Marilyn A. Fingerhut

Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

BACKGROUND In both animal and epidemiologic studies, exposure to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD) has been associated with an increased risk of cancer. METHODS We conducted a retrospective cohort study of mortality among the 5172 workers at 12 plants in the United States that produced chemicals contaminated with TCDD. Occupational exposure was documented by reviewing job descriptions and by measuring TCDD in serum from a sample of 253 workers. Causes of death were taken from death certificates. RESULTS Mortality from several cancers previously associated with TCDD (stomach, liver, and nasal cancers, Hodgkins disease, and non-Hodgkins lymphoma) was not significantly elevated in this cohort. Mortality from soft-tissue sarcoma was increased, but not significantly (4 deaths; standardized mortality ratio [SMR], 338; 95 percent confidence interval, 92 to 865). In the subcohort of 1520 workers with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency, however, mortality was significantly increased for soft-tissue sarcoma (3 deaths; SMR, 922; 95 percent confidence interval, 190 to 2695) and for cancers of the respiratory system (SMR, 142; 95 percent confidence interval, 103 to 192). Mortality from all cancers combined was slightly but significantly elevated in the overall cohort (SMR, 115; 95 percent confidence interval, 102 to 130) and was higher in the subcohort with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency (SMR, 146; 95 percent confidence interval, 121 to 176). CONCLUSIONS This study of mortality among workers with occupational exposure to TCDD does not confirm the high relative risks reported for many cancers in previous studies. Conclusions about an increase in the risk of soft-tissue sarcoma are limited by small numbers and misclassification on death certificates. Excess mortality from all cancers combined, cancers of the respiratory tract, and soft-tissue sarcoma may result from exposure to TCDD, although we cannot exclude the possible contribution of factors such as smoking and occupational exposure to other chemicals.

Impact of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls on human and environmental health, with special emphasis on application of the toxic equivalency factor concept

A scientific evaluation was made of the mechanisms of action of polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls. Distinction is made between the aryl-hydrocarbon (Ah) receptor-mediated and non-Ah receptor-mediated toxic responses. Special attention is paid to the applicability of the toxic equivalency factor (TEF) concept.

Review and update of the results of the NIOSH medical study of workers exposed to chemicals contaminated with 2,3,7,8‐tetrachlorodibenzodioxin

In 1987, the National Institute for Occupational Safety and Health conducted a cross-sectional medical study to examine the long-term health effects of occupational exposure to chemicals and materials contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). This study compared living workers employed more than 15 years earlier in the production of sodium trichlorophenol (NaTCP), and 2,4,5-trichlorophenoxyacetic ester (2,4,5-T ester) with an unexposed comparison group. Health status of the worker and comparison populations was collected through a comprehensive set of standardized interviews and medical examinations. Lipid adjusted serum TCDD levels were also measured. Workers had a statistically significantly elevated mean serum lipid-adjusted TCDD level (workers = 220 pg per g of lipid [range = not detected-3,400 pg per g of lipid], and referents 7 pg per g of lipid [range not detected-20 pg per g of lipid], P < 0.001). Compared to a community-based referent population, the prevalence of chronic bronchitis, chronic obstructive pulmonary disease, peripheral neuropathy, depression, cardiovascular outcomes (myocardial infarction, angina, cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow), abnormal porphyrin levels, and abnormal ventilatory function parameters FEV1.0, FVC, or FEV1.0/FVC% in workers, was not statistically significantly different. In contrast, relationships were observed between serum 2,3,7,8-TCDD levels and the enzyme gamma-glutamyltransferase (GGT), the reproductive hormones serum testosterone, luteinizing, and follicle-stimulating hormones, and abnormal high-density lipoprotein concentration, counts of CD3/Ta1 cells (helper lymphocytes), and fasting serum glucose levels. Current diagnosis of chloracne was associated with the highest levels of serum 2,3,7,8-TCDD. Analysis of other endpoints continues.

A retrospective job exposure matrix for estimating exposure to 2,3,7, 8-tetrachlorodibenzo-p-dioxin.

BACKGROUND A job exposure matrix was developed to estimate the 2,3, 7,8-tetrachlorodibenzo-p-dioxin exposure of 3,538 workers who produced 2,4,5-trichlorophenol and its derivatives. METHODS Daily TCDD exposure scores that were plant, process, and period specific were estimated for each job title as the product of 1) the concentration of TCDD (microg/g); 2) a qualitative factor to account for the extent of worker contact and 3) time exposed to TCDD contamination. Daily scores were summed to compute individual cumulative TCDD exposure scores. RESULTS Daily TCDD exposure scores ranged from 0.001 to 1,250. Cumulative TCDD scores ranged from 0.002 to 1,559,430. The 393 workers with records of chloracne in the TCDD exposure cohort (11%) had markedly higher cumulative scores than those with no record of chloracne (a median score of 11,546 vs. 77). CONCLUSIONS The cumulative TCDD exposure scores incorporate both duration and level of exposure, and permit the relative ranking of worker exposures for the evaluation of exposure-response relationships between TCDD exposure and mortality in an updated cohort study analysis.

Levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the serum of U.S. chemical workers exposed to dioxin contaminated products: Interim results

Abstract NIOSH is conducting a medical study to evaluate the current health status of 400 chemical workers who made products contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and an unexposed referent group matched for age, sex, race and neighborhood of residence. The workers are from two U. S. facilities which produced 2,4,5-trichlorophenol and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) between 1951 and 1972. As a measure of their exposure to 2,3,7,8-TCDD, serum from each worker and from a sample of referents was analyzed for the concentration of this isomer. In this preliminary report, we present the results of the analyses for 2,3,7,8-TCDD found in the serum of 46 study participants. In general, the mean of 8.2 parts per trillion (ppt) 2,3,7,8-TCDD found in the unexposed group is comparable to levels found in unexposed persons in industrialized nations. However, the mean level of 208.2 ppt found in the workers greatly exceeds background levels (p

Serum levels of PCDDS and PCDFS among workers exposed to 2,3,7,8-TCDD contaminated chemicals

Abstract The National Institute for Occupational Safety and Health (NIOSH) collected serum from workers exposed to chemicals contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and from unexposed referents. A subset of serum samples were analyzed for polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). In addition to a marked difference in serum levels between workers and referents for 2,3,7,8-TCDD, there was a small but significant difference for 2,3,7,8-PnCDF and 1,2,3,4,7,8-HxCDF. Funding was received for this study from the Agency for Toxic Substances and Disease Registry.

Immunological markers among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

OBJECTIVES: To examine the association of immune cell number and function with occupational exposure to substances contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). METHODS: A cross sectional medical survey. The exposed participants were employed at two chemical plants between 1951 and 1972 in the manufacture of 2,4,5-trichlorophenate and its derivatives. The reference group consisted of people with no occupational exposure to phenoxy herbicides who lived within the communities of the workers. Data from a total of 259 workers and 243 unexposed referents were included in the analysis of immune function. Laboratory tests for immune status included enumeration of circulating leukocyte and lymphocyte populations, proliferative responses of circulating lymphocytes to mitogens and antigens, and serum concentrations of the major immunoglobulins and complement factor C3. RESULTS: The workers had substantial exposure to substances contaminated with TCDD, as indicated by a lipid adjusted mean serum TCDD concentration of 229 ppt compared with a mean of 6 ppt in the unexposed referents. Workers were divided into categories based on their serum TCDD concentration. For all categories except the lowest, with values of serum TCDD comparable with the unexposed referents, there were increased odds of having lower counts of CD26 cells (activated T cells) (odds ratio (OR) 1.0, 95% confidence interval (95% CI) 0.5 to 1.8 for TCDD < 20 ppt; OR 1.6, 95% CI 0.8 to 3.2 for TCDD 20-51 ppt; OR 2.7, 95% CI 1.4 to 5.1 for TCDD 52-125 ppt; OR 2.6, 95% CI 1.4 to 4.9 for TCDD 125-297 ppt; OR 2.4, 95% CI 1.3 to 4.6 for TCDD 298-3389 ppt). A less consistent finding was decreased spontaneous proliferation of cultured lymphocytes. However, increases were found in proliferation of lymphocytes in response to concanavalin and pokeweed in workers in the high TCDD category. Age, cigarette smoking, and alcohol were significant predictors of several immunological outcomes. CONCLUSIONS: Associations between serum TCDD concentration and both a decrease in circulating CD26 cells and decreased spontaneous background proliferation were the major findings of this study. These results are unlikely to be of clinical importance but may reflect limited evidence for an association between immunological changes in workers and high serum concentrations of TCDD, or chance findings resulting from the evaluation of multiple immunological variables.

Induction of P-450 in workers exposed to dioxin.

OBJECTIVES--To examine the effects of occupational exposure to substances contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cytochrome P-4501A2 activity in a cross sectional medical survey. METHODS--The exposed workers had been employed at two chemical plants > 15 years earlier in the manufacture of 2,4, 5-trichlorophenol and its derivatives. The control group consisted of people with no occupational exposure to phenoxy herbicides and who lived within the communities of the exposed workers. A total of 58 workers and 125 unexposed controls participated in the analysis. Cytochrome P-450 activity was assessed with test that measures caffeine metabolites in the urine. A ratio of metabolites of caffeine (CMR) constituted a measure of P-4501A2 activity. RESULTS--Compared with the control group in multivariate logistic regression, raised non-significant associations were found for three of four categories of TCDD in exposed workers (TCDD < 20 pg/g, odds ratio (OR) 1.7, 95% confidence interval (95% CI) 0.6 to 5.0, TCDD 20-66, OR 0.3, 95% CI 0.0 to 1.7; TCDD 67-147, OR 2.3, 95% CI 0.6 to 8.8; TCDD > or = 148, OR 3.1, 95% CI 0.8 to 12.5). We found a strongly significant association of CMR and urinary cotinine, a measure of smoking, and urinary free ethanol. We found weak non-significant associations between P-4501A2 activity and increased serum TCDD among workers. CONCLUSIONS--The absence of an association between serum TCDD and cytochrome P-4501A2 may be due to the size of the study, insensitivity of the CMR to assess cytochrome P-4501A2 activity, or inadequate levels of exposure, although these were among the highest in human groups tested.

Comparison of serum levels of 2,3,7,8-TCDD in TCP production workers and in an unexposed comparison group

Abstract Serum 2,3,7,8-TCDD levels were measured as an estimate of exposure to this isomer in 143 workers who were employed at either of two plants in New Jersey and Missouri which manufactured chemicals contaminated with 2,3,7,8-TCDD and in 54 unexposed referents. The mean serum 2,3,7,8-TCDD levels for all workers was 251.7 parts per trillion (ppt) and, for all referents combined, the mean serum level was 7.8 ppt. The mean level of 2,3,7,8-TCDD present in the serum of workers at the date of termination of exposure (half-life extrapolated) was 2600 ppt and 870 ppt for the New Jersey and Missouri workers, respectively. Overall, the levels in the workers significantly correlated with duration of exposure in 2,3,7,8-TCDD-contaminated processes (r = 0.83, p

Progress of the NIOSH cross-sectional medical study of workers occupationally exposed to chemicals contaminated with 2,3,7,8-TCDD

Abstract In 1987–1988, the National Institute for Occupational Safety and Health conducted a cross-sectional epidemiologic study of 400 living individuals who worked at two U.S. facilities which manufactured chemicals contaminated with 2,3,7,8-TCDD. For comparison, unexposed referents matched to each worker by age, race, sex and current resident community of the worker were studied. The study was designed to evaluate those health outcomes previously reported to be associated with exposure to 2,3,7,8-TCDD contaminants, including dermatologic, neurologic, hepatic, immunologic, and psychological disorders. Participation involved completion of an occupational history questionnaire and a two-day medical exam. The following is a preliminary report of the study design, referent selection and subject participation rates.