Comparing Toxicologic and Epidemiologic Studies: Methylene Chloride‐A Case Study

Abstract

Exposure to methylene chloride induces lung and liver cancers in mice. The mouse bioassay data have been used as the basis for several cancer risk assessments. The results from epidemiologic studies of workers exposed to methylene chloride have been mixed with respect to demonstrating an increased cancer risk. The results from a negative epidemiologic study of Kodak workers have been used by two groups of investigators to test the predictions from the EPA risk assessment models. These two groups used very different approaches to this problem, which resulted in opposite conclusions regarding the consistency between the animal model predictions and the Kodak study results. The results from the Kodak study are used to test the predictions from OSHA's multistage models of liver and lung cancer risk. Confidence intervals for the standardized mortality ratios (SMRs) from the Kodak study are compared with the predicted confidence intervals derived from OSHA's risk assessment models. Adjustments for the "healthy worker effect," differences in length of follow-up, and dosimetry between animals and humans were incorporated into these comparisons. Based on these comparisons, we conclude that the negative results from the Kodak study are not inconsistent with the predictions from OSHA's risk assessment model.

Using Epidemiological Studies to Check the Consistency of the Cancer Risks Predicted by High‐Dose Animal Experiments: A Methodological Review

“…These authors showed that the gavage data originally used by the EPA generally produced "high" predictions, but that most linear-at-low-dose models of the rat inhalation data fit relatively well. Similarly, Stayner and Bailer (4) showed that the multistage models and assumptions used by the Occupational Safety and Health Administration (OSHA) were more consistent with the negative results reported for the Kodak MC cohort than an EPA risk assessment.…”

“…(2,4,19) However, two studies presented arguments based on statistical power. Tollefson et al (11) suggested that the human and animal evidence for MC were consistent, because the Kodak cohort study did not have sufficient power to detect a predicted SMR of 1.01 to 1.4.…”

“…(3,4,13) This inherently adjusts the prediction to the length of follow-up of the human data. The accuracy of these adjustments depends on the accuracy of the particular temporal model used, which is generally uncertain.…”

“…Most of the investigators that made statistical comparisons provided either a 95% CI around the observed number of deaths, (2,3) a 95% CI around the predicted SMR, (4) or a p value for the difference between the observed and predicted. (2,4,19) However, two studies presented arguments based on statistical power.…”

Human cancer risk and exposure to 1,3-butadiene - a tale of mice and men

“…Several investigators have explored the concordance between the risk estimates derived from animal bioassay studies with those developed from epidemiologic studies in which both sources of information exist (22)(23)(24). These analyses have generally found a relatively high degree of concordance, with some notable exceptions.…”