Carcinogenic risk estimation discussion

There have been a number of recent survey articles and theoretical papers describing the available models for low-dose extrapolation. Through a literature review the most prominent models have been selected and discussed below. However, there are other models, less commonly used, that were not mentioned here for the sake of brevity. The models addressed below represent a good cross-section of the different features and capabilities that are pertinent to carcinogenic risk estimation. 

Three more National Research Council committees (the first, second, and third Committees on the Biological Effects of Ionizing Radiations—BEIR I, II, and III) issued reports in 1972, 1977, and 1980.301-303 They emphasized risk estimation, rather than recommendation of standards. There also has been discussion of carcinogenicity as a low-dose, delayed effect. The United Nations, through its Scientific Committee on the Effects of Atomic Radiation, has continued to produce periodic encyclopedic reviews of the literature.1+68-473... 

As discussed above, the Delaney clause applies to substances proposed for use as food additives, but does not apply to individual constituents of a food additive. Examples of constituents would include residual monomers or catalysts. The constituents policy, subjected to judicial review in Scott v. FDA, 728 F. 2d 322 (6th cir. 1984), states that FDA may consider the potential risks of constituent exposure under the general safety standards set forth in FFDCA. The notification process places the responsibility upon the notifier for addressing the carcinogenic risk of constituent exposure from a proposed use of a food additive. FDA recommends that notifiers include in their food contact notification a safety narrative that addresses the safety of each carcinogenic constituent at any exposure (in addition to the recommendations listed in Table 7.1). This narrative should include an estimate of the potential human cancer risk from the constituent due to the proposed use of the food contact material (FDA, 2002). 

For the purposes of converting risks observed in one species to risks for another, it is assumed that the relationship between the ED and the probability of cancer is the same in all species. This assumption is critical to the estimation of carcinogenic risks since it provides the framework making species conversion a logical exercise (that is, if there were no equivalent toxic compound in both species, there is no logical reason to believe that tumor induction in the test species will result in tumor induction in humans). The estimation of the ED has generated a considerable amount of interest because the relationship between D and ED may be nonlinear (Hoel, Kaplan and Anderson, 1983). Failure to correctly model a nonlinear relationship could lead to an overestimate or an underestimate of the carcinogenic risk, a problem we will discuss later in this paper. 

We shall begin with a little history, and then move to a discussion of cancer statistics and the causes of cancer, and then provide some background on cancer biology and the mechanisms of tumor development. Some of the general characteristics of chemical carcinogens will also be covered. The methods for identifying chemical carcinogens are the subject of Chapter 6. How their risks are estimated is left to later chapters. 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for PCBs as discussed in Chapter 2 (Section 2.3). An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure. 

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