Dioxin: Exposure-Response Analyses and Risk Assessment (original) (raw)
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Health Effects of Dioxin Exposure: A 20-Year Mortality Study
American Journal of Epidemiology, 2001
Follow-up of the population exposed to dioxin after the 1976 accident in Seveso, Italy, was extended to 1996. During the entire observation period, all-cause and all-cancer mortality did not increase. Fifteen years after the accident, mortality among men in high-exposure zones A (804 inhabitants) and B (5,941 inhabitants) increased from all cancers (rate ratio (RR) = 1.3, 95% confidence interval (CI): 1.0, 1.7), rectal cancer (RR = 2.4, 95% CI: 1.2, 4.6), and lung cancer (RR = 1.3, 95% CI: 1.0, 1.7), with no latency-related pattern for rectal or lung cancer. An excess of lymphohemopoietic neoplasms was found in both genders (RR = 1.7, 95% CI: 1.2, 2.5). Hodgkin's disease risk was elevated in the first 10-year observation period (RR = 4.9, 95% CI: 1.5, 16.4), whereas the highest increase for non-Hodgkin's lymphoma (RR = 2.8, 95% CI: 1.1, 7.0) and myeloid leukemia (RR = 3.8, 95% CI: 1.2, 12.5) occurred after 15 years. No soft tissue sarcoma cases were found in these zones (0.8 expected). An overall increase in diabetes was reported, notably among women (RR = 2.4, 95% CI: 1.2, 4.6). Chronic circulatory and respiratory diseases were moderately increased, suggesting a link with accident-related stressors and chemical exposure. Results support evaluation of dioxin as carcinogenic to humans and corroborate the hypotheses of its association with other health outcomes, including cardiovascular-and endocrine-related effects. Am J Epidemiol 2001;153:1031-44. period only, sustained mainly by suggestive increases in a number of cancer types and sites (including digestive, lung, melanoma, and bladder) and by deaths due to circulatory dis-ease. Lung cancer and non-Hodgkin's lymphoma increased steeply after 15 years. Increased circulatory disease mortality characterized the first 10-year period, with the exception of * Adjusted for age, calendar period, and gender. † ICD-9, International Classification of Diseases and Causes of Death, Ninth Revision; Obs, observed no.; Exp, expected no.; RR, rate ratio; CI, confidence interval.
Toxicological Sciences, 2001
The United States Environmental Protection Agency (U.S. EPA) has concluded that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a human carcinogen, and it has stated that the lifetime all-cancer mortality risk attributable solely to the current background body burden of dioxin-like compounds could be as high as 1.3 per 100. U.S. EPA's most current human cancer risk estimate was obtained from a linear dose-response model fit to the data from three epidemiology studies of TCDD-exposed chemical workers. Herein it is shown that the U.S. EPA model fails to provide an adequate fit to that data, whereas an intercept-only model, having no slope whatsoever, is entirely adequate. Although the epidemiology data used by U.S. EPA are consistent with a significant elevation in all-cancer mortality, by about 32%, among TCDD-exposed workers, this elevation should not be attributed to the workers' TCDD exposure.
Significant Issues Raised by Meta-analyses of Cancer Mortality and Dioxin Exposure
Environmental Health Perspectives, 2003
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 10-3 per picogram per kilogram per day for 2,3,7,8-tetrachlorodibenzop-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 (Starr 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 metaanalysis "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. Selection of a Dose Metric Average TCDD body burden. The U.S. EPA (2000) and I (Starr 2001) both employed average TCDD body burden as the dose metric. Fingerhut et al. (1991), in a study of the NIOSH cohort (5,172 workers from 12 U.S. plants), provided all cancer standardized mortality ratios (SMRs) for four exposure duration categories-< 1, 1 to < 5, 5 to < 15, and ≥ 15 years-all with at least 20 years elapsed since first exposure; SMRs [95% confidence intervals (CIs)] for these categories are 102
Cancer risk for chemical workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin
Occupational and Environmental Medicine, 2003
Aims: To describe the long term mortality experience of a cohort of 2187 male chemical production workers previously exposed to substantial levels of dioxin. Methods: Vital status for a previously identified cohort was determined for an additional 10 years, to 1995. Dioxin exposures took place before 1983 and were sufficient to result in chloracne in 245 individuals. Mortality rates were compared with national figures and with a large pool of co-workers in unrelated production jobs. Results: All cancers combined (standardised mortality ratio (SMR) = 1.0, 95% CI 0.8 to 1.1) and lung cancer (SMR = 0.8, 95% CI 0.6 to 1.1) were at or below expected levels. Rates for soft tissue sarcoma (SMR = 2.4, 95% CI 0.3 to 8.6) and non-Hodgkin's lymphoma (SMR = 1.4, 95% CI 0.6 to 2.7) were greater than expected overall, but below expectation in the update period. No trend of increasing risk with increasing exposure was observed for these cancers. Workers who developed chloracne had very low all-cancer rates (SMR = 0.5, 95% CI 0.3 to 1.0), and lung cancer rates (SMR = 0.3, 95% CI 0.0 to 1.1). Conclusions: We found no coherent evidence of increased cancer risk from dioxin exposure in this cohort. Our study highlights the wide range of cancer rates and the lack of consistency across dioxin studies.
The Seveso Studies on Early and Long-Term Effects of Dioxin Exposure: A Review
Environmental Health Perspectives, 1998
The industrial accident that occurred in the town of Seveso, Italy, in 1976 exposed a large population to substantial amounts of relatively pure 2,3,7,8-tetrachlorodibenzo-p-dioxin. Extensive monitoring of soil levels and measurements of a limited number of human blood samples allowed classification of the exposed population into three categories, A (highest exposure), B (median exposure), and R (lowest exposure). Early health investigations including liver function, immune function, neurologic impairment, and reproductive effects yielded inconclusive results. Chloracne (nearly 200 cases with a definite exposure dependence) was the only effect established with certainty. Long-term studies were conducted using the large population living in the surrounding noncontaminated territory as reference. An excess mortality from cardiovascular and respiratory diseases was uncovered, possibly related to the psychosocial consequences of the accident in addition to the chemical contamination. An excess of diabetes cases was also found. Results of cancer incidence and mortality follow-up showed an increased occurrence of cancer of the gastrointestinal sites and of the lymphatic and hematopoietic tissue. Experimental and epidemiologic data as well as mechanistic knowledge support the hypothesis that the observed cancer excesses are associated with dioxin exposure. Results cannot be viewed as conclusive. The study is continuing in an attempt to overcome the existing limitations (few individual exposure data, short latency period, and small population size for certain cancer types) and to explore new research paths (e.g., differences in individual susceptibility). -Environ Health Perspect 106(Suppl 2): 625-633 (1998). http://ehpnetl.niehs.nih.gov/docs/1998/Suppl-2/625-633bertazzi/abstract.html
Human exposure to dioxins from food, 1999–2002
Food and Chemical Toxicology, 2005
In response to aggressive attempts to control dioxin emissions over the last 35 years, human exposures to dioxins from the environment have declined significantly. The primary source of human exposure to dioxins at present is food. The sources of dioxins in food are not well understood and are probably varied. Data on the levels of dioxins measured in various foods for samples collected from 2000 to 2002 have recently been released by the US Food and Drug Administration as part of its Total Diet Study. Data on samples collected in 1999, and released in 2002, are also available. Based on those data and on the US Department of AgricultureÕs most recent food consumption survey (1994-1996 & 1998 Continuing Survey of Food Intakes by Individuals), estimates of dioxin intake for the total US population and for three age groups of children were obtained. Results show that the most recent mean dietary exposures for all groups are below 2 pg TEQ/kg BW/day, the tolerable daily intake established for dioxins by the World Health Organization. Between 1999 and 2002 mean dioxin intakes from food appear to have decreased, but when estimates are adjusted based on a standardized limit of detection and evaluating only those {congener · food} combinations common to all 4 years, no trend is apparent. When dioxin concentrations below the limit of detection are represented by one-half the limit, approximately 5% of the intake estimates for 2-year-olds and 1% of the intake estimates for 6-year-olds exceed the tolerable daily intake by about 10%, although such upper-percentile estimates should not be equated with excess risk. When non-detectable dioxin values are set to zero (i.e., when only dioxin values actually measured are used), only 1% of intake estimates exceed the tolerable daily intake for 2-year-olds. As expected, about 50% of daily dietary dioxin intake by the total US population is attributable to meat and dairy products, based on the same food group classifications used by the National Academy of SciencesÕ Committee on the Implications of Dioxin in the Food Supply. This information may be useful for targeting future risk management activities.
Occupational and Environmental Medicine, 2012
Objectives To examine the long-term effects of dioxinexposure, particularly with regard to cancer mortality, in a follow-up 23 years after closure of the chemical plant (Hamburg, Germany). Methods The study comprised all persons (1191 men/ 398 women) employed in the plant on a full-time basis for a minimum of 3 months between 1952 and 1984 when the plant was closed down. Mortality follow-up was performed for the period from 1952 up to the reference date of 31 December 2007. Subjects entered the cohort at the date of their first employment in the plant. We calculated standardised mortality ratios (SMRs) using the population of Hamburg as reference. Results The vital status could be determined for 96.5% of the study group (1145 men and 389 women). For men, there was an increase in overall mortality (ICD-9 1e999) (SMR¼1.14, 95% CI 1.06 to 1.23), all-cancer mortality (SMR¼1.37, 95% CI 1.21 to 1.56) and specific mortality from respiratory cancer (ICD-9 161, 162, 163) (SMR¼1.64, 95% CI 1.32 to 2.03), oesophageal cancer (ICD-9 150) (SMR¼2.56, 95% CI 1.27 to 4.57), rectum cancer (ICD-9 154) (SMR¼1.96, 95% CI 0.98 to 3.51), as well as diseases of the circulatory system (ICD-9 390e459) (SMR¼1.16, 95% CI 1.02 to 1.31). For women, there was an increase in breast cancer mortality (ICD-9 174) (SMR¼1.86, 95% CI 1.12 to 2.91). Conclusions The results of this extended follow-up are consistent with those of previous analyses of the cohort and with those of other cohorts. Our findings support the carcinogenic effect of dioxin compounds.
Dioxin exposure and non-malignant health effects: a mortality study
Occupational and Environmental Medicine, 1998
Objective-To investigate, in a population heavily exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the possible unusual occurrence of diseases other than cancer. Methods-Five year extension of the follow up of the cohort involved in the Seveso accident. Soil measurements identified three exposure zones: (A) highest contamination, (B) substantial, and (R) low but higher than background contamination. Blood TCDD measurements, although limited in number, confirmed zone exposure ranking. The 15 year mortality in the exposed cohort was compared with that of a large population in the surrounding non-contaminated territory. Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated with Poisson regression techniques. Results-The already noted increased occurrence of cardiovascular deaths was confirmed, in particular in zone A, among males for chronic ischaemic heart disease (five deaths, RR 3.0, 95% CI 1.2 to 7.3), and among females for hypertensive disease (three deaths, RR 3.6, 95% CI 1.2 to 11.4) and chronic rheumatic heart disease. Novel findings were the increase of chronic obstructive pulmonary disease, most notably among males in zone A (four deaths, RR 3.7, 95% CI 1.4 to 9.9) and females in zone B (seven deaths, RR 2.4, 95% CI 1.1 to 5.1); and from diabetes, which was significantly increased in females in zone B (13 deaths, RR 1.9, 95% CI 1.1 to 3.2). In zone R, chronic ischaemic heart disease (males and females), hypertension (females), and diabetes (females) showed less pronounced, although significant excesses. Conclusions-As well as high TCDD exposure, the accident caused a severe burden of strain in the population. Both these factors might have contributed to the noted increased risks (in particular, circulatory and respiratory). The cardiovascular and immune toxicity of TCDD, as well as its complex interaction with the endocrine system, might be relevant to the explanations of these findings. These results, although not conclusive, concur with previous data in suggesting cardiopulmonary and endocrine eVects in humans highly exposed to TCDD. (Occup Environ Med 1998;55:126-131)