenyl Ethers from U.S. Houses and Garages

PCBs: Recent Advances in Environmental Toxicology and Health Effects

Quinoid metabolites of 4-monochlorobiphenyl induce gene mutations in cultured Chinese hamster v79 cells.

2-(4'-chlorophenyl)-1,4-benzoquinone increases the frequency of micronuclei and shortens telomeres.

Recent studies identified polychlorinated biphenyl (PCB) sulfate esters as a major product of PCB metabolism. Since hydroxy-PCBs (HO-PCBs), the immediate precursors of PCB sulfates and important contributors to PCB toxicity, were shown to have estrogenic activity, we investigated the estrogenicity/androgenicty of a series of PCB sulfate metabolites. We synthesized the five possible structural sulfate monoester metabolites of PCB 3, a congener shown to be biotransformed to sulfates, a sulfate ester of the paint-specific congener PCB 11, and sulfate monoesters of two HO-PCBs reported to interact with sulfotransferases (PCB 39, no ortho chlorines, and PCB 53, 3 ortho chlorines). We tested these PCB sulfates and 4'-HO-PCB 3 as positive control for estrogenic, androgenic, anti-estrogenic, and anti-androgenic activity in the E- and A-screen with human breast cancer MCF7-derived cells at 100 μM-1 pM concentrations. Only 4'-HO-PCB 3 was highly cytotoxic at 100 μM. We observed structure-activity relationships: compounds with a sulfate group in the chlorine-containing ring of PCB 3 (2PCB 3 and 3PCB 3 sulfate) showed no interaction with the estrogen (ER) and androgen (AR) receptor. The 4'-HO-PCB 3 and its sulfate ester had the highest estrogenic effect, but at 100-fold different concentrations, i.e., 1 and 100 μM, respectively. Four of the PCB sulfates were estrogenic (2'PCB 3, 4'PCB 3, 4'PCB 39, and 4'PCB 53 sulfates; at 100 μM). These sulfates and 3'PCB 3 sulfate also exhibited anti-estrogenic activity, but at nM and pM concentrations. The 4'PCB 3 sulfate (para-para' substituted) had the strongest androgenic activity, followed by 3'PCB 3, 4'PCB 53, 4PCB11, and 4PCB 39 sulfates and the 4'HO-PCB 3. In contrast, anti-androgenicity was only observed with the two compounds that have the sulfate group in ortho- or meta- position in the second ring (2'PCB 3 and 3'PCB 3 sulfate). No dose-response was observed in any screen, but, with exception of estrogenic activity (only seen at 100 μM), endocrine activity was often displayed at several concentrations and even at 1 pM concentration. These data suggest that sulfation of HO-PCBs is indeed reducing their cytotoxicity and estrogenicity, but may produce other endocrine disruptive activities at very low concentrations.

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Susanne Flor

Papers

Quinoid metabolites of 4-monochlorobiphenyl induce gene mutations in cultured Chinese hamster v79 cells.

2-(4'-chlorophenyl)-1,4-benzoquinone increases the frequency of micronuclei and shortens telomeres.

Estrogenicity and androgenicity screening of PCB sulfate monoesters in human breast cancer MCF-7 cells

Polyploidy-induction by dihydroxylated monochlorobiphenyls: Structure-activity-relationships

Toxicity assessment of air-delivered particle-bound polybrominated diphenyl ethers.