Risk characterization is the estimate of the incidence of health effects that are likely to occur under specific conditions of exposure. This is dependent on the exposure levels and the toxicity of the compound. Simply, risk = toxicity x exposure. Risk characterization requires a judgment of the applicability of the science to the potential human exposure conditions.
For noncarcinogens, the approach is to ensure that the estimated intake or exposure does not exceed the RfD. Intakes at levels below this level are considered to be without appreciable risk. The amount of additive or pesticide residue that is allowed in foods (ie, the tolerance) is based on the lowest amount needed for efficacy, not safety. As a result, the tolerance may be many folds lower than the safe level based on the RfD. See Table 4 for an example of the determination of tolerance levels.
For carcinogens, the risk assessment is based on the assumption that there is no threshold for carcinogenesis and that the dose-response relationship observed at high doses is similar to that at low doses. An acceptable level of risk has been set at a consumption level estimated to produce no more than one cancer in a million individuals. The insensitivity of the animal bioassay for detecting carcinogens has led to the use of high doses in order to generate a sufficiently high frequency of response to be statistically significant. Results from these studies then need to be ex-
Table 4. Example of Determination of Maximum
1. The synthetic food color additive Rosy Red was tested in rats and dogs in a chronic feeding study. A NOAEL of 1,000 mg/kg body weight per day (mg/kg/day) was determined.
2. Safety factor = 10 (extrapolation to humans) X 10 (individual variation) = 100
4. Rosy Red is being developed for use in licorice candy. Using food consumption survey data, it was found that the person with the highest intake would consume 100 g of candy per day.
5. The maximal permissible intake per day (MPI) = RfD X 60 kg (adult body weight) = 10 mg/kg X 60 kg = 600 mg per day.
6. Assuming that Rosy Red will not be added to any other foods, the maximum permissible level (MPL) (also called tolerance level) that would be approved would be MPL = MPI/food factor. Food factor represents an estimation of the amount of that food in the diet. MPL = 600 mg + 100 g licorice = 6 mg Rosy Red/g licorice. However, if only 1 mg Rosy Red/g candy was needed for the desired color, the MPL would be 1 mg/g.
7. The RfD is usually well above the EDI of a food additive.
trapolated to the low-dose range that represents the human exposure levels. A very large number of animals would be required to obtain a statistically valid response level if low doses were used, resulting in increased testing costs. Therefore, the dose used may be up to the maximum tolerated dose (MTD), which is the highest dose that does not produce overt toxic responses in subchronic studies. Concerns with the use of the MTD are that this dose may result in depressed food intake and may saturate other physiological processes, such as activation and inactiva-tion by enzyme systems, active transport, and DNA repair. Cytotoxicity caused by high doses may result in mito-genesis or increased cell proliferation, enhancing the carcinogenesis process. Thus, use of the MTD may result in the ability of a compound to induce cancer through mechanisms that do not occur at low doses.
In part to address this issue, the EPA proposed new guidelines for cancer risk assessment in 1996 (27). The 1986 cancer guidelines classified compounds as A, Bl, B2, C, D, or E carcinogens. Classification as an A carcinogen was based on "sufficient evidence of carcinogenecity from human studies," and an E classification was based on "evidence of noncarcinogenecity." Tumor findings in animals or humans were the dominant components of the classification. The 1996 proposed guidelines will use a narrative description of the likelihood and conditions of human hazard, such as "not likely to be a human carcinogen, because animal data shown to be not relevant to humans." Therefore, consideration of the route of exposure, the dose-response relationship, and mode of action information are changes in the proposed guidelines. Further discussion on the proposed guidelines can be found in the Science Advisory Board review (28).
A major difference in the cancer risk assessment process for food additives and for pesticides is that the Dela-ney clause still applies to food additives, but has been re moved for pesticides by the FQPA. The Delaney clause of the FD&C Act states that "no additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animal, or if it is found, to induce cancer in man or animal" (Food Additive Amendment of 1958, section 409). The Delaney clause therefore does not allow for consideration of dose or mechanism of action. Therefore, even if it is clearly demonstrated that the mechanism of cancer induction in animals is not relevant to humans, the Delaney clause would prohibit the use of the product in foods. This is one reason why the new FQPA eliminated the Delaney clause from pesticide regulations.
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