skin, and lungs. Studies have demonstrated an increased incidence of liver cancer after TCDD exposure but only after other adverse changes in the liver were observed. TCDD is also an extremely potent promoter of neoplasia in laboratory rats. Decreased rates of some cancers—including those of the uterus, pancreas, and pituitary and mammary glands—have also been reported. The sites at which effects were observed and the exposure needed to induce them varied considerably from species to species.

The mechanism by which TCDD exerts its carcinogenic effects is not established. TCDD has a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of cellular processes involving growth, maturation, and differentiation; those effects could influence tumor formation. Data on female rats suggest that complex hormonal interactions are involved in TCDD-induced carcinogenesis.

Studies are consistent with the hypothesis that the effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR), a protein in animal and human cells to which TCDD can bind. After the binding of TCDD, the TCDD–AhR complex has been shown to bind DNA and lead to changes in transcription (that is, genes are differentially regulated). In many cases, the differential gene regulation leads to transformation of a normal cell into an abnormal cell. Furthermore, data on animals genetically modified not to express the AhR suggest that the AhR plays a role in normal growth, and this supports the hypothesis that TCDD could affect cell growth.

The transcriptional alterations induced by TCDD result in alterations in some forms of cellular regulation and metabolism at a very basic level. For example, TCDD has been shown to induce cytochrome P4501A1 (CYP1A1) and other metabolizing enzymes. Those changes result in altered cell metabolism and could be involved in TCDD's carcinogenic activity, especially as this may involve the metabolic activation of other chemicals to carcinogenic intermediates. An accumulation of data also indicates that genes and pathways modulating cell cycle, altering the pattern of cell death, involved in the production and activity of hormones and growth factors, and involved in cellular oxidative stress appear to be predominantly affected. Those data are consistent with findings that TCDD alters cell pathways involving growth, maturation and differentiation, all of which could modulate processes involved in the tissue-specific formation of tumors. On the other hand, tissue-specific protective cellular mechanisms can affect the response to TCDD, further complicating the carcinogenic effects of this chemical.

There are differences among various experimental animals in susceptibility to TCDD-induced effects; the sites at which tumors are induced also vary from species to species. Modulated gene expression by TCDD is also highly specific for species and cell type. Differences in the induction or repression of responsive genes likely play a role in the different responses seen in different cell types and species.