Carcinogenicity, mechanisms initiation

For classification mode of action and potency of a compound are either not taken into account, or at best is used as supporting arguments. The advancing knowledge of reaction mechanisms and the different potencies of carcinogens have initiated a re-evaluation of the traditional concepts. 

Another problem concerns the identiflability of carcinogenic mechanism using tumor incidence data. Using a simpler model than that shown in Figure 3, Fortier (1987) examined the ability of tumor incidence data to accurately differentiate between a low-dose linear chemically induced increase in the rate of mutations from normal cells to initiated cells and a low-dose nonlinear chemically induced increase in the birth rate of initiated cells. It was shown that the probability of incorrectly classifying one mechanism as the other was quite high, exceeding 50% in some cases. 

The key to hexavalent chromium s mutagenicity and possible carcinogenicity is the abiHty of this oxidation state to penetrate the cell membrane. The Cr(VI) Species promotes DNA strand breaks and initiates DNA—DNA and DNA-protein cross-links both in cell cultures and in vivo (105,112,128—130). The mechanism of this genotoxic interaction may be the intercellular reduction of Cr(VI) in close proximity to the nuclear membrane. When in vitro reductions of hexavalent chromium are performed by glutathione, the formation of Cr(V) and glutathione thiyl radicals are observed, and these are beHeved to be responsible for the formation of the DNA cross-links (112). 

Human data as well as studies in animals have provided negative evidence of carcinogenicity for endosulfan (Hack et al. 1995 Hoechst 1988b, 1989a). However, endosulfan promoted the development of altered hepatic foci in rats initiated with nitrosodiethylamine (Fransson-Steen et al. 1992). Although the mechanism of tumor promotion of endosulfan is not known, it has been suggested that it involves inhibition of cellular communication (Kenne et al. 1994). A brief discussion of this topic is provided in Section 2.5 under Cancer Effects. 

One important point of controversy in risk extrapolation is the existence of the threshold level for carcinogenic and mutagenic response to a pollutant. Some argue that an organism is able to cope with low doses of a substance through metabolic processes or repair mechanisms, so that harmful effects do not appear until a certain minimum threshold, or "safe dose", is surpassed. Others contend that a carcinogenic substance must be considered potentially harmful at any dose, and that even a single molecule may initiate a tumor at the cellular level. This is the so-called "one-hit" hypothesis. 

Areas in which additional information is still needed relates to the role and relative importance of different adducts and the mechanisms by which they initiate cells. General principles are developing which will allow better predictions to be made at each of the stages of chemical carcinogenesis outlined in Table I. The ultimate goal therefore, would be, by a combined analysis of all these steps, to predict accurately the carcinogenicity of newly discovered or untested PAH derivatives. 

Covalent binding of chemical carcinogens to cellular macromolecules, DNA, RNA and protein, is wel1-accepted to be the first step in the tumor initiation process ( 1, 2). Most carcinogens, including polycyclic aromatic hydrocarbons (PAH), require metabolic activation to produce the ultimate electrophilic species which react with cellular macromolecules. Understanding the mechanisms of activation and the enzymes which catalyze them is critical to elucidating the tumor initiation process. 

These somewhat simplified descriptions of mechanisms that initiate cellular injury, and of the ways in which cells and tissues respond to these injuries will, as noted at the outset, be helpful as we describe various manifestations of toxicity and carcinogenicity. We distinguish between toxic injuries, which are typically seen in animal experiments and are usually described in the terms defined in the foregoing, and the various medical conditions we call diseases. Many toxic responses can lead to disease, but we also consider toxic injuries to be adverse effects, whether or not they are known to lead to specific diseases. 

Not all of the biochemical events in this complex pathway from PPAR-alpha activation to tumors are completely understood, but much is known. It seems that at least some peroxisome-proliferating chemicals that also produce tumors in rodent livers do so through this pathway. If it can be demonstrated that such a mechanism is at work, then it seems that the risk of tumorigenicity for such compounds would be limited to doses that are sufficient to activate PPAK-alpha sufficiently to initiate the dangerous cascade of events within the cell. Experts have developed a number of experimental criteria that should be met if a compound is to be put in this class of carcinogens. Study of P PAR-alpha activation as a route of carcinogensis is an extremely active area of research. 

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