Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains (original) (raw)
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Molecular Nutrition & Food Research, 2006
The cancer bioassay for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) conducted by the Dow Chemical company in the mid 70s been used extensively for conducting quantitative cancer risk assessments for human exposure to TCDD. More recently the National Toxicology Program (NTP) conducted a cancer bioassay of similar design as part of its evaluation of the dioxin TEF methodology. This report compares the design and the results of these two cancer bioassays. This comparison confirms, in most cases, previously published and widely used carcinogenic response characteristics with respect to dose, time course, organ selectivity, tumor type and maximum intensity of TCDDinduced carcinogenicity and toxicity in the Sprague-Dawley rat. Specifically increased in the incidences of neoplasms were seen in both studies in the liver, lung and oral mucosa. The most notable difference was the significant increase in the incidence of cholangiocarcinoma of the liver seen in the NTP study but not in the Dow study. The experimental designs for the two studies are similar but some protocol parameters differed such as vehicle, dosing schedule, diet and rat sub-strain utilized. Differences in the shapes of the dose response curves for several neoplasms were noted between the studies, with the NTP study showing non-linearity for all neoplasms. This may result from differences in the experimental protocols as well as divergence in the biological behavior of the different stocks of Sprague-Dawley rat strains used.
Toxicology and Applied Pharmacology, 2003
Line A, B, and C rats were selectively bred from TCDD-resistant Han/Wistar (Kuopio; H/W) and TCDD-sensitive Long-Evans (Turku/AB; L-E) rats. Line A rats are the most resistant to TCDD acute lethality followed by line B and line C rats. The resistance in line A rats is associated with a mutated H/W-type aryl hydrocarbon receptor (Ahr) allele (Ahr hw ) and in line B rats the resistance is associated with an allele of an unknown gene B (B hw ), while line C rats are almost as sensitive to TCDD as L-E rats. The dose-responses of characteristic short-term effects (day 8 postexposure) of TCDD were used to evaluate the efficacy (magnitude of effect) and potency relationships between these lines. Line A rats showed similar efficacies as line C (line A:line C efficacy ratio more than 0.7) for thymus weight, EROD activity, and incisor tooth defects. In contrast, efficacies in line A were decreased (efficacy ratios 0.19 -0.37) for body weight change, serum bilirubin, and FFA levels, and serum ASAT activity. For most endpoints the efficacies in line B rats seem to be lower than in line C rats. The potencies were close to each other in line A and B rats, but somewhat lower than in line C rats. The results support our previous concept of two different AHR-mediated signaling pathways leading to dioxin type I and type II endpoints. Rats with the Ahr hw/hw genotype show a markedly decreased efficacy for type II endpoints, but B hw allele had only a minor effect on efficacies for most endpoints. Both H/W-type resistance alleles also decreased the potency of TCDD. However, the potency differences in short-term toxicity seem not to explain, at least alone, the differences seen in acute lethality among the rat lines.
Cancer Letters, 1996
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a more potent hepatocarcinogen in female than in male or ovariectomized rats. A possible mechanism for this increased sensitivity is through enhanced metabolic activation of estrogens by TCDDinduced enzymes leading to oxidative damage in the cell. As a marker for oxidative DNA damage, 8-oxo-deoxyguanosine (8oxo-dG) was quantitated in livers of intact and ovariectomized Sprague-Dawley rats chronically treated with TCDD (125 ng/kg per day) with and without diethylnitrosamine as initiator. Elevated levels of 8-oxo-dG were detected in a significantly greater number of the intact compared to ovariectomized TCDD-treated rats. Expression of CYP1B1 mRNA, a newly identified cytochrome P450 with proposed estrogen hydroxylase activity, was highly induced by TCDD. The results are consistent with the hypothesis that increased metabolism of endogenous estrogens to catechols by TCDD-induced enzymes may lead to increased oxidative DNA damage and hence contribute to TCDD-mediated hepatocarcinogenicity in female rats. contaminants . It is one of the most potent carcinogens tested in laboratory animals and is a multi-site and multi-species carcinogen in both sexes of rodents . As such it is considered a probable human carcinogen and the hepatic tumor incidence in female rats is widely used as the basis for human risk-assessment. Female rats are considerably more sensitive to the hepatocarcinogenic action of TCDD than male or ovariectomized rats . This
The Effect of TCDD Dioxin on the Rat Liver in Biochemical and Histological Assessment
Folia Biologica, 2009
Eighteen male Wistar rats were divided into 3 groups of 6 animals each. Two groups received different intraperitoneal doses of TCDD (0.75 and 8Fg) in DMSO solution and the third group (control) received only DMSO on days 0, 7 and 14. On day 21 the animals were sacrificed, and then blood tests, pathological examination and CYP1A1 activity measurement were performed. In rats that received a high dose of dioxin (8 Fg) hepatic lobules revealed parenchymal degeneration and vacuolization of hepatocytes was observed, and also an increased CYP reaction was found in central parts of lobules, around the central vein. The reaction in control and low dose groups was weak. The resorufin level was significantly (P<0.05) higher in the group receiving a low dose of dioxin as compared to the control group. The study confirmed that TCDD damages the rat liver in a dose-dependent manner. Administration of high TCDD doses causing major liver damage also damaged CYP1A1 (based on higher resorufin levels in epiluminescence). TCDD activates CYP1A1, which was confirmed by increased immunohistochemical reactivity of central areas of hepatic lobules.
Toxicological Sciences, 1989
rodibenzo-p-dioxin (TCDD) is unknown. It was recently discovered that two strains of rat, Long-Evans (L-E) and Han/Wistar (H/W), differ widely in susceptibility to TCDD. Employing this strain divergence as a probe, the present study set out to assess the role of various biochemical and morphological effects in TCDD lethality. In the main experiment, the rats were treated once ip with 0,5,50, or (H/W) 500 &kg TCDD and killed 1 to 16 days postexposure. Several target organs were evaluated by light microscopy and a number of serum lipid and carbohydrate parameters as well as a few major regulatory hormones were analyzed. The results demonstrated that most alterations caused by TCDD were essentially similar in both strains. TCDD reduced circulating thyroxine to a slightly greater extent and more permanently in the sensitive L-E strain. Moreover, a highly significant interaction on thyroid-stimulating hormone was found among strain, dose, and time. Serum concentrations of corticosterone and free fatty acids were increased only in the L-E rats given 50 &kg TCDD, i.e., at an apparent LDlOO dose level for this strain. Yet, the most striking interstrain difference was seen in the liver which was distinctly affected after Day 4 in L-E rats given 50 pg/kg TCDD but only marginally affected in rats from any H/W group. The lesion, while showing no necrotic cell changes, was suggestive of plasma membrane damage, possibly reflecting the production of free radicals. The relation of the findings to possible mechamsms of TCDD action is &scussed. Q 1989 society o~To~~~~I~. 2 , 3 ,7 ,8-Tetrachlorodibenzo p-dioxin Knutson, 1982) that arises as an unwanted (TCDD) is a toxicological prototype of halo-by-product in several thermochemical progenated aromatic hydrocarbons (Poland and cesses, for example, waste combustion (Wakimoto and Tatsukawa, 1985; Benfenati et ' Preliminary results were published in Toxicol. Lett. al., 1986). It has also been detected in auto-31(Suppl.), Pl-46 (1986) and in Pharmacol. Toxicol. mobile exhaust (Marklund et al., 1987).
Fundamental and applied toxicology, 1989
rodibenzo-p-dioxin (TCDD) is unknown. It was recently discovered that two strains of rat, Long-Evans (L-E) and Han/Wistar (H/W), differ widely in susceptibility to TCDD. Employing this strain divergence as a probe, the present study set out to assess the role of various biochemical and morphological effects in TCDD lethality. In the main experiment, the rats were treated once ip with 0,5,50, or (H/W) 500 &kg TCDD and killed 1 to 16 days postexposure. Several target organs were evaluated by light microscopy and a number of serum lipid and carbohydrate parameters as well as a few major regulatory hormones were analyzed. The results demonstrated that most alterations caused by TCDD were essentially similar in both strains. TCDD reduced circulating thyroxine to a slightly greater extent and more permanently in the sensitive L-E strain. Moreover, a highly significant interaction on thyroid-stimulating hormone was found among strain, dose, and time. Serum concentrations of corticosterone and free fatty acids were increased only in the L-E rats given 50 &kg TCDD, i.e., at an apparent LDlOO dose level for this strain. Yet, the most striking interstrain difference was seen in the liver which was distinctly affected after Day 4 in L-E rats given 50 pg/kg TCDD but only marginally affected in rats from any H/W group. The lesion, while showing no necrotic cell changes, was suggestive of plasma membrane damage, possibly reflecting the production of free radicals. The relation of the findings to possible mechamsms of TCDD action is &scussed. Q 1989 society o~To~~~~I~. 2 , 3 ,7 ,8-Tetrachlorodibenzo p-dioxin Knutson, 1982) that arises as an unwanted (TCDD) is a toxicological prototype of halo-by-product in several thermochemical progenated aromatic hydrocarbons (Poland and cesses, for example, waste combustion (Wakimoto and Tatsukawa, 1985; Benfenati et ' Preliminary results were published in Toxicol. Lett. al., 1986). It has also been detected in auto-31(Suppl.), Pl-46 (1986) and in Pharmacol. Toxicol. mobile exhaust (Marklund et al., 1987).
Cell Biology and Toxicology, 1991
These "'dioxins, "" as well as many of the other polychlorinated dibenzodioxins (PCDDs) and dibenzofuran (PCDFs) derivatives, are chlorinated aromatic compounds which are chemically stable, insoluble in water, and highly soluble in fats and oils. TCDD acts as a complete carcinogen in several species, causing both common and uncommon tumors at multiple sites. It is a highly potent chemical carcinogen in chronic animal studies, producing carcinogenic effects in laboratory animals with doses as low as 0.001 #g/kg/ day. In rats, TCDD induces neoplasms in the lung, oral~nasal cavities, thyroid and adrenal glands, and liver. In mice, TCDD induces neoplasms in the liver and subcutaneous tissue, thyroid gland, and thymic lymphomas. In hamsters, it induces squamous cell carcinomas of the facial skin. Tumors of the integumentary system are reported after oral (mice and rats), intraperitoneal (hamsters), and dermal (mice) administration. A mixture of HCDDS (defined as the mixture of the 1,2,3,6,7,2,3, 7,8,9 isomers used in the NTP experiments) are potent liver carcinogens in mice and rats. Pharmacokinetic studies in laboratory animals indicate that 50-90% of dietary TCDD is absorbed. It concentrates in adipose tissue and the liver. In mammals, the TCDD present in the liver is slowly redistributed and stored in fatty tissue. Elimination of TCDD occurs via excretion of metabolites in the bile and urine I.
Regulatory Toxicology and Pharmacology, 2010
In this study, differences in sensitivity between Long-Evans (L-E; dioxin sensitive) and Han/Wistar (H/W; dioxin resistant) rats following long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were statistically and quantitatively investigated. Sensitivity differences were analyzed by comparing benchmark doses (BMDs) for the two strains considering a number of toxicological endpoints including data on body and organ weights, hepatic foci, hepatic CYP1A1 induction, as well as tissue retinoid levels. Dose-response relationships for L-E and H/W rats, described by the Hill function, were assumed to be parallel, which was supported according to statistical analysis. It was concluded that L-E and H/W rats differed statistically in their response to TCDD treatment for most of the parameters investigated. Differences between the strains were most pronounced for hepatic foci; L-E rats were approximately 20-40 times more sensitive than H/W rats. For body and organ weight parameters, L-E rats were approximately 10-20 times more sensitive than H/W rats. For retinoid parameters and hepatic CYP1A1 induction, estimated differences between the strains were generally about 5-fold, and associated with a low uncertainty. In conclusion, the present study employs a dose-response modeling approach suitable for statistical evaluation of strain and species differences in sensitivity to chemical exposure. The study demonstrates quantitatively the differences in sensitivity between the L-E and H/W rat strains following long-term TCDD exposure.
BMC Genomics, 2008
Background: Mouse and rat models are mainstays in pharmacology, toxicology and drug development -but differences between strains and between species complicate data interpretation and application to human health. Dioxin-like polyhalogenated aromatic hydrocarbons represent a major class of environmentally and economically relevant toxicants. In mammals dioxin exposure leads to a broad spectrum of adverse affects, including hepatotoxicity of varying severity. Several studies have shown that dioxins extensively alter hepatic mRNA levels. Surprisingly, though, analysis of a limited portion of the transcriptome revealed that rat and mouse responses diverge greatly (Boverhof et al. Toxicol Sci 94:398-416, 2006).
European journal of pharmacology, 1995
This study was undertaken to compare the tumour promoting effects induced by 3,4,5,3',4'-pentachlorobiphenyl (PCB 126) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition, interactive effects in rats treated with combinations of PCB 126 and TCDD were studied. Partially hepatectomized female Sprague-Dawley rats were initiated with nitrosodiethylamin. After 5 weeks of recovery the promotion treatment started and continued for 20 weeks. The results from the present study demonstrate that PCB 126 elicit approximately 10% of TCDD's tumour promoting activity measured as enhancement of the development of gamma-glutamyl-transpeptidase-positive altered hepatic foci in the liver. The factor required for the PCB to match the response of TCDD was adopted as a toxic equivalency factor and was in this case 0.1, which is the same as the factor suggested by Ahlborg et al. (1994). In the groups treated with a mixture of PCB 126 and TCDD the tumour promoting effect indicated an ad...