into a normal host and a new malignant tumor would arise. This implies that the underlying abnormality that led to the transformation of a normal cell into a malignant cell is present in the genetic material of the cell itself or in the way the genetic information is expressed.

It is now well accepted that a malignant tumor develops from a single cell that has passed through a series of steps or stages of transformation. The initial stage of transformation, or "initiation," is thought to involve a mutation—that is, damage to DNA. The initiated cell and its progeny, most of which are destroyed by the body, then must pass through one or more additional stages (progression) before a clone of fully transformed malignant cells will acquire the essential properties of a malignant tumor. These generally include loss of normal specialization, faster than normal rates of cell division, and loss of normal limits on cell division.

Many carcinogens that have been identified thus far are initiators and are believed to interact directly with DNA. It is also known, however, that certain substances may promote tumor formation by initiated cells, even though they are not capable of the initial cell mutation. Based on its effects in animal studies, TCDD is considered a tumor promoter, not a tumor initiator. The potential mechanisms by which TCDD can act as a tumor promoter are discussed in Chapter 4.

It follows from an initiation/promotion model that tumor initiators should act early in the carcinogenic process, often decades before a cancer is diagnosed, while tumor promoters may exert their effect at any time between initiation and clinical diagnosis.

The experimental evidence suggesting that TCDD acts as a tumor promoter comes from studies in laboratory animals. It is possible, though not proven, that TCDD could also promote the formation of cancer in humans after exposure to another potential carcinogen. Understanding the biological mechanism whereby TCDD interacts with the process of cancer production is critical to the committee's analysis of the plausibility of an association between human cancer and exposure to Agent Orange and other herbicides. Although direct evidence may not be available regarding the biologic plausibility of a specific tumor site, this does not preclude examination of epidemiologic data for potential association in a population.

In evaluating the epidemiologic studies, the committee noted that in many studies, insufficient time had passed since exposure for many types of tumors to develop; this is an issue of minimum latency needed for an adequate study. However, if TCDD is acting as a promoter, studies that evaluate health outcomes before the usual minimum latency period has passed may be appropriate since this function may require a shorter latency period for its hypothesized mechanism of action.

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