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  4. Review and Update of the Results of the NIOSH Medical Study

Review and Update of the Results of the NIOSH Medical Study of Workers Exposed
to Chemicals Contaminated With 2,3,7,8- Tetrachlorodibenzodioxin

    Marie Haring Sweeney, Geoffrey M. Calvert, Grace A. Egeland, Marilyn A. Fingerhut, William E. Halperin, and Laurie A. Piacitelli

    1 National Institute for Occupational Safety and Health, Cincinnati, Ohio
    2 State of Alaska Department of Health and Social Services, Section of Epidemiology, Anchorage, Alaska

    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 γ-glutamyltransferase (GGT), the reproductive hormones serum testosterone, luteinizing, and follicle-stimulating hormones, and abnormal high-density lipoprotein concentration, counts of CD3/Tal 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. Teratogenesis Carcinog. Mutagen. 17:241–247, 1997/98. © 1998 Wiley-Liss, Inc.

    Key words: dioxin; lipids; serum glucose; male reproductive hormones; NIOSH study

    *Correspondence to: Marie Haring Sweeney, Ph.D., Acting Chief, and Document Development Branch, NIOSH, Mailstop C-15, 4676 Columbia Parkway, Cincinnati, OH 45226.

    © 1998 Wiley-Liss, Inc.

    INTRODUCTION

    In 1987, the National Institute for Occupational Safety and Health (NIOSH) conducted a cross-sectional medical study to examine the long-term noncancer health effects of occupational exposure to chemicals and materials contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The details of the study design were previously described .

    METHODS

    This study compared living individuals (workers) employed more than 15 years earlier in the production of sodium trichlorophenol (NaTCP) or one of its derivatives, which were substances contaminated with TCDD, with an unexposed comparison group. The workers were employed in one of two plants located in Newark, New Jersey, and Verona, Missouri. Four hundred ninety (490) workers were employed at the New Jersey facility from 1951 through 1969 in the production of NaTCP, 2,4,5-T ester and other chemicals. At the facility in Verona, Missouri, 96 individuals were involved in the production of NaTCP, 2,4,5-T ester or hexachlorophene. Production of NaTCP and 2,4,5-T ester occurred for approximately 4 months in 1968 and production of 2,4,5-trichlorophenol and hexachlorophene occurred from April 1970 to January 1972. Both plants produced a variety of other chemicals. The referent (comparison) group was composed of individuals with no self-reported occupational exposure to TCDD-contaminated substances. Referents selected to participate in the study lived within the neighborhood of a worker and matched the worker by age (within 5 years), race, and gender.

    Information on worker and referent health status was collected through a comprehensive set of standardized interviews and medical examinations. A lifetime medical history was elicited from each participant using interviewer-administered questionnaires. To reduce observer bias, all individuals conducting the medical histories, examinations, and tests were blind to the exposure status (worker or referent) of the participant. An interviewer-administered lifetime occupational history was elicited from each participant separate from the medical history. Duration of each job and duration of occupational exposure to specific substances were recorded beginning with the participant's 16th birthday. Duration of exposure to TCDD-contaminated products was also calculated from personnel records.

    In this paper, we review and update the findings of the analyses of noncancer health effects in this highly exposed population of chemical workers. System-specific analyses were conducted and reported for chronic bronchitis, chronic obstructive pulmonary disease, and ventilatory function , hepatic and gastrointestinal intestinal effects , diabetes and serum glucose concentration, depression , peripheral neuropathy , porphyria cutanea tarda , serum testosterone and gonadotropin , P-450 induction , lipid concentrations , immunologic function , chloracne status, and cardiovascular morbidity . Serum concentrations of polychlorinated dibenzodioxins and dibenzofurans were also measured on all workers and a weighted sample of referents . Detailed descriptions of the system-specific analytic strategies can be found in the publications cited above.

    RESULTS

    Of the 586 workers at the two plants who were eligible for the study, 400 (68.3%) were alive and could be located at the time of the study. A total of 142 (24.2%) workers were deceased, and 44 (7.5%) could not be located. All 400 workers from the two plants who were living and could be located were invited to participate in the study; 281 (70%) were examined. A total of 938 referents were invited to participate in the study, of whom 260 (28%) were examined. Descriptive information on the study cohort has been previously reported .

    Serum TCDD Concentration

    Workers had a statistically significantly elevated mean serum lipid-adjusted TCDD concentration (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). The mean halflife-extrapolated lipid-adjusted serum TCDD concentration was also statistically significantly elevated among workers (workers = 1,900 pg per g of lipid, referents = 6 pg per g of lipid, P < 0.001). There were no statistically significant differences or consistent patterns of differences between workers and referents for demographic characteristics (age, race, gender, education, income) except alcohol-years, which was attributed to seven individuals with extremely high alcohol-year values and for most PCDDs or PCDFs other than 2,3,7,8-TCDD, 2,3,4,7,8-pentachlorodibenzofuran, and 1,2,3,4,7,8-hexachlorodibenzofuran (Table I). The significant difference in TCDD concentration between workers and referents validated worker exposure. Differences in the concentrations of the two furans were due to high values in a few workers in the New Jersey plant, the source of which has not been established.

    Health Outcomes

    Compared to the community-based referent population, the prevalence of the following conditions was not statistically significantly different in the TCDD-exposed workers: chronic bronchitis, chronic obstructive pulmonary disease , peripheral neuropathy , depression, cardiovascular outcomes (myocardial infarction, angina, cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow) , abnormal porphyrin concentrations, and abnormal ventilatory function parameters forced expiratory volume at one second (FEV1.0), forced vital capacity (FVC) or the ratio of FEV1.0 to FVC (FEV1.0/FVC%). On the other hand, statistically significant positive relationships were observed between serum 2,3,7,8-TCDD concentrations and the enzyme γ-glutamyltransferase (GGT) , serum testosterone, luteinizing hormone and follicle-stimulating hormone , concentrations of triglycerides and abnormal high density lipoprotein , counts of CD3/Tal cells (helper lymphocytes) , diagnosis of chloracne, and fasting serum glucose concentrations .

    Out-of-Range γ-Glutamyltransferase

    In the analysis of liver function and gastrointestinal disorders, 10.7% of workers and 5.0% of the referents had an out-of-range concentration of the enzyme γ-glutamyltransferase (GGT) (OR = 2.27; 95% CI, 1.17, 4.39). In the logistic regression analyses, the elevation in risk for an out-of-range GGT was confined only to workers with a history of alcohol consumption. Workers did not have increased liver disease nor elevations in other liver enzymes compared to unexposed comparisons.

    Serum Glucose Concentrations and Diabetes

    Fasting serum glucose concentrations were measured in each study participant on the first day of the examination and repeated if the concentration was 140 mg/dl or

    TABLE I. Lipid-Adjusted Serum Concentrations in Picograms Per Gram of Lipid for Selected PCDDs and PCDFs†

      Workers Referents
    Analyte Number    Mean    Median Range Number Mean    Median Range
    2387D 273    220   69 2–3,400  79   7§     6 2–20
    12378D 161 13   11 4.5–50  54 12   10 3.5–51
    123478D 153 12   11 1.9–41  49 13   11 3.2–58
    123678D 150 90   84 38–290  53 84   73 17–183
    1234678D 111    160 150 41–520  40    160 130 39–460
    OCDD 102 1,090 990 270–3,800  42 1,010 920 480–2,300
    2387F 118   2.4  — 160  41   1.2  — 3.5
    23478F 131 15   12 3.8–170  44 11     9.4 3.3–28
    123478F  94 15   13 4.2–120  44 11     9.6 4.2–28
    123678F 102 10     8.7 3.3–49  37   8.5     7.5 3.7–18
    1234678F  82 23   22 8–49  30 20   19 8.7–46
    OCDF  73   0.95   — 21  26

      1.1

    		  — 16

    †PCDDs, polychlorinated dibenzodioxins; PCDFs, polychlorinated dibenzofurans. Reproduced from Piacitelli et al. [14] with permission of the publisher.
    aLess than 50% of samples for this analyte were detectable values.
    bMaximum concentration detected in samples analyzed.
    *P < 0.05.

    greater . We noted a slight but statistically significant and positive increase in the risk of diabetes (OR = 1.12, P < 0.003) and fasting serum glucose (P < 0.001) with increasing serum concentrations of 2,3,7,8-TCDD. However, in this population, traditional risk factors for diabetes, age, weight, and family history or diabetes appear to be more influential than TCDD in the development of diabetes.

    Serum Testosterone, Follicle-Stimulating Hormone, and
    Luteinizing Hormone

    In linear regression analysis of total serum testosterone and gonadotrophin concentrations, current serum dioxin concentration was positively and significantly related to luteinizing hormone and follicle-stimulating hormone and inversely related to total testosterone concentrations after adjustment for potential confounders . These trends were also apparent in logistic regression analysis of high luteinizing hormone (>28 IU/liter), high follicle-stimulating hormone (>31 IU/liter), and low testosterone (<10.4 IU/liter) by serum dioxin quartiles (Table II). The trends observed in these data suggest some evidence of alterations in male reproductive hormone concentrations associated with TCDD exposure. Further studies are needed to clarify these results.

    Serum Lipid Concentrations

    Total cholesterol, high-density lipoprotein (HDL), and triglyceride concentrations were measured for each study participant [10]. The total cholesterol/HDL cholesterol ratio was calculated for each participant. A statistically significant association was noted between serum TCDD concentration and triglyceride concentration (test for trend, P < 0.05), while there was a positive but moderate relationship for an abnormal HDL (≤0.91 mmol/L) (test for trend, P < 0.09) (Table III). Although overall triglyceride concentration increased by 0.4 mmol/L over the range of serum TCDD values, there was no association demonstrated between an abnormally elevated tri-

    TABLE II. Adjusted Odd Ratios and 95% Confidence Intervals for High Serum Luteinizing Hormone, High Serum Follicle-Stimulating Hormone, and Low Serum Testosterone by Serum 2,3,7,8-TCDD Category (479 Observations)*

     

    High luteinizing hormone

    High follicle-
    stimulating hormone

    Low testosterone

    Serum
    2,3,7,8-TCDD
    category (pg/g)    		 Adjusted
    odds ratio    		 95%
    confidence
    limit    		 Adjusted
    odds ratio    		 95%
    confidence
    limit    		 Adjusted
    odds ratio    		 95%
    confidence
    limit
    Referents < 20 1.0 — 1.0 — 1.0 —
    Workers 1.6 0.8, 3.3 1.5 0.7, 3.3 2.1 1.0, 4.6
    <20 0.8 0.2, 3.0 1.1 0.3, 3.9 0.9 0.2, 4.5
    20–75 1.9 0.7, 5.5 1.7 0.5, 5.4 3.9 1.3, 11.3
    76–240 2.5 0.9, 7.3 1.7 0.5, 5.6 2.7 0.9, 8.2
    241–3,400 1.9 0.7, 5.0 2.0 0.7, 5.6 2.1 0.8, 5.8

    *Reproduced from Egeland et al., [8] with permission of the publisher.
    a>28 IU/liter.
    b>31 IU/liter.
    c<10.4 IU/lliter.
    dAdjusted for age, body mass index, alcohol, smoking, and diabetes mellitus.
    eAdjusted for age, alcohol, smoking, and diabetes mellitus.
    fAdjusted for age, body mass index, alcohol, smoking, and diabetes melllitus.

    TABLE III. Mean HDL Cholesterol and Triglyceride Concentrations and Adjusted Odds Ratios (OR) for an Abnormal HDL Cholesterol by Serum TCDD Category†

    Serum 2,3,7,8-
    TCDD category
    (fg/g serum)    		 HDL cholesterol Triglyceride
    No. Mean SE %Abnormal OR 95% CI Mean SE
    Referents <158  259 1.2 1.01 12.7 1.0   1.15 1.03
    Workers  273 1.2 1.01 16.8 1.2 0.7, 2.1 1.20 1.03
    <158    87 1.3 1.03   9.2 0.6 0.3, 1.4 1.04 1.06
    158–520    62 1.2 1.03 21.0 1.6 0.8, 3.5 1.26 1.07
    521–1515    62 1.1 1.03 12.9 1.0 0.4, 2.4 1.23 1.07
    1,516–19,717    62 1.1 1.03 25.8 2.2 1.1, 4.7  1.35 1.07
    Test for trend   P=0.15   P=0.09   P=0.05

    †fg/g = femtograms/gram; OR = odds ratio; CI = confidence interval. Reproduced from Calvert et al. [13] with permission of the publisher.
    aGeometric means (mmol/L) adjusted for gender, body weight index, pack years, use for beta-blocker medication, and current diabetes.
    bGeometic standard error term.
    cAbnormal defined as an HDL cholesterol concentration ≤ 0.91 mmol/L.
    dAdjusted for body weight index, use of beta-blocker medication, age, and current diabetes.
    eGeometric means (mmol/L) adjusted for body weight index, pack years, use of beta-blocker medication, race, gender, and current diabetes.
    *P < 0.05 when compared to the referent group.

    glyceride (>2.82 mmol/L) concentration and category of serum TCDD concentration. These data suggest that there is evidence to suspect a slight effect on lipid metabolism in this group of highly exposed workers. However, the magnitude of the effect of TCDD on lipid concentration is small when compared to that of other factors such as gender, body weight index, use of beta-blocker medication, and smoking.

    Chloracne

    Diagnosis of chloracne at the time of the study was associated with the highest stratum of serum TCDD (Odds Ratio 2.3, 95% CI 1.1, 4.3) .

    DISCUSSION

    In this population, we evaluated a series of health outcomes hypothesized to be related to exposure to TCDD. These endpoints were selected for study because previous studies or case reports had observed these outcomes in exposed populations. Although our population was clearly highly exposed to TCDD-contaminated chemicals, we found relatively few outcomes to be associated with TCDD exposure. The prevalence of the following was not related to serum TCDD concentrations: chronic bronchitis, chronic obstructive pulmonary disease, peripheral neuropathy, depression, cardiovascular outcomes (myocardial infarction, angina, cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow), abnormal porphyrin concentrations, and abnormal ventilatory function parameters forced expiratory volume at one second (FEV1.0), forced vital capacity (FVC), or the ratio of FEV1.0 to FVC (FEV1.0/FVC%). On the other hand, modest, but statistically significant positive relationships were observed between serum TCDD concentrations and the enzyme γ-glutamyltransferase (GGT), serum testosterone, luteinizing hormone and follicle-stimulating hormone, concentrations of triglyceride and abnormal high density lipoprotein, counts of CD3/Tal cells (helper lymphocytes), diagnosis of chloracne, and fasting serum glucose.

    REFERENCES

    1. Sweeney MH, Fingerhut MA, Connally LB, Halperin WE, Moody PL, Marlow DA: Progress of the NIOSH cross-sectional medical study of workers occupationally exposed to chemicals contaminated with 2,3,7,8-TCDD. Chemosphere 19:973–977, 1989.

    2. Calvert GM, Sweeney MH, Morris JA, Fingerhut MA, Hornung RW, Halperin WE: Evaluation of chronic bronchitis, chronic obstructive pulmonary disease (COPD) and ventilatory function among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Am Rev Respir Dis 144:1302–1306, 1991.

    3. Calvert GM, Hornung RW, Sweeney MH, Fingerhut MA, Halperin WE: Hepatic and gastrointestinal effects in an occupational cohort exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. JAMA 267:2209–2214, 1992.

    4. Sweeney MH, Hornung RW, Wall DK, et al: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-related increase in diabetes and serum glucose levels in workers exposed to TCDD-contaminated chemicals. Presented at 12th International Symposium on Chlorinated Dioxins and Related Compounds (Dioxin '92), Tampere, Finland, August 1992.

    5. Alderfer R, Sweeney M, Fingerhut M, Hornung R, Wille K, Fidler A: Measures of depressed mood in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemosphere 25:247–250, 1992.

    6. Sweeney MH, Fingerhut MS, Arezzo JC, Hornung RC: Peripheral neuropathy after occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Am J Ind Med 23:845–858, 1993.

    7. Calvert GM, Sweeney MH, Fingerhut MA, Hornung RW, Halperin WE: Evaluation of porphyria cutanea tarda in U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Am J Ind Med 25:559–571, 1994.

    8. Egeland GM, Sweeney MH, Fingerhut MA, Wille KK, Schnorr TM, Halperin WE: Total serum testosterone and gonadotropins in workers exposed to dioxin. Am J Epidemiol 139:272–281, 1994.

    9. Halperin WE, Kalow W, Sweeney MH, Tang BK, Fingerhut M, Tompkins B, Wille KK: Induction of P-450 in workers exposed to dioxin. Occup Environ Med 52:86–89, 1995.

    10. Calvert GM, Wille KK, Sweeney MH, Fingerhut MA, Halperin WE: Evaluation of serum lipid abnormalities among U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. p-dioxin. Arch Environ Health 51:100–107, 1996.

    11. Halperin WE, Vogt R, Sweeney MH, Shopp G, Fingerhut MA, Peterson M, Kelsey K, Christiani D, Ware J: Immunologic markers among workers exposed to dioxin.

    12. Halperin WE, O'Malley M, Sweeney MH, Fingerhut MA, Westenforf D, et al: Historical and current chloracne as indicators of current serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

    13. Calvert GM, Wall DK, Sweeney MH, Fingerhut MA: An evaluation of cardiovascular outcomes among US workers exposed to 2,3,7,8-TCDD-contaminated substances. In van den Berg M, Brouwer A, Birnbaum L, Bueno-de-Mesquita B, Koppe J, Lambert G, Lindstrom G, Lynge E, Needham L, Theelen R, van Zorge J, van Wijnen J, eds: Proceedings of the Sixteenth International Symposium on Chlorinated Dioxins and Related Compounds. Organohalogen Compounds. Amsterdam: University of Amsterdam 30:190–193, 1996.

    14. Piacitelli LA, Sweeney MH, Fingerhut MA, Patterson DG, Turner WE, Connally LB, Wille KK, Tompkins B: Serum levels of PCDDs and PCDFs in a workers exposed to 2,3,7,8-TCDD contaminated chemicals. Chemosphere 25:251–254, 1992.

    15. Sweeney MH: “Evaluation of the Peripheral Nervous System Among Workers Employed in the Production of Chemicals Contaminated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin.” Dissertation. Ann Arbor: University of Michigan, 1990.

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