Dioxins are a collective group of structurally related compounds that are by-products of industrial and combustion activities such as smelting, bleaching of paper and pulp, the manufacture of some pesticides, waste incineration, and burning fuels such as wood, coal, or oil. They are also released from natural processes such as volcanic eruptions and forest fires.2 Dioxins are found throughout the world in air, soil, water, and food sources. These compounds break down very slowly and therefore tend to bioaccumulate in the environ ment. Dioxins also tend to accumulate in the tissues of both mammalian and aquatic species. The major route of exposure is now thought to be via food sources.2

Environmental exposure to dioxins has been a concern for decades. Two of the best publicized accounts of dioxin exposure include the industrial accident in Seveso, Italy, in 19767 and the use of Agent Orange during the Vietnam War in the 1960s and 1970s.58 Epidemiologic data from these incidents imply that there is sufficient evidence of an association between dioxins and various cancers including soft tissue sarcomas, lymphomas, leukemias, and Hodgkin disease.

TCDD is the most well-studied dioxin. TCDD is regarded by the NTP as a known human carcinogen (Ninth Report on Carcinogens, 2001) based on sufficient evidence from human epidemiologic and mechanistic studies. Experimental animal studies also support TCDD as a carcinogen because it produces tumors in multiple species including mice, rats, and hamsters. Mutations in the proto-oncogene H-ras have also been observed in TCDD-exposed animals.59 Despite the decision of the National Institute of Environmental Health Sciences (NIEHS) to add TCDD to the list of known carcinogens, scientists argue that current scientific data suggesting the carcinogenic potential of TCDD in humans are weak and inconsistent.60

The best-studied mode of action of TCDD-induced carcinogenesis is via the aryl hydrocarbon (Ah) receptor. The Ah receptor controls the expression of genes containing a xeno-biotic response element (XRE) in their promoters. Studies have shown activation of the Ah receptor by TCDD produces a wide spectrum of biologic responses, including altered metabolism, growth, differentiation,61 stress, DNA repair, and motility,62 that may contribute to carcinogenesis.

The effect of TCDD on specific signaling pathways has recently been studied. For example, the MAPK-ERK pathway has been implicated in TCDD-induced carcinogenesis through activation of tumor necrosis factor-alpha (TNF-a) and epidermal growth factor (EGF).62 Whether activation of this pathway by dioxins is independent of the Ah receptor remains to be elucidated. New scientific approaches including gene arrays are currently being employed to gain a better understanding of the mechanisms responsible for dioxin-mediated carcinogenesis. Recently, Martinez et al.63 showed that TCDD alters multiple integrated cell signaling pathways associated with lung cancer in human airway epithelial cells using a gene array approach.

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