The Problem of the Potency of Carcinogenic Agents

29 May

It should be apparent by now that not all carcinogenic agents are equally effective in inducing neoplasia, i.e., they exhibit differing carcinogenic potencies. The potency of an agent to induce neoplasia has been simply defined as the slope of the dose-response curve for induction of neo- plasms (Choy, 1996). However, such a definition has generally not been the basis for estimates of carcinogenic potency based on data from chronic bioassays with continuous administration of the agent. In Table 13.8 may be seen a listing of some methods for the measurement of the po- tency of carcinogens, beginning with the early study by Iball (1939) resulting in the Iball Index, which was used for a number of years thereafter.  The relationship  of Meselson  and Russell (1977) may also be derived from the results of bacterial mutagenesis assays. The potency rela- tionship developed by Crouch and Wilson (1979) is dependent on a linear, no-threshold extrapo- lation of the animal bioassay result, giving the slope as β in the equation seen in the table (Barr,1985). The TD50  has been extensively  used, and values were recently compiled by Gold and Zeiger (1997) for a large number of chemicals. The range of carcinogenic potencies developed from such a relationship may be seen in Figure 13.13. Tennant and his associates (1997) have modified the TD50 potency relationship, using a different fraction of animals that develop neo- plasms. The T25 is defined by these workers as the chronic dose rate in mg/kg of body weight per day that will give 25% of the animals neoplasms  at a specific tissue site, after correction  for spontaneous incidence, within the standard lifetime of the test species. As expected, since the relationship is basically the same as that noted in Table 13.8 except for only half the percentage, the T25 values are usually roughly one-half those of the TD50 values. Pepelko (1991) has pointed out one of the difficulties of these absolute potency measurements in that differences in solubil- ity, bioavailability, and some other pharmacokinetic  parameters do cause considerable variabil- ity in some of the potency values reported.

While the four relationships noted in the table under “absolute” do analyze carcinogenic potency of a chemical from the data on the bioassay of that chemical alone, Glass and associates (1991) proposed a relative potency relationship that has some degree of flexibility and may have some application in risk assessment different from the absolute analyses. Pitot et al. attempted to determine indices relating the stages of initiation and promotion to the potency of the agents inducing such stages. In the case of the initiation index, which is relatively straightforward, the values obtained are absolute. In the case of the promoting index, the value is always given in relation to the nontreated control, which does develop focal lesions from endogenous promo- tion of spontaneously initiated hepatocytes (Chapter 7). These measures of initiating and pro- moting potencies have been applied only to multistage hepatocarcinogenesis  in the rat. But it is quite feasible to extend such analyses to multistage carcinogenesis  in a number of other solid organs where the immediate results of initiation can be quantitated and the relative growth of lesions from the initiated  cell population  can be determined  with some degree of accuracy (Pitot et al., 1987).

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