Regulation of Carcinogens

We propose a procedure, suitable for regulatory use, for estimating individual and societal risks of carcinogenic materials by using information on interspecies comparisons of carcinogenic potency. The consistent treatment of uncertainties allows evaluation of confidence limits and hence regulatory measures of risk which incorporate safety factors and incentives for better information. Numerical examples are given, together with discussion of the treatment of undetected carcinogens. Applications of the procedure to setting priorities for carcinogenicity testing and to product substitution are mentioned.     

Improving the Regulation of Carcinogens by Expediting Cancer Potency Estimation1

The statutory language of the Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65; California Health and Safety Code 25249.5 et seq.) encourages rapid adoption of “no significant risk levels” (NSRLs), intakes associated with estimated cancer risks of no more than 1 in 100,000. Derivation of an NSRL for a carcinogen listed under Proposition 65 requires the development of a cancer potency value. This paper discusses the methodology for the derivation of cancer potencies using an expedited procedure, and provides potency estimates for a number of agents listed as carcinogens under Proposition 65. To derive expedited potency values, default risk assessment methods are applied to data sets selected from an extensive tabulation of animal cancer bioassays according to criteria used by regulatory agencies. A subset of these expedited values is compared to values previously developed by regulatory agencies using conventional quantitative risk assessment and found to be in good agreement. Specific regulatory activities which could be facilitated by adopting similar expedited procedures are identified.     

Using Average Lifetime Dose Rate for Intermittent Exposures to Carcinogens

The effect of using the average dose rate over a lifetime as a representative measure of exposure to carcinogens is investigated by comparing the true theoretical multistage intermittent-dosing lifetime low-dose excess risk to the theoretical multistage continuous-dosing lifetime risk corresponding to the average lifetime dose rate. It is concluded that low-dose risk estimates based on the average lifetime dose rate may overestimate the true risk by several orders of magnitude, but that they never underestimate the true risk by more than a factor of k/r, where k is the total number of stages in the multistage model and r is the number of stages that are dose-related.     

Relative Potency of Chemical Carcinogens in Rodents

Extensive carcinogenesis data compiled by Gold et al. for 770 compounds tested in 2944 chronic bioassays in animals provided an opportunity to compare cancer rates across animal species for a wide variety of compounds administered by various routes of exposure. The comparisons in this paper are restricted to the most frequently tested species: rats, mice, and hamsters. When sufficient experimental data exist, Gold et al. provide estimates of the TD50 (the chronic dose rate expressed in mg/kg body weight/day which halves the actuarially adjusted percentage of tumor-free animals at the end of a standard lifetime experiment). Since the current practice generally is to base risk assessments upon the data set producing the highest cancer risk, the ratio of the minimum TD50's provides a measure of the relative potency between two species for each compound administered to animals by the same route. The geometric means of the ratios of minimum TD50's for rats:mice are 1/2.2 and 1/1.3 for diet and gavage, respectively. A mean ratio for rats: mice of 1/1.48 is obtained for compounds administered in the diet when the tumor site is the liver for both species. In general the minimum TD50 is lowest for the rat and highest for the hamster. Although limited data are available for inhalation studies, this route of administration resulted in the poorest agreement between rats and mice. In general, comparisons of minimum TD50's across the three rodent species are generally within a factor of 100 for a wide variety of compounds.     

Reducing Conservatism in Risk Estimation for Mixtures of Carcinogens

The excess cancer risk that might result from exposure to a mixture of chemical carcinogens usually must be estimated using data from experiments conducted with individual chemicals. In estimating such risk, it is commonly assumed that the total risk due to the mixture is the sum of the risks of the individual components, provided that the risks associated with individual chemicals at levels present in the mixture are low. This assumption, while itself not necessarily conservative, has led to the conservative practice of summing individual upper-bound risk estimates in order to obtain an upper bound on the total excess cancer risk for a mixture. Less conservative procedures are described here and are illustrated for the case of a mixture of four carcinogens.     

An Evaluation of Risk Estimation Procedures for Mixtures of Carcinogens

The estimation of health risks from exposure to a mixture of chemical carcinogens is generally based on the combination of information from several available single compound studies. The current practice of directly summing the upper bound risk estimates of individual carcinogenic components as an upper bound on the total risk of a mixture is known to be generally too conservative. Gaylor and Chen (1996, Risk Analysis) proposed a simple procedure to compute an upper bound on the total risk using only the upper confidence limits and central risk estimates of individual carcinogens. The Gaylor-Chen procedure was derived based on an underlying assumption of the normality for the distributions of individual risk estimates. In this paper we evaluated the Gaylor-Chen approach in terms of the coverage probability. The performance of the Gaylor-Chen approach in terms the coverages of the upper confidence limits on the true risks of individual carcinogens. In general, if the coverage probabilities for the individual carcinogens are all approximately equal to the nominal level, then the Gaylor-Chen approach should perform well. However, the Gaylor-Chen approach can be conservative or anti-conservative if some or all individual upper confidence limit estimates are conservative or anti-conservative.     

In Reply to the Learned

Liberal education may be highly valued for its humanizing effect, its social value, and its place as a school for wisdom. Each of these reasons for prizing liberal education are discussed in light of distinctions between education as a task and education as an achievement, epistemically slight thought and epistemically robust thought, inherent value and instrumental value as types of extrinsic value, and the historical notion and commencement speaker's notion of liberal education. Consideration is given to the roles of the arts and sciences in liberal education and the limits of philosophy in a school for wisdom.