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  4. A Pilot Epidemiologic Study of Possible Health Effects

A Pilot Epidemiologic Study of Possible Health Effects Associated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Contaminations in Missouri

    REFERENCE 4 ABSTRACT.

    In 1971, 2,3,7,8-tetrachlorodibenzodioxin (TCDD)-containing waste oils were sprayed for dust control on residential, recreational, and work areas in Missouri. In several of these areas, the magnitude and the extent of this environmental contamination were not known until late 1982 or 1983. In the first phase of the investigation, a group of persons considered to be at highest risk of exposure and an appropriate comparison group were selected from reviews of Health Effects Survey screening questionnaires. These persons received complete medical examinations and a series of laboratory tests focused on detecting presymptomatic effects in key target organ systems (i.e., hepatic, dermatologic, immunologic, and neurologic effects). Comparisons of these two groups did not produce any firm indications of increased disease prevalence directly related to the putative exposures; of significance is the fact that no cases of chloracne or porphyria cutanea tarda were seen. Nevertheless, no overall definitive conclusion should be based just on this initial pilot study. Insights were provided that are being examined in more refined epidemiologic studies using different designs and strategies—especially of larger, more homogenous population groups in which exposure status can be better characterized—focused primarily on discerning any potential effects on the urinary tract, liver, neurological, and immune systems. Concurrently, research into the development of replicable laboratory analytical methods and reference ranges for measuring TCDD body burden are being pursued.

    IN EARLY 1971, waste byproducts from a hexachlorophene and 2,4,5-trichlorphenoxyacetic acid (2,4,5-T) production facility in southwestern Missouri were mixed with waste oils and sprayed on various sites (including horseback riding arenas) throughout the state for dust control. The contaminants included 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic member of a large group of chlorinated, oxygen-linked aromatic compounds commonly referred to as dioxins. The geographic distribution and levels of these environmental contaminations found by the Environmental Protection Agency (EPA) have been described in a previous paper.1

    The research was conceived as a pilot study of a group of persons presumed to be at highest risk of exposure to environmental TCDD. It was intended to provide preliminary information on possible health effects from these exposures so as to enable investigators to develop more refined and specific epidemiologic protocols to be used in further investigations. The reasons for choosing this approach included: (a) the limited environmental data at the time of planning this pilot survey that precluded rigorous classification of exposure for large study groups; (b) the lack of available direct measures of exposure, such as TCDD body burden; and (c) uncertainties about the types of health effects to be expected, since data on chronic human health effects and extrapolations from animal studies are limited. Therefore, the purpose was to provide perspectives on the general levels and types of health problems and to generate hypotheses for further, rigorous epidemiologic studies.

    MATERIALS AND METHODS

    We assessed potential health effects related to dioxin exposures by three means. First, we developed a Health Effects Survey questionnaire to elicit information on each person’s exposure risk (residential history; type, frequency, and duration of recreational activities; and occupational history), medical history (physician-diagnosed and/or self-reported conditions), and potentially confounding influences (e.g., life-style habits). We administered the questionnaire to individuals (or their nearest relative) believed to be at risk of exposure because they lived near, worked at, or frequently participated in activities near a contaminated site. The initial interviews were conducted among those individuals who had responded to general media announcements from public health officials urging participation in this survey/screening process. More active efforts were subsequently taken to find and interview all potentially exposed individuals and comparison populations from noncontaminated areas.

    Second, we sponsored a dermatology screening clinic available to anyone from the general population who had a current skin condition and had reason to suspect that he or she may have been exposed to environmental TCDD. The primary purpose was to screen for persons with chloracne for referral for a complete medical workup.

    Third, we reviewed approximately 800 completed questionnaires and selected 130 persons for inclusion in a pilot medical study. Since we were unable to directly measure exposure or uptake (i.e., measurements of body burden), we used the criteria discussed below for selecting the study cohorts so as to enhance the contrast in risk of exposure between the two groups.

    We selected as the high-risk group individuals who reported: (a) living or working for at least 6 months in areas contaminated with TCDD levels in soil exceeding 100 ppb or for at least 2 yr in areas contaminated at 20–100 ppb, or (b) participating more than once per week, on the average, in activities that involved close contact with the soil (such as gardening, field/court sports, horseback riding, or playing in soil) for at least 6 months in areas contaminated with TCDD levels in soil exceeding 100 ppb or for at least 2 yr in areas contaminated at 20–100 ppb. In general, the 82 persons in this group had the longest periods of exposure (up to 12 yr) to the highest levels of soil contamination (as high as 33,000 ppb) and/or reported having the most frequent high-soil-contact activities in these highly contaminated areas. This selection was to maximize our likelihood of identifying individuals with potential exposure.

    We also selected a low-risk comparison group of persons (most of whom were among the 800 who had completed the questionnaires) with the lowest risk of exposure frequency matched with the high-risk group on the basis of type of exposure site, age, sex, race, and socioeconomic status characteristics in a 2:1 ratio of high-to low-risk subjects. This group of 40 persons had no known access to or regular high-soil-contact activities in any known contaminated area.

    In addition to being assessed according to their responses on the Health Effects Survey questionnaire, the study groups were assessed under a clinical protocol that included six elements.

    (1.) Physical examination.
    (2.) Neurologic examination. (Separate questionnaires and reporting forms were prepared by a consulting neurologist, and the neurological examinations were conducted separately from the rest of, the physical examinations.)
    (3.) Dermatologic examination.
    (4.) Laboratory analyses:
    SMA liver function profile II plus beta-glucuronidase (included as an indirct measurement of hepatic microsomal enzyme induction by putative TCDD exposures) in serum;
    Serum thyroid stimulating hormone (TSH), thyroxine (T4), and cortisol;
    hepatitis B surface antigen (HBsAg) titers;
    high density lipoprotein-cholesterol (HDL-C);
    urinary porphyrins (total and pattern) and D-glucaric acid (included as an indirect measurement of hepatic microsomal enzyme induction by putative TCDD exposures);
    complete blood count (with differential);
    routine urinalysis.
    (5.) Immune Response Tests:
    Standard skin tine tests reaction to Candida, old tuberculin, Streptococcus, Proteus, diptheria, tetanus, triciphyton, and a glycerine control (marketed by Merieux Institute USA under U.S. Food and Drug Administration approval);
    T-cell subset assays;
    Lymphocyte proliferation response to phytohemagglutinin (PHA), concanavalin A (Con-A), pokeweed mitogen (PWM), and tetanus toxoid.
    (6.) Frozen serum kept for long-term storage to be used for TCDD-serum analyses when such tests become available.

    Examining physicians did not know each person’s risk of exposure, and the identification code was revealed only after all examinations, laboratory analyses, and data encoding had been completed.

    To ensure objectivity, we had separate but analogous statistical analyses conducted by the Centers for Disease Control, the Missouri Division of Health, and St. Louis University. Consistent with the exploratory nature of this pilot study, the broad-based questionnaires and physical/laboratory examinations were designed to elicit any clustering of abnormalities or trends (i.e., patterns) suggestive of abnormalities in specific organ systems. In addition, statistical analyses were conducted to test for differences between the high- and low-risk groups. Because of the relatively small sample size, most of the statistical analyses were conducted for total groups; however, when appropriate, analyses were stratified by subgroups with characteristic exposure patterns or with patterns based on other variables. Qualitative data (e.g., demographics, abnormal findings on physical examinations) were examined via a contingency table approach (Χ2 and Fisher’s exact test analyses) to determine if categorical differences existed between the high- and low-risk groups. When appropriate, parametric statistics (e.g., analyses of variance, t tests for means) were used to compare grouped and stratified means for various analytes. For measurements with a low expected proportion of positive results (e.g., inverted T-cell ratios or abnormally elevated serum cholesterol levels), analyses were conducted comparing these positivity proportions in the high-risk group with the corresponding proportion in the low-risk group. Distributions of “normal” or expected population values were taken from statistical results specific to the laboratory at which the analyses were done.

    RESULTS

    Of the 122 persons in the study group, 17.1% of the high-risk group and 10.0% of the low-risk group either refused to participate or failed to appear for the examinations (this difference was not significant, P > .05), yielding a study population of 104 (68 at high risk and 36 at low risk of exposure [Table 1]).

    Table 2 summarizes the results of all of the statistical analyses performed. The high- and low-risk groups were comparable in terms of age, race, sex, education of head of household, and interview respondent distributions. Similarly, the groups had equivalent participation

    in outdoor activities on which data were collected. The two groups did not differ significantly in the consumption of locally caught wild game or fish, the use of pest-control or lawn-care services, the use of any type of pesticide (i.e., other potential sources of exposure), or the use of prescription medicines—although the high-risk group reported more frequent use of sedatives and tranquilizers (P = .09).

    In regard to potentially confounding factors, there was no difference in the proportion of workers in hazardous occupations (only two in the low-risk and four in the high-risk group reported such occupations, P = 1.00. Hazardous occupations were defined as jobs involving the manufacture, use, transport, or disposal of chemicals (e.g., pesticides, fertilizers, and petroleum products) or use of electrical equipment (e.g., transformers or capacitors). Similarly, only one low-risk and no high-risk persons had served in the Armed Forces in Vietnam (P = .35). The high-risk group had nonsignificantly higher proportions of persons who had ever regularly consumed alcohol (P = .15) or tobacco products (P = .41). Use of tobacco products among current users was equivalent between the two groups, as was alcohol consumption among current drinkers. The only statistically significant difference in life-style habits was that the high-risk group reported exercising more regularly (P < .01).

    Regarding the prevalence of specific generalized disorders as reported in the medical history section of the Health Effects Survey questionnaire, we found no differences or consistent trends. Of the five cases of cancer reported (three in the high-risk group and two in the low-risk group, P > .05), none were soft-tissue sarcomas. Results of the general physical examinations showed no consistent differences between the two groups (e.g., for blood pressure, weight, and pulse), although there was a weak trend of diminished peripheral pulses in the high-risk group. Routine hematology tests showed no consistent differences except that the mean platelet counts were elevated in the high-risk group (meanHigh = 281,927 and meanLow = 249,061, P < .05). However, all platelet counts were within normal ranges, with none below 100,000 in either group and none below 150,000 in the high-risk group; no persons were considered thrombocythemic. In addition, laboratory analyses showed no differences in mean serum hormone measurements or increased prevalence among individuals in the high-risk cohort compared with the low-risk group of abnormally elevated or low (i.e., outside of expected age- and sex-specific ranges) serum analyte measurements, e.g., for calcium, phosphorus, uric acid, and glucose.

    No consistent overall trends or statistically significant individual diagnostic differences were detected for reproductive health outcomes from the medical histories. No difference was found for males in prevalence of reported sexual dysfunction. Although responses showed no differences regarding an increased prevalence of female reproductive health problems, the high-risk group showed a later mean age at menarche (P = .06). Similar results were obtained when the analysis was restricted

      Table 2.—Summary of Findings

    Category

    Results

    Statistically Significant
    Individual Findings

    Evidence of
    Patterns or Trends
     

    Demographics

    		 Regular exercise HR > LR NONE

    General Disorders

    		 NONE Diminished peripheral pulses HR > LR
      Minor musculoskeletal abnormalities HR > LR

    Routine diagnostics

    		 Platelet count HR > LR NONE

    Cardio-pulmonary

    		 NONE Minor pulmonary abnormalities HR > LR

    Reproductive health

    		 NONE NONE

    Dermatological

    		 NONE NONE

    Neurological

    		 NONE NONE

    Immunological

    		 Palpable axillary nodes LR > HR Palpable nodes LR > HR

    Hepatic

    		 “Other liver diseases” LR > HR NONE
      Urinary heptacarboxylporphyrin LR > HR  

    Renal/urinary tract

    		 NONE All previously diagnosed problems HR > LR
        Abnormal urinalyses results HR > LR

    NOTES: HR = high-risk group, LR = low-risk group, and > = greater prevalence or mean value in former risk group.

    to only those women who had reached menarche after the time at which they would have been potentially exposed to environmental dioxin (P = .17). Although 30 births were reported in the entire study population since 1972, no trends were reflected in the reproductive outcome section of the medical histories. No birth defects were reported among children born to women in the high-risk group after the time at which exposures could have occurred.

    In the dermatology screening clinic conducted in addition to this epidemiologic study, no cases of chloracne were seen in the 140 persons examined. For the 104 persons in the study population, no significant differences in dermatological findings were demonstrated by either medical histories or physical examination. Eleven persons, 7 (10.3%) in the high-risk group and 4 (11.1%) in the low-risk group, were referred to dermatologists for other than chloracne-like conditions.

    Results of the neurological examinations showed no significant differences or patterns between the two groups for the self-reported neurological conditions either from the neurological examination or from the medical histories. Except for diminished vibration sense at 256 Hz for those in the high-risk group versus the low-risk group (P = .13), none of the differences on neurological examination approached statistical significance.

    There appeared to be a trend of increased urinary tract problems among the high-risk cohort on the basis of the medical history section of the questionnaire and the urinalysis, although no statistically significant differences were demonstrated. Urinalysis also suggested a consistent pattern of abnormal findings including a non-statistically significant higher prevalence of leukocyturia, defined as > 5 WBC/hpf, (P = .09) and microscopic hematuria, defined as > 3 RBC/hpf, (P = .17) in the high-compared to the low-risk group.

    In regard to the hepatic system, no trends or significant specific problems were reported in the medical histories except an increased prevalence in “other, nonspecified liver diseases” in the low-risk cohort (P < .05) as reported in the medical history section of the questionnaire. On physical examination, there was a greater prevalence of hepatomegaly in the high-risk group, but this finding also was not statistically significant. In general, the measurements of serum and urinary analytes showed no statistically significant differences between the two groups and no evidence of trends or marked abnormalities in specific liver function test results. The mean urinary heptacarboxylporphyrin for the low-risk group was elevated (P < .05) as was the mean serum beta-glucuronidase level in the high-risk cohort, but this result was not statistically significant (P = .08). Furthermore, no excess prevalence of abnormally elevated or low serum analyte measurements for liver function occurred in the high-risk group. The two groups showed no difference in characteristic urinary porphyrin patterns, and no case of overt porphyria cutanea tarda (PCT) or any precursor conditions (latent PCT or Type B porphyria) were detected.

    As reported in the medical histories, there were no differences in prevalence of immune disorders. On physical examination, the only significant difference noted was a higher prevalence of palpable axillary lymph nodes in the low-risk cohort (P < .05) and a trend suggestive of a greater prevalence of palpable nodes in the low-risk group. Laboratory analyses showed no differences between the two groups in regard to total induration in response to the seven antigenic skin tests (taken together or separately) or the in vitro lymphocyte proliferative responses to the three mitogens and one antigen. There was no difference between the two groups in an overall evaluation of marked depression of cell-mediated immune response (based on the lymphocyte proliferation assays). An evaluation of T-cell subset assays did not show a statistically significant difference in proportions of the two groups with helper:suppressor cell ratios below 1.0 (13.2% in the high-risk versus 6.1% in the low-risk group).

    DISCUSSION

    The potential health effects considered in this study were based primarily on the animal toxicology of diox- and results from studies of long-term industrial and accidental acute human exposures. Animal toxicity studies are commonly used to predict health effects in humans (although the existence of species-specific and even organ-specific effects of TCDD make extrapolations tenuous); the organ systems most prominently affected are the liver (acute toxicity and hepatocarcinogenesis), the immune system (thymic atrophy and decreased cell-mediated immunity), the skin (chloracne-like changes), and reproductive effects

    Most of our direct knowledge of human health effects has been obtained from workers who were exposed to dioxin during the production or subsequent handling of 2,4,5-trichlorophenol (2,4,5-TCP) or 2,4,5-T. In some plants, chloracne, but no systemic illnesses, developed in exposed workers. Other authors have reported weight loss, easy fatigability, myalgias, insomnia, irritability, and decreased libido; the liver has been shown to become tender and enlarged and sensory changes, particularly in the lower extremities, have occurred; total serum lipids may be increased, and the prothrombin times may be prolonged. Porphyria cutanea tarda, an acquired form of porphyria characterized by chronic skin lesions and other symptoms, has also been observed. The most specific of these findings are chloracne (which can also be caused by other structurally related compounds such as polychlorinated bi-phenyls [PCBs] and chlorinated naphthalenes) and PCT which also has a variety of potential causes). A number of studies addressing the association of TCDD exposures to soft tissue sarcoma have been conducted in the occupational setting: two Swedish studies reported a sixiold increase in risk of soft tissue sarcomas among persons exposed to chlorphenols and phenoxy herbicides; however, these results could not be substantiated by investigations of worker cohorts in New Zealand and elsewhere

    Information on health effects involving nonoccupational environmental exposure is sparse. After an explosion in 1976 at the ICMESA plant in Seveso, Italy, chloracne developed in exposed children, some elevated liver function test results were detected in the exposed population,+and the incidence of abnormal nerve conduction tests was statistically significantly elevated in subjects with chloracne. A child in Missouri who played in dirt in a riding arena contaminated with up to 33 ppm TCDD had hemorrhagic cystitis.

    In the current study, there was a high degree of comparability between the high- and low-risk groups on potentially crucial confounding factors such as age, sex, race, education, relationship of interview respondent to subject, smoking and alcohol consumption, occupational and other exposures, and use of selected types of prescription drugs. The high-risk group reported exercising more regularly, thereby potentially enhancing the general health status of this group. Although not likely to introduce significant confounding influences, these variables might have been partially controlled by use of multivariate or other analytical techniques (e.g., stratification); however, this was not feasible because of the relatively small sample size.

    The analysis did not produce any firm indications of increased disease prevalence directly related to the putative exposures. No cases of chloracne or overt PCT (as well as precursor conditions such as latent PCT or Type B porphyria) were seen in either of the groups. It seems plausible to suggest that such findings may not be indicative manifestations of chronic, low-dose exposures to TCDD but, rather, that they are diagnostic of high-dose exposures. The findings of no cases of soft tissue sarcomas in inconsequential because no increase could be expected with such a small sample size and in the relatively short induction period available for this study cohort.

    These results do, however, offer some insights and leads for further study. With regard to specific significant findings, it is unclear as to how to interpret the elevated mean platelet count demonstrated in the high-risk cohort (which was still in the normal range), since this runs counter to findings from previous animal toxicological work. Of greater interest is the apparent trends indicative of urinary tract abnormalities in the high-risk group. The trend was suggested by the non-statistically significant increased prevalence of reported physician-diagnosed kidney/urinary problems from the questionnaire medical histories and the finding of a possibly higher proportion of leukocyturia. Of the seven persons in the high-risk group (versus none in the low-risk group) with leukocyturia, only one reported a history of kidney/urinary problems which might explain the current findings. Similarly, there was a suggestion of greater prevalence of microscopic hematuria in the high-risk cohort; however, four of the six cases were in women from the high-risk group between the ages of 14 and 44 yr for whom no detailed records of menstrual cycle were available. Because of a previous finding of hemorrhagic cystitis in an exposed person, 22 these associations require further and more detailed investigation.

    The findings of no significant differences in standard liver function test results is important because previous investigative work detected such abnormalities in both animal and human populations. As mentioned above, previous investigators have reported increased serum lipids to be associated with TCDD exposure, but our results showed no statistically significant differences in abnormal laboratory test results for any of the analytes (i.e., elevated or low serum levels within expected age- and sex-specific ranges), although a larger percentage of individuals with elevated serum cholesterols (23.1% vs. 12.1%) and serum triglycerides (17.9% vs. 11.4%) (high- and low-risk groups, respectively) were seen in the high-risk group. There was not a greater prevalence of porphyria in the high-risk group or elevation of D-glucaric acid, however, a non-statistically significant elevation of mean beta-glucuronidase levels was demonstrated. Neither of the two individuals from the high-risk group considered to have signs of hepatomegaly (a liver span of ≥ 12 cm on percussion) reported a history of disease that might explain these findings; both were obese and showed above-normal serum triglyceride and cholesterol levels. Because of the extensive animal and high-dose human data suggesting hepatotoxic effects of TCDD exposure, hepatic function should continue to be evaluated in future studies.

    Although none of the findings from the immune function tests and assays demonstrated statistically significant differences, several results were of note. There was some indication of an increased prevalence of helper:suppressor T-cell ratios < 1.0 in the high-risk group, although the functional tests of the immune system revealed no overall abnormalities. In light of the rapidly evolving work in this area, follow-up and/or further investigation of these effects in exposed cohorts should be conducted before conclusions can be drawn.

    Many of the other statistically significant differences, such as some of the physical findings, are not obviously related to what has been previously reported in cases of TCDD exposure. Given the large number of comparisons made, these findings should be interpreted with caution.

    There were no definitive indications of specific patho-physiologic effects of dioxin exposure. Several factors could explain at least part of these overall negative findings. First, the power to detect significant differences was restricted by the relatively small sample size, which also limited our application of analytical methods to control for some potential confounders. Because of conceptual and logistical limiting factors, the sample size for this pilot study could not be increased. Second, a large percentage of the pool of persons from which the study and comparison groups were chosen was self-selected, thereby introducing the possibility of potential biases (the magnitude and direction of which are unknown). Because of the absence of an objective direct measure of exposure status, the possibility of individual misclassification errors is fairly high. The ability to directly measure body burden and/or uptake and metabolism of TCDD is a critical factor useful in deriving accurate, reliable conclusions in these situations of environmental contaminations. Problems such as the occurrence of long-term effects (such as cancer and other rare disease end-points) with long latency periods, other potential effects such as neurobehavioral changes, and the development and testing of more specific and sensitive indicators of early stage changes may require different investigatory approaches. In addition, because of the time intervals from exposures to examination, in many instances, if individuals were in a reparative or post-effect phase, reversible effects may have been missed. Finally, it is conceivable that uptake of dioxin from contaminated soils was generally less than estimated for this study group or that chronic exposure to environmental TCDD have actually induced little or no adverse health effects as measured in this study.

    CONCLUSION

    Although the results appear to be largely negative, no overall definitive conclusion should be based just on this initial pilot study of the potential health effects of chronic exposures to environmental 2,3,7,8-TCDD. Insights were provided which have been helpful in designing more refined epidemiologic studies of larger, more homogenous population groups in which exposure status can be better characterized. The extensive environmental sampling performed by EPA since the start of this pilot study will continue to be used in identifying and characterizing groups for further study.

    On the basis of the findings herein, attention should be focused primarily on discerning any potential effects on the urinary tract, liver, neurological, and immune systems. Also, research into the development of replicable laboratory analytical methods and establishing reference ranges for measuring TCDD body burden are being pursued. Sophisticated epidemiological studies to detect subtle effects of dioxin will be dependent on rigorous classification of exposure status, and this can undoubtedly be done more effectively by such direct measures of cumulative exposure.

    Finally, public health policy in situations such as this environmental contamination with TCDD must continue to be focused on the prevention of any potential health effects, even if such effects were not demonstrated in a small pilot study. For this reason, all appropriate efforts need to be made to prevent human exposure.

    Use of trade names in this study is for identification only and does not constitute endorsement by the Public Health Service or by the U.S. Department of Health and Human Services.

    Submitted for publication August 25, 1984; revised; accepted for publication July 24, 1985.

    Requests for reprints should be sent to: Paul A. Stehr, Dr. P.H., Center for Environmental Health, Centers for Disease Control, Public Health Service, U.S. Department of Health and Human Services, 1600 Clifton Rd. NE, Atlanta, GA 30333.

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