Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent tumor promoter in two-stage models of hepatocarcinogenesis. This study focuses on the persistence or reversibility of TCDD-mediated changes in livers after 30 weeks of treatment and cessation of treatment. Diethylnitrosamine (DEN) initiated animals (175 mg/kg) were promoted bi-weekly with TCDD at a dose equivalent to 125 ng/kg/day for 30 weeks without or with a following waiting period of 32 weeks before necropsy. 2,3,7,8-Tetrachlorodibenzo-p-dioxin liver concentration decreased 300-fold above background. Induction of CYP1A1 dependent enzyme activity decreased according to TCDD tissue levels. In contrast, cell proliferation, as measured by BrdU-labeling index, was still 2.8-fold increased over controls in the TCDD group with waiting period compared to a 4-fold increase over controls at the end of the 30 week dosing period. Enzyme altered hepatic foci expressing the placental form of glutathione S-transferase decreased in number but the remaining foci were significantly increased in size and the percent of liver occupied by foci was higher at the end of the waiting period as compared to livers at the end of the dosing period. Liver tumor incidence at the end of the waiting period was 71% (5 of 7 animals) and the livers showed an increase in bile duct lesions with only mild toxicity. There was pronounced bile duct proliferation in DEN/TCDD treated animals after the waiting period with intense expression of TGF alpha in bile duct epithelial cells at detected by immunohistochemical methods. In comparison, at the end of the 30 week dosing period the livers showed more severe toxicity and only mild bile duct proliferation. Also, one small hepatocellular adenoma was observed. It is concluded that as opposed to CYP1A1 induction the more complex biological responses, cell proliferation and selective growth of certain preneoplastic foci, are persistent after prolonged TCDD treatment within the experimental framework of our study.
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PMID:Persistence of TCDD-induced hepatic cell proliferation and growth of enzyme altered foci after chronic exposure followed by cessation of treatment in DEN initiated female rats. 758 2

Numerous studies have associated colorectal adenoma with smoking and large bowel cancer with consumption of foods potentially containing polycyclic aromatic hydrocarbons. Enhanced metabolic activation of polycyclic aromatic hydrocarbons has recently been observed in homozygotes for a MspI mutation in the 3'-end of CYP1A1. We conducted a population-based case-control study to investigate whether CYP1A1 polymorphisms were related to colorectal cancer risk. Using polymerase chain reaction-based methods, we assessed the frequency of the MspI polymorphism in the 3'-end of CYP1A1 and another mutation in exon 7 of the gene (Ile-Val polymorphism) among 43 patients with in situ adenocarcinoma of the large bowel and 129 population controls. Homozygosity for the MspI mutant genotype was found to be positively associated with in situ colorectal cancer in Japanese (P = 0.008) and Hawaiians/part-Hawaiians (P < 0.001), whereas the study lacked power to detect a similar association in Caucasians. The odds ratio for the homozygous variant genotype compared to the heterozygous and wild-type genotypes was 7.9 (95% confidence interval, 1.4-44.4) in Japanese. A similar association was suggested for the exon 7 mutation homozygosity in Japanese, as the two polymorphisms are in genetic disequilibrium. Thus, this study suggests a potentially important role for CYP1A1 and polycyclic aromatic hydrocarbons in the etiology of colorectal cancer in populations with a high gene frequency.
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PMID:CYP1A1 genetic polymorphisms and in situ colorectal cancer. 791 6

Tumour formation may involve interactions between genetic factors and environmental carcinogens. Adenoma formation in APCMin/+ mice is associated homozygous adenomatous polyposis coli (APC) gene mutation, but the effects on carcinogen susceptibility are unknown. This study tests the hypothesis that APCMin/+ adenoma formation is accompanied by changes in metabolic proficiency and carcinogen susceptibility. Cytochrome P450 (CYP)1A1/1A2, glutathione S-transferase (GST)alpha, mu and pi classes and DNA adduct formation were assayed in adenomas and uninvolved mucosa from APCMin/+ mice, before and after benzo[a]pyrene (B[a]P) treatment. In untreated adenomas and mucosa, CYP1A1/1A2 and B[a]P-DNA adducts were undetected but GSTalpha, mu and pi class enzymes were constitutively expressed. In adenomas, B[a]P only induced CYP1A1/1A2 to low level while GSTalpha and pi class enzymes were unaffected. A GST mu band which was absent from mucosa, was induced in adenomas. In mucosa, B[a]P induced CYP1A1/1A2 and GSTalpha and pi, to high levels. B[a]P-DNA adduct levels were 56 +/- 15/10(8) nucleotides (median +/- SE) in adenomas versus 89 +/- 19/10(8) nucleotides in mucosa (P < 0.0001). APCMin adenomas show reduced bioactivation capacity and sustain less DNA damage from B[a]P exposure, than APCMin uninvolved mucosa. These properties could influence mutagenesis and subsequent neoplastic transformation of adenomas.
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PMID:Metabolic proficiency and benzo[a]pyrene DNA adduct formation in APCMin mouse adenomas and uninvolved mucosa. 1035 94

Cigarette use is a risk factor for colorectal adenoma, a known precursor of colorectal cancer. Polymorphic variants in NQO1 and CYP1A1 influence the activation of carcinogenic substances in tobacco smoke, possibly impacting on tobacco-associated risks for colorectal tumors. We investigated the association of cigarette smoking with risk for advanced colorectal adenoma in relation to the CYP1A1 Val(462) and NQO1 Ser(187) polymorphic variants. Subjects were 725 non-Hispanic Caucasian cases with advanced colorectal adenoma of the distal colon (descending colon, sigmoid and rectum) and 729 gender- and ethnicity-matched controls, randomly selected from participants in the prostate, lung, colorectal and ovarian cancer screening trial. Subjects carrying either CYP1A1 Val(462) or NQO1 Ser(187) alleles were weakly associated with risk of colorectal adenoma; however, subjects carrying both CYP1A1 Val(462) and NQO1 Ser(187) alleles showed increased risks (OR = 2.2, 95% CI = 1.1-4.5), particularly among recent (including current) (OR = 17.4, 95% CI = 3.8-79.8, P for interaction = 0.02) and heavy cigarette smokers (>20 cigarettes/day) (OR = 21.1, 95% CI = 3.9-114.4, P for interaction = 0.03) compared with non-smokers who did not carry either of these variants. These genotypes were unassociated with risk in non-smokers. In analysis of adenoma subtypes, the combined gene variants were most strongly associated with the presence of multiple adenoma (P = 0.002). In summary, joint carriage of CYP1A1 Val(462) and NQO1 Ser(187) alleles, particularly in smokers, was related to colorectal adenoma risk, with a propensity for formation of multiple lesions.
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PMID:CYP1A1 Val462 and NQO1 Ser187 polymorphisms, cigarette use, and risk for colorectal adenoma. 1573 Nov 66

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 that 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. 3,3',4,4',5-Pentachlorobiphenyl (PCB 126) was produced commercially before 1977 for the electric industry as a dielectric insulating fluid for transformers and capacitors. Manufacture and use of the chemical was stopped because of 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 combustion of some waste materials. Bioaccumulation of PCB 126 results in persistent levels in animal and human tissues and the biological responses to PCB 126 are similar to those of TCDD, a known human carcinogen. PCB 126 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 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 126 was included since this is the most potent coplanar PCB that has dioxin-like activities. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report only the results of the PCB 126 study are presented and discussed. Female Harlan Sprague-Dawley rats were administered PCB 126 (99% pure) in corn oil with acetone by gavage for 14, 31, or 53 weeks or 2 years. 2-YEAR STUDY: Groups of 81 female rats were administered 30, 100, 175, 300, 550, or 1,000 ng PCB 126/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 104 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. A group of 28 rats received 10 ng/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 1,000 ng/kg PCB 126 in corn oil:acetone (99:1) by gavage for 30 weeks then the vehicle for the remainder of the study. Mean body weights of 30 and 100 ng/kg rats were similar to those of the vehicle controls during most of the study, mean body weights of 175 and 300 ng/kg rats were less than those of the vehicle controls during year 2 of the study, and mean body weights of 550 ng/kg, 1,000 ng/kg core study, and 1,000 ng/kg stop-exposure rats were less than those of the vehicle controls after week 17. THYROID HORMONE CONCENTRATIONS: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31- and 53- week interim evaluations. In the 550 and 1,000 ng/kg rats, total thyroxine (T4) and free T4 were significantly lower than vehicle controls and serum triiodothyronine (T3) and thyroid stimulating hormone (TSH) levels were significantly higher than vehicle controls at the 14-week interim evaluation. Serum T3 was also significantly higher in the 300 ng/kg rats compared to vehicle controls at 14 weeks. At 31 weeks, T3 was significantly higher at doses of 100 ng/kg or greater compared to vehicle controls. TSH levels were higher in 550 and 1,000 ng/kg rats than in vehicle controls. At 53 weeks, significantly lower serum concentrations of total T4 and free T4 were observed compared to vehicle controls in groups administered 175 ng/kg or greater and 30 ng/kg or greater, respectively. Serum T3 levels were significantly higher at doses of 175 ng/kg or greater compared to vehicle controls. No changes in TSH were observed between vehicle controls and dosed rats at 53 weeks. HEPATIC CELL PROLIFERATION DATA: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. The hepatocellular labeling index was significantly higher at doses of 300 ng/kg or greater at 14 weeks and 175 ng/kg or greater at 31 weeks compared to vehicle controls. No statistically significant differences were observed between vehicle controls and PCB 126 dosed rats at 53 weeks. However at 53 weeks, a 5.8-fold increase above the vehicle controls was observed in the 1,000 ng/kg group. CYTOCHROME P450 ENZYME ACTIVITIES: To evaluate the expression of known dioxin-responsive genes, CYP1A1 associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide 4-hydroxylase (A-4-H) activity were evaluated at the 14-, 31-, and 53-week interim evaluations. In addition, CYP2B associated pentoxyresorufin-O-deethylase (PROD) activity was also analysed. Hepatic PROD (CYP2B1) and hepatic and pulmonary EROD (CYP1A1) activity were significantly greater in all dosed groups than in vehicle controls at weeks 14, 31, and 53. Hepatic A-4-H (CYP1A2) activity was significantly greater in the 30, 100, 175, 300, 550, and 1,000 ng/kg groups compared to vehicle controls at weeks 14, 31, and 53. DETERMINATIONS of PCB 126 CONCENTRATIONS IN TISSUES: The tissue disposition of PCB 126 was analyzed in the liver, lung, fat, and blood of all rats in vehicle controls and all dosed groups at the 14-, 31-, and 53-week interim evaluations and in 10 rats per group including vehicle controls at the end of the 2-year study (104 weeks). Detectable concentrations of PCB 126 were observed in the liver, fat, lung, and blood. Measurable concentrations of PCB 126 were present in the liver and fat at weeks 31, 53, and 104. Hepatic and fat concentrations increased with increasing doses of PCB 126. Measurable concentrations of PCB 126 were present in vehicle control lung tissue at 53 and 104 weeks. No PCB 126 was observed in the blood from the vehicle control rats. Lung and blood concentrations tended to increase with increasing doses of PCB 126, with a few exceptions. In the stop-exposure group, PCB 126 concentrations in liver and fat were lower than the levels observed in the 30 ng/kg group. In the stop-exposure group, lung tissue PCB 126 concentrations were equivalent to the levels observed in the 30 ng/kg group. In blood from the stop-exposure group, PCB 126 concentrations were equivalent to the levels observed in the 100 ng/kg group. PATHOLOGY AND STATISTICAL ANALYSES: Absolute and relative liver weights were significantly increased at all time points and correlated with increased incidences of hepatocellular hypertrophy. At 2 years, there were significant treatment-related increases in the incidences of cholangiocarcinoma and hepatocellular adenoma. Three hepatocholangiomas were seen in the 1,000 ng/kg core study group and a single incidence of cholangioma each occurred in the 550 and 1,000 ng/kg core study groups. 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, multinucleated hepatocytes, diffuse fatty change, bile duct hyperplasia, bile duct cyst, oval cell hyperplasia, necrosis, pigmentation, inflammation, nodular hyperplasia, portal fibrosis, cholangiofibrosis, and toxic hepatopathy. The incidences of these lesions were generally decreased in the 1,000 ng/kg stop-exposure group compared to the 1,000 ng/kg core study group. The lung weights of 1,000 ng/kg rats were generally significantly increased at weeks 14, 31, and 53. At 2 years, treatment related increases in the incidences of cystic keratinizing epithelioma and squamous cell carcinomas were observed. In addition, dose-related increases in the incidences of bronchiolar metaplasia of the alveolar epithelium and squamous metaplasia were also observed. The incidence of gingival squamous cell carcinoma of the oral mucosa was significantly increased in the 1,000 ng/kg core study group at 2 years. Gingival squamous cell carcinoma, although reduced in incidence as compared to the 1,000 ng/kg core study group, was still present in the 1,000 ng/kg stop-exposure group. At 2 years, adenomas and/or carcinomas were present in the adrenal cortex of most core study groups and in the 1,000 ng/kg stop-exposure group. Dose-related effects on the incidences of adrenal cortex atrophy and cytoplasmic vacuolization were also seen. (ABSTRACT TRUNCATED)
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PMID:NTP toxicology and carcinogenesis studies of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage Studies). 1662 45

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 body tissue, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves 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. TCDD is not manufactured commercially other than for scientific research purposes. The main sources of TCDD releases into the environment are from combustion and incineration; metal smelting, refining, and processing; chemical manufacturing and processing; biological and photochemical processes; and existing reservoir sources that reflect past releases. TCDD (dioxin) 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 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. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report, only the TCDD results are presented and discussed. TCDD was included because it is the reference compound for the dioxin TEF methodology. Female Harlan Sprague-Dawley rats were administered TCDD (at least 98% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. 2-YEAR STUDY: Groups of 81 or 82 female rats were administered 3, 10, 22, 46, or 100 ng TCDD/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. A stop-exposure group of 50 female rats was administered 100 ng/kg TCDD in corn oil:acetone (99:1) by gavage for 30 weeks and then just the vehicle for the remainder of the study. Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of 100 ng/kg core study and stop-exposure groups were less than those of the vehicle control group after week 13 of the study. Mean body weights of 46 ng/kg rats were less than those of the vehicle controls during year 2 of the study, and those of 22 ng/kg rats were less than those of the vehicle controls the last 10 weeks of the study. THYROID HORMONE CONCENTRATIONS: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31- and 53-week interim evaluations. At 14 weeks, there were significant decreases in serum total and free thyroxine (T4) levels and increases in serum total triiodothyronine (T3) and thyroid stimulating hormone (TSH). At 31 weeks, there were significant decreases in serum total and free T4 levels and increases in serum total T3 but no significant effect on TSH. At 53 weeks, there were significant decreases in serum total T4 levels and increases in serum total T3. There were no significant effects on total T4 or TSH levels. HEPATIC CELL PROLIFERATION DATA: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. The hepatocellular labeling index was significantly higher in the 22 ng/kg group compared to vehicle controls at 14 weeks. At the 31-week interim evaluation, the labeling indices in hepatocytes were significantly higher in all dosed groups than in the vehicle controls. At 53 weeks, labeling indices were significantly higher in the 46 and 100 ng/kg groups than in the vehicle controls. CYTOCHROME P450 ENZYME ACTIVITIES: To evaluate the expression of known dioxin-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity were evaluated at 14, 31, and 53 weeks. In addition, pentoxyresorufin-O-deethylase (PROD) activity was analyzed. Hepatic EROD, PROD, and A4H activities were significantly higher in all dosed groups relative to vehicle controls at the 14-, 31-, and 53-week interim evaluations. Pulmonary EROD was also significantly higher in all dosed groups compared to vehicle controls at 14, 31, and 53 weeks. DETERMINATIONS OF TCDD CONCENTRATIONS IN TISSUES: The tissue disposition of TCDD was analyzed in the liver, lung, fat, and blood of all animals in each group at the 14-, 31-, and 53-week interim evaluations and in 10 animals per group at the end of the 2-year study (105 weeks). The highest concentrations of TCDD were observed in the liver, followed by fat tissue. Liver and fat tissue concentrations of TCDD increased with increasing doses of TCDD. No measurable concentrations of TCDD were observed in blood from vehicle control or treated rats at any of the interim evaluations. Mean levels of TCDD in the liver and fat in the 100 ng/kg group at the end of the 2-year study were 9.3 and 3.2 ng/g, respectively. In liver tissue from the stop-exposure group, TCDD concentrations were slightly higher than those observed in the 3 ng/kg group. In the stop-exposure group, TCDD concentrations in fat were below the limits of quantitation. PATHOLOGY AND STATISTICAL ANALYSES: Absolute and/or relative liver weights were increased at 14, 31, and 53 weeks, with more severe effects occurring in the higher dosed groups. Increased liver weights correlated with increased incidences of hepatocyte hypertrophy at 14, 31, and 53 weeks. Exposure led to a treatment-related increase in hepatic toxicity with a broad spectrum of lesions. Incidences and severities of lesions increased at higher doses and longer durations of exposure. The earliest effects were increased incidences and severities of hepatocyte hypertrophy at 14 weeks. At 2 years, there was a significant increase in toxic hepatopathy characterized by increased incidences of numerous nonneoplastic liver lesions including hepatocyte hypertrophy, multinucleated hepatocytes, altered hepatocellular foci, inflammation, pigmentation, diffuse fatty change, necrosis, portal fibrosis, oval cell hyperplasia, bile duct hyperplasia, bile duct cysts, cholangiofibrosis, and nodular hyperplasia At 2 years, the incidence of hepatocellular adenoma was significantly increased in the 100 ng/kg core study group. Dose-related increased incidences of cholangiocarcinoma were seen in core study rats administered 22 ng/kg or greater. The highest incidence of cholangiocarcinoma was seen in the 100 ng/kg core study group and included a significant number of animals with multiple cholangiocarcinomas. Two cholangiocarcinomas and two hepatocellular adenomas were seen in the 100 ng/kg stop-exposure group. Two hepatocholangiomas were seen in the 100 ng/kg core study group, and one cholangioma was seen in the 100 ng/kg stop-exposure group. In the lung, the incidence of cystic keratinizing epithelioma of the lung was significantly increased at 2 years in the 100 ng/kg core study group. Nonneoplastic effects in the lung included increased incidences of bronchiolar metaplasia. The incidence of gingival squamous cell carcinoma of the oral mucosa was significantly increased in the 100 ng/kg core study group at 2 years and was accompanied by an increased incidence of gingival squamous hyperplasia. At 2 years, the incidence of squamous cell carcinoma of the uterus in the 46 ng/kg group was significantly increased, and there were two squamous cell carcinomas in the 100 ng/kg stop-exposure group. At 2 years, one acinar adenoma and two acinar cell carcinomas of the pancreas were seen in the 100 ng/kg core study group; one acinar carcinoma was seen in the 100 ng/kg stop-exposure group. The incidences of acinar cell adenoma or carcinoma (combined) exceeded the historical vehicle control range. Nonneoplastic effects in the lung included acinar cytoplasmic vacuolization, chronic active inflammation, acinar atrophy, and arterial chronic active inflammation. (ABSTRACT TRUNCATED)
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PMID:NTP technical report on the toxicology and carcinogenesis studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in female Harlan Sprague-Dawley rats (Gavage Studies). 1683 33

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 human tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves 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. 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) is not manufactured commercially other than for scientific research purposes. The main sources of PeCDF releases into the environment are from combustion and incineration sources. PeCDF 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 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. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report only the results of the present PeCDF study are presented and discussed. Female Harlan Sprague-Dawley rats were administered PeCDF (at least 97% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. 2-YEAR STUDY: Groups of 81 female rats were administered 6, 20, 44, 92, or 200 ng PeCDF/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. A stop-exposure group was administered 200 ng/kg PeCDF in corn oil:acetone (99:1) by gavage for 30 weeks and then the vehicle for the remainder of the study. The PeCDF in this study was at least 97% pure. Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of the 200 ng/kg core and stop-exposure groups were less than those of the vehicle controls during year 2 of the study. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31- and 53-week interim evaluations. There were significant decreases in total serum thyroxine (T(4)) levels at the 14-week interim evaluation. There were no significant differences observed in serum free T(4), total triiodothyronine (T(3)), or thyroid stimulating hormone (TSH) at 14 weeks. At both 31 and 53 weeks, there were treatment-related decreases in free and total T(4) concentrations and increases in serum T(3) levels. Serum TSH levels in dosed groups at 31 and 53 weeks were not significantly different than in the vehicle controls. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine (BrdU) was conducted at the 14-, 31-, and 53-week interim evaluations. At 14 and 53 weeks, hepatocyte BrdU-labeling indices were significantly higher in the 200 ng/kg groups compared to time-matched vehicle controls. No significant differences were observed between the dosed groups and vehicle controls at 31 weeks. Cytochrome P450 Enzyme Activities: To evaluate the expression of known dioxin-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity were evaluated at the 14-, 31-, and 53-week interim evaluations. Hepatic EROD and A4H activities were significantly higher in all groups administered PeCDF relative to the vehicle controls at all three interim evaluations. Pulmonary EROD was also significantly higher in all dosed groups compared to vehicle controls at 14, 31, and 53 weeks. Determinations of PeCDF Concentrations in Tissues: The tissue disposition of PeCDF was analyzed in the liver, lung, fat, and blood of all animals at the 14-, 31-, and 53-week interim evaluations, and in 10 animals per group at the end of the 2-year study (105 weeks). In the liver of vehicle controls, PeCDF concentrations were detectable at 105 weeks. Measurable concentrations of PeCDF were not detected in fat or lung from vehicle control rats at any of the interim evaluations or at 105 weeks. Hepatic and fat concentrations were higher in groups with increasing doses of PeCDF, demonstrating a dose-related increase in tissue burden of PeCDF at each time point. No measurable concentrations of PeCDF were detected in the lungs of vehicle controls or any of the dosed groups at 14 weeks or in the lungs of the vehicle control group at 31, 53, and 105 weeks, or the 6 ng/kg group at 31 and 53 weeks. In groups with measurable levels, PeCDF concentrations were higher with respect to increasing doses. Mean levels of PeCDF in the liver, fat, lung, and blood in the 200 ng/kg group at the end of the 2-year study were 500 ng/g, 7.75 ng/g, 0.28 ng/g and 0.04 ng/mL, respectively. Negligible PeCDF concentrations were observed in blood of the 200 ng/kg group at 53 weeks and the 92 and 200 ng/kg groups at 105 weeks. In liver and fat from the stop-exposure group, the PeCDF concentrations were between the levels observed in the 6 and 20 ng/kg groups. In the stop-exposure group, PeCDF concentration in lung was comparable to levels observed in the 6 ng/kg group. No measurable concentrations were observed in blood from the stop-exposure group. Pathology and Statistical Analyses: There were dose-dependent increases in both absolute and relative liver weights at 4, 31, and 53 weeks, and these tended to correlate with increased incidences of hepatocellular hypertrophy. In the liver at 14 weeks, the only significant effect was an increase in the incidences of hepatocellular hypertrophy. At 53 weeks, there were significant increases in the incidences of hepatocellular hypertrophy and pigmentation. At 2 years, there were significant dose-dependent trends for increased incidences of hepatocellular adenoma and cholangiocarcinoma of the liver. A significant dose-dependent increase in hepatic toxicity was observed and was characterized by increased incidences of numerous nonneoplastic lesions including hepatocellular hypertrophy, multinucleated hepatocytes, oval cell hyperplasia, diffuse fatty change, pigmentation, nodular hyperplasia, eosinophilic foci, hepatocellular necrosis, bile duct hyperplasia, bile duct fibrosis, cholangiofibrosis, and toxic hepatopathy. At 2 years, three gingival squamous cell carcinomas of the oral mucosa were seen in the 200 ng/kg core and stop-exposure groups, two occurred in the 6 ng/kg group, and one occurred in each of the vehicle control, 20 ng/kg, and 92 ng/kg groups. Gingival squamous hyperplasia occurred in all groups including the vehicle controls, with increasing incidences in groups administered 44 ng/kg or greater. The incidence of carcinoma of the uterus was marginally increased in the 92 ng/kg group at 2 years. Increased incidences of chronic active inflammation of the uterus were observed in all dosed groups, and the incidence in the 200 ng/kg stop-exposure group was greater than those in the vehicle control and 200 ng/kg core study groups. Increased incidences of squamous metaplasia of the uterus occurred in all dosed groups. In the 200 ng/kg stop-exposure group, the incidence of squamous metaplasia was significantly greater than that in the vehicle controls, but was lower than that in the 200 ng/kg core study group. At 14-weeks, lung weights were significantly increased in the 200 ng/kg group compared to the vehicle controls. A single occurrence of a multiple cystic keratinizing epithelioma of the lung was observed in the 200 ng/kg core study group. There were increases in the incidences of bronchiolar metaplasia of the alveolar epithelium and sporadic incidences of squamous metaplasia. One pancreatic acinar adenoma and one pancreatic acinar carcinoma were each observed in the 92 ng/kg group and in the 200 ng/kg stop-exposure group at 2 years. Significantly increased incidences of acinar cytoplasmic vacuolization and arterial chronic active inflammation and increased severity of chronic active inflammation were observed in the 200 ng/kg core study group. Numerous nonneoplastic effects were seen in other organs including thyroid follicular cell hypertrophy, thymic atrophy, adrenal cortex cystic degeneration, nephropathy, cardiomyopathy, and squamous hyperplasia of the forestomach.
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PMID:Toxicology and carcinogenesis studies of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (Cas No. 57117-31-4) in female Harlan Sprague-Dawley rats (gavage studies). 1716 Jan 3

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 bio-concentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in body tissues, mainly adipose, 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, 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. 2-YEAR STUDY: The 2-year study of a binary mixture of PCB 126 and PCB 153 was designed to assess the carcinogenicity of a constant ratio mixture of PCB 126 and PCB 153. In addition, varying ratio mixture groups were used to assess the impact of increasing PCB 153 on the carcinogenicity of PCB 126. Dose groups were divided into two study arms (Figure 1). TCDD equivalent (TEQ) doses are based on the PCB 126 doses after adjustment for the PCB 126 TEF of 0.1. Groups of 81 (Groups 2, 3, 5, and 7) or 80 (Groups 4 and 6) female rats received a mixture of PCB 126 and PCB 153 in corn oil:acetone (99:1) by gavage 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle only and served as the vehicle control (Group 1). Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of Groups 4 and 5 were generally less than those of the vehicle controls after week 25. The mean body weights of Group 6 were less after week 12, and those of Group 7 were less after week 8. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. In the constant ratio groups, serum total thyroxine (T(4)) and free T(4) generally showed a treatment-related decrease relative to controls. Serum total triiodothyronine (T(3)) exhibited a treatment-related increase at the 14-, 31-, and 53-week interim evaluations, but serum thyroid stimulating hormone (TSH) levels were increased at the 14-week time point only. In the varying ratio groups, the decrease in total and free T(4) was more pronounced in those groups dosed with the increasing proportion of PCB 153 at the 31- and 53-week time points. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. At 31 and 53 weeks, a significant increase in the hepatocellular labeling index occurred in Group 7. In the varying ratio groups, the labeling index at the 53-week interim time point was significantly higher in Group 6, which had the highest proportion of PCB 153 compared to the other varying ratio groups. Cytochrome P450 Enzyme Activities: To evaluate the expression of known PCB 126-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations. In addition, PCB 153-inducible CYP2B-associated 7-pent-oxyresorufin-O-dealkylase (PROD) activity was analyzed. In the constant ratio Groups 2, 3, 5, and 7, hepatic and pulmonary EROD (CYP1A1) activities, hepatic A4H (CYP1A2) activities, and hepatic PROD (CYP2B) activities were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. In the varying ratio groups, hepatic EROD, A4H, and PROD activities at 14 weeks were higher in groups receiving a greater proportion of PCB 153 in the PCB mixture. At 31 and 53 weeks, hepatic CYP1A1 and CYP1A2 enzyme activities in Group 6 were generally lower than in Groups 4 and 5. Determinations of PCB 126 and PCB 153 Concentrations in Tissues: Concentrations of PCB 126 and PCB 153 were determined in fat, liver, lung, and blood at the 14-, 31-, and 53-week interim evaluations and at the end of the 2-year study (105 weeks). PCB 126 was not detectable in vehicle control animals, but increased with increasing dose of PCB 126 and duration of exposure; the highest concentrations were found in liver and fat, and lower levels were seen in lung and blood. Increasing the proportion of PCB 153 in the mixture relative to PCB 126 led to a general decrease in the amount of PCB 126 in liver and lung at the later time points, whereas in fat and blood, there was generally either no effect of PCB 153 on the disposition of PCB 126, or there was an increase in the amount of PCB 126 in the tissue. In vehicle control animals, PCB 153 was detectable in the fat at all time points, in the lung at all time points except 53 weeks, and in the liver and blood at 2 years. PCB 153 was measurable in all examined tissues of treated animals, with the highest concentrations found in fat at the end of the 2-year study in groups administered the highest doses of PCB 153. Pathology and Statistical Analyses -- Constant Ratio Mixture of PCB 126 and PCB 153: At 14, 31, and 53 weeks, the absolute and relative liver weights of all dosed groups were generally greater than those of the vehicle controls. Exposure to the PCB mixture led to significant toxicity in the liver. At 14 weeks, the incidences of several nonneoplastic liver lesions were increased compared to the vehicle controls including hepatocyte hypertrophy, pigmentation, multinucleated hepatocytes, and diffuse fatty change. The spectrum and severity of effects increased with dose and duration of exposure. At the end of the 2-year study, there were significantly increased incidences and severities of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, diffuse and focal fatty change, eosinophilic focus, nodular hyperplasia, cholangiofibrosis, oval cell hyperplasia, bile duct cysts, bile duct hyperplasia, necrosis, and portal fibrosis. Significantly increased incidences of hepatocellular adenoma, cholangiocarcinoma, and hepatocholangioma were observed in the study. In addition, two animals in the highest dose group had hepatocellular carcinoma. The incidences of these lesions generally exceeded the historical vehicle control ranges. At 2 years, a significantly increased incidence of cystic keratinizing epithelioma of the lung was observed in Group 7. In addition, single occurrences of squamous cell carcinoma were seen in the top two dose groups. Nonneoplastic effects whose incidences were increased in the lung included bronchiolar metaplasia of the alveolar epithelium and squamous metaplasia. Significantly increased incidences of squamous cell carcinoma (gingival) of the oral mucosa were seen at the end of the 2-year study and were accompanied by increased incidences of gingival squamous hyperplasia. In the pancreas at 53 weeks, the incidence of acinar cytoplasmic vacuolization was significantly increased in the highest dose group. At 2 years, increased incidences of acinar atrophy and acinar cytoplasmic vacuolization were seen in addition to pancreatic acinar neoplasms in dosed groups. In Groups 5 and 7, these incidences exceeded the historical vehicle control ranges. In the uterus at 2 years, there was a marginal increase in the incidence of squamous cell carcinoma in Group 5. Numerous nonneoplastic effects were seen in other organs at the interim time points including atrophy of the thymus and follicular cell hypertrophy of the thyroid gland. These responses were also affected by administration of the mixture of PCB 126 and PCB 153 at the end of the 2-year study and were accompanied by additional nonneoplastic responses in numerous organs including atrophy of the adrenal cortex and cortical hyperplasia, severity of nephropathy, and incidences of pigmentation of the kidney. Other nonneoplastic lesions that were treatment related were forestomach hyperplasia, hyperplasia of the nasal respiratory epithelium, metaplasia of the olfactory epithelium, and ectasia of the mandibular lymph node. Varying Ratio Mixture of PCB 126 and PCB 153: An effect of increasing the proportion of PCB 153 in the PCB mixture was seen in several tissues, most notably in the liver. Treatment-related nonneoplastic effects seen across the varying ratio groups were generally the same as those seen in the constant ratio groups. In general there was a positive effect of PCB 153 in the mixture on the incidences and severities of these lesions with higher incidences and higher severities being seen in Group 6, which had the highest proportion of PCB 153. (ABSTRACT TRUNCATED).
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PMID:Toxicology and carcinogenesis studies of a binary mixture of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (Cas No. 57465-28-8) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (gavage studies). 1716 Jan 4

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 body tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves 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. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) are not manufactured commercially other than for scientific research purposes. The main sources of TCDD and PeCDF releases into the environment are from metal smelting, refining, and processing; combustion and incineration sources; chemical manufacturing and processing; biological and photochemical processes; and existing reservior sources that reflect past releases. PCB mixtures were commercially produced and used in the electric power industry as dielectric insulating fluids in transformers and capacitors and used in hydraulic fluids, plastics, and paints. TCDD, PeCDF, and PCB 126 were selected for study by the National Toxicology Program as part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLC's, structurally related PCBs, and mixtures of these compounds. Female Harlan Sprague-Dawley rats were administered a mixture of TCDD, PeCDF, and PCB 126 (henceforth referred to as the TEF mixture) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report only the results of the present study of the mixture of TCDD, PeCDF, and PCB 126 are presented and discussed. 2-YEAR STUDY: Groups of 81 female rats were administered 10, 22, 46, or 100 ng toxic equivalents (TEQ)/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. Actual doses used for each compound in the mixture were: for 10 ng TEQ/kg: 3.3 ng/kg TCDD, 6.6 ng/kg PeCDF, and 33.3 ng/kg PCB 126; for 22 ng TEQ/kg: 7.3 ng/kg TCDD, 14.5 ng/kg PeCDF, and 73.3 ng/kg PCB 126; for 46 ng TEQ/kg: 15.2 ng/kg TCDD, 30.4 ng/kg PeCDF, and 153 ng/kg PCB 126; and for 100 ng TEQ/kg: 33 ng/kg TCDD, 66 ng/kg PeCDF, and 333 ng/kg PCB 126. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control group. Mean body weights of the 22 and 46 ng TEQ/kg groups were less than those of the vehicle control groups after week 69 of the study. Mean body weights of the 100 ng TEQ/kg group were less than those of the vehicle control group after week 37 of the study. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone concentrations were evaluated at the 14-, 31-, and 53-week interim evaluations. At 14, 31, and 53 weeks, there were dose-dependent reductions in total serum and free thyroxine concentrations. There were dose-dependent increases in serum triiodothyronine concentrations at 14 and 31 weeks. No changes in serum thyroid stimulating hormone concentrations were observed at any time point. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the interim evaluations. At 14 weeks, no effects on the hepatocellular labeling index were observed in the dosed groups compared to the vehicle controls. At 31 and 53 weeks, the hepatocellular labeling index was significantly higher in the 46 and 100 ng TEQ/kg groups compared to the vehicle controls. Cytochrome P450 Enzyme Activities: To evaluate the expression of known dioxin-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity were evaluated at the interim time points. Liver and lung EROD (CYP1A1) activities and hepatic A4H (CYP1A2) activities were significantly greater in all dosed groups than in the vehicle controls at all interim evaluations (14, 31, and 53 weeks). Determinations of TCDD, PeCDF, and PCB 126 Concentrations in Tissues: Tissue concentrations of TCDD, PeCDF, and PCB 126 were analyzed in the fat, liver, lung, and blood at each interim evaluation and at the end of the 2-year study (105 weeks). The highest concentrations of TCDD, PeCDF, and PCB 126 were observed in the liver followed by fat. Liver and fat concentrations of TCDD, PeCDF, and PCB 126 at each interim evaluation and at 105 weeks were higher in groups with increasing doses of the mixture and generally increased with duration of dosing. In the lung, PeCDF was present at detectable concentrations in the 46 and 100 ng TEQ/kg groups at 14 and 31 weeks. Measurable concentrations of TCDD and PCB 126 were observed at 14 and 31 weeks in the lung of rats in all dosed groups with the highest concentrations observed in the 100 ng TEQ/kg group. At 53 weeks, concentrations of TCDD, PeCDF, and PCB 126 in the lung generally increased with increasing dose. At 105 weeks, detectable concentrations of TCDD, PeCDF, and PCB 126 in the lung were observed in all dosed groups. In blood, TCDD and PCB 126 concentrations at 14 and 31 weeks generally increased with increasing dose. Blood concentrations of PeCDF were detectable in the 46 and 100 ng TEQ/kg groups at 14 weeks and at 22 ng TEQ/kg or greater at 31 weeks. At 53 and 105 weeks, concentrations of TCDD, PeCDF, and PCB 126 in blood generally increased with increasing dose and duration of dosing. Pathology and Statistical Analyses: Relative liver weights were significantly increased in all dosed groups at 14, 31, and 53 weeks and correlated with increased incidences of hepatocellular hypertrophy. Increasing duration of exposure led to an increase in the spectrum, incidence, and severity of nonneoplastic effects. The only significant effect at 14 weeks was increased incidences of hepatocellular hypertrophy. At 53 weeks, there was a significant effect on the incidences of hepatocellular hypertrophy, multinucleated hepatocytes, pigmentation, focal fatty change, bile duct hyperplasia, and toxic hepatopathy. At 2 years, there were significant increases in the incidences of hepatocellular adenoma and cholangiocarcinoma of the liver. There was an increase in hepatic toxicity characterized by increases in the incidences of numerous nonneoplastic lesions including hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, inflammation, diffuse fatty change, bile duct hyperplasia, oval cell hyperplasia, nodular hyperplasia, eosinophilic focus, cholangiofibrosis, bile duct cysts, necrosis, portal fibrosis, mixed cell focus, and toxic hepatopathy. In the lung, there were dose-dependent increases in the incidences of bronchiolar metaplasia of the alveolar epithelium at 53 weeks and at 2 years and squamous metaplasia at 2 years. At 2 years, there was a dose-dependent increase in the incidences of cystic keratinizing epithelioma. In the pancreas, there were increases in the incidences of numerous nonneoplastic lesions including arterial chronic active inflammation, acinar cytoplasmic vacuolization, acinar atrophy, chronic active inflammation, and duct dilatation. At 2 years, incidences of acinar adenoma or acinar carcinoma that exceeded the historical control ranges were seen in all dosed groups except the 100 ng TEQ/kg group. Treatment-related increases in the incidences of nonneoplastic lesions were seen in other organs including hyperplasia, cystic degeneration, atrophy, and cytoplasmic vacuolization of the adrenal cortex; gingival squamous hyperplasia of the oral mucosa; squamous metaplasia of the uterus; atrophy of the thymus (incidence and severity); chronic active inflammation of the ovary; nephropathy of the kidney (incidence and severity); cardiomyopathy; bone marrow hyperplasia; transitional epithelium of the urinary bladder; chronic active inflammation of the mesenteric artery; and follicular cell hypertrophy of the thyroid gland. (ABSTRACT TRUNCATED).
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PMID:Toxicology and carcinogenesis studies of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Cas No. 1746-01-6), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (Cas No. 57117-31-4), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (Cas No. 57465-28-8) in female Harlan Sprague-Dawley rats (gavage studies). 1734 95

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 body tissue, mainly adipose, 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. Mixtures of polychlorinated biphenyls (PCBs) including 3,3',4,4',5-pentachlorobiphenyl (PCB 126) and 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 mixture study was conducted as part of the dioxin TEF evaluation that 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. This study was originally a study of PCB 118 alone. However, midway through the study PCB 126 was identified as one of the minor contaminants (0.622%) of the bulk PCB 118 (98.5% pure). Given the 1,000-fold higher potency of PCB 126 for inducing dioxin-like effects (based on the TEFs for PCB 126 and PCB 118 of 0.1 and 0.0001, respectively), it was expected that the effects of administration of this compound would be due to the combined dioxin-like effects of both PCB 126 and PCB 118. Therefore, this study was reclassified as a mixture study of PCB 126 and PCB 118. 2-YEAR STUDY: Groups of female Harlan Sprague-Dawley rats were administered the PCB mixture containing PCB 126 and PCB 118 by gavage in corn oil:acetone (99:1) or vehicle alone, 5 days per week for up to 104 weeks. Dose groups are referred to by the total levels of TCDD toxic equivalents (TEQ) provided by the PCBs in the mixture in each dose group. Groups of 81 female rats were administered 7, 22, 72, or 216 ng TEQ/kg; a group of 86 female rats was administered 360 ng TEQ/kg; and a group of 81 female rats was administered the corn oil:acetone vehicle alone. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. No animals in the 360 ng TEQ/kg group were examined at 53 weeks. A group of 50 female rats was administered 360 ng TEQ/kg for 30 weeks and then the vehicle alone for the remainder of the study. Nominal doses of PCB 118 and levels of PCB 126 in each dose group used were: 7 ng TEQ/kg dose group: 62 ng/kg PCB 126 and 10 microg/kg PCB 118 7 ng TEQ/kg dose group: 62 ng/kg PCB 126 and 10 microg/kg PCB 118 22 ng TEQ/kg dose group: 187 ng/kg PCB 126 and 30 microg/kg PCB 118 72 ng TEQ/kg dose group: 622 ng/kg PCB 126 and 100 microg/kg PCB 118 216 ng TEQ/kg dose group: 1,866 ng/kg PCB 126 and 300 microg/kg PCB 118 360 ng TEQ/kg dose group: 3,110 ng/kg PCB 126 and 500 microg/kg PCB 118 No animals in the 216 or 360 ng TEQ/kg core study groups survived to the end of the study, and survival in the 360 ng TEQ/kg stop-exposure group was significantly less than in the vehicle control group. Mean body weights of 72 ng TEQ/kg rats were less than those of the vehicle controls after week 33 of the study, and mean body weights of the 216 and 360 ng TEQ/kg core study rats and the 360 ng TEQ/kg stop-exposure group rats were less than those of the vehicle controls throughout most of the study. Clinical findings related to the administration of the binary mixture of PCB 126 and PCB 118 included abnormal breathing, thinness, and ruffled hair. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. Total thyroxine (T4) and free T4 were significantly lower in most dose groups than in vehicle controls at the 14- and 31-week interim evaluations. Serum T3 was significantly lower in the 360 ng TEQ/kg group compared to vehicle controls at 31 weeks only. TSH levels were higher in the 216 and 360 ng TEQ/kg groups than in vehicle controls at 31 weeks only. Hepatic Cell Proliferation Data To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. Labeling indices were elevated at doses above 216 ng TEQ/kg at 31 weeks and at doses above 72 ng TEQ/kg at 53 weeks. Cytochrome P450 Enzyme Activities: CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations to evaluate the expression of known dioxin-responsive genes. In addition, CYP2B-associated pentoxyresorufin-O-deethylase (PROD) activity was also analyzed. Hepatic and pulmonary EROD (CYP1A1) activity, hepatic A4H (CYP1A2) activity, and hepatic PROD (CYP2B1) activity were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. Determinations of PCB 126 and PCB 118 Concentrations in Tissues: The tissue disposition of PCB 126 and PCB 118 was analyzed in the liver, lung, fat, and blood of up to 10 rats in each group at the 14-, 31-, and 53-week interim evaluations, except for the 360 ng TEQ/kg group at 53 weeks. The tissue disposition of PCB 126 and PCB 118 was also analyzed in 10 rats per group at the end of the 2-year study in the vehicle control, 7, 22, and 72 ng TEQ/kg core study groups and the 360 ng TEQ/kg stop-exposure group. Detectable concentrations of PCB 126 and PCB 118 were observed in the liver, fat, lung, and blood. The highest levels of PCB 126 were seen in the liver whereas the highest levels of PCB 118 were seen in the fat. In general, tissue concentrations increased with increasing doses of the mixture and increasing duration of exposure. Hepatic levels of PCB 126 and PCB 118 in the 72 ng TEQ/kg group at the end of the 2-year study were 284 ng/g and 3,769 ng/g, respectively. On a TCDD equivalents basis this corresponds to 28 ng TEQ/g and 0.4 ng TEQ/g for PCB 126 and PCB 118, respectively. Cessation of administration of the mixture in the stop-exposure group led to declines in the tissue concentrations of both PCB 126 and PCB 118 to levels comparable to those observed in the 7 ng TEQ/kg group at the end of the 2-year study. Pathology and Statistical Analyses: At 14, 31, and 53 weeks, liver weights were significantly increased in treated groups with more pronounced effects occurring in the higher dose groups. At 14 weeks, hepatocyte hypertrophy and pigmentation were seen at doses less than 72 ng TEQ/kg. Exposure to the PCB mixture led to significant toxicity in the liver. At higher doses, the incidences of toxic hepatopathy were increased as indicated by increased incidences of multinucleated hepatocytes and diffuse fatty change. At 31 weeks, most rats in the 216 and 360 ng TEQ/kg groups had multiple hepatic nonneoplastic lesions. At 53 weeks all animals administered 216 ng TEQ/kg had multiple nonneoplastic lesions. The spectrum of effects and the severity of effects at the interim and 2-year time points increased with dose and duration of exposure. At the end of the 2-year study in all dosed groups, there were significantly increased incidences and severity of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, toxic hepatopathy, diffuse fatty change, nodular hyperplasia, centrilobular fibrosis, cholangiofibrosis, oval cell hyperplasia, bile duct cyst, bile duct hyperplasia, and portal fibrosis. There were also increased incidences of hepatocyte glandular structures, necrosis, centrilobular degeneration, eosinophilic focus, and metaplasia. The incidences of cholangiocarcinoma (multiple and/or single) were significantly increased in groups administered 22 ng TEQ/kg or greater at 2 years. The incidences of hepatocellular adenoma were also significantly increased in the 216 and 360 ng TEQ/kg core study groups. In addition, single occurrences of hepatocholangioma, cholangioma, or hepatocellular carcinoma were observed in some dosed groups administered 72 ng TEQ/kg or greater. In the lung at 53 weeks, the incidences of cystic keratinizing epithelioma and bronchiolar metaplasia were significantly increased in the 216 ng TEQ/kg group. (ABSTRACT TRUNCATED).
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PMID:Toxicology and carcinogenesis studies of a binary mixture of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (Cas No. 57465-28-8) and 2,3',4,4',5-pentachlorobiphenyl (PCB 118) (Cas No. 31508-00-6) in female Harlan Sprague-Dawley rats (gavage studies). 1734 96


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