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      Dioxins and Cardiovascular Disease Mortality

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          Abstract

          Objective

          In this systematic review we evaluated the evidence on the association between dioxin exposure and cardiovascular disease (CVD) mortality in humans.

          Data sources and extraction

          We conducted a PubMed search in December 2007 and considered all English-language epidemiologic studies and their citations regarding dioxin exposure and CVD mortality. To focus on dioxins, we excluded cohorts that were either primarily exposed to polychlorinated biphenyls or from the leather and perfume industries, which include other cardiotoxic coexposures.

          Data synthesis

          We included results from 12 cohorts in the review. Ten cohorts were occupationally exposed. We divided analyses according to two well-recognized criteria of epidemiologic study quality: the accuracy of the exposure assessment, and whether the exposed population was compared with an internal or an external (e.g., general population) reference group. Analyses using internal comparisons with accurate exposure assessments are the highest quality because they minimize both exposure misclassification and confounding due to workers being healthier than the general population (“healthy worker effect”). The studies in the highest-quality group found consistent and significant dose-related increases in ischemic heart disease (IHD) mortality and more modest associations with all-CVD mortality. Their primary limitation was a lack of adjustment for potential confounding by the major risk factors for CVD.

          Conclusions

          The results of this systematic review suggest that dioxin exposure is associated with mortality from both IHD and all CVD, although more strongly with the former. However, it is not possible to determine the potential bias, if any, from confounding by other risk factors for CVD.

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          Most cited references56

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          The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds.

          In June 2005, a World Health Organization (WHO)-International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4',5-tetrachlorbiphenyl (PCB 81) (TEF = 0.0003), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho-substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that non-dioxin-like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4'-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and "systemic" TEFs for blood and adipose tissue and TEQ for body burden.
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            Standardized mortality ratios and the "healthy worker effect": Scratching beneath the surface.

            The age-standardized mortality ratio (SMR) is a relative index of mortality, expressing the mortality experience of the study population relative to that of a comparison ("standard") population. With the general population as the "standard", the SMR for an occupational population will underestimate the mortality experience of that latter population (since it comprises individuals necessarily healthy enough to be employable --and whose mortality risk is therefore initially lower than the general population average). However, this "healthy worker effect" does not equally to all groups within the study population. Therefore, if one attempts to adjust for this effect, the summary nature of the SMR must be recognized, and allowance must be made for variation in the healthy worker effect between different age groups, different races, different work-status groups, different causes of death, and different elapsed-time periods of observation.
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              Does nondifferential misclassification of exposure always bias a true effect toward the null value?

              The authors present some examples to demonstrate that in certain nondifferential misclassification conditions with polychotomous exposure variables, estimates of odds ratios for categories at intermediate level of risk can be biased away from the null or can change direction. In addition, the authors present two examples to demonstrate that the slope of the dose-response trend for the true distributions can change direction, creating a false inverse trend, even if the misclassification is nondifferential.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                1552-9924
                November 2008
                22 July 2008
                : 116
                : 11
                : 1443-1448
                Affiliations
                [1 ] Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA
                [2 ] Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA
                [3 ] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
                [4 ] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
                [5 ] Cardiovascular Epidemiology Research Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
                Author notes
                Address correspondence to R. Hauser, Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Building I, Room 1405, Boston, MA 02115 USA. Telephone: (617) 432-3326. Fax: (617) 432-0219. E-mail: rhauser@ 123456hohp.harvard.edu

                The authors declare they have no competing financial interests.

                Article
                ehp-116-1443
                10.1289/ehp.11579
                2592261
                19057694
                69374d5f-830c-4b30-a03c-219057993f21
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                History
                : 14 April 2008
                : 22 July 2008
                Categories
                Review

                Public health
                herbicides,dioxin,pcb,ischemic heart disease,epidemiology,occupational exposure,tcdd,healthy worker effect,mortality,cardiovascular disease

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