A multi-factor ranking scheme for comparing the carcinogenic activity of chemicals

Abstract

A scheme for ranking the quantitative activity of chemical carcinogens is described. This activity scheme uses as its base, dose potency measured as TD 50, the chronic dose rate that actuarially halves the adjusted percentage of tumor-free animals at the end of the study (Gold et al., Environ. Health Perspect., 67, 161–200, 1986). The TD 50 is converted into an inverse log scale, a decile scale, and then adjusted by weighting factors that describe other parameters of carcinogenic activity. These factors include positive or negative weightings for: the induction of tumors at tissues or organs associated with high historical control tumor incidences; the induction of tumors at multiple sites; the induction of tumors in both sexes of the species; and the induction of tumors in more than one species. These factors were chosen as they represented qualitative descriptions of the general specificity or non-specificity of chemicals with regard to the activity in rodents and have some bearing on the potential activity of chemicals in humans. In order to construct a measure to express the inactivity of chemicals towards the induction of cancer, a measure analogous to the TD 50 has been developed: the highest average daily dose or HADD. The HADD is the highest average daily dose in mg chemical/kg body weight administered in a chronic cancer study and that did not induce a statistical increase in tumors. HADD values were similarly converted to log decile units and adjusted by weighting factors according to lack of activity in both sexes of a species, and the lack of activity in more than one species. In order to explore the use of this multi-factor activity scheme for both carcinogens and non-carcinogens, a group of 142 chemicals was selected that had been tested according to an oral dosing protocol in two sexes of two species of rodents and whose data was peer-reviewed and available for this analysis. This data came from the National Toxicology Program/National Cancer Institute Bioassay Technical Reports. Three activity ranking schemes were developed: the Carcinogen Activity-F344 Rat, an activity scheme based on cancer data obtained with the F344 rat; the Carcinogen Activity-B6C3F1 Mouse, an activity scheme based on cancer data obtained with the B6C3F1 mouse, and the Carcinogen Activity-Combined, an activity scheme based on selecting data from both the F344 rat and the B6C3F1 mouse. This selection was based on the most sensitive rodent responding to the carcinogenic activity of active chemicals and the least sensitive rodent responding to the toxic effects of inactive chemicals. This paper discusses the construction and development of these ranking schemes and analyzes the results in terms of distributions of values within each ranking scheme, and the relative contributions of TD 50 (or HADD) and the weighting factors in the activity schemes.