Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxins (HCDDs) are among the most toxic and carcinogenic of "man-made" chemicals. 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 micrograms/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 1,2,3,6,7,8- and 1,2,3,7,8,9 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 and passively through the gut wall. Metabolism is slow: the biological half-life of TCDD varies from weeks (rodents) to years (humans), and is strongly dependent upon the rate of TCDD metabolism. Many of the toxic effects of TCDD, including teratogenicity, may arise by receptor-mediated mechanisms. The induction of cytochrome P-448 and related enzymes by TCDD occurs by such a mechanism, and is related to the binding of TCDD to the Ah receptor. The specific mechanism(s) by which TCDD exerts its carcinogenic effects is unclear: receptor-binding may be part of the story. The role of the Ah receptor has been indicated in a skin promotion assay. The evidence for mutagenicity is inconclusive. TCDD did not induce lethal mutations, chromosomal aberrations, micronuclei or sister chromatid exchanges in rodents treated in vivo, nor was it mutagenic to bacteria, but it did enhance transformation of mouse C3H 10T1/2 cells by N-methyl-N'-nitro-N-nitrosoguanidine and was mutagenic to mouse lymphoma cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

“…In long-term bioassays, TCDD increased the incidence of liver tumors in female, but not male, rats (Kociba et al, 1978;Huff et al, 1991;Sawyer et al, 1999). In general, female rats have been shown to be more susceptible to TCDD-induced oxidative stress (Stohs, 1990), oxidative DNA damage (Wyde et al, 2001b) and hepatocarcinogenesis (Huff et al, 1994).…”

The Seveso studies on early and long-term effects of dioxin exposure: a review.

“…Fear for the health of local residents was justified by the known high toxicity of TCDD in animals and its ability to cause cancer under experimental conditions (2). Little was known at that time about its effects on human beings, especially after environmental exposure (3).…”

Integrated approach for evaluating species and interindividual differences in responsiveness to dioxins and structural analogs.

“…In chronic bioassays for its carcinogenicity in rats, tumor incidences were increased at a number of sites. Available studies on TCDD carcinogenesis have been reviewed (4) and carcinogenic responses were seen after either long-term or short-term exposures to TCDD in every species studied. Tumors of various types have been induced in several organ systems, and these do not appear to be restricted to the site of application.…”

“…TCDD is a trans-species (rat, hamster, mouse), trans-strain, trans-sex, multisite, complete carcinogen. It induced carcinogenic effects in laboratory animals at exposures as low as 0.01 ,ug/kg body weight/day in rat liver and 0.001 ,ug/kg/day in rat thyroid and is clearly among the most potent of all identified chemical carcinogens (4).…”