Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

BACKGROUND: In 1997, the International Agency for Research on Cancer classified 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a group 1 human carcinogen, based largely on four highly exposed industrial cohorts that showed an excess of all cancers combined. In this study, we extended the follow-up period for the largest of these cohorts by 6 years and developed a job-exposure matrix. METHODS: We did cohort mortality analyses involving 5132 chemical workers at 12 U.S. plants by use of life table techniques (U.S. population referent) and Cox regression (internal referent). We conducted exposure-response analyses for 69% of the cohort with adequate work history data and adequate plant data on TCDD contamination. All P values are two-sided. RESULTS: The standardized mortality ratio (SMR) for all cancers combined was 1.13 (95% confidence interval = 1.02-1.25). We found statistically significant positive linear trends in SMRs with increasing exposure for all cancers combined and for lung cancer. The SMR for all cancers combined for the highest exposure group was 1.60 (95% confidence interval = 1.15-1.82). SMRs for heart disease showed a weak increasing trend with higher exposure (P = .14). Diabetes (any mention on the death certificate) showed a negative exposure-response trend. Internal analyses with Cox regression found statistically significant trends for cancer (15-year lag time) and heart disease (no lag). CONCLUSIONS: Our analyses suggest that high TCDD exposure results in an excess of all cancers combined, without any marked specificity. However, excess cancer was limited to the highest exposed workers, with exposures that were likely to have been 100-1000 times higher than those experienced by the general population and similar to the TCDD levels used in animal studies.

Cytogenetic effects of formaldehyde exposure in students of mortuary science.

The effect of low-level exposure to formaldehyde on oral, nasal, and lymphoycte biological markers was studied prospectively in a group of 29 mortician students who were about to take a course in embalming. During the 85-day study period, the subjects performed an average of 6.9 embalmings and had average cumulative formaldehyde exposures of 14.8 ppm-h, with an average air concentration of 1.4 ppm during embalming. Since the average time spent embalming was 125 min, formaldehyde exposures calculated as an 8-h time-weighted average were 0.33 ppm on days when embalmings were done, which was less than the Occupational Safety and Health Administration permissible exposure limit of 0.75 ppm. Epithelial cells from the buccal area of the mouth showed a 12-fold increase in micronucleus frequency during the study period, from 0.046 +/- 0.17/1000 cells preexposure to 0.60 +/- 1.27/1000 cells at the end of the course (P < 0.05). Nasal epithelial micronuclei increased 22%, from 0.41 +/- 0.52/1000 cells to 0.50 +/- 0.67/1000 cells (P = 0.26). In blood cells, the frequency of micronucleated lymphocytes increased 28%, from 4.95 +/- 1.72/1000 cells to 6.36 +/- 2.03/1000 cells (P < 0.05), while sister chromatid exchanges decreased 7.5% (P < 0.05). A dose-response relationship was observed between cumulative exposure to formaldehyde and increases in buccal micronuclei in the 22 male subjects but not in the 7 female subjects. We conclude that low-level exposure to formaldehyde is associated with cytogenetic changes in epithelial cells of the mouth and in blood lymphocytes. These cytogenetic effects may be useful as markers of biologically effective dose.

Evaluation of cardiovascular outcomes among U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Some animal studies and some human studies suggest that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may be associated with adverse effects on the cardiovascular system. As part of a cross-sectional medical study comparing workers employed 15 years earlier in the manufacture of 2,4,5-trichlorophenol or one of its derivatives at two U.S. chemical plants with an unexposed comparison group, we examined the association between TCDD exposure and various cardiovascular outcomes. A total of 281 workers and 260 unexposed referents participated. The workers had substantial exposure to TCDD, as demonstrated by significantly elevated mean serum TCDD concentration of 220 pg/g of lipid, compared with 7 pg/g of lipid among the referents. No significant association was found between TCDD exposure and any of the cardiovascular outcomes including myocardial infarction, angina, cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow. Although our study had sufficient statistical power to detect an elevated risk for cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow, it had low power (approximately 50%) to detect an elevated risk for myocardial infarction and angina. Our review of the literature suggests that our negative findings are consistent with those from other cross-sectional medical studies. Although several mortality studies of TCDD-exposed cohorts found significantly increased risks for cardiovascular disease mortality, similar increased risks were not observed in other mortality studies. The data available do not provide definitive conclusions but indicate that further examination of the association between TCDD exposure and cardiovascular disease should be pursued.

Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

There is conflicting research regarding an association between fetal death and paternal exposure to Agent Orange, a phenoxy herbicide widely used in Vietnam that was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Men who worked in the U.S. factories that produced Agent Orange were exposed to TCDD at levels hundreds of times higher than TCDD levels in the general population. Wives of TCDD-exposed chemical workers and wives of nonexposed neighborhood referents were interviewed to determine reproductive history. Paternal serum TCDD level at time of conception was estimated for each pregnancy using serum samples taken in 1987. Estimated TCDD levels of workers during or after exposure were high (median, 254 ppt; range, 3-16,340 ppt) compared to referent levels (median, 6 ppt; range, 2-19 ppt). No association between paternal TCDD level at the time of conception and spontaneous abortion was observed among pregnancies fathered by workers with TCDD levels of < 20 ppt [odds ratio (OR) = 0.77; 95% confidence interval (CI), 0.48-1.22], 20 to < 255 ppt (OR = 0.81; 95% CI, 0.40-1.63), 255 to < 1,120, (OR = 0.69; 95% CI, 0.30-1.58), and >or= 1,120 ppt (OR = 0.95; 95% CI, 0.42-2.17) compared to pregnancies fathered by referents. The sex ratio [males/(males + females)] of offspring also did not differ by TCDD exposure (0.53 and 0.54 among workers and referents, respectively). We did not find an association between paternal serum TCDD level and spontaneous abortion or sex ratio of offspring in this population. The estimated TCDD levels in this exposed worker population were much higher than in other studies, providing additional evidence that paternal TCDD exposure does not increase the risk of spontaneous abortion at levels above those observed in the general population. The study could not evaluate the effect of father's childhood or prenatal TCDD exposure on subsequent sex ratio.

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.

Mortality of workers employed in shoe manufacturing.

A retrospective cohort mortality study was conducted among 7814 white shoe manufacturing workers followed from 1940 through 1982. The workers were potentially exposed to solvents (including toluene) and solvent-based adhesives. Benzene may have been present as an impurity of toluene. Mortality due to leukemia and aleukemia was not statistically significantly elevated. Statistically significant excess mortality due to cancer of the trachea, bronchus and lung was observed in the total cohort [standardized mortality ratio (SMR) 147, 95% confidence interval (95% CI) 120-180] and showed a statistically significant trend in standardized relative risk with increasing potential latency, but not with increasing duration of employment. Chronic nonmalignant respiratory disease was significantly elevated among the men (SMR 158, 95% CI 114-217) but was less than expected among the women (SMR 79), a finding suggesting a possible contribution of smoking to the mortality from respiratory cancer. However, adjustment for the potential effects of smoking did not completely eliminate the increased risk for lung cancer.

An evaluation of reports of dioxin exposure and soft tissue sarcoma pathology among chemical workers in the United States.

A review of employment records and tissue specimens of seven workers, reported previously as having occupational dioxin exposure and soft tissue sarcomas, confirms that four workers had employment of 2 to 19 years in the production of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or trichlorophenol, products contaminated with 2,3,7,8-tetrachlorodibenzodioxin, the most toxic dioxin isomer. Of these individuals, two have confirmed soft tissue sarcomas. In addition three individuals who worked for companies which made 2,4,5-T also have confirmed soft tissue sarcomas. Their employment records do not show specific assignment to 2,4,5-T or trichlorophenol departments; however, one individual worked for 10 d in the production of pentachlorophenol, which is contaminated with different isomers of dioxin. Methodological problems are discussed which must be addressed in the epidemiologic evaluation of the outcome of soft tissue sarcoma.

Evaluation of serum lipid concentrations among U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

2,3,7,8-Tetrachlorodibenzo-p-dioxin alters lipid metabolism in animals; however, evidence for such an effect in humans is conflicting. This conflict was addressed using data from a cross-sectional medical study conducted between 1987 and 1988. The exposed participants had been employed at least 15 y earlier in the manufacture of 2,4,5-trichlorophenol or one of its derivatives at two chemical plants in the United States. A total of 281 workers and 260 unexposed referents participated. Workers had substantial exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin, evidenced by a median serum 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration of 406.6 femtograms/gram of serum (fg/g serum), compared with 36.9 fg/g serum among the referents. A slight association between triglyceride concentration and serum 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration was found (p = .05). Over the range of observed 2,3,7,8-tetrachlorodibenzo-p-dioxin values (i.e., 37-19000 fg/g serum), triglyceride concentration increased only about 0.4 mmol/I. No association was found between an abnormally elevated triglyceride (i.e., > 2.82 mmol/I) concentration and serum 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration. An association was also found between serum 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration and an abnormal high-density lipoprotein concentration (p = .09). in summary, there was evidence of an effect on lipid metabolism in a group of workers with high serum 2,3,7,8-tetrachlorodibenzo-p-dioxin concentrations. The influence of serum 2,3,7,8-tetrachlorodibenzo-p-dioxin on lipid concentrations, however, was small, compared with the influence of other factors.

Identification of soft tissue sarcoma deaths in cohorts exposed to dioxin and to chlorinated naphthalenes.

Identification of soft tissue sarcomas (STSs) in epidemiologic mortality studies is complicated by nosologic coding rules that require that STSs arising in a visceral organ must be coded in the International Classification of Diseases (ICD) category for that organ, rather than in the ICD category for malignant neoplasms of connective tissue. Moreover, prior studies have shown poor agreement between diagnoses recorded on death certificates compared with those in hospital records for these tumors. We reviewed deaths from STS among workers in a registry of 6,716 dioxin-exposed workers at the National Institute for Occupational Safety and Health (NIOSH) and in a NIOSH cohort mortality study of 10,240 workers exposed to chlorinated naphthalenes. We identified 19 subjects with STSs. Of these, 17 (89%) were identifiable by reading the entries on selected death certificates, and two (11%) were found only by reviewing medical records of cases coded to ICD categories likely to have contained STS. Of the 17 STSs identified from death certificates, only nine (53%) had been coded as underlying cause of death to the ICD category "malignant neoplasms of soft and connective tissue." Medical records were obtained for 14 of the 17 cases (82%), and in each case, the STS diagnosis was verified. Tissue blocks from tumors were available for review in nine of the 17 cases identified from death certificates, and the diagnosis of STS was verified in seven (78%). Nosologic rules reduce the sensitivity of cohort mortality studies to detect excesses of STS.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancing the quality of epidemiologic studies.

Three principles can improve epidemiologic studies (1) Conduct open scientific review of research protocols and final reports, (2) Disseminate study results to all appropriate parties, and (3) Incorporate new scientific methods into the research and utilize expertise from other disciplines. The procedures we describe are used within the Industrywide Studies Branch of the National Institute for Occupational Safety and Health to implement these principles.

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.

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.

A mortality study of workers at seven beryllium processing plants.

The International Agency for Research on Cancer (IARC) has found that the evidence for the carcinogenicity of beryllium is sufficient based on animal data but "limited" based on human data. This analysis reports on a retrospective cohort mortality study among 9,225 male workers employed at seven beryllium processing facilities for at least 2 days between January 1, 1940, and December 31, 1969. Vital status was ascertained through December 31, 1988. The standardized mortality ratio (SMR) for lung cancer in the total cohort was 1.26 (95% confidence interval [CI] = 1.12-1.42); significant SMRs for lung cancer were observed for two of the oldest plants located in Lorain, Ohio (SMR = 1.69; 95% CI = 1.28-2.19) and Reading, Pennsylvania (SMR = 1.24; 95% CI = 1.03-1.48). For the overall cohort, significantly elevated SMRs were found for "all deaths" (SMR = 1.05; 95% CI = 1.01-1.08), "ischemic heart disease" (SMR = 1.08; 95% CI = 1.01-1.14), "pneumoconiosis and other respiratory diseases" (SMR = 1.48; 95% CI = 1.21-1.80), and "chronic and unspecified nephritis, renal failure, and other renal sclerosis" (SMR = 1.49; 95% CI = 1.00-2.12). Lung cancer SMRs did not increase with longer duration of employment, but did increase with longer latency (time since first exposure). Lung cancer was particularly elevated (SMR = 3.33; 95% CI = 1.66-5.95) among workers at the Lorain plant with a history of (primarily) acute beryllium disease, which is associated with very high beryllium exposure. The lung cancer excess was not restricted to plants operating in the 1940s, when beryllium exposures were known to be extraordinarily high. Elevated lung cancer SMRs were also observed for four of the five plants operating in the 1950s for workers hired during that decade. Neither smoking nor geographic location fully explains the increased lung cancer risk. Occupational exposure to beryllium compounds is the most plausible explanation for the increased risk of lung cancer observed in this study. Continued mortality follow-up of this cohort will provide a more definitive assessment of lung cancer risk at the newer plants and among cohort members hired in the 1950s or later at the older plants. Further clarification of the potential for specific beryllium compounds to induce lung cancer in humans, and the possible contribution of other exposures in specific processes at these plants, would require a nested case-control study. We are currently assessing whether available industrial hygiene data would support such an analysis.

Women: work and health.

OBJECTIVES: This report describes the sociodemographics, household characteristics, and health of women according to workforce status and job conditions. The report also presents data on men for comparison. METHODS: This report combines data from numerous data systems, including: The National Health Interview Survey, National Health and Nutrition Examination Survey, National Maternal and Infant Health Survey, National Hospital Ambulatory Medical Care Survey, National Traumatic Occupational Fatalities Surveillance System, and the National Occupational Mortality Surveillance System, which are conducted by the U.S. Department of Health and Human Services; the Census of Fatal Occupational Injuries and Annual Survey of Occupational injuries and illnesses conducted by the U.S. Department of Labor; and the Current Population Survey conducted by the U.S. Department of Commerce. The report also presents selected tables from publications of the Women's Bureau and the Bureau of Labor Statistics, U.S. Department of Labor. RESULTS: The report presents summary data on physical conditions and exposures, health conditions attributed to work, other health conditions that impact on work, health promotion in the workplace, and health-related benefits provided by employers. Most estimates are shown according to sex, age, race, ethnicity, educational attainment, and major occupational group.

Peripheral neuropathy after occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Reports of human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) describe signs and symptoms consistent with exposure-related peripheral neuropathy. In a cross-sectional study, prevalence of peripheral neuropathy was measured in 265 workers exposed 15 years earlier to chemicals contaminated with TCDD and in 244 unexposed, age-, race-, gender- and community-matched comparisons. Cases of peripheral neuropathy were defined from examination, electrophysiologic and quantitative sensory tests, and symptoms. Exposure was assessed by measuring lipid-adjusted serum TCDD levels. The mean serum TCDD level for workers (220 parts per trillion (ppt)) was significantly higher than for referents (7 ppt) (p < .0001). Thirty-two percent of both worker and referent groups met the case definition for peripheral neuropathy. In the logistic regression analyses, serum TCDD level was not related to peripheral neuropathy. These data suggest that despite continued high serum TCDD levels, peripheral neuropathy is not a long-term sequela of high exposure to TCDD-contaminated chemicals. However, the study cannot preclude the occurrence and subsequent resolution of acute effects caused by high exposure, as experienced in Seveso and possibly by some workers, while exposed to high levels of TCDD-contaminated substances.

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.

Evaluation of porphyria cutanea tarda in U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

A cross-sectional medical study was performed to evaluate whether occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-contaminated substances is associated with porphyria cutanea tarda or porphyrinuria. The exposed participants were employed more than 15 years earlier in the manufacture of sodium trichlorophenol and its derivatives. The referent group consisted of individuals with no occupational exposure to phenoxy herbicides. A total of 281 workers and 260 referents participated. The pattern of urinary porphyrin excretion for each participant was assessed to determine if symptomatic or subclinical porphyria cutanea tarda was present. None of the participants were found to have symptomatic porphyria cutanea tarda. No difference was found between workers and referents in the prevalence of subclinical porphyria cutanea tarda (odds ratio [OR] = 0.93, 95% confidence interval [CI] 0.19, 4.54). There were also no differences in the risk between workers and referents for an out-of-range urinary uroporphyrin or coproporphyrin concentration. In conclusion, this study did not find an elevated risk for porphyria cutanea tarda or porphyrinuria among workers with high serum TCDD levels. Our review of the literature indicates that there is insufficient evidence available to convincingly support or refute an association in humans between TCDD exposure and porphyria cutanea tarda or porphyrinuria.