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

https://doi.org/10.1016/0041-008X(78)90075-3Get rights and content

Abstract

Rats were maintained for 2 years on diets supplying 0.1, 0.01, and 0.001 μg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg/day. Analysis of these diets indicated 2200, 210, and 22 parts per trillion (ppt) of TCDD. Ingestion of 0.1 μg/kg/day caused an increased incidence of hepatocellular carcinomas and squamous cell carcinomas of the lung, hard palate/nasal turbinates, or tongue, whereas a reduced incidence of tumors of the pituitary, uterus, mammary glands, pancreas, and adrenal gland was noted. Other indications of toxicity at this dose level included increased mortality, decreased weight gain, slight depression of erythroid parameters, increased urinary excretion of porphyrins and δ-aminolevulinic acid, along with increased serum activities of alkaline phosphatase, γ-glutamyl transferase and glutamic-pyruvic transaminase. Gross and histopathologic changes were noted in the hepatic, lymphoid, respiratory, and vascular tissues. The primary hepatic ultrastructural change at this high dose level was proliferation of the rough endoplasmic reticulum. Terminal liver and fat samples from rats at this high dose level contained 24,000 and 8100 ppt of TCDD, respectively. Rats given 0.01 μg/kg/day for 2 years had a lesser degree of toxicity than that seen at the highest dose level. This included increased urinary excretion of porphyrins in females, liver lesions (including hepatocellular nodules), and lung lesions (including focal alveolar hyperplasia). Terminal liver and fat samples from rats of this dose level contained 5100 and 1700 ppt of TCDD, respectively. Ingestion of 0.001 μg of TCDD/kg/day (∼22 ppt in the diet) caused no effects considered to be of any toxicologic significance. At this lower dose level, terminal liver and fat samples each contained 540 ppt of TCDD. These data indicate that continuous doses of TCDD sufficient to induce severe toxicity increased the incidence of some types of tumors, while reducing other types. During the 2-year study in rats, no increase in tumors occurred in those rats receiving sufficient TCDD to induce slight or no manifestations of toxicity.

Cited by (25)

  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters hepatic polyunsaturated fatty acid metabolism and eicosanoid biosynthesis in female Sprague-Dawley rats

    2020, Toxicology and Applied Pharmacology
    Citation Excerpt :

    Integration of differential gene expression with complementary untargeted metabolomics demonstrated that PUFA metabolism and eicosanoid biosynthesis were disrupted by TCDD. These changes increased inflammatory lipid mediators which may be contributing to increased inflammation in chronically exposed rats (Kociba et al., 1978; NTP, 1994; Walker et al., 2006). Based on BMD values for differential gene expression with correlative changes in metabolites, the cytochrome P450 hydroxylation/epoxidation pathway and the lipoxygenase pathways were more sensitive to TCDD than the cyclooxygenase pathway.

  • Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on spontaneous movement of human neuroblastoma cells

    2020, Science of the Total Environment
    Citation Excerpt :

    Epidemiological study on the long-term health impacts of TCDD exposure showed that the incidence of all cancers was increased in the population exposed to TCDD in Seveso, Italy (Bertazzi et al., 1989). Moreover, after a two-year chronic exposure to TCDD at a relative low concentration (0.01 μg/kg/day, equivalent to 210 ppt), the rats encountered an increased risk of various squamous cell carcinomas and hepatocellular carcinoma (Kociba et al., 1978). In addition to the increased risk of cancer occurrence, a retrospective cohort study in the United States indicated that workers exposed to TCDD had an increased mortality from various cancers, especially those with the longest occupational exposure to TCDD (Fingerhut et al., 1991).

  • The impact of maternally derived dioxins on embryonic development and hepatic AHR signaling in a long-lived apex predator

    2019, Chemosphere
    Citation Excerpt :

    Despite these possible effects, very little is known regarding toxicokinetics of these contaminants in the alligator, including inducibility of the AHR-responsive gene battery that mediates toxicity and clearance (but see Ertl and Winston, 1998; Ertl et al., 1998; Ertl et al., 1999a,b). Nonetheless, dioxins are capable of eliciting adverse effects at low doses during development (Sato et al., 2008; Ohsako et al., 2001; Haijima et al., 2010; Faqi et al., 1998) and in adulthood following chronic exposure (Brulport et al., 2017; Kociba et al., 1978), suggesting that dioxin and related contaminants might pose a substantive threat in exposed alligator populations. Given the persistent nature of these contaminants and the important ecological role for crocodilians (Mazzotti et al., 2009), we believe that a broader investigation of the prevalence and effects of dioxin in wild populations is warranted.

  • Updates on Larynx Cancer: Risk Factors and Oncogenesis

    2023, International Journal of Molecular Sciences
View all citing articles on Scopus
View full text