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Journal of
Occupational Health
Generalized Skin Reactions in Relation to Trichloroethylene
Exposure: A Review from the Viewpoint of Drug-Metabolizing
Enzymes
Tamie NAKAJIMA1, Osamu YAMANOSHITA1, Michihiro KAMIJIMA1, Reiko KISHI2 andGaku ICHIHARA1 1Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine and2Department of Public Health Sciences, Hokkaido University Graduate School of Medicine, Japan Abstract: Generalized Skin Reactions in Relation
dermatitis, Glutathione S-transferase, Polymorphism, to Trichloroethylene Exposure: A Review from the
Stevens-Johnson syndrome, Trichloroethylene Viewpoint of Drug-metabolizing Enzymes: Tamie
NAKAJIMA, et al. Department of Occupational and
Trichloroethylene is mainly used as a solvent to remove Environmental Health, Nagoya University Graduate
grease from metal parts or lenses, and as a chemical to School of Medicine—The literature was reviewed to
make other chemicals. Occupational exposure to study cases of intoxication with systemic dermatitis trichloroethylene is known to cause a variety of health associated with exposure to trichloroethylene. The hazards. Together with anesthetic action, hepatic damage, average age of patients in the reports reviewed to date polyneuropathy, trigeminal neuropathy, and dermatitis was twenty-nine; these diseases were found in with skin irritation are familiar diseases which occur as a relatively young persons and no difference was foundaccording to gender. Many cases occurred within one month after the onset of exposure to trichloroethylene, In addition to the non-specific skin irritation resulting and were accompanied by hepatitis, jaundice, by the defatting action, severer generalized dermatitis hepatomegaly or hepatosplenomegaly. Most of the with hepatitis, which includes Stevens-Johnson syndrome patients had no history of drug abuse or herpes and toxic epidermal necrolysis, sometimes occurs after infection. The level of exposure to trichloroethylene exposure to trichloroethylene3–10). Such dermatitis is was not recorded in many cases, but ranged from less generally known to occur subsequent to the administration than 9 ppm to 800 ppm. In the severest cases, the of various medicines and infections-i.e., antibiotics such lesions involved mucous membranes such as the as sulfonamides, anticonvulsives such as carbamazepine conjunctiva and oral cavity, and the patients were and phenobarbital, anti-inflammatory medications such diagnosed with Stevens-Johnson syndrome, but the as acetylsalicylic acid and paracetamol, anti-parasitic etiology of the disease after trichloroethylene exposureremains unclear. Since several drugs have also been medications such as albendazole and tinidazole, viruses, shown to cause systemic dermatitis with hepatitis, mycoplasma, and other bacterial infections11–15). As for susceptibility factors are discussed. Many patients other types of chemical exposure, there have been a few were found to have the slow acetylator genotype of N- case reports on the dermatitis, that of a young woman acetyltransferase (NAT) 2, suggesting that the NAT2 who used pesticide spray16), and students who were genotype is a susceptibility factor. This hypothesis may exposed to 9-bromofluorene in a lab setting17). Thus, also be applicable to trichloroethylene because NAT is although many kinds of chemicals have the potential to involved in the glutathione-mediated metabolism.
cause severer generalized dermatitis with hepatitis, trichloroethylene must be one of the most importantcausative chemicals as shown in an epidemic of the Key words: N-acetyltransferase, Generalized
disease in China; an epidemic reported as involving over100 workers occupationally exposed to trichloroethylene Received July 29, 2002; Accepted Oct 24, 2003 in Guangdong, China, who suffered from dermatitis with Correspondence to: T. Nakajima, Department of Occupational and Environmental Health, Nagoya University Graduate School of A review of the literature was performed to study cases Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan of intoxication with systemic dermatitis associated with Tamie NAKAJIMA, et al.: Generalized Skin Reactions in Relations in Relation to Trichloroethylene Exposure exposure to trichloroethylene and tetrachloroethylene3).
including Stevens-Johnson syndrome associated with Since almost all of these patients suffered from hepatitis, trichloroethylene exposure, are summarized in Table 1.
the possible involvement of the metabolism of Bauer and Robens6) first reported four patients who trichloroethylene in liver drew our attention. In this developed generalized dermatitis after exposure to review, we discussed the mechanism in relation to the trichloroethylene. All of the patients had been engaged genetic polymorphism of enzymes involved in the in the cleaning of metals or bomb casings with trichloroethylene, but the time from the use of thisparticular solvent until the onset of dermatitis was not Clinical manifestation of trichloroethylene-related
mentioned. Only one patient (case 3) had developed generalized skin reactions
hepatitis, as determined by increased aspartate The occupational and clinical characteristics of thirteen aminotransferase (AST), alanine aminotransferase (ALT), typical patients who suffered from generalized dermatitis, lactate dehydrogenase (LDH), and bilirubin levels.
Table 1. Occupational background and clinical findings of patients with generalized dermatitis after exposure to trichloroethylene
TCA in urine, TCA in urine, TCA in urine, TRI, trichloroethylene; TCA, trichloroacetic acid; TCE, trichloroethanol aTwin sisters, bThis subject was working in an air-conditioned room in which there was a partially closed degreasing tank containing TRI. The TCA levels in the urine from 18 workers were 21 to 165 mg/l. , cThis subject was working in the same factory as case 7., dThis subject had sufficient exposure to TRI to develop degreaser’s flush., eThe unit of concentration reported by these authors (mg/m3) was converted to ppm by the Phoon et al.4) reported five cases. Cases 5 and 6 were the same condenser manufacturing plant, using twin sisters who had worked in the same factory. Case 5 trichloroethylene to clean ceramics and equipment used trichloroethylene to remove epoxy resins from products. The concentration in the workplace was transistor parts, and case 6 checked the cleaned parts and between 40 and 169 ppm. Five wk after case 7 began occasionally assisted case 5 in her work. Three weeks work and two wk after case 9 did so, multiform exudative after commencing work, fever appeared in case 5 and erythema was observed on the body and around the lips.
three days later, in case 6, and multiform exudative Biochemical findings for both cases were equivocal, but erythema was also observed on the face, arms and mouth liver dysfunction and hepatomegaly were presumably in both cases. Their ALT levels were high, and observed. Neither case had a history of drug use or of hepatomegaly was observed. Neither had a history of previous herpes simplex infection. Case 8 worked at a drug use or herpes infection. Cases 7 and 9 worked in factory where metal parts such as bearings and rollers Tamie NAKAJIMA, et al.: Generalized Skin Reactions in Relations in Relation to Trichloroethylene Exposure were manufactured. He alloyed metals, and wrapped the underlying illness, and no history of blood transfusion or products manufactured. Although this patient had no of drug or alcohol abuse. Approximately one month after direct exposure to trichloroethylene in the workplace, a beginning work, she began to have fevers, erythema and tank of trichloroethylene was found in the room where jaundice, and she experienced nausea and vomiting.
he worked. Therefore, his trichloroethylene exposure When she visited a regular hospital, the doctor described level was thought to be relatively low. Three wk after her as having mild jaundice, hepatomegaly, and erythema beginning work, systemic erythema, liver dysfunction, on the face, trunk, and extremities. She was treated for hepatomegaly, and jaundice appeared in this patient.
salmonella infection, but no improvement was seen. She Thirteen wk after his condition had improved for the first was then transferred to the hospital where one of the time, his erythema and liver dysfunction reappeared after authors of the study was on the medical stuff. In addition exposure to trichloroethylene at his workplace. This to the symptoms mentioned above, there was enlargement particular patient refused hospitalization, and returned to of the cervical lymph nodes. Liver function tests indicated work two days later, but his symptoms increased to AST levels of 115 IU/l, ALT levels of 56 IU/l, alkaline include hepatosplenomegaly, as well as exfoliative phosphatase (ALP) levels of 113IU/l, albumin at 38.8 dermatitis, the following week. He continued going to mg/l, and total protein at 61.1 mg/l. Tests for the hepatitis A, B and C viruses, rickettsial diseases, melioidosis and Nakayama et al.7) reported a patient intoxicated by the HIV were negative. A biopsy of the left cervical lymph use of trichloroethylene as a degreasing agent. Two wk node indicated hyperplasia. In a liver biopsy, thickened after commencing work, systemic erythema and liver liver cell cords, the appearance of multinucleated giant dysfunction with high fever were observed in this patient.
liver cells, liver cell necrosis in the centrilobular zone Patch tests for trichloroethylene and trichloroethanol caused by invasion of polymorphonuclear leukocytes, and turned up positive, but exposure levels at the workplace lymphocytic infiltration in the portal vessel, similar to were unknown. Schattner and Malnick5) also reported findings seen with chronic hepatitis, were observed. Patch the case of a female with dermatitis concomitant with tests were performed to examine allergic responses to hepatitis. She had been cleaning machine parts with trichloroethylene and trichloroacetic acid, but she showed trichloroethylene at work. Her syndrome, which was only a positive reaction to 50% trichloroethylene. The accompanied by hepatitis, was thought to have occurred patient’s liver functions returned to normal within three after chronic exposure to the solvent.
months after she was first admitted to the hospital.
Bond8) reported the case of a thirty-yr-old man who used As shown in Table 1, in many cases symptoms trichloroethylene as part of a degreasing process (case 12 developed within a month after beginning to use in Table 1). The patient had no underlying illness, but trichloroethylene. Jaundice was observed and began to complain a few weeks after commencing work hepatomegaly was noted in many cases. Most patients of weakness, dizziness, loss of appetite, nausea, abdominal had no history of drug use or herpes infection. The levels pain, diarrhea, fever, chills, eczema, peeling face and of exposure to trichloroethylene in the majority of cases itchiness. He had high ALT values (1,250 IU/l), and were unclear, but ranged from less than 9 ppm to 800 showed an increase in atypical lymphocytes. This male ppm when measured. It should be noted that symptom patient was exposed to a level of trichloroethylene that development started at an exposure level of 9 ppm or caused a symptom called degreaser’s flush. His history of lower. There was no difference according to gender, and alcohol use was determined to be one or two bottles of all cases appeared in relatively young persons.
beer on weekdays, and four or five bottles of beer on his Tr i c h l o ro e t h y l e n e a n d t h e d e v e l o p m e n t a l
days off. After two wk, his ALT values decreased from mechanism of generalized skin reactions and
1,250 IU/l to 717 IU/l. He tested negative for hepatitis associated liver dysfunction
viruses A, B and C, as well as for HIV and cytomegalovirus.
On the night of the day he recommenced using Trichloroethylene is mainly metabolized by trichloroethylene at work, he experienced a recurrence of cytochrome P450 (CYP) to chloral hydrate, which is systemic diffuse erythema concomitant with a severe itch.
further converted by alcohol (ADH) and aldehyde In spite of not drinking any alcohol, the erythema spread.
dehydrogenases (ALDH) to trichloroethanol and This patient took a few days off from work, but the trichloroacetic acid, respectively19). Most of the erythema continued and began to scale. Even after one t r i c h l o r o e t h a n o l i s c o n j u g a t e d w i t h U D P - week, the erythema scaling and edema continued. His glucuronyltransferase to form urochloral acid, some of ALT level was 517 IU/l, and his leukocyte count was which is converted by microsomal alcohol oxidation 10,100/mm3; 27% of his leukocytes were eosinophilic.
enzyme to trichloroacetic acid via chloral hydrate. Of Chittasobhaktra et al.9) reported the case of an eighteen- CYP isozymes, CYP2E1 is a major form in the yr-old woman who used trichloroethylene as a cleaning metabolism either in rodents19) or human20, 21), and also agent at a sock factory (case 13 in Table 1). She had no plays an important role in trichloroethylene-induced when using phenobarbital or alcohol, AST and ALT levels Another metabolic pathway of trichloroethylene is a became increased to about 10,000 IU/l after exposure to glutathione-mediated metabolism by glutathione S- high levels of trichloroethylene, and serious liver damage transferase: relatively small amounts of trichloroethylene was observed. But no similar results were observed when are conjugated with GSH to form S-(1, 2-dichlorovinyl) using chloral hydrate. These results indicate that any glutathione (DCVG)24). DCVG is further converted to intermediate metabolites between trichloroethylene and S-(1, 2-dichlorovinyl)-L-cystein (DCVC) by γ- chloral hydrate may cause serious liver damage related glutamyltransferase and dipeptidase. The DCVC formed to trichloroethylene, but it is unclear whether skin is acetylated to N-acetyl-S-(1, 2-dichlorovinyl)-L-cystein damage, such as erythema, was observed in the rats used by N-acetyltrasferase, or is converted to pyruvic acid, in the study. If we consider these results in light of the ammonia and reactive thiols by β-lyase. It is generally observation that a patch test for trichloroethanol was thought that trichloroethylene is detoxicated or positive in patient 10, involvement of CYPs in the disease bioactivated through the former and the latter step, with trichloroethylene exposure seems to be unlikely.
Polymorphism of drug-metabolizing enzymes and
Patients who develop generalized skin reactions may generalized skin reactions induced by various
be sensitive to trichloroethylene or its metabolites. A chemicals
patch test was performed with a 5% tincture oftrichloroethylene in olive oil on patient 7, and a negative Some studies have assumed a genetic link to the cause result was observed. Patch tests for trichloroethylene, of drug-induced generalized skin reactions. Green et al.26) trichloroethanol, and trichloroacetic acid were performed studied the relation between high sensitivity to on patient 10. A weak positive response was found for carbamazepine and epoxide hydrolase (EH) genetic trichloroethylene levels at 10 and 25%, but at the 5% polymorphism based on the findings that 1) the cellular level, a negative result was observed. A medium positive toxicity of carbamazepine is neutralized by EH, 2) result was seen when using 0.005–5% trichloroethanol, metabolized carbamazepine epoxide is neutralized by but at 5% trichloroacetic acid, a negative result was glutathione S-transferase (GST) and/or EH, 3) in observed. In two cases (cases 10 and 13), the epidemiological studies, an increased incidence of fetal trichloroacetic acid patch tests returned negative results, disorder was observed in pregnant women to whom making it difficult to identify trichloroacetic acid as a sodium valproate, an inhibitor of EH, was administered, cause. Considering the weak positive at high levels of and 4) there is an inverse correlation in animal trichloroethylene, and only one positive response at a low experiments between EH levels and fetal disorder caused level of trichloroethanol, the cause appears to lie with by phenitoin, which induces the same side effects as the trichloroethanol itself or the metabolite(s). It may be carbamazepine. DNA was extracted from a control group possible to determine the cause(s) of the disease by using of ten healthy individuals and from ten patients suggestive patch tests of trichloroethylene or its metabolites; but, of hypersensitivity to carbamazepine (toxic epidermal considering that patient 8 died after repeated exposure to necrolysis, Stevens-Johnson syndrome, hepatitis and trichloroethylene, caution is necessary when deciding to pneumonitis; all cases exhibited skin reactions). PCR- SSCP was used to perform the screening for nine exon It remains unclear how trichloroethylene causes variations within the EH gene, and the variations generalized skin reactions and the associated liver identified were analyzed directly by sequence analysis.
dysfunction. Trichloroethylene inhibits the activity of A higher frequency of variation was observed in the ALDH and the metabolism of low-molecular-weight patient group than in the control group, but the results aldehyde with short carbon chains25). Therefore, were inconsistent. In the most serious case, the EH gene aldehydes may easily accumulate in the body after was a wild type gene. In addition to the difficulty in exposure to trichloroethylene. Since degreaser’s flush drawing conclusions based on a study of only ten persons, occurred after alcohol consumption in case 12, only one variation in the coding region of the EH gene occupational exposure to trichloroethylene might have may be insufficient to serve as a predictor for sensitivity blocked ALDH (in particular, ALDH2, which has an to carbamazepine. As for the trichloroethylene affinity for acetaldehyde). This led to the hypothesis that metabolism, the contribution of EH must lie somewhere this blockage of ALDH might be the trigger for the between trichloroethylene and chloral hydrate. If the generalized skin reactions. It is still unclear whether many causative metabolite is to be trichloroethanol or the of the possibly causative agents block ALDH.
metabolite(s), it would as yet be difficult to pinpoint the No serious liver damage was observed in either rats polymorphism of the EH gene as a factor.
exposed to high levels of trichloroethylene or rats with Acetylation catalyzed by N-acetyltransferase (NAT) is prolonged exposure22, 23). If, however, CYP isozymes the major route of conjugation reaction of many (CYP2B1/2 and CYP2E1, respectively) were induced xenobiotics. The two genes (NAT1 and NAT2) that encode Tamie NAKAJIMA, et al.: Generalized Skin Reactions in Relations in Relation to Trichloroethylene Exposure NATs have been sequenced27). NAT1 is polymorphically observed in the control group. A good correlation between distributed in humans, and individuals that inherit rapid the activity of NAT in the hair roots and that in the liver N AT 1 a r e a t a h i g h r i s k o f b l a d d e r c a n c e r 28).
was demonstrated by caffeine tolerance, allowing us to Independently of this, NAT2 exhibits a polymorphism due conclude that NAT activity in the patients’ livers was to a point mutation in the coding region, and individuals lower than that in the controls, and that all patients had possessing it can be designated as phenotypically slow the slow-type phenotype of NAT. In comparison, 58% or fast metabolizers29). Rapid acetylators are either of the control group had the slow type of NAT. Therefore, heterozygous or homozygous for wild-type alleles of the NAT2 genotype is considered to be a factor in NAT2. Slow acetylators that carry NAT2 mutant alleles susceptibility to serious adverse skin reactions associated produce proteins that are either poorly expressed, unstable, or have partially reduced catalytic activities.
NAT2 is also involved in the glutathione-mediated Patients with generalized skin reactions due to drugs metabolism of trichloroethylene. Very recently, which are metabolized by NAT may have had a greater relationships between trichloroethylene-induced frequency of the slow type of NAT2 than the control generalized skin reaction and genetic polymorphisms of group. Wolkenstein et al.30) explored the relation between NAT2 as well as other drug-metabolizing enzymes Stevens-Johnson syndrome or a toxic epidermal reaction C Y P 1 A 1 , G S T M 1 , G S T P 1 , a n d G S T T 1 w e r e associated with either sulfonamide or anticonvulsive investigated in 43 patients and 47 healthy workers drugs, such as carbamazepine and phenobarbital and a exposed to trichloroethylene by Huang et al.18). Of these genetic polymorphism for NAT2 and GSTM1. Patients enzyme polymorphisms, only NAT 2 slow genotype without HIV (18 from among groups associated with significantly increased the risk of trichloroethylene- sulfonamide, and 14 from among groups associated with induced dermatitis. Unfortunately, CYP2E1 and UDP- anticonvulsive drugs) were studied, along with 20 healthy glucuronyltransferase polymorphisms were not involved individuals of the same age, who were included in a in the study. Furthermore, it is unclear whether it is control group. DNA was extracted from the peripheral involved in the trichloroethanol metabolism. Therefore, l e u k o c y t e s , a n d a n a l y s e s w e r e p e r f o r m e d f o r if trichloroethanol is responsible for trichloroethylene- polymorphism in both groups. Seventeen of the 18 associated generalized skin reactions, it might be patients with sulfonamide-related Stevens-Johnson necessary to demonstrate a correlation between syndrome were demonstrated as having the slow type of NAT2; this showed a clearly higher frequency than that In conclusion, genetic polymorphism for NAT2 may of the control group, where this type of NAT2 was b e a f a c t o r t h a t i n c r e a s e s s u s c e p t i b i l i t y t o demonstrated in only ten out of twenty individuals. Of trichloroethylene-induced generalized skin reactions.
the fourteen patients with anticonvulsive-related Stevens- But, in all cases, the research was limited by the use of Johnson syndrome, eight had the slow type of NAT2, small groups; therefore, epidemiological studies of large showing no difference from the control group. For the GSTM1 gene, there was no difference in the frequencyof the defective type of gene between the patients with References
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