8. EFFECT OF PCDDs ON HUMAN BEINGS - EPIDEMIOLOGICAL AND CASE STUDIES
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8.4 Epidemiological Studies
Signs and symptoms related to accidental exposure to TCDD are given in Table 64. However, it should be observed that all the accidents and occupational contamination concern exposure to a mixture of compounds where TCDD was only one component. In all cases, its concentration in the mixtures was unknown. Only two cases of intoxication with "pure" TCDD have been reported.
The story of the discovery of TCDD is by now well documented (Holmstedt, 1980; Sandermann, 1984a,b). TCDD was synthetized in 1955. Four people were intoxicated, one co-worker severely so while drying crystals. In all cases, decreased libido was the first symptom, followed by other symptoms such as moderate to severe chloracne, sleeping difficulties, inability to concentrate, depression, and, in at least one case, swelling of the lymph nodes. In all cases, the signs and symptoms disappeared within a couple of years, with the exception of the chloracne in the most heavily exposed man.
The second occasion of exposure to what one must assume to be pure TCDD is the one reported by Oliver (1975). The toxic effects on three young scientists who suffered "transient minimal exposure to TCDD" were described. Two of them suffered from typical chloracne. Delayed symptoms about two years after initial exposure occurred in two of the scientists. These symptoms were said to have included personality changes, other neurological disturbances, and hirsutism.
All three scientists were found to have raised serum cholesterol levels, but no other biochemical disturbances and no porphyrinuria or liver damage were demonstrated. Whether the unusually delayed physiological effects were in fact due to the initial dioxin exposure is a question that was discussed by the author. Although conclusive evidence is lacking, it seems likely that these delayed effects were in fact due to dioxin intoxication. The conditions of exposure remain unexplained.
Of the many cases of exposure reported in Table 63, only two (at Monsanto in 1949 and at BASF in 1953) have been adequately followed up epidemiologically with matched control groups.
The workers of Monsanto, USA, have been investigated several times between 1949 and 1984. Immediately after the accident, Ashe & Suskind (1949) hospitalized and studied four cases of severe poisoning among the workers. These four workers were diagnosed as having chloracne, but by the time of examination these men had recovered from earlier symptoms of peripheral neuropathy. In 1950, a further examination of these four workers and two additional men revealed continued irritability, nervousness, and insomnia (Ashe & Suskind, 1950). A consistent loss of libido and some impotence was reported. Further clinical examination revealed hepatomegaly, altered prothrombin times, and disturbed lipid metabolism.
A further study of 36 workers from this plant was undertaken in 1953 (Suskind et al., 1953). It was noted that even those who developed, to a moderate or severe degree, the skin eruptions, pains in back, dyspnoea, fatigue, nervousness, and decreased libido generally improved. Even those suffering the most severe cutaneous eruptions initially had only a few or no lesions in 1953.
More recent studies on these workers are those of Zack & Suskind (1980) and Zack & Gaffey (1983). Zack and Gaffey reported on a 121-member study cohort, with a presumptive high-peak exposure to TCDD base on chloracne occurrence, which was followed for mortality until 1978. The entire cohort was traced; there were 32 deaths; 89 people were still alive. There was no excess in total mortality or in deaths from malignant neoplasms.
The proportional mortality analysis of decedents according to exposure by 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) indicated no unusual patterns of mortality. The proportional mortality ratio (PMR) for malignant neoplasms was low (PMR = 82) in the exposed group. Lung cancer was the only site among the malignant neoplasms for which the value was somewhat higher in the exposed group.
The Monsanto workers were again examined in 1984 (Suskind & Herzberg, 1984). A clinical epidemiological study was conducted to determine the long-term health effects of workplace exposures during the process of manufacturing the herbicide 2,4,5-T, including contaminants such as TCDD. The population consisted of two cohorts, 204 clearly exposed and 163 not exposed (controls). Among the exposed workers, clinical evidence of chloracne persisted in 55.7%.
None of the controls experienced chloracne development. An association was found between the persistence of chloracne and the presence and severity of actinic elastosis of the skin. There was an association between exposure and the history of ulcers of the gastrointestinal tract. Pulmonary function values among those who were exposed and who currently smoked were lower than those who were not exposed and who currently smoked. No disturbances of sexual functions were found at this time after age adjustment. The data assembled in the study indicated no evidence of increased risk for cardio-vascular disease, hepatic disease, renal damage, or central or peripheral nervous system problems.
Another selection of the population from the same plant has been examined by another group of epidemiologists (Moses et al., 1984). Since the degree of exposure was unknown to these investigators and since chloracne is generally considered a quite reliable indicator of heavy dioxin exposure, it was decided to use chloracne as a "surrogate" for exposure and to classify the study population by its presence or absence. It was recognized that those without chloracne, but with appropriate work-exposure history, might also have had TCDD exposure and were not therefore used as "unexposed controls".
Chloracne was found in 52% of 226 workers in a 1979 cross-sectional survey at the plant where 2,4,5-T had been manufactured from 1948 to 1969. Mean duration of residual chloracne was 26 years, and in 29 subjects it had been present for 30 years. A significantly increased prevalence of abnormal gamma-glutamyl transpeptidase (GGT) and higher mean GGT were found in those with chloracne compared to those without.
Although mean triglyceride values were higher in those with chloracne, the difference was not statistically significant. Neurological examination showed a statistically significant higher prevalence of abnormal sensory findings in those with chloracne. Increased prevalence of angina and reported myocardial infarction in those with chloracne was not significant when age-adjusted.
Increased prevalence of reported sexual dysfunction and decreased libido in those with chloracne, compared to those without, was statistically significant after age adjustment. No differences were found between those with and without chloracne in serum cholesterol, total urinary porphyrins, or in reproductive outcomes. Exposure to TCDD in 2,4,5-T production may thus result in apparently permanent changes in the skin.
Sensory changes in peripheral nerves and possible changes in liver metabolism in those with current or past chloracne are also suggested by these data. Based on worker histories, even severe acute toxicological effects of TCDD are reversible, or improve markedly over time. While the cross-sectional nature of this study, the low participation rate, and the highly select nature of the population limit the conclusions that can be drawn, it is unlikely that permanent, severe, and debilitating toxicological sequelae are inevitable after exposure toTCDD sufficient to produce chloracne. It must be noted, however, that individual susceptibility may make certain workers with heavy exposures more vulnerable.
The exposure of workers at BASF in 1953 has been the subject of several reviews, the latest one being that of Thiess et al. (1982). Twenty-seven years after the accident that occurred in the BASF Ludwigshafen plant, a mortality study was undertaken of people exposed in the uncontrolled reaction which occurred during the trichlorophenol process. The follow-up was 100% successful and involved 74 people. Overall mortality (21 deaths) did not differ in this group from the rate expected in three external reference populations, or from that observed in two internal comparison groups, where 18-20 deaths were observed. Of the 21 deceased people, 7 had had cancer, compared with 4.1 expected.
In addition, two other cases of cancer (one bronchial carcinoma and one carcinoma of the prostate) were still alive at the time of writing. Three deaths due to stomach cancer at ages 64, 66, and 69 years, were found, compared with 0.6 expected from regional mortality data. One stomach cancer occurred among 148 individuals in the two comparison cohorts. The incidence of cancer in these workers was considerably greater than expected and cannot be explained only as a chance event. Of 74 people, 66 had severe chloracne or severe dermatitis.
There is a possibility that some members of the BASF cohort were exposed to other unknown occupational hazards before or after the accident. However, the use of two internal comparison groups composed of matched controls from the same factory was designed to control for, as far as possible, other occupational exposures that could be important etiological or confounding factors. Because of the small size of the cohort and the small absolute number of deaths from any particular cause, the results of this study do not permit any definite conclusions concerning the carcinogenic effect of exposure.
In comparison with the above-mentioned, well conducted long-term epidemiological studies, a host of other follow-up studies have been published, none of which used adequate controls. They are, therefore, of less value but will be briefly summarized here. Jirasek et al. (1973, 1976) and Pazderova et al. (1974, 1980, 1981) examined 55 of a total of 80 workers who suffered intoxication during the manufacture of sodium pentachlorophenate and the sodium salt and butyl ester of 2,4,5-T.
One worker died from severe acute intoxication at an early stage (Jirasek et al., 1976), and 76 workers developed chloracne. The following additional symptoms were found: porphyria cutanea tarda, disorders of the metabolism of lipids, porphyrins, and carbohydrates, and alteration of plasma proteins. Hepatic lesions were also present. Neurological and electromyographic (EMG) examinations revealed peripheral nerve changes in 17 people, first detected in 8 people during the second year of the study.
A neurasthenic syndrome was also observed. The patients with porphyria cutanea tarda showed hyperpigmentation, hypertrichosis, and bullosis actinica mechanica. Porphyrin excretion in urine ranged from 172 to 2230 µg/24 h. Polyneuropathies, confirmed by EMG examination, were noted, predominantly in the lower extremities. In this outbreak, the disease was progressive during the first 2 years; subsequently the dermatological symptoms as well as the porphyric disease and the neurological disorders improved. The impaired lipid metabolism improved only very slowly.
In this plant, the toxic substances were led off through the breathing zone of the workers. The concentrations of the chlorinated hydrocarbons in the air were never measured. Due to insufficient data, the real hygienic conditions at the work place could not be accurately reconstructed. The manufacturing of 2,4,5-T was halted permanently in 1968 so that it was impossible to obtain the necessary information in an adequate manner.
From 1959 to 1964, according to information from the plant, only sodium pentachlorophenate was manufactured. Not until1965 was the manufacture of sodium 2,4,5-T commenced on a pilot scale, and later the butyl ester of 2,4,5-T was also manufactured. After each year of production, something was always changed or modified in the process and technology so that actually there was never full-scale production in the true sense of the word. Many of the herbicides manufactured could not be found from the documentation (Pazderova et al., 1974).
The uncertain mixture of compounds involved in the Spolana episode makes interpretation of signs and symptoms almost impossible. In all likelihood the porphyria observed was due to the hexachlorobenzene stated to be produced at this factory.
Signs of disturbance in the porphyrin metabolism in workers manufacturing 2,4,5-T was also described by Poland et al. (1971). Chloracne was not correlated significantly with job location within the plant, duration of employment, or coproporphyrin excretion.
Although 11 subjects with uroporphyria and at least three with overt porphyria cutanea tarda had been found in a study of the same plant six years earlier (Bleiberg et al., 1964), no clinical porphyria could be documented at the time of the second investigation, and only one worker had persistent uroporphyrinuria.
Evidence of toxicity in other organ systems was markedly less than that reported in previous studies and in most instances there was no difference from normal populations. In all likelihood the porphyria cutanea tarda in this case, as in the study from Czechoslovakia, was due to a compound other than TCDD. This is corroborated by a recent re-evaluation of the literature (Jones & Chelsky, 1986).
A study from northern Germany was published by Bauer et al. (1961). It is not clear where the cases orginated and only nine patients were studied in depth. A summary of the findings from these patients, and another person suffering from chloracne after occupational exposure to trichlorphenol, was reported by Kleu & Göltz (1971).
These patients were followed for 15 years after exposure. The severity and types of symptoms varied in a dose-related manner. Major complaints were decreased sexual activity, muscular weakness, easy fatigability, irritability, and loss of appetite and memory. The authors concluded that a permanent defect had occurred, the late form of which resembled a cerebral involutionary syndrome, combined with mental depression and neurasthenia.
A follow-up study of 11 of the 24 employees at Boehringer exhibiting skin lesions in 1955 was published by von Krause & Brassow (1978). Many continued to suffer from their earlier complaints. In seven of the eleven, nausea and intolerance to heavy fatty food was still common, and six men complained of alcohol intolerance. Although conjunctivitis had disappeared, chloracne was still clearly visible in most of the 11 subjects. Neurological problems were still severe in six of the workers.
Ten years after the incident at Coalite in 1968 when 79 workers developed chloracne due to exposure to a chlorophenol-TCDD mixture, a study was undertaken to establish the state of health of the affected employees (46) remaining in the company's employment (May, 1982). Forty-one of the 46 employees participated. The opportunity was used to examine effects on mortality, morbidity, carcinogenesis, reproduction, teratogenicity, fetotoxicity, biochemistry, immunology, and genetic changes.
Concurrently, two control groups were established, one with no dioxin exposure and the other with possible dioxin exposure. These groups were selected from within the works and matched the study group with respect to sex and age, but it was not possible to match them for occupation and social status. Half the affected subjects still had minor chloracne. Other than this finding, the authors concluded that the subjects had not been had been adversely affected in any way.
Data on the mortality of workers at the Dow Chemical company have been provided in two papers (Cook et al., 1980; Ott et al., 1980). The first of these studies describes the mortality of a cohort of 61 males involved in the preparation of trichlorophenol. Forty-nine of these workers developed chloracne, presumably as a result of skin absorption of the process contaminant TCDD.
Within the limitations posed by cohort size and length of follow-up, the exposure to chlorophenol-TCDD mixtures did not appear to have adversely affected mortality experience. Overall, four deaths occurred and 7.8 were expected. Of these, one death was due to cardiovascular disease (3.8 expected) and three deaths were attributed to cancer (1.6 expected). None of the findings was statistically significant. The second paper examined the mortality experience of 204 people exposed to 2,4,5-T during its manufacture from 1950 to 1971.
Length of employment within the 2,4,5-T process area ranged from less than one year to a maximum of approximately ten years. Efforts to minimize TCDD contamination of the product resulted in non-detectable concentrations (less than 1 mg/kg) near the end of this period. Within the scope of this mortality survey, no adverse effects were observed with respect to occupational exposure to 2,4,5-T or to its feedstock, 2,4,5-trichlorophenol.
Hardell and his co-workers in Sweden have conducted a series of case-control studies and reported an increased risk of soft-tissue sarcomas in men who were exposed to phenoxy herbicides and/or chlorophenols (Hardell & Sandsstrom, 1979; Hardell, 1981; Hardell et al., 1981; Hardell & Ericksson, 1981).
These authors also reported a case-control study that suggested that phenoxyacetic acids and chlorophenols may predispose to Hodgkin's lymphoma (Hardell et al., 1981). The relative risk was higher for a group exposed to phenoxy herbicides including 2,4,5-T and chlorophenols, i.e., pesticides that may be contaminated with PCDDs and PCDFs. However, an increased risk was still found in a group exposed mainly to phenoxy herbicides such as MCPA, 2,4-D, mecoprop and dichloroprop, i.e., pesticides with low or no contamination with PCDDs and PCDFs.
Analysis of fat levels of PCDDs and PCDFs in patients with soft tissue sarcomas and in controls failed to reveal any differences between the two groups (Nygren et al., 1986) (section 220.127.116.11).
A cohort study on Swedish farmers and gardeners has been carried out recently (Wiklund & Holm, 1986). Despite the greatly increased use of phenoxyacetic acid herbicides from 1947 to 1970, no time-related increase in the relative risk of soft-tissue sarcoma was found in the cohort or in any of the subcohorts.
The same was found by Hoar et al. (1986) although the latter study points to an increase in non-Hodgkin lymphoma. It should be noted that in all these studies the majority of the herbicides used did not contain TCDD.
In follow-up studies of workers exposed to 2,4,5-T and its precursor 2,4,5-trichlorophenol (and therefore, presumably, also to TCDD), no excessive deaths due to any cause were registered (Cook et al., 1980; Ott et al., 1980; Zack & Suskind, 1980; Zack & Gaffey, 1983). Honchar & Halperin (1981) merged the above four cohorts and found that three (2.9%) of the total 105 deaths were reported to be from soft-tissue sarcoma.
Based on national statistics only 0.07% was expected to be due to this cause. Fingerhut et al. (1984) reviewed the employment records, medical and pathological reports, tissue specimens, and death certificates for these three cases and four additional cases of deaths from soft-tissue sarcomas in these and related cohorts reported by Cook (1981), Moses & Selikoff (1981), and Johnson et al. (1981).
Three out of the seven cases had a record of chloracne and one of dermatitis. After review of the tissue specimens, five of the seven cases were diagnosed as soft-tissue sarcoma. The remaining two (which were among the three cases in the merged cohort of Honchar & Halperin (1981)) were found to be carcinoma. For three of the cases with confirmed soft-tissue sarcoma the exposure was not well documented, although an undocumented contact with 2,4,5-T, 2,4,5-trichlorophenol, or TCDD could not be excluded.