Dioxin Toxic Equivalency Factor Evaluation Overview- 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 that bind to the AhR and exhibit
biological actions similar to
TCDD are commonly referred to as "
dioxin-like compounds"(DLCs). 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 adipose tissue resulting in chronic lifetime human exposure. Since human exposure to DLCs always occurs 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, which is the most potent congener. This allows for the estimation of the potential
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.
Polychlorinated biphenyls (
PCBs) and their mixtures including
2,3',4,4',5-pentachlorobiphenyl (
PCB 118) were produced commercially before 1977 for the electric industry as dielectric insulating fluids for transformers and capacitors. Manufacture and use of these chemicals were stopped because of increased PCB residues in the environment, but they continue 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, during combustion of some waste materials, and during atmospheric recycling. This
PCB 118 study was conducted as part of the
dioxin TEF evaluation that included multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related
PCBs, and mixtures of these compounds. Female Harlan Sprague-Dawley rats were administered
PCB 118 (at least 99% pure) in
corn oil:
acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. 2-YEAR STUDY: Groups of 80 female rats were administered 100, 220, 460, 1,000, or 4,600 g
PCB 118/kg
body weight in
corn oil:
acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 80 vehicle control female rats received the
corn oil/
acetone vehicle alone. Groups of 30 female rats received 10 or 30 g/kg for up to 53 weeks only. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. A stop-exposure group of 50 female rats was administered 4,600 g/kg
PCB 118 in
corn oil:
acetone (99:1) by gavage for 30 weeks then the vehicle for the remainder of the study. Survival of all dosed groups of rats was similar to that of the vehicle control group. Mean
body weights of 1,000 g/kg rats were 7% less than those of the vehicle controls after week 36, and those of the 4,600 g/kg core study and stop-exposure groups were 7% less than those of the vehicle controls after week 7. Following
cessation of treatment, the
body weight gain in the stop-exposure group was similar to that of the vehicle control group. In general, exposure to
PCB 118 lead to dose-dependent decreases in the concentrations of serum total
thyroxine (T4) and free T4 in all dosed groups. There were no effects on
triiodothyronine or
thyroid stimulating hormone levels in any dosed groups evaluated at the 14-, 31-, and 53-week interim evaluations. There were increases in hepatic cell proliferation in the 4,600 g/kg group at 14, 31, and 53 weeks. Administration of
PCB 118 led to dose-dependent increases in CYP1A1-associated 7-ethoxyresorufin-O-deethylase, CYP1A2-associated acetanilide4-hydroxylase, and CYP2B-associated
pentoxyresorufin-O-deethylase activities at the 14-, 31-, and 53-week interim evaluations. Analysis of
PCB 118 concentrations in dosed groups showed dose- and duration of dosing-dependent increases in fat, liver, lung, and blood. The highest concentrations were seen in fat at 2 years with lower concentrations observed in the liver, lung, and blood. At the 53-week interim evaluation, three 4,600 g/kg rats had liver
cholangiocarcinoma and one had
hepatocellular adenoma. At 2 years, there were significant treatment-related increases in the incidences of
cholangiocarcinoma and
hepatocellular adenoma. Four incidences of hepatocholangioma occurred in the 4,600 g/kg core study group. At 2 years, a significant dose-related increase in hepatic toxicity was observed and was characterized by increased incidences of numerous lesions including hepatocyte
hypertrophy,
inflammation, oval cell
hyperplasia, pigmentation, multinucleated hepatocyte, eosinophilic and mixed cell foci, diffuse fatty change, toxic hepatopathy, nodular
hyperplasia,
necrosis, bile duct
hyperplasia and
cyst, and cholangiofibrosis. The incidences of these lesions were often decreased in the 4,600 g/kg stop-exposure group compared to the 4,600 g/kg core study group. In the lung at 2 years, a significantly increased incidence of cystic keratinizing
epithelioma occurred in the 4,600 g/kg core study group compared to the vehicle control group incidence. Incidences of bronchiolar
metaplasia of the alveolar epithelium were significantly increased in the groups administered 460 g/kg or greater, and the incidence of squamous
metaplasia was significantly increased in the 4,600 g/kg core study group. The incidence of
carcinoma of the uterus in the 4,600 g/kg stop-exposure group was significantly greater than those in the vehicle control and 4,600 g/kg core study groups at 2 years. A marginal increase in
squamous cell carcinoma occurred in the 220 g/kg group. At 2 years, there were marginally increased incidences of exocrine
pancreatic adenoma or
carcinoma in the 460, 1,000, and 4,600 g/kg core study groups. Numerous nonneoplastic effects were seen in other organs including: adrenal cortical
atrophy and cytoplasmic vacuolization, pancreatic acinar cell cytoplasmic vacuolization and arterial chronic active
inflammation, follicular cell
hypertrophy of the thyroid gland,
inflammation and respiratory epithelial
hyperplasia of the nose, and kidney pigmentation.
CONCLUSIONS: Under the conditions of this 2-year gavage study, there was clear evidence of carcinogenic activity of
PCB 118 in female Harlan Sprague-Dawley rats based on increased incidences of
neoplasms of the liver (
cholangiocarcinoma, hepatocholangioma, and
hepatocellular adenoma) and cystic keratinizing
epithelioma of the lung. Occurrences of
carcinoma in the uterus were considered to be related to the administration of
PCB 118. Occurrences of
squamous cell carcinoma of the uterus and acinar
neoplasms of the pancreas may have been related to administration of
PCB 118. Administration of
PCB 118 caused increased incidences of nonneoplastic lesions in the liver, lung, adrenal cortex, pancreas, thyroid gland, nose, and kidney. Synonyms:
1,1'-Biphenyl, 2,3',4,4',5-pentachloro-(9CI);
1,1'-biphenyl, 2,3',4,4',5-pentachloro-; 2,3',4,4',5-pentachloro-1,1'-
biphenyl; 2,4,5,3',4'-pentachlorobiphenyl; 3,4,2',4',5'-pentachlorobiphenyl;
biphenyl, 2,3',4,4',5-pentachloro-; CB 118.