Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats

Kociba, R.J.; Keyes, D. G.; Beyer, J; Carreón, Rita; Wade, C. E.; Dittenber, D. A.; Kalnins, R.; Frauson, L.E.; Park, C.N.; Barnard, Stephen D.; Hummel, Richard A.; Humiston, C. G.

doi:10.1016/0041-008x(78)90075-3

Cited by 1,009 publications

(440 citation statements)

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“…Additionally, it has been proposed that DNA repair proteins can be impaired by mutations caused by the slow accumulation of DNA adducts over a long period of time [37]. This argument is supported by the findings from previous studies that reported sustained DNA adduct (i.e., 8-OH-dG) accumulation, toxicity, and carcinogenesis [12,36,37,41].…”

Section: Resultsmentioning

confidence: 68%

Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons

Jeong

Walker

Burgin

et al. 2008

Free Radical Biology and Medicine

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Oxidative DNA damage is one of the key events thought to be involved in mutation and cancer. The present study examined the accumulation of M 1 dG, 3-(2′-deoxy-β-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one, DNA adducts after single dose or one-year exposure to polyhalogenated aromatic hydrocarbons (PHAH) in order to evaluate the potential role of oxidative DNA damage in PHAH toxicity and carcinogenicity. The effect of PHAH exposure on the number of M 1 dG adducts was explored initially in female mice exposed to a single dose of either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or a PHAH mixture. This study demonstrated that a single exposure to PHAH had no significant effect on the number of M 1 dG adducts compared to the corn oil control group. The role of M 1 dG adducts in polychlorinated biphenyl (PCB) induced toxicity and carcinogenicity was further investigated in rats exposed for a year to PCB 153, PCB 126, or a mixture of the two. PCB 153, at doses up to 3000 μg/kg/d, had no significant effect on the number of M 1 dG adducts in liver and brain tissues from the exposed rats compared to controls. However, 1000 ng/kg/ d of PCB 126 resulted in M 1 dG adduct accumulation in the liver. More importantly, co-administration of equal proportions of PCB 153 and PCB 126 resulted in dose-dependent increases in M 1 dG adduct accumulation in the liver from 300-1000 ng/kg/d of PCB 126 with 300-1000 μg/kg/d of PCB 153. Interestingly, the co-administration of different amounts of PCB 153 with fixed amounts of PCB 126 demonstrated more M 1 dG adduct accumulation with higher doses of PCB 153. These results are consistent with the results from cancer bioassays that demonstrated a synergistic effect between PCB 126 and PCB 153 on toxicity and tumor development. In summary, the results from the present study support the hypothesis that oxidative DNA damage plays a key role in toxicity and carcinogenicity following long-term PCB exposure.

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Section: Resultsmentioning

confidence: 68%

Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons

Jeong

Walker

Burgin

et al. 2008

Free Radical Biology and Medicine

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“…Asphalt workers are potentially exposed to organic solvents, and asphalt also contains different polyaromatic hydrocarbons with carcinogenic properties. In animal studies, dioxins have induced HCC among other cancer types (van Miller et al, 1977;Kociba et al, 1978). They are found as impurities in phenoxy acids and chlorophenols.…”

Section: Discussionmentioning

confidence: 99%

Aetiological aspects on primary liver cancer with special regard to alcohol, organic solvents and acute intermittent porphyria - an epidemiological investigation

Hardell¹,

Bengtsson²,

Jonsson³

et al. 1984

Br J Cancer

179

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Some environmental factors of possible aetiological importance for primary liver carcinoma (PLC) in males were analysed in a case-control study including 83 cases of hepatocellular carcinoma (HCC), 15 cases of intrahepatic cholangiocellular carcinoma (CC), 3 cases of haemangiosarcoma and 1 case of unspecified sarcoma in the liver--102 cases in total. Two matched controls were used in each case. One case with haemangiosarcoma was exposed to polyvinyl chloride. The case with unspecified soft-tissue sarcoma was exposed to phenoxy acids. A 4-fold increase in the risk of HCC was seen in alcoholics, and regular drinking gave a 3-fold increase in the risk. Exposure to organic solvents gave a 2-fold increase in the risk of HCC. No increased risk was observed for cases exposed to various other chemicals. Three cases of HCC had a previous diagnosis of porphyria acuta intermittens (PAI), versus no control. Six cases of HCC had a previous diagnosis of porphyria acuta intermittens (PAI), versus no control. Six cases with PLC had polyphyria cutanea tarda (PCT) which in 4 cases was related to alcoholism and in one case to haemochromatosis.

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“…In comparison, the data from earlier animal studies were clearer and more intriguing. While chronic administration of TCDD to female rats enhanced the tumor incidence in liver and also many other organ sites, this treatment inhibited the formation of spontaneous tumors in the uterus, mammary gland, and pituitary [11][12][13], which are target tissues for endogenous estrogens.…”

Section: Introductionmentioning

confidence: 98%

“…TCDD is a developmental and reproductive toxicant and causes immunotoxicity, dermal and hepatic toxicity, and a plethora of endocrine-disrupting effects [3][4][5][6][7][8]. In addition, TCDD is also considered a carcinogen, increasing the incidence of a variety of cancers in humans as well as in laboratory animals [4,[9][10][11][12][13]. Tumors of the breast are common in humans, but at present epidemiological data are conflicting with respect to the link between TCDD exposure and the risk of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Zhu

Gallo

Burger

et al. 2008

Toxicology and Applied Pharmacology

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We studied the effect of administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by i.p. injection once every two weeks in combination with a high-fat (HF) diet for 8 or 16 weeks on the body and organ weight changes as well as on the hepatic enzyme activity for estrogen metabolism in C3H/HeN female mice. Administration of TCDD at 100 μg/kg b.w. once every two weeks for 8 weeks increased the body weight by 46% in the HF diet-fed animals, but not in the regular diet-fed animals. This is the first observation suggesting that TCDD, a potent Ah receptor agonist, may have an obesity-inducing effect in animals fed a HF diet. While TCDD increased liver weight and decreased thymus weight in animals, these effects were enhanced by feeding animals a HF diet. Metabolism studies showed that TCDD administration for 8 or 16 weeks increased the liver microsomal activity for the 2-and 4-hydroxylation of 17β-estradiol in animals fed a control diet, but surprisingly not in animals fed a HF diet. Treatment with TCDD dose-dependently increased the hepatic activity for the O-methylation of catechol estrogens in both control and HF diet-fed animals, and it also decreased the levels of liver microsomal sulfatase activity for hydrolysis of estrone-3-sulfate. TCDD did not significantly affect the hepatic enzyme activity for the glucuronidation or esterification of endogenous estrogens. It is suggested that enhanced metabolic inactivation of 1 This study was supported, in part, by a grant from the American Cancer Society (RSG-02-143-01-CNE to BTZ) and also by grants from the NIH (CA92391, CA97109 and ES05022). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. endogenous estrogens by hepatic estrogen-metabolizing enzymes in TCDD-treated, control diet-fed animals contributes importantly to the reduced incidence of estrogen-associated tumors in animals treated with TCDD. NIH Public Access

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Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats

Cited by 1,009 publications

References 5 publications

Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons

Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons

Aetiological aspects on primary liver cancer with special regard to alcohol, organic solvents and acute intermittent porphyria - an epidemiological investigation

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

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