Cancer Dose-Response Modeling of Epidemiological Data on Worker Exposures to Aldrin and Dieldrin

The paper applies classical statistical principles to yield new tools for risk assessment and makes new use of epidemiological data for human risk assessment. An extensive clinical and epidemiological study of workers engaged in the manufacturing and formulation of aldrin and dieldrin provides occupational hygiene and biological monitoring data on individual exposures over the years of employment and provides unusually accurate measures of individual lifetime average daily doses. In the cancer dose-response modeling, each worker is treated as a separate experimental unit with his own unique dose. Maximum likelihood estimates of added cancer risk are calculated for multistage, multistage-Weibull, and proportional hazards models. Distributional characterizations of added cancer risk are based on bootstrap and relative likelihood techniques. The cancer mortality data on these male workers suggest that low-dose exposures to aldrin and dieldrin do not significantly increase human cancer risk and may even decrease the human hazard rate for all types of cancer combined at low doses (e.g., 1 g/kg/day). The apparent hormetic effect in the best fitting dose-response models for this data set is statistically significant. The decrease in cancer risk at low doses of aldrin and dieldrin is in sharp contrast to the U.S. Environmental Protection Agency's upper bound on cancer potency based on mouse liver tumors. The EPA's upper bound implies that lifetime average daily doses of 0.0000625 and 0.00625 g/kg body weight/day would correspond to increased cancer risks of 0.000001 and 0.0001, respectively. However, the best estimate from the Pernis epidemiological data is that there is no increase in cancer risk in these workers at these doses or even at doses as large as 2 g/kg/day.     

Ethylene Oxide Cancer Risk Assessment Based on Epidemiological Data: Application of Revised Regulatory Guidelines

Ethylene oxide (EO) research has significantly increased since the 1980s, when regulatory risk assessments were last completed on the basis of the animal cancer chronic bioassays. In tandem with the new scientific understanding, there have been evolutionary changes in regulatory risk assessment guidelines, that encourage flexibility and greater use of scientific information. The results of an updated meta-analysis of the findings from 10 unique EO study cohorts from five countries, including nearly 33,000 workers, and over 800 cancers are presented, indicating that EO does not cause increased risk of cancers overall or of brain, stomach or pancreatic cancers. The findings for leukemia and non-Hodgkin's lymphoma (NHL) are inconclusive. Two studies with the requisite attributes of size, individual exposure estimates and follow up are the basis for dose-response modeling and added lifetime risk predictions under environmental and occupational exposure scenarios and a variety of plausible alternative assumptions. A point of departure analysis, with various margins of exposure, is also illustrated using human data. The two datasets produce remarkably similar leukemia added risk predictions, orders of magnitude lower than prior animal-based predictions under conservative, default assumptions, with risks on the order of 1 × 10^–6 or lower for exposures in the low ppb range. Inconsistent results for lymphoid tumors, a non-standard grouping using histologic information from death certificates, are discussed. This assessment demonstrates the applicability of the current risk assessment paradigm to epidemiological data.