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2 JAN 1990 Liver Disease Associated With Expos to 1,1,1-Trichloroethane Michael J. Hodgson. MD. MPH; Alma . Heyl, RT: David H. Van Thiel. MD JAN 2 9 1990 ENVIRONMENTAL AFFAIRS | 1,1,1-Trichloroethene is a halogeneted hydrocarbon solvsnt commonly used in industry because of Its supposed lack of hepatotoxieity. Nonetheless, animal studies performed by sever al independent groups have shown the solvent to induce fat deposition, vacuolar degeneration, and eentrilobular necrosis, changes similar to those seen after exposure to carbon tetrachlo ride, albeit of a much reduced magnitude, in animals exposed to the agent Pour patients with fatty liver disease whose work entailed substantial exposure to this agent were seen at the Uiu/ersity of Pittsburgh (Pa). Based on this clinical experience, we believe that 1,1,1 -trichloroethans should be reconsidered as an agent with potential hepatotoxieity in men. k (Arch Intmm Med. 1989:149:1793-1798) T"\ eath from cirrhosis and liver disease ranks 10th amongthe leading causes of death in the United States and 9th among the leading causes of lost years oftife before the age of 65 years.1* Although fatty liver disease (FLD) need not neces sarily progress to cirrhosis, it is a well-known antecedent of this condition. The prevalence of FLO has been reported in several autop sy series of accidental deaths. Kuller et al* described FLD as being present in 111 of428, or 25%, of sudden, nontraumatic deaths occurring between the ages of 25 and 64 years in Baltimore, Md. In that series, the proportion ofcases of FLD attributable to alcohol was unknown. It is of some interest that Ground/ after excluding alcohol-related fatalities, re ported FLD as being present in 21% of individuals between the ages of 18 and 58 years who died in road or aircraft accidents in Great Britain in 1984. Similarly, Alcastra* re ported FLD in 32% of 1534 autopsies performed in Spain, of which less than half could be attributed to alcohol. Moreover, Hartz and Komhuber* reported FLD in 84% of men and 72% ofwomen who died in accidents in Germany, rates one third as high were recorded in nonaccidental deaths. Fatty liver dis ease has been described in 60% to 90% of morbidly obese individuals and in an uncertain proportion ofdiabetics/'1* Nine Accepted for publicationJanuxry 13.1989. Prom the Occupational and Environmental Medicine Program. Division of General Medicine (Dr Hodgson), and the Division of Gastroenterology (Ms Heyi and Dr Van Thiel), Department of Medicine, University of Pittsburgh (Pb) School of Medicine. Reprint requests to Occupational and Environmental Medicine Program, University of Pittsburgh School of Medicine. Lothmp Hall M9. iSOLothropSt. h. PA 1S261 (Dr Hodgson). percent of persons undergoingjejunoileal bypass for therapy of obesity who have FLD go on to develop cirrhosis.11 Sirr^arly, FLD associated with diabetes mellitus or obesity is kr.own to progress to cirrhosis.1* Despite this sequence of ever.ts. many primary care physicians ignore the minor elevations in liver injury parameters frequently seen in patients, particu larly in those with fatty livers as defined by computed tomo graphic scanning techniques. This lack of interest exists de spite the fact FLD may be an early indicator of progressive liver disease. Clearly, most cases ofFLD are attributed to alcohol abuse. However, only rarely are searches for additional environmen tal or occupational exposures even undertaken when physi cians are faced with a nonalcoholic with a fatty liver. This is the case despite the fact that styrene,'1" other aromatic com pounds,and trichloroethylene (inhaled during glue sniff ing)1*'1* have been implicated as important agents in the patho genesis of liver disease in humans, and these agents are thought to be rare contributors to the problem of cirrhosis on a population basis. On the other hand, 1,1,1-trichloroethane (1,1,1-TCE) is not considered to have great hepatotoxic potential primarily on the basis of several short-term human laboratory exposure studies,**1 one cross-sectional human study in the work place,11 and several animal studies.** As a result of its per ceived low hepatotoxic potential, it is widely used in industry. Nevertheless, Klaassen and Plaa* have described hepatotoxidty after 1,1,1-TCE and trichloroethylene exposure in dogs, which pathologically appeared to range in severity some where between that oftetrachloroethylene and dichloromethane. In rats, hepatotoxieity of 1,1,1-TCE has been seen a: 200 times the dose required to produce hepatotoxieity with car bon tetrachloride.* McNutt et al* described acute inflamma tion, centrilobar swelling of hepatocytes, vacuolar degenera tion and necrosis, and an increase in triglyceride deposits after 1,1,1-TCE exposure. These changes closely resembled those induced by carbon tetrachloride. Finally, Thiele et al" have reported a case ofFLD that, although originally induced by trichloroethylene exposure, appeared to have its progres sion and improvement clearly related to an associated 1.1.1TCE exposure. Zimmerman1' has reviewed the factors associated with in creasing hepatotoxieity resulting from halogenated hydro carbon exposure. He states: "Tbxicity appears inversely pro portional to the negative charge on the halogen atom, to Aid) Intern Med-Vol 149. August 1989 Liver Disease--Hodgson etal 1793 SL 037300 ca. bon-halogen bond energy, and to chain length and directly , proportional to ease of homolytic cleavage, number of halo gens in the molecule, and to the atomic number of the halo gen." Based on this algorithm and on findings of the available ^unimal studies, 1,1,1-TCE would be expected to have some ^Hepatotoxicity potential. We report four cases of FLD associated with exposure to 1,1,1-TCE seen at the University of Pittsburgh (Pa) in the last 2 years. Three of the first 10 patients seen in our occupa tional medicine clinic in a study assessing the risk factors for FLD had very similar jobs entailing substantial exposure to this commonly used industrial solvent. Hie fourth patient, who required liver transplantation, had had intermittent sub stantial exposures. Although a case series such as this does not prove a causal association, the frequency of the associa tion was striking and raises the question of a causal associa tion between 1,1,1-TCE and FLD. REPORT OF CASES Case 1.--A 28-year-old white man was referred for the evaluation of FLD. An occupational history revealed that he began working in a powdered metal plant in 1984 as a "quality control inspector." His job included cleaning parts with 1,1,1-TCE in a cold bath approximately 1 to 2 hours per day. In September 1965, his job station was moved to within 4.6 cm (15 ft) oftwo hot tanks in which 1,1,1-TCE was used as a degreasing agent. No direct exposure to other hepatotoxins could be identified. The plant management at the patients place of employ ment stated that perchloroethylene was used at times on rags to wipe parts clean. Industrial hygiene studies, obtained after diagnosis, showed 8-hour time-weighted average exposures of 1,1,1-TCE else where in the plant (after physical modification of the patients work site) in the range of approximately one tenth of the permissible exposure level. No estimates were available for his former job. Before working for his current employer, he had worked in a textile mill as a spool changer, as a clerk in a grocery store, and as a moldingpress operator in s powdered metal plant, all without known expo- re to hepatotoxins. rA history of present illness revealed that in the fall of 1985 the patient noted the gradual onset of anorexia, fevers, chills, and unin tentional weight loss, and suffered recurrent, episodic illnesses that were never diagnosed or treated specifically. He was removed from work for 10 days and told to abstain from alcohol because ofthe clinical diagnosis of hepatitis, with resulting improvement in the assessed liver injury parameters and improvement in his symptoms. When he returned to work, with recurrence of exposure but with continuing abstinence from alcohol, his symptoms recurredand slowly worsened through the fall of 1986, when he was again removed from work. No pertinent medical, social, or family history ef liver disease was obtained. Tlie patient had consumed on average six to eight 360-mL (12-ox) cans of beer per weekend since the age of 18 years. However, he failed to meet criteria for a diagnosis ofalcohol abuse or alcoholism according to the Diagnostic and Statistical Manual ofMenial Disor ders (Third Edition) and did not score excessively on the Alcohol Use Inventory,0 a standardized measure for detecting past as well as current alcohol abuse or addiction. The patient was shown to have FLD by liver biopsy. His clinical characteristics and laboratory results are listed inTable 1. Ofparticu lar interest is that his serum alanine aminotransferase levels were consistently greater than his aspartate aminotransferase levels, a finding quite atypical for alcohol-associated liver disease. He had never been exposed to blood or blood products and had no other risk factors for chronic viral hepatitis. Serological teats for viral hepatitis were negative. After the patient was no longer exposed to 1,1,1-TCE, his symp toms and liver injury parameters again improved. A subsequent liver biopsy showed markedly less steatosis. Case 2. --A 27-year-old white man was referred for the evaluation of toxic hepatitis. An occupational history revealed that in 1980 he had begun working as a process technician for a specialty steel manufacturer, with minimal exposure to all finishing processes. His work primarily involved exposure around a heated 1,1,1-TCE tank ^MlMd1 for degreasing finished pieces. He was exposed between 5% and ^7*4 Arch Intern Mad-Vbt 149, August 1989 100% of an 8-hour workday. No separate fume hood was available for the tank. He also had occupational exposures to perchloroethylene and 1,1,1-TCE in cold form, as he used both substances daily to weekly, for periods ofgenerally less than 1 hour, on a wipe rag and in open cans used for brush cleaning. Industrial hygiene samples for 1,1,1-TCE obtained over an 11-year period were reviewed. They ranged from 35 ppm (one tenth of the permissible exposure level of 350 ppm) to 17 718 ppm (50-fold the permissible exposure level). Approximately 6 months (November 1983) before referral and diagnosis, the patient developed progressive fatigue, and 4 months before referral began to note intermittent but progressive pyrosis. The month before evaluMion (March 1984), he put in a considerable amount of overtime and noted that all of his symptoms worsened. A diagnosis of "hepatitis" was made on the basis of elevated serum enzyme levels (Table 11 No prior measures of liver injury were available. An upper gastrointestinal series, barium enema, and a liver-spleen scan were performed and the findings were interpreted as normal. The patient's medical, family, and social histories were noncontrib utory. He consumed approximately one six-pack ofbeer per week. He had never been exposed to blood or blood products and had no other risk factors for chronic viral hepatitis. Serological tests for hepatitis B were negative. The results of physical examination were normal. Liver injury parameters and the findings of the liver biopsy are shown in Table 1. As in the previous case, the alanine aminotransferase levels were always greater than the aspartate aminotransferase levels, and the level ofy-glutamyltransferase was only minimally increased. Case 3.--A 45-year-old white man was referred for evaluation of abnormal results on liver function studies. An occupational history revealed that he had worked as a machinist for 19 years in a tool-anddie section. He cleaned parts by dipping them into cold 1,1,1-TCE. Although he occasionally used several other nonhalogenated hydro carbons and one halogesated paraffin in his work, each of these agents was considered to possess even less hepatotoxicity than 1,1,1TCE. He had, on very rareoccasions, used perchloroethylene, also on wipe rags. A review of the patientfc medical history revealed that in 1981 an elevation in alanine aminotransferase level (twice normal) was identi fied. Serological tests performed at that time were negative for hepatitis A and B. In 1983 the patient reported recurrent episodes of abdominal pain and cramping. In 1984 aspartate aminotransferase and y-g)utamyltransferase levels were found to be just above the upper limit ofnormal. The patient's medical, social, and family histor ies were noncontributory. The patient credibly denied all alcohol consumption and scored appropriately on the Alcohol Use Inven tory.9 He had never been exposed to blood or blood products and had no other risk factors for chronic viral hepatitis. Serological tests for hepatitis B were negative- physical examination revealed a mildly enlarged firm liver with a rounded edge. An uppergastrointestinal series, barium enema, and a liver-spleen scan were performed and the findings were interpreted as normal except for the presence of possible gastric varices. Upper gastrointestinal endoscopy confirmed the finding of esophageal and gastric varices; liver biopsy revealed fatty metamorphosis and inac tive cirrhosis. Case 4.--A 50-year-old man was referred for evaluation for liver transplantation because efsolvent-induced cirrhosis. An occupation al history revealed that be had worked for a public utility as a machinist beginning in 1975. In his first 5 years he remembered working with trichloroethylene on approximately five occasions. Be ginning in 1980, he worked with cold 1,1,1-TCE one to four 8-hour shifts at a time. He estimated his exposure to that agent at approxi mately 10% of his working hours. In addition, he was in the vicinity while electricians sprayed 1,1,1-TCE on several occasions (simula tions revealed exposures in the range of 350 to 500 ppm). He had worked as a lathe operator in a variety of tool-and-die and machine shops from 1957 to 1975. Only between 1963 end 1965 was there even a remote possibility of solvent exposure, through the presence of a vapor degreaser far away from his job station in his workplace. He presented with fetigue, nausea, and pain in the right upper quadrant of his abdomen in 1985. Physical examination revealed an obese man whose liver was firm with a rounded edge. Because ofliver function abnormalities in a never-in-a-lifetime drinker, a biopsy spec imen was obtained and demonstrated cirrhosis. Moreover, the pa tient had never been exposed to blood or blood products and had no Liver Disease--Hodgson et el SL 037301 Table 1.--CHnicaJ Parameters and Liver Biopsy Results* Case No. Age. y Height, cm weight kg Ouetelet indexf Laboratory studies ALT, IU/L (<37) 1 28 170 M 34.2 96-136 2 27 175 90 29.4 24-121 3 45 163 76 29.2 97-151 4 51 165 99 36.7 38-38 AST. IU/L (<34) rGT <<44) 45-72 88 25-45 34-53 46-98 41 52-64 56 Alkaline phosphatase. IU/L (<100) Albumin, g/L (3.5-5.0) Prothrombin time, a (11-13) Liver size (by CT seen), cm* (1200-1500) Uver biopsy Histologic findings Degree oMat Zone Psrivenular fibrosis Sinusoidal fibrosis Periportal fibrosis Cellular infiltrate 79-61 4.1 13.1 (11.8) 2761 Macrovsiiculsr 4+ Ul + + + Polynuclear cafis 65-90 3.3 12.4 (11.8) 1779 Macrovssicuiar 1+ Mned - - + Mononuclear and polynuclear cells. eosmopWts 30-97 4.6 ,,, .. MacrovesicUar 34 KM - f MononudMr oHs 115-129 2.4-S.6 14.1 (11.8) 1269 Macronodular ctrrhosis snth dysplastic nuclei and piecemeal necrosis 34 III + Mononuclear ceHs Architecture Intact Intact Intact Intact 'ALT indicatM alanine amjnotranataresa; AST aspartate aminotransferase; y-GT. y-glutamyttransterase; CT. computed tomographic; plus sign, present; and minus sign, abaant. tWeight in kilograms divided by height in meters squared. other risk factors for chronic viral hepatitis. Serological tests for hepatitis B were negative. COMMENT Ail four patients presented with FLD without other predis posing causes, although two can be classified as obese (Quetelet index greater than 30). Alcohol consumption was not in the range associated with steatosis (maximum, 66 mL [2.2 oz] per day). The one patient whose pattern of liver injury parame ters was consistent with alcohol injury had never consumed alcohol. None of the patients had received blood or blood products, was diabetic, had sexual habits associated with viral hepatitis, or demonstrated serological evidence of prior hepatitis B or other viral infection. The primary exposure in all four was 1,1,1-TCE, although minimal exposures to other known hepatotoxins (perchloroethylene and ethanol) could be documented in three and two ofthe four cases, respectively. Nonalcoholic FLD is a well-recognized though poorly stud ied syndrome." Known risk factors include obesity, diabetes, and intestinal bypass surgery. Although between 40% and 85% of morbidly obese patients presenting for therapeutic intervention have FLD on biopsy, only 2.7% of morbidly obese individuals in a working population had evidence of abnormal results on liver tests.9 Hepatotoxin exposure is generally considered a rare cause, although, to our knowl edge, no reports of nonalcoholic FLD have systematically investigated the presence of liver toxins.9* Although 1,1,1- Arch Intern Med-Vol 149, August 1989 TCE is reportedly a very frequently used solvent, we have seen no patients with such exposures with other forms ofliver disease among hospitalized patients at our institution and were therefore struck by the frequency ofthe association. The industrial and environmental use of 1,1,1-TCE as a solvent has increased substantially during the last several decades, because of its assumed lack of hepatotoxicity. This assumption, however, is based on the findings of a single cross-sectional study and several laboratory exposure studies performed on a few humans and ignores a body of data ob tained in animal studies that suggest that 1,1,1-TCE may be hepatotoxic. Because the usual criteria for liver toxicity, such as alter ations in the results of liver injury tests, are not readily translated into dose-response curves, Plaa et al" evaluated the toxicity of seven halogenated hydrocarbons in mice by measuring sleeping time, sulfobromophthalein retention time, and morphological characteristics of the liver. In these studies, 1,1,1-TCE demonstrated the least toxicity of the several agents investigated but nonetheless showed hepato toxic potential. In a later study, Klaassen and Plaa9 compared the hepato toxicity of seven different compounds by constructing doseresponse curves for aspartate aminotransferase and liver histology. They divided the hydrocarbons they studied into two groups, those causing centrilobular necrosis at nearlethal doses (carbon tetrachloride, chloroform, and 1,1,2- Uver Disease--Hodgson et al 1795 SL 037302 TCE) and those that did not (1,1,1-TCE, diehloromethane, trichloroethylene, and tetrachloroethylene). At 50% of the dose necessary to cause measurable organ dysfunction, only 1,1,1-TCE failed to cause vacuolization of centrilobular hepatocytes. The duration of induced alanine aminotransferase abnormalities, on the other hand, was similar for the five hydrocarbons other than chloroform and carbon tetra chloride. Prendergast et alr examined rats, guinea pigs, and several other types of animals under long-term (90 days) continuous and intermittent (5 days per week, 8 hours per day) exposure to 1,1,1-TCE. No evidence of liver injury was seen after continuous exposure at 370 or 135 ppm, although at the latter dose a surprising number of animals died. McNutt et al" exposed mice over varying periods of time to 1,1,1-TCE and found changes closely resembling those in duced by carbon tetrachloride. They described acute inflam mation, centrilobar swelling of hepatocytes, vacuolar degen eration and necrosis, and an increase in triglyceride deposits, all changes consistent with and suggestive of FLD. Further supporting studies, published earlier, were sum marized by Aviado et al." These authors reviewed the hepatotoxicity of 1,1,1-TCE in dogs, rabbits, guinea pigs, rats, and mice, as known before 1976. A series ofstudies performed at the Dow Chemical Toxicol ogy Research Laboratories, Midland, Mich," demonstrated that a concentration of 500 ppm of 1,1,1-TCE was safe for animals, even after long-term exposures. These studies and two others'1-" also examined the effects of 1,1,1-TCE vapors on humans. The results are summarized in Table 2. Only after the induction of anesthesia were minimal functional abnor malities of the liver demonstrated. On the other hand, the longest duration of exposure was only 5 days, and no long term follow-up was performed. Finally, one cross-sectional study has been published com paring workers exposed to 1,1,1-TCE with an unexposed population." Exposures over a 2-year period ranged from 100 to 350 ppm. Mean alanine aminotransferase levels were actu ally significantly lower in the exposed workers than in the unexposed workers. Recently, such phenomena in cross-sec tional studies have been interpreted as evidence for a "survi vor effect." If ill individuals leave the work force preferential ly, the remaining members are "healthier," showing fewer laboratory abnormalities and better survival characteristics. Interestingly, a greater proportion of exposed than unex posed workers (28 vs 21) experienced "abnormalities of the gastrointestinal system" by history, although the significance ofthis finding is uncertain. The excess symptom rate could be interpreted as an early indication of liver disease not yet associated with abnormal results of liver tests. When disease then becomes severe enough to produce measurable abnor malities, individuals would leave the work force. Thiele et al" described a patient with liver disease that was initially thought to have been caused by exposure to trichlo roethylene. After removal from exposure and subsequent improvement, exposure to 1,1,1-TCE was associated with progressive deterioration of liver function. Cessation of expo sure was again temporally related to improvement. Several earlier reports concerning acute toxicity in humans'1'18 have also been published. Two independent mechanisms are considered to contribute to the hepatotoxicity ofhalogenated hydrocarbons. First, the blockage of nascent lipoprotein coupling with triglyceride leads to accumulation of triglyceride within cells. This accu mulation of fat can lead to progressive liver injury." Howev er, the exact cause or mechanism responsible for fat-induced hepatic necrosis is unclear. The second hypothesis is that FLD may be related, at least in part, to the production of toxic-free radicals and/or peroxidation injury. 4,'li In general, metabolites formed in phase 1 reactions (mixed-function oxi dase reactions) are more toxic than are their parent compounds."Thus, even xylene and other nonhalogenated hydro carbons, currently considered nontoxic, can give rise to toxic intermediaries as a consequence of mixed-function oxidase metabolism prior to their excretion. Alcohol, which is thought to lead to hepatic damage, at least in part, as a result of free radical formation,"'" has been shown to potentiate the toxic effects of organic solvents and drugs that can exert at least some of their toxicity through lipid peroxidation.11*" Recent evidence indicates that short-chain aliphatic hydrocarbons without intrinsic hepatotoxicity may potentiate halogenated hydrocarbon exposures; eg, acetone increases both the acute Table 2.--Summary of Human Exposure Chamber Studies of 1,1,1-Tbchtoroethane* Source, y TorVetson et al." 1958 Stewart et al," 1961 Row et al,* 1963 Stewart et al,'* 1969 No. or Subjects ?1 ?1 ?1 ?1 ?1 6 6 3 2 3 7 NM 2-S (a total of It volunteers in 31 exposures) Exposure Concentration, ppm 546 506 1000 920 1900 500 500 1000 1000 1000 To anesthesia (<2650) 520 500 Duration, min 90 450 30 70-75 S 78 186 73 35 20 15 420 6.5-7 *NM indicates not mentioned. AST. aspartate aminotransterase; and IDH, lactate dehydrogenase. tTwo of the seven suhiects developed transient elevation of uroporphyrin excretion Frequency (No. of Timet Expoeed) 1 1 1 1 1 1 1 1 1 1 1,4,5 5 Health Effects/ Uver ln|ury NM NM NM NM NM Normal Normal Normal Normal Normal Normalf None AST, LDH unchanged 1796 Arch Intern Med--Vbl 149, August 1989 Liver Disease--Hodgson etal SL 037303 and chronic hepatotoxicity of carbon tetrachloride in animals." The histologic characteristics of FLD are well described. Currently, most investigators classify it by its zonal distribu tion within the liver and according to the size of the fat droplets within hepatocytes." Although a considerable amount of literature has been accumulated on drug-induced hepatitis, little information is available on the importance of occupational and environmental risk factors for liver disease in general and for steatosis specifically. In one recent study of blood donors with elevated alanine aminotransferase levels," 22% were obese and 63% consumed alcohol "daily." No men tion was made of occupational or environmental exposures to liver toxins. Moreover, the role of steatosis as a cause for or predecessor of cirrhosis in nonalcoholics who are neither obese nor diabetic and who show no evidence of viral disease has not been assessed. Exceptions are the recent epidemics resulting from exposures to kepone," trichloroethylene," and dimethyIformamide.* However, only chloroform- and carbon tetrachloride-induced liver disease (both steatosis and cir rhosis) have been well described and are generally accepted to be causes of both acute hepatotoxicity and chronic liver disease. Two of our four patients were clearly obese, ie, 30% over weight. The other two were not thin. Two mechanisms might play a role involving the interaction of obesity and hydrocar bon exposure in the development of liver disease. First, it is known that the potentiation of hydrocarbon toxicity by alco hol is dependent in part on the relative timing of alcohol administration." The presence of obesity may continuously present the liver with more substrate to form more epoxides. Hie continuous low-level presence of free radicals may then allow additional exposure to the more potent halogenated hydrocarbons and thereby induce overt damage more readily. Second, fatty tissue may itself serve as a reservoir of haloge nated hydrocarbons. These would then be continuously re leased over a much longer period of time than in individuals with less body fat, leading to an effectively much longer duration ofexposure. A final additional contribution to toxic ity in these cases may result from minimal exposures through contamination ofcommercially available 1,1,1-TCE or ground water with minimal amounts of solvents with substantially greater hepatotoxicity, such as trichloroethylene and perchloroethylene. Although we cannot absolutely discount such "part per million" contamination, we think it unlikely to play a major role. In animal experiments, alcohol potentiates the effects of other hepatotoxins. Three of the four patients consumed minor quantities of alcohol, of a magnitude not generally associated with the development of FLD. We obviously can not exclude an interaction between the toxicities of alcohol and 1,1,1-TCE. Both obesity and alcohol may therefore have played a role in the pathogenesis of liver disease in these cases. In summary, 1,1,1-TCE has been assumed to be free of hepatotoxicity in humans because the scanty evidence avail able has failed to demonstrate clear evidence of hepatotoxic ity rather than because it has been studied extensively--a type II error, or lack of power in documenting safety, rather than the certainty of safety. In addition to epidemiological evidence, animal bioassays and structure-activity relation ships are commonly used by toxicologists in interpreting possible causal associations." Although many physicians hesi tate to use animal studies to support causal associations in humans, in this case human hepatotoxicity might reasonably be expected, based on the evidence from animal studies. Human studies have not demonstrated lack of effects. Case aeries such as this cannot conclusively document the hazard ous nature ofan agent. Still, we are left with an agent (1) that has been shown to induce liver disease in animals, (2) that is associated with some degree of liver dysfunction in humans after substantial exposure, and (3) that has not been shown to be safe. On the basis ofthese four cases, we believe that 1,1,1TCE may be a potential hepatotoxin in humans. Tliis work woo supported in put by grants from the Nation*) Institute for Occupational Safety and Health. Centers for Disease Control, Atlanta, Ga (KOI OH00071-0U and the National Institutes of Health. Bethesd*. Md (NIDDK 3tS6andNIAAA 06601). The authors wish to thank Daniel H. Gregory, MD, John PSntalone. MD, UMter Ubinger, MD, and David Dunkert. MD, for the referral of their patients. 1. Premature mortality--United States, 1983. MMWR. 1986;33:357-365. 2. Changes in premature mortality--United States, 1963-1984. MMWR. 1966;35:29-31. 3. Kulier LH. Perper JA, Cooper M, Fisher R. An epidemic of deaths attributed to btty liver in Baltimore. Pm Med. 1974;3:61-79. 4. Ground KEU. Prevalence offatty liver in healthy male adults accidentally IdDad. Anal Spot* Environ Med. 1984;55:59-61. 5. Alcaatre MA. Inddenda de aapecto* etiopalogtnico* de la esteatosis: reviaion de 1534 autopaias. Rev Clin Eep. 1981:161:7883. 6. Harts F, Kornhuber HH. Haeuligkeit von Fettleber in Deutschland. DteehMed Wxhensche 1985:110:1232. 7. Kern WH, Heger AH, Psync JH. DeWind LT. 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