Differential effects of two lots of Aroclor 1254 on enzyme induction, thyroid hormones, and oxidative stress. (Articles).

Aroclor 1254 is a commercial mixture of polychlorinated biphenyls (PCBs), which is defined as being 54% chlorine by weight. However, the congener composition varies from lot to lot. Two lots which have been used in toxicity studies, 124-191 and 6024 (AccuStandard), were analyzed for their congener composition. Lot 6024 has approximately 10 times the dioxin toxic equivalents (TEQ) of lot 124-191. The purpose of this study was to determine if the difference in the TEQ of the two lots explains the different in vivo responses seen on a weight basis. Male Long-Evans rats (70 days old) were treated orally with a single dose of 0-1,000 mg/kg of each lot. Hepatic ethoxy-, methoxy-, and pentoxyresorufin O-deethylase (EROD, MROD, and PROD, respectively) activities as well as serum thyroxine ([T.sub.4]) concentrations and measures of oxidative stress were determined 4 days after treatment. Results, on a weight basis, indicate that lot 6024 led to a greater induction of EROD, MROD, and PROD but not total [T.sub.4] reduction. The differences in TEQ between the lots explained the differential induction of EROD and MROD but did not account for the induction of PROD nor decreases in [T.sub.4]. PROD induction is not due to dioxin-like congeners, whereas the decrease in serum [T.sub.4] levels may involve multiple mechanisms. Effects on the antioxidants ascorbic acid and uric acid were seen only at the highest mass dose for both lots and were not explained by the difference in TEQ. These results illustrate that the differences in the TEQ explain the differences in the strict dioxin-like effects (EROD, MROD induction), but the non-dioxin-like congeners cause other effects that are not associated with the aryl hydrocarbon receptor (e.g., PROD). In addition, supra-additive effects also occur in the mixture ([T.sub.4], oxidative stress). Thus, current results demonstrate that overall toxicity cannot be predicted on the basis of the TEQ values. It is also critical that the lot number is reported in studies conducted with Aroclor 1254 because the congener composition and therefore the effects observed can be very different. Key words:. Aroclor 1254, dioxin, hepatic enzymes, oxidative stress, polychlorinated biphenyls, thryroid hormones, toxic equivalents. Environ Health Perspeet 109:1163-1168 (2001). [Online 5 November 2001]

http:// ehpnet1.niehs.nih.gov/docs/2001/109p1163-1168burgin/abstract.html

Polychlorinated biphenyls (PCBs) were widely used in a variety of industrial and consumer products before their production was banned in the United States in the 1970s. More than 1 million tons of PCBs have been produced (1) and more than than 70% of the PCBs made are still in use (2). The chemical properties that made PCBs desirable in industrial applications (inflammability, chemical stability, and miscibility with organic compounds, or lipophilicity) are the same properties that have contributed to their environmental problems. Once in the environment, stable PCBs degrade slowly and undergo cycling and transport and are thus ubiquitous environmental contaminants. They are frequently found as complex mixtures of congeners in soil and dust and on surfaces in homes and factories. Of the 209 possible PCB congeners, only around 130 are detectable in commercial mixtures, and far fewer are found in the environment (3-6).

PCB mixtures induce a variety of biochemical and toxic responses in humans and animals (4). Many of these effects resemble those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons that act through the aryl hydrocarbon receptor (AhR) signal transduction pathway (7). Dioxin-like PCBs principally include the coplanar PCBs such as IUPAC 77, 81, 126, 169. Dioxin-like effects include weight loss, thymic atrophy, enzyme induction, immunotoxicity, teratogenicity, dermatologic effects, carcinogenicity, and endocrine disruption (4). The mono-ortho coplanar PCBs such as 105, 114, 118, 123, 156, 157, 167, 189 have both dioxin-like effects via the AhR and other mechanisms of action, such as a phenobarbital-like spectrum of enzyme induction. Ortho-substituted PCBs, those that do not bind to the AhR, elicit a different pattern of toxicity. For example, ortho-substituted nonplanar PCB congeners elicit enzyme induction, neurotoxicity, carcinogenicity, and endocrine disruption (7-9). Exposure to complex mixtures of polychlorinated dibenzofurans (PCDFs) and PCBs have been linked to developmental and cognitive dysfunctions seen in children born to mothers who consumed PCDF- and PCB-contaminated rice oil in Japan (Yusho) and Taiwan (Yu-Cheng) (10). Reduced levels of thyroid hormones are detected after developmental exposure to TCDD, non-ortho, mono- and di-ortho chlorinated PCB congeners as well as after exposure to technical mixtures of PCBs (9,11).

Oxidative stress involves a depletion of the protective antioxidant defenses of the body. Oxidative stress from TCDD exposure causes increased production of reactive oxygen species, enhanced lipid peroxidation, decreased glutathione content, decreased hepatic membrane fluidity, and DNA damage (12,13). Persistent organohalogen compounds are tumor promoters (14), and there is evidence that this promotion is mediated at least in part by reactive oxygen species such as superoxide or hydrogen peroxide (15). The mechanism by which this effect occurs remains to be elucidated, but it appears to be AhR mediated (13). Markers of oxidative stress were evaluated because PCBs and dioxins induce oxidative stress (16), which has been implicated in the promotion of cancer (17) and developmental toxicity (12); thus, it is important to evaluate both dioxin-like and non-dioxin-like PCBs for similar activity. In the Aroclor mixtures there are both dioxin-like and non-dioxin-like PCB congeners so measures of oxidative stress were used to evaluate biochemical and toxic effects.

2,3,7,8-TCDD is never found alone in the environment, but rather as a component of a complex mixture of compounds, many of which share a common AhR-mediated mechanism of action and which elicit similar biological responses. Because of this, a relative potency-ranking scheme was created ...