Significant Issues Raised by Meta-Analyses of Cancer Mortality and Dioxin Exposure

By Starr, Thomas B. | Environmental Health Perspectives, September 2003 | Go to article overview

Significant Issues Raised by Meta-Analyses of Cancer Mortality and Dioxin Exposure


Starr, Thomas B., Environmental Health Perspectives


TBS Associates, Raleigh, North Carolina, USA

Consistent with results from an earlier U.S. Environmental Protection Agency meta-analysis of three occupational cohorts, Cramp et al. [Environ Health Perspect 111:681-687 (2003)] recently concluded that "dioxin TEQ [toxic equivalent] exposures within roughly 3-fold of current background levels maybe carcinogenic" to humans. In contrast, my meta-analysis using an intercept-only model implied zero additional human cancer deaths from all exposures to dioxin-like compounds, including those arising via dietary intake. How can different investigators reach such markedly different conclusions from similar analyses of essentially the same data? The answer lies in different selections for a dose metric, different assumptions regarding the elimination half-life for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans, different assumptions regarding the importance of the most recent 15 years of exposure, and extrapolations from potential effects of TCDD exposure to potential effects of TEQ exposures. Resolution of the ongoing debate regarding the potential human carcinogenicity of dioxin will require detailed information on exposure to TCDD and on direct-acting carcinogen in the workplace, as well as a dose--response model that adequately reflects TCDD's characteristics as a promoter. Key words: dioxin, direct-acting carcinogen, dose--response assessment, meta-analysis, occupational cohort, promoter. Environ Health Perspect 111:1443-1447 (2003). doi:10.1289/ehp.6219 available via http://dx.doi.org/[Online 22 May 2003]

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Scientific debate about the potential human carcinogenicity of dioxin-like compounds has been ongoing for nearly 25 years, and recent meta-analyses of data from three occupationally exposed cohorts have reached such different conclusions that the debate is certain to continue. The first meta-analysis [U.S. Environmental Protection Agency (U.S. EPA) 2000] produced an upper-bound estimate of the additional risk of death from any cancer of approximately [10.sup.-3] per picogram per kilogram per day for 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD) intake, which the U.S. EPA generalized to all "dioxin-like" compounds via toxic equivalency factors (TEFs). This potency estimate implies that about 4,000 additional cancer deaths occur per year in the United States solely from background intake of dioxin-like compounds [about 1 pg toxic equivalents (TEQ)/kg/day], 95% of which comes from normal dietary sources, and only 10% of which is due to TCDD (U.S. EPA 2000).

Subsequently, in 2001, I (Start 2001) showed that the U.S. EPA's model did not fit the data adequately because it failed to account for a significant baseline elevation of all cancer mortality in the three cohorts; this meta-analysis demonstrated that "these data are entirely consistent with an intercept-only model, a model that has no slope component whatsoever in relation to estimated TCDD body burden," which implies zero additional human cancer deaths from any and all exposures to dioxin-like compounds. Finally, Crump et al. (2003), using updated data for the National Institute for Occupational Safety and Health (NIOSH) cohort (Steenland et al. 1999, 2001), concluded that their meta-analysis "provides some evidence that TEQ exposures near current background levels are carcinogenic."

How is it possible for different investigators to reach such markedly different conclusions from similar analyses of essentially the same data? The answer lies in a) a failure to allow for causes of elevated cancer mortality other than dioxin exposure; b) differences in choices for a dose metric; c) selective use of different assumptions regarding the elimination half-life of TCDD in humans; and d) selective use of different assumptions regarding the impact on cancer mortality of the most recent 15 years of exposure. Resolution of the disparate conclusions will require detailed worker exposure data for TCDD and for direct-acting carcinogens, as well as a more general dose--response model that adequately reflects TCDD's characteristics as a promoter. …

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