Age-Related Differences in Susceptibility to Carcinogenesis—Toward an Improved Analysis of Data on Age-Related Differences in Cancer Sensitivity in the EPA Children’s Cancer Risk Guidance Document Researchers: Dale Hattis, Principal Investigator Rob Goble, Research Professor Abel Russ, Research Associate Jen Ericson and Jill Mailloux, Student Research Assistants Margaret Chu, EPA Project Monitor

INNOVATIVE ASPECTS OF THE ANALYSIS NOW IN PROCESS Compare measures of potency, rather than uncorrected cancer incidence, among groups. Where dosage spans multiple age groups, use dummy variables to represent the observed tumor risk as the sum of cancer contributions from dosing in different periods: –The periods are: fetal (gd 12-19), pre-weaning (1-21 d); weaning - 2 mo; adult (2 mo - 2 yr). –Where continuous dosing occurs in only a fraction of a period that fraction is used as the corresponding “dummy” rather than 1. Use likelihood methods to first derive appropriate statistical weighting of the different observations, and (eventually) to avoid bias from excluding “0” points (two phases of analysis). Express dosage for animals of different weights on a metabolically consistent basis (either concentration in air or food, or per unit body weight to the three quarters power).

Other Improvements--Correcting Various Data Problems (With the aid of Hugh Barton) Adding esophageal tumors for DEN (liver, but not esophageal tumors included in “Table 4” analysis) Correcting exposure time for vinyl chloride; adding additional control and comparison group information for 52 week exposures Consolidating 6000 and dose groups for vinyl chloride--both well over saturating levels

The Poisson One-hit Transformation--From the Fraction of Animals with at Least One Tumor to The Number of Tumors Per Animal

Effect of the One-Hit Transformation for Various Observations of % Tumors in Animal Groups

EPA “Table 4” Analysis for Continuously-Dosed Mutagenic Carcinogens

Effect of the One-Hit Transformation on the Calculations of Tumor Risks in the Juvenile Groups for Continuously- Administered Mutagenic Carcinogens

Effect of the One-Hit Transformation on the Existing Distribution of Juvenile/Adult Risk/Dosing Time Ratios for Continuously-Administered Mutagenic Carcinogens

Use of Part-Period Dummy Variables in Combination To Represent Different Exposure Patterns--Maltoni Vinyl Chloride Experiments