Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds with similar physio-chemical properties that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Additional compounds not structurally or physiochemically related to TCDD have been identified as AhR ligands and include some of the carotinoids, indoles, flavinoids, isoflavones, and arachidonic acid metabolites (Amakura et al., 2003; Denison and Nagy, 2003; Zhang et al., 2003). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in body tissues, mainly adipose tissue, resulting in chronic lifetime human exposure.
Since human exposure to DLCs always involves as a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, the most potent congener. This allows for the estimation of the potential total dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR.
The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds.
Chemical Formula: C12 H4 Cl6 - Molecular Weight: 360.88
2,2',4,4',5,5'-Hexachlorobiphenyl (PCB 153) was produced as a component of some commercial PCB mixtures before 1977 for the electric industry as a dielectric insulating fluid for transformers and capacitors. Manufacture and use of the chemical was stopped due to increased PCB residues in the environment, but it continues to be released into the environment through the use and disposal of products containing PCBs, as by-products during the manufacture of certain organic chemicals, and during the combustion and biodegradation of some waste materials. Bioaccumulation of PCB 153 results in persistent levels in animal and human tissues. PCB 153 was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. PCB 153 was included since it is present at the highest PCB concentrations in human samples on a molar basis. PCB 153 was also included in a mixture study with PCB 126, since previous studies have demonstrated interactions between PCB 153 and DLCs on pharmacokinetic and biological effects. While one of the aims of this study was a comparative analysis of effects seen with PCB 126 and the mixture of PCB 126 and PCB 153, in this Technical Report only the results of the present study of PCB 153 are presented and discussed.
Female Harlan Sprague-Dawley rats were administered PCB 153 (greater than 99% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. Groups of 80 (3,000 µg PCB 153/kg body weight), 81 (100, 300, and 1,000 µg/kg), or 82 (10 µg/kg) female rats received PCB 153 in corn oil:acetone (99:1) by gavage at doses of 10, 100, 300, 1,000, or 3,000 µg/kg 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle alone. A stop-exposure group of 50 female rats was administered 3,000 µg/kg for 30 weeks and then the vehicle for the remainder of the study.
Dose selection for the PCB 153 study was based on the range of PCB 153 doses used in the mixture study of PCB 126 and PCB 153 (10 to 3,000 µg/kg).
Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of 3,000 µg/kg core study rats were less than those of the vehicle controls after week 69 of the study.
Serum total thyroxine (T4), free T4, and total triiodothyronine (T3) concentrations in the 3,000 µg/kg group were significantly lower than those in the vehicle controls at the 14-week interim evaluation. At the 31-week interim evaluation, no significant differences were observed in serum total T4, free T4, T3, or thyroid stimulating hormone concentrations. At the 53-week interim evaluation, serum total T4 and free T4 concentrations in the 3,000 µg/kg group were significantly lower than in the vehicle controls.
No significant differences in hepatocellular labeling index were observed between the vehicle control and dosed groups at any of the interim evaluations.
Hepatic pentoxyresorufin-O-deethylase activities were highly and significantly elevated relative to the vehicle control groups. Maximum increases over controls at 14, 31, and 53 weeks were 136-, 140-, and 40-fold, respectively. Hepatic 7-ethoxyresorufin-O-deethylase (EROD) and acetanilide-4-hydroxylase (A4H) activities were significantly elevated over controls at 14 and 31 weeks; increases were less than twofold. At 14 weeks, EROD activities in the lung were dose-dependently reduced compared to vehicle controls.
In the fat from vehicle controls, detectable levels of PCB 153 were observed at 14, 31, and 53 weeks and at the end of the 2-year study. Fat concentrations of PCB 153 increased with increasing doses of PCB 153 and tended to increase with the longer exposure durations. In the fat of the 3,000 µg/kg stop-exposure group, PCB 153 concentrations were between the levels observed in the 300 and 1,000 µg/kg groups. In the liver of vehicle controls, no measurable concentrations of PCB 153 were observed at any time point. In dosed groups, hepatic concentrations of PCB 153 increased with increasing dose and longer exposure duration. Measurable concentrations of PCB 153 were observed in the lungs of vehicle control rats at 31 and 53 weeks and at 2 years. At all time points, PCB 153 lung and blood concentrations increased with increasing dose, and blood concentrations increased with duration of exposure. In liver, lung, and blood of rats from the 3,000 µg/kg stop-exposure group, PCB 153 concentrations were slightly above or below the levels observed in the 1,000 µg/kg group.
Absolute liver weights of 1,000 µg/kg rats and absolute and relative liver weights of 3,000 µg/kg rats were significantly greater than those of vehicle controls at week 14. At week 31, relative liver weights of 1,000 µg/kg rats and absolute and relative liver weights of 3,000 µg/kg rats were significantly greater than those of vehicle controls. At week 53, absolute and relative liver weights were significantly greater in rats administered 100 µg/kg or greater compared to vehicle controls. Absolute kidney weights of all exposed groups and the relative kidney weight of 3,000 µg/kg rats were significantly increased at week 53.
The incidences of hepatocyte hypertrophy were significantly increased in the 1,000 and 3,000 µg/kg groups at 14 weeks and in all groups administered 300 µg/kg or greater at 31 and 53 weeks.
At 2 years, the incidences of hepatocyte hypertrophy were significantly increased in all dosed groups. The incidences of diffuse fatty change in the 300 µg/kg or greater groups and bile duct hyperplasia of the liver in 300 µg/kg and 3,000 µg/kg (core and stop-exposure) groups were significantly increased. The incidences of oval cell hyperplasia and pigmentation of the liver were significantly increased in the 3,000 µg/kg core study group. At 2 years, two cholangiomas were seen in the 1,000 µg/kg group and two cholangiomas were seen in the 3,000 µg/kg stop-exposure group. A single hepatocellular adenoma was observed in the 3,000 µg/kg core study group.
At 53 weeks, sporadic incidences of minimal to mild follicular cell hypertrophy of the thyroid gland occurred in all groups (except 10 µg/kg). At 2 years, the incidences of minimal to mild follicular cell hypertrophy were significantly increased in the 300 µg/kg and 3,000 µg/kg (core and stop-exposure) groups.
At 2 years, significantly increased incidences of chronic active inflammation in the ovary and oviduct occurred in the 1,000 and 3,000 µg/kg core study groups. Incidences of suppurative inflammation of the uterus in the 1,000 µg/kg group and chronic active inflammation in the 3,000 µg/kg core study group were significantly greater than those in the vehicle control group.
Under the conditions of this 2-year gavage study there was
equivocal evidence of carcinogenic activity of PCB 153 in female Harlan Sprague-Dawley rats based on the occurrences of cholangioma of the liver.
PCB 153 administration caused increased incidences of nonneoplastic lesions of the liver, thyroid gland, ovary, oviduct, and uterus in female rats.
Synonym: 1,1'-Biphenyl, 2,2',4,4',5,5'-hexachloro-(9CI)
Doses in corn oil/acetone by gavage
0, 10, 100, 300, 1,000, 3,000 µg/kg, and 3,000 µg/kg (stop-exposure)
3,000 µg/kg core study group less than the vehicle control group
24/53, 16/54, 28/53, 21/53, 20/53, 21/51, 20/50
hepatocyte hypertrophy (0/53, 5/54, 5/53, 24/53, 39/53, 41/51, 32/50);
diffuse fatty change (3/53, 7/54, 2/53, 11/53, 21/53, 17/51, 15/50);
bile duct hyperplasia (5/53, 3/54, 2/53, 14/53, 10/53, 17/51, 12/50);
oval cell hyperplasia (0/53, 0/54, 0/53, 1/53, 0/53, 4/51, 2/50);
pigmentation (1/53, 1/54, 2/53, 5/53, 5/53, 9/51, 3/50)
follicular cell hypertrophy (5/51, 9/52, 9/53, 12/53, 10/53, 17/51, 12/49)
chronic active inflammation (0/53, 0/53, 2/53, 1/53, 5/53, 7/50, 0/49)
chronic active inflammation (1/50, 0/38, 2/44, 1/35, 5/39, 7/45, 2/46)
suppurative inflammation (5/53, 6/54, 6/53, 2/53, 16/53, 8/50, 9/49);
chronic active inflammation (2/53, 1/54, 5/53, 4/53, 2/53, 8/50, 1/49)
cholangioma (0/53, 0/54, 0/53, 0/53, 2/53, 0/51, 2/50)
Level of evidence of carcinogenic activity
Report Date: May 2006