8. EFFECT OF PCDDs ON HUMAN BEINGS - EPIDEMIOLOGICAL AND CASE STUDIES
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8.1 Occupational Studies - Historical Perspective
The illness most frequently observed in workers engaged in the manufacture of trichlorophenol, 2,4,5-T, and related products is a skin disease called chloracne. This skin disease has also been called "Pernakrankheit" (perchlorinated naphthalene illness or halogen wax acne) and was described by Herxheimer (1899). In addition to the halogenated phenols, chloracne is caused by a number of chlorinated compounds such as the chlorinated biphenyls and chlorinated naphthalenes (Muller, 1937; Braun, 1955; Crow, 1970; Kimbrough, 1974).
Although chloracne is well known to those engaged in the treatment of occupational diseases, many outbreaks that have occurred over the years, particularly in the USA, have not been reported in the scientific literature. In the Federal Republic of Germany, chloracne is now considered an occupational disease for which compensation is mandatory (Braun, 1970).
Herxheimer (1899) also described general toxic signs and symptoms in his patients, such as lack of appetite, weight loss, headache, and vertigo. After his original observations and publication, several other reports followed. The technique of obtaining chlorine gas consisted of an electrolytic procedure where a mixture of potassium, sodium, and magnesium chlorides was subjected to a current with a central carbon electrode where the chlorine was obtained and piped off. The workers who took care of the chlorine gas never developed chloracne thus refuting the original hypothesis by Herxheimer.
By contrast, those who handled the electrodes and cleaned the reaction vessels were those afflicted with chloracne. Already at this time chlorinated phenolic compounds were considered as possible noxious agents (Fraenkel, 1902). This however could never be proven and even at present, when satisfactory analytical techniques are now available, no analysis of the so-called "tuffy tar" has been carried out.
Another class of chlorinated organic compounds causing skin damage appeared during the First World War (1914-1918). At this time perchlorinated naphthalenes had come into use as insulation materials, e.g., in the radio and electronic industry. The first description of Pernakrankheit was that by Wauer (1918). The use of the unspecified technical mixture of chlorinated naphthalenes spread all over the world and caused numerous intoxications notably among workers in manufacture. The perna disease has been summarized by von Wedel et al. (1943) and described in particular detailed by Braun (1955). Apart from chloracne the systemic effects of the same compounds have been dealt with by Drinker et al. (1937) and Greenburg et al. (1939).
Both in man and experimental animals, serious liver damage occurred after exposure to chlorinated naphthalenes, consisting of liver necrosis and toxic jaundice (acute yellow liver atrophy). Among several hundred cases of chloracne due to these compounds, Braun (1955) tabulated 24 deaths due to toxic jaundice and 14 recoveries. It should be pointed out that a fulminant liver disease with jaundice of this kind is an extremely rare condition. For comparison, it has never occurred after exposure to trichlorophenol (TCP) and TCDD as described below.
Note should also be taken of the fact that not only were the perchlorinated naphthalenes an ill identified mixture of chemical species, but exposure frequently occurred at the same time to mixtures of chlorinated biphenyls, the latter now known to be contaminated with chlorinated dibenzofurans. The potentiation of toxicity by these mixtures and other chlorinated compounds were discussed by Drinker et al. (1937), Greenburg et al. (1939), von Wedel et al. (1943), and Risse-Sunderman (1959).
Several accidental ingestions of chloracnegenic compounds have occurred. They are of particular importance in relation to discussions on whether chloracne is a systemic or local disease. The so-called Yusho disease is discussed in section 11. Herzberg (1947) described several cases of chloracne, in which other toxic signs and symptoms were seen, due to consumption of "chlorinated paraffin" used as a substitute for butter during cooking in postwar Berlin.
Among general signs and symptoms observed were gastrointestinal disturbances with abdominal pain, headache, pain in joints, neuropathy, depression, and lack of appetite. The dermatological symptoms were erythema, exanthema, comedones, and retention cysts in sebaceous glands. It was noted as remarkable that the skin signs had a follicular predilection, as in seborrhoea (face, head, bosom, and back).
The slow development of chloracne, and particularly the fact that the sebaceous glands were affected, led the author to conclude that it was a secretory disease(Ausscheidungstoxikose). With regard to the chloracnegenic component, it is unlikely that paraffin itself was active. Herzberg speculated that something else, possibly a pyrolysis product that arose during cooking, could have caused the disease.
The first reported intoxication with a mixture probably containing TCDD, although the chemical structure was not given, occurred in February 1910. Five people were said to have been contaminated after a reactor explosion and two of these were described in some detail in a dermatological thesis (Teleky, 1913; Wahle 1914). Wahle (1914), however, in his thesis emphasized that this intoxication was not due to any of the chlorinated naphthalene derivatives that were well known by then.
An industrial poisoning was reported in 1949, due to the formation of TCDD in uncontrolled exothermic reactions occurring during the manufacture of TCP at a 2,4,5-T-producing factory in Nitro, West Virginia, USA. The temperature in one of the reactors containing tetrachlorobenzene, methanol, and sodium hydroxide increased, a relief valve opened, and the contents of the vessel were discharged into the interior of the building and over a wide area outside of the building.
A total of 228 people were affected. Symptoms included chloracne, nausea, vomiting, headaches, severe muscular aches and pains, fatigue, emotional instability, and intolerance to cold. Laboratory findings showed an increase in total serum lipids and an initially prolonged prothrombin time. Among those affected were not only workmen, but also laboratory personnel, medical personnel, and even the Safety Director who visited the area of exposure. Several wives who had never visited the plant also developed acne, usually at the same time as their husbands working at the plant.
A man from the nearby town who purchased a truck that was parked in the vicinity of the accident at the time it occurred, and his child, also developed chloracne. The disabling symptoms, which kept men from their jobs for as long as 2 years, were severe aches and pains and fatigability, the manifestations of peripheral neuropathy. Liver tests 4 years later were normal, but mild cases of acne were common. TCDD was still an unknown chemical. The follow-up to this accident will be discussed in section 8.4.
In 1953, at the Badische Anilin and Soda Fabrik, during the alkaline hydrolysis of 1,2,4,5-tetrachlorobenzene to 2,4,5-trichlorophenol, the temperature and pressure in an autoclave increased rapidly and resulted in an exothermic reaction releasing a great deal of steam through a safety valve of the reaction vessel. This steam covered the walls, windows, doors, and machinery in the rooms of four floors, and finally precipitated in solid form on everything in these rooms.
Forty-two workers involved in the clean-up operations developed chloracne, and even after the extensive clean-up operations occasional workers still developed chloracne. Thereafter the autoclaves were used for 2 years without incident but in 1958 a mechanic who conducted repair work on an autoclave subsequently developed chloracne (Hofmann, 1957; Goldmann, 1972). In 1968 and 1969 the building containing the autoclaves was dismantled.
Goldmann (1972, 1973) conducted a study of the 42 workers exposed in this accident. In 21 cases, the chloracne was preceded by a non-specific dermatitis and in two cases very persistent chronic conjunctivitis and blepharitis were observed; 14 cases also showed involvement of other organs. In four instances the liver was affected, and microscopic examination of the liver again showed a very characteristic grey pigment that did not stain positive for iron.
A transient involvement of the myocardium was also noted. In five instances the upper respiratory tract was involved with tracheitis and bronchitis. There was one instance of haemorrhagic pleuritis and one instance of afebrile gingivitis and stomatitis. In a number of cases a high susceptibility to infection was noted, sometimes accompanied by a decrease in gamma-globulin. One worker died of pancreatitis, in seven cases the central nervous system was affected, three instances of toxic polyneuritis were recorded, and in two instances hearing, sense of smell, and taste were impaired. The child of one of these workers also developed chloracne, and in most of the workers active chloracne persisted for many years - in one instance for 18 years. Follow-up studies are described in section 9.4.
Of particular interest is a study by Risse-Sundermann (1959). According to oral reports by the treating physician, all 24 members of a team working in a trichlorophenol operation became ill after the production process was switched to the pressurized phenol process in the spring and summer of 1954. Slightly different acneiform skin conditions appeared as symptoms of the toxic exposure. In addition, the patients suffered from dizziness, nausea, vomiting, lacrimation, burning of the eyes, difficulty in hearing, gastrointestinal spasms, intolerance to fatty foods, diarrhoea, jaundice, hepatitis (which was fatal in one case), and paresthesias and hyperesthesias, as well as extreme irritability. One patient became psychotic and committed suicide. In addition, some of the patients complained of impotence. Ten workers at this chemical factory were followed for five years by Risse-Sundermann (1959).
In addition to the signs and symptoms mentioned above, she noticed swollen lymph glands and a considerable decrease in body weight. The patients underwent neurological examination, with no objective signs being observable. Of particular interest in this well documented study is the fact that in three patients the general symptoms (e.g., tiredness, depression, lack of appetite, stomach pains, sexual dysfunction) preceded that of the skin manifestations .
Bauer et al. (1961) reported a study of workers affected by three different outbreaks of chloracne. In this study more than 100 workers were examined. Of these, 31 Hamburg workers had been exposed 5 years earlier. Nine were examined in detail and their symptoms tabulated. Initially, there was dermatitis and irritation of the face, sometimes accompanied by conjunctivitis, and followed by the gradual development of chloracne and patchy pigmentation of the skin. In some cases irritations of the mucous membranes of the face and upper respiratory tract, together with a persistent blepharoconjunctivitis, were also noted.
In the follow-up study, a number of cases of liver injury were observed and, at liver biopsy, a typical grey pigment was observed in liver sections, which did not stain positive for iron. Viral hepatitis was suspected. In a few cases, chronic bronchitis and occasional myocardial damage were also observed. In all cases, fatigue was the main complaint and muscle weakness and muscle pain were described by the workers, particularly in the proximal muscles of the lower extremities. All nine also reported decreased libido.
In a few instances, paresthesia and hyperesthesia or pronounced sensory neuropathy were observed, and minor circumscribed pareses were found. A psychovegetative syndrome occurred in most of the workers. Other signs recorded were: inability to concentrate, memory deficits, sleep disturbances, particularly increased somnolence, decreased drive, and alcohol intolerance. Psychological tests also showed abnormalities.
Following the malfunction of a reaction vessel in northern Italy, in which 2,4,5-trichlorophenol was produced, the temperature in the vessel increased rapidly and an intense black vapour filled the work-room covering everything with a black deposit. Five workers engaged in clean-up operations developed chloracne (Hofmann & Meneghini, 1962). None of those involved in the clean-up exhibited any involvement of general systemic toxicity (even after 16 months) that could be related to exposure to the tar and soot.
However, one 15-year-old worker developed folliculitis and superficial nodular elements on the face a few days after initial exposure. A slow but progressive generalization of the dermatosis developed on the trunk, scalp, and lower extremities. An examination several months later revealed no damage to the renal or liver parenchyma. However, this worker was found to still suffer from outbursts of chloracne in 1980 (Holmstedt, 1980).
Duverne et al. (1964) reported a case that occurred at a plant at Lyon, France, where products that used 2,4,5-tri-chlorophenol as a starting material were manufactured. This worker developed chloracne as well as serofibrinous pleuritis. Ten workers also developed chloracne at a plant near Grenoble,France, which produced 2,4,5-trichlorophenol that served as the starting material for phenoxy pesticides and germicides for cosmetics. These workers showed symptoms of systemic poisoning similar to those reported by Goldmann (1972), and hepatic insufficiency with lipaemia and elevated serum cholesterol levels (Dugois & Colomb, 1956). Another accident resulting in TCDD exposure of workers occurred in the same factory in 1966 (Dugois et al., 1967).
An exothermic reaction resulted in an explosion at a plant in Chesterfield, England, in 1968. The company made 2,4,5-trichlorophenolfrom tetrachlorobenzene and the explosion occurred during the process involving ethylene glycol and caustic soda under atmospheric pressure (Milnes, 1971). In this incident, 79 workers developed chloracne but there was no evidence of systemic illness (May, 1973). In 1971, 3 years after the explosion, two workers who had not been involved in the explosion or its aftermath were employed as pipe-fitters at a new installation, away from the site of the explosion, to refit one of the cleaned tanks.
They both developed severe chloracne, and the son of one of these workers and the wife of the other also developed this condition (Jensen & Walker, 1972). May (1973) cited two incidents involving explosions in a similar process. In the first incident, fatal injuries were recorded; in the second incident, all 50 exposed persons fell ill after 10 days and had liver injury.
In the USA, an outbreak of chloracne occurred among workers manufacturing 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid (Bleiberg et al., 1964); 29 workers developed chloracne and 11 of these had elevated urinary uroporphyrins and exhibited varying degrees of acquired porphyria cutanea tarda. At least one of these workers had abnormal liver-function tests and microscopic examination of a liver biopsy specimen showed parenchymal cell regeneration and haemofuscin pigment.
Many of the workers with chloracne showed hyperpigmentation of the skin. A second study of the workers at this plant was conducted in 1969 by Poland et al. (1971). A total of 73 male employees were examined, and moderate to severe chloracne was found in 13 workers (18%), mild chloracne in 35 (48%), hyperpigmentation in 30, and uroporphyrinuria in 1.
No definite systemic illness could be documented in these workers. Of those studied, 33 had been employed at the plant for 0-4 years, 10 for 4-8 years, and 30 for more than 9 years. The mean duration of employment was 8.3 ± 7.6 years (mean ± 1 SD). The trichlorophenol manufactured in this plant contained 10-25 mg TCDD/kg. Twenty-six of the workers seen by Bleiberg et al. (1964) were also seen in a follow-up study. Six months prior to the second survey (Poland et al., 1971), the manufacturing process was altered so that the 2,4,5-T produced contained less than 1 mg TCDD/kg.
In 1964, in the USSR, many workers developed chloracne while engaged in producing 2,4,5-T. Production was then discontinued (Telegina & Bikbulatova, 1970). On 10 July 1976, an explosion occurred at the ICMESA plant at Meda, near Seveso, Italy, when 12 workers were present. All 176 workers of the plant were examined 3 or 4 weeks after the accident. Chloracne was suspected in 1 of them; the others showed minor symptoms that could not be correlated with exposure.
Alkaline phosphatase and delta-glutamyltransferase seemed slightly increased in 32 and 37 cases, respectively, while five workers showed a reduction in their delta-aminolevulinic acid dehydratase blood levels, and three showed moderately increased urinary gamma-aminolevulinic acid (Zedda et al., 1976). Similar findings were reported by Fara et al. (1976) and Reggiani (1978). The follow-up of the general population is described in section 8.2