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

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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 µg/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 chromotid 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.

Under the State of California's Safe Drinking Water and Toxic Enforcement Act of 1986 (“Proposition 65”), TCDD and HCDDs were listed as chemicals known to the state to cause cancer. The International Agency for Research on Cancer (IARC) has classified TCDD as a Group 2B carcinogen (“possibly carcinogenic to humans”). Similarly, the EPA classified TCDD and HCDDs as Group B2 carcinogens (“probable human carcinogens”); and the DHHS' National Toxicology Program placed TCDD into the category of “substances which may reasonably be anticipated to be carcinogens for humans.”

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Authors and Affiliations

  1. National Institute of Environmental Health Sciences, 27709, Research Triangle Park, NC

    J. E. Huff

  2. California Department of Health Services, Reproductive and Cancer Hazard Assessment Section, 2151 Berkeley Way, Annex 2, 94704, Berkeley, CA

    A. G. Salmon, N. K. Hooper & L. Zeise

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Huff, J.E., Salmon, A.G., Hooper, N.K. et al. Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins. Cell Biol Toxicol 7, 67–94 (1991). https://doi.org/10.1007/BF00121331

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