Document DvKQwgmLkr97Z3LD6YwnYoJGn

in Environmental Medicine I+\c u%& 'e, va!A.& yq ST. MARY'S HOSPITAL, THE CATHOLIC UNIVERSITY OF KOREA Aplastic Anemia in a Petrochemical Factory Worker ! Young Mann Baak, Byoung Yong Ahn, Hwang Shin Chang, Ji Hong Kim, Kyoung Ah Kim, and Young Lim Department of Industrial Medicine, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea A petrochemical worker with aplastic anemia was referred to our hospital. He worked in a petro- leum resin-producing factory and had been exposed to low-level benzene while packaging the powder resin and pouring lime into a deactivation rank. According to the yearly environmental survey of the working area, the airborne benzene level was approximately 0.28 ppm. Exposure to benzene, a common chemical used widely in industry, may progressively l a d to pancytopenia, aplastic anemia, and leukemia. The hematotoxicityof benzene is related to the amount and duration of exposure. Moa risk predictions for benzene a p o s u r u ; have been based on rubber worken who were exposed to high concentrations. In the petroleum indusq, the concentraaon of benzcne is relatively low, and there are disputes over the toxicity of low-lml benzene because of a lack of evidence. In this paper we report the case of aplastic anemia induced by low-level benzene exposure. K;r word: aplastic anemia, benzene, petrochemicalworker. Envimn He& Pmprct 107:851-853 (1999). [Online 13 September 19991 b n p / / r ~ n r t l . n i r l n . n i b . ~ / & c ~ l 9 9097/pI85I-853baaWabsrna~ht.tml Case Presentation A 45-year-old petrochemical worker with aplastic anemia was referred to our depanment of industrial medicine in November 1998 to evaluate a relationship benveen his job history and the disease. The patient worked in a petroleum resin-producing factory that used heavy raw pyrolysis gasoline (H-RPG)containing 0.3% benzene as a raw material. The petroleum resins are used primarily in the production of paints and adhesives. In 1977 the patient began working in a packaging-process area where he packed powder resin into bags. Each bag weighed 80 kg, and the patient normally worked 8 hr/day. In May 1993 he moved to a deactivation-process area where he poured lime into a deactivation tank twice a day, 40 kg each time, and drained the tank after the chemical reaction (Figure 1). The patient actually spent c 30 minlday in the deactivation process; for the remainder of the work day, he waited in a control room. Other than doing routine work in the packaging and deactivation processes, he also occasionally cleaned the reaction tank; because of this the patient may have been exposed to high-level benzene for short periods. While working he wore a facial mask for protection from resin powder and noxious gas. In September 1998 the patient complained of fatigue and lethargy. He visited a local clinic and routine physical and laboratory examinations were performed. The blood test performed at this rime showed pancytopenia and the patient was referred to St. Mary's Hospital. After admission to the department of hematology, a bone marrow biopsy was performed. This biopsy showed hypocellular- ity with htty infiltration. which is consistent with aplastic anemia. A chromosomal study showed a normal male karyotype without any aberrations. The patient did not smoke cigarettes or drink alcoholic beverages, and his history of drug and radiation exposure was insignificant. His serologic markers and history of viral infection were negative. There were no abnormal hematologic findings in the patients's yearly occupational fitness examination at the fictory, which was &en before the onset of his symptoms (Table 1). Because there was no marching compatible donor, the patient was given blood transfusions, antilymphocyte immunoglobulins, and cyclosporin. H e was discharged in December 1998 with symptomatic improve- ment and laboratory stabilization. In January 1999, he was readmitted and treated for opportunistic herpes zoster infection. Industrial hygienists performed routine environmental surveys of the factory twice each year horn 1993 to 1998; the air concentrations of benzene were approximately 0.28 ppm. We performed an environmental survey of the workplace again after the patient was referred (Table 2). We also measured -EnvironmentalHealth Perspectives Volume 107, Number IO,October I999 nancnummuconic acid (n-MA) in the urine of workers to assess benzene exposure. Discussion Benzene, an aromatic hydrocarbon, is used widely in industries as a solvent for rubber and inks and as a starcing material in chemical synthesis. It is a natural constituent of petroleum, and the general population is exposed to benzene from gasoline, indoor air, smoking, car exhaust, and groundwater. The hematotoxicity of benzene is related to the amount and duration of exposure (I).At high levels of exposure (air concentration > 100 ppm), the incidence of aplastic anemia is approximately 1/100 individuals exposed; at lower levels of exposure (10-20 ppm), this drops abruptly to approximately 1/ 10,000 (2).In the past, benzene exposure > 100 ppm frequently occurred in workplaces, and the causal relationship between high-level benzene exposure and its toxicity has been known since the nineteenth century. As data indicating carcinogenecity of benzene increased (3,4)t,he standards of occupational exposure and the airborne level in work- places have been progressively lowered. In Korea, benzene levels in paint production, printing, and glue adhesion are approximate- ly 2.0 pprn [geometrical mean (31;in the petroleum industry in the United States, the level of benzene is 0.3 ppm for an 8-hr timeweighted average (TWA) (@. Risk assessment studies have demonstrat- ed that there is significant excess risk associated with a lifetime exposure to 10 ppm benzene and that this risk would be lowered with a decrease in the exposure level. In 1987, the U.S.government lowered the Address correspondence ro Y. Lim, Deparrmcnr of Indusrrial Medicine, St. Mary's Hospiral, The Catholic Universiry of Korea, 62 Youido-dong, Youngdungpo-gu. Seoul, 150-010, Korea. Telephone: 82 02 3779 1401. Fax:82 03 782 6017. E-mail: nglim@cmc.cuk.ac.kr We thank Y.H. Choi and S.K. Kang (Indusrrial Safety and Health Rcsarch Instirure). and J.W. Lee (Deparrmenr of Internal Medicine. St. Mary's Hospital) for their profasiorul and technical support. Received 1 June 1999; accepted 9 July 1999. 85 1 \ .Grand Rounds in Environmental Medicine Baak et al. Aplastic anemia may be acquired from the use of drugs (e+ antimetabolites, antitumor agents, gold, chloramphenicol, phenylbutazone, sulfonamides); radiation; chemicals (e.g., benzene, solvents, insecticides); viruses (e.g., non-A, non-B. non-C hepatitis virus, human immunodeficiency virus, Epstein-Barr virus); paroxysmal noc- The data regarding benzene-induced clastogenesis in hematopoietic cells are not conclusive, however (4. Some investigators indicated that numerical or structural chromosomal aberrations were increased in workers who had long-term exposure to benzene; the ratios were increased in leukemia that occurred h e r benzene exposure. Others were turnal hemoglobinuria; pregnancy; connec- not able to show any significant differences tive tissue disorders; and graft versus host between the exposed and control groups (13. disease. Hereditary causes of aplastic anemia Pancytopenia and aplastic anemia are are Fanconi anemia, dyskeratosis congenita, not distinct diseases, but rather a continuum and Schwachmansyndrome. of changes reflecting the severity of bone Fifty percent of cases are idiopathic, and marrow damage. Funher, Aksoy and Erdem even for patients for whom a well-defined (3)reponed the progression of aplastic ane- association between exposure and subse- mia in a benzene-exposed individual through quent development of aplastic anemia has a preleukemic phase into frank acute been established, it remains unclear why leukemia. These findings were observed with only a small proponion of those exposed to a high-level benzene exposure and not with given agent develop the disease. low-level exposure. Hematotoxicity and carcinogenecity. In Chemical, medical, or toxic substances acquired aplastic anemia, the disease results may cause aplastic anemia in a dose-depen- from two main pathogenic mechanisms: an dent or idiosyncratic way. To date, there is Figure 1. Demonstration of draining lime from a acquired intrinsic stem cell defect and an no evidence that low-level benzene exposure drainage tank after the deactivation process. immunosuppressive mechanism (9). Benzene induces aplastic anemia through an idiosyn- itself is not myelotoxic or mutagenic. It is cratic mechanism ( 13).However, benzene occupational benzene standard from 10 ppm principally metabolized in the liver, and the metabolism is quantitatively different at dif- to 1 pprn on the basis of qualitative and metabolites are transported to the bone mar- ferent dose levels. A relatively higher propor- quantitative risk asessments of leukemia (7). row and other organs. The active metabolites tion of benzene is converted to toxic However, the cause-effect relationship of of benzene exert direct toxicity and alter dif- metabolites at low doses, suggesting that lin- low-level benzene exposure is under consid- ferentiation patterns in the bone marrow. The ear extrapolation of risk from high-dose `i erable debate because the studies of risk immunosuppressive function of benzene is studies may underestimate the true risk of assessment depend not only on an assump- keepingwith its lymphocytotoxic effect (2. low-dose benzene exposure (7). tion of a particular carcinogenic model but The carcinogenic mechanism of benzene Risk assessment. The establishment of also on dose-response information from epi- is different from that of other chemicals. benzene toxicity and setting of current sran- demiologic studies. Also, the studies did not Some carcinogens, such as benzopyrene, aro- dards has been primarily because of epidemi- successfully demonstrate excess risk at partic- matic amines, and aflatoxin, are thought to ologic studies. Most investigators base risk ular concentrations; the-reduction of current be activated to a single, ultimate carcino- predictions for exposures on rubber workers standards is still in dispute worldwide. The genic metabolite, which is highly elec- who were exposed to high concentrations of 8-hr-TWA exposure standard is 10 ppm trophilic; these carcinogens are also thought benzene; an exposure-response analysis by (e.g., Belgium, Denmark, Finland, Japan, to bind strongly to DNA in a covalent fash- Rabbe and Wong (14) indicated that there Korea, and the Netherlands) or 5 pprn (e.g., ion (la).Benzene is thought to be carcino- was no increase of acute myeloid leukemia Germany and the United Kingdom) in genic because of the combined effects of its ( M L ) for cumulative exposure < 200 ppm- many countries (8). metabolites (e.g., hydroquinone, pbenzo- years. The exposure levels of petroleum Etiologies of aplastic anemia. Aplastic quinone, 1,2,4.-benzenetriol); the potential industry workers are generally < 1 ppm on an anemia can be caused by both hereditary and mechanism involves these metabolites bind- 8-hr TW,4 basis, and the excess cases of acquired factors. Drugs, viruses, organic ing to DNA and causing oxidative stress leukemia were inconsistently observed. compounds, and radiation are implicated (11).These active metabolites are involved Christie et al. ( 1 5 ) reported a significant causes of the acquired form. Fanconi anemia in the causation of chromosome damage excess of myeloid leukemia in Australian is a well-known inherited abnormality that such as strand breaks, hyperploidy, and dele- causes the disease. At least five different genetic defects may induce Fanconi anemia, and one variant has a mutation of the FACC gene, which is involved in the cellular tions in humans and animal species exposed to benzene. These chromosomal aberrations may lead to the inactivation of p53 or other rumor-suppressor genes, and these events Table 2 Concentrations of airborne benzene and urinary muconic acid resulting from environmental surveys of the patient's workplace (November 1998). response to DNA damage (3). may be involved in leukemogenesis (7). Airborne benzene Urinary muconic Table ~~ ~ 1. B- lo.o.d_t.e-s.t.re.s.u_lt.s-. Workplace (ppm) acid (mq/L) RBC Date (no./mm3) 5 October 1993 (vearlv health exam1 27 April 1998(yearlyhealth exam) 5 November 1998 (aplastic anemia) 26 February 1999 (follow-up exam) 495~10~ 485~10~ 2 52 x 106 1 95 x lo6 Abbreviations. RBC. red blood cells, WBC. white blood cells. Hemoglobin (g/dL) 15.0 15 1 a3 63 Hematocrit (%I 44 44 25 17 9 WEC (no./mm3) 6.,.6_0-0 6.400 2.600 2.200 Deactivation process (personal sampling) Packaging process (personal sampling) Drainage tank (area sampling) Packaging process (area sampling) 0.07-0.40 0.004.04 0.14-0.26 0.02 0.03-0.08 0 034.18 - - 852 -Volume 107, Number IO. October 1999 Environmental Health Perspectrves .Grand Rounds in Environmental Medicine Aplastic anemia and benzene exposure petroleum industry workers. Jakobsson et al. (16)also reported a significandy elevated risk of AML in male gasoline station attendants in Sweden, but in many other studies, no increased risk of AML was observed in petroleum workers (14). In a study of Canadian petroleum distribution workers, Schnarter et al. (17) examined leukemia risk by benzene exposure level and noted the possibility that long-term exposure, regardless of the concentration. can result in leukemia. Recently, there have been increasing con- cerns about low-level benzene toxicity in communities and work areas because benzene is ubiquitous in the environment; a few case repom imply that < 0.1 ppm benzene, even for a short time, induced hematologic abnor- malities. In 1994 Stern et al. (18) reported a case of aplastic anemia in an American soldier who fought in the Gulf WG the disease was aruibured to a possible exposure to benzene in the toxic smoke produced by burning oil wells. The smoke contained 3.1-9.1 ng/m3 polycyclic aromatic hydrocarbons. Molinini et al. (19)reported a case of aplastic anemia in a young coke plant worker who was exposed to low-level benzene for 3 years. In 1994 the Italian Toxicology Commission reported that 3-50 cases of leukemia out of 1,000could be caused by benzene from motor vehicle exhaust (19. Bwmonitoring. Measurement of blood benzene concentrations and benzene in exhaled breath are good means of assessing exposure, but the timing of measurement is important because of the short half-life of benzene. Urinary phenol has traditionally been used to biomonitor benzene exposure because roughly one-fourth to one-half of administered benzene is metabolized to phenol. However, there are other sources of urinary phenol, including dietary intake (20. When exposures are to relatively low levels of benzene, the background level of phenol obscures the benzene exposure. The measurement of phenol can be used to determine if someone has been recendy exposed to high levels of benzene, but it is not useful for screening in the workplace, pmicularly if the level of benzene is low. Urinary Sphenylmercapruric acid (S-PMA) and K-MA are now used instead of phenol in biologic monitoring of benzene. Although the analytical sensi- tivity of the S-PMA assay is much higher than that of tt-MA, tt-MA is a more sensitive biomarker than S-PMA and the assay is easier to perform and is more readily available (21). Shortcomings of the tt-MA assay are that there are other sources of this urinary metabolite, such as metabolism of sorbic acid (a food additive), and that E-MA has a relatively shorter urinary half-life than S-Ph.IA ( 2 3 The mean postshifi tt-MA concenrrations corresponding to a benzene 8-hr TWA exposure of 0.5-1.0 ppm are 0.8-1.4 mg/g creatinine (23),and exposure to 5.0 ppm benzene resulted in 3-8 mg/L urine (24). We measured urinary K-MA of the coworkers of the patient in this case to assess benzene exposure. Airborne benzene concentrations were higher in the deactivation process than in the packaging process, but urinary tt-MA levels were higher in the packaging workers. The packaging process was an indoor process, and the workers packed the products continuously through the work day. In the outdoor deactivation process, however, the workers poured the lime into the tank and drained the tank afcer the reaction; exposure was intermittent and total exposure time was < 30 min. For the packaging workers, the longer exposure time in a relatively closed space seems to result in higher levels of urinary K-MA. Conclusion The patient in this casewas otherwisehealthy, and there was no extraoccupational exposure to hematotoxic agents in his daily life (e.g., hobbies, medications, etc). He had not lived near a nudear power station. The serologic markers and history for viral infection was negative. The chromosomal study was normal, with no aberrations observed. Based on the environmental investigation of the patient`s workplace, he was exposed to lowlevel benzene for 21 years while pa+ng the powder resin and pouring lime into rhe deactivation tank We also suspect that he had been exposed to high-level benzene for a short f i e when he cleaned the reaction tank The toxicity of low-level benzene is not only an occupational problem; environmental exposures of the general population to benzene from car exhaust, cigarette smoking, and indoor air should also be of concern. More research is needed to establish the toxicity of low-level benzene. REFERENCEAND NOTES I . Ruga HS. Oamon LE. Occupational hematology. In: Occupaoonal and Environmental Medicine (LaOou J. ed). 2nd ed. East Norwalk. CT:Appleton and Lange. 1997MC220 2. Smith MT. Overview of benzene-induced aplastic anemia. Eur J Haematol57:107-110 (15961. 3. Aksoy M. Erdem S.Followup study on the m o r t a l i and the development of leukemia in Upancytopenic patients with chronic exposure to benzene. Blood 52121:285292 119781. 4. Rinsky RA, Smith JB, Hornung R. Filloon TG, Young RJ, Okun AH. Landrigan PJ. Benzene and leukemia. An epidemiologic risk assessment. N EnglJ Med 316:1044-1050 (19871. 5. Cha CW. Kim KJ. Kim JC. Development of technology for environmental assessment and biological monitoring of workers exposed to benzene. Korean J Occup Mad 6~122-133(19941. 6. Pauaenbach DJ. Bass RO. Price P Benzene toxicity and risk assessment 1972-1992: implicaoons for future regulation. Environ Health Perspect I0llsuppl6l:177-200 (19931. 7. LandriganPJ, Nicholson WJ. Benzene. In: Environmental and Occupational Medicine (Rom WN, ed). 3rd ed. Philadelphia, PA:Lippincott and Raven, 199&1109-1113. 8. Worksafe Aumalia. Exposure Standard: Benzene. Sydney. Austra1ia:National Occupational Health and Safety Administration. Available: http://www.worksafe.gov.au/ worksafe/exp/az/benzene.htm[cited30April 1999l. 9. Castro-Malaspina H. O'Reilly RJ. Aplastic anemia and myelodysplastic syndromes. In: Harrison's Principles of Internal Medicine (Fauci A. Braunwald E. lsselbacher J. Wilson 0, Martin JB. Kasper OL Hanson SL Longo OL edsl. 14th ed. New York:McGraw-Hill, 1998;672-679. IO. Smith MT. The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect 104(suppl 6):1219-1225 11996). 11. Snyder R. Hedli CC. An overview of benzene metabolism. EnvimnHeakh Perspect 1Wsuppl6):116~1171(1996). 12 Tunca BT. Egeli U. Cytogenetic findings on shoe workers exposed long-term to benzene. Environ Health Perspect lWsuppl6):1313-1317 (1996). 13. Snyder R, WiQ G. Goldstein BO. The toxicology of benzene. Environ Haakh Perspect 100:293-306 (1993). 14. Rabbe GK. Wong 0. Leukemia mortality by cell type in petroleum workers with potential exposure to benzene. Environ Health Perspect 1Wsuppl61:l381-1392 (1996). IS. Christie 0. Robinson K, Gordon I, Bitby J. A prospectwe studv in the Australian petroleum indushy. (I. Incidence of cancer. Br J Ind Med 48511-514 (1991). .16. Jakobsson R. Ahlbom 4 Bellander T, Lundberg I.Acute myeloid leukemia among petrol station anendants. Arch Environ Health 48(4):255259(19931. 17. Schnatter AR. KaQ AM. Nicolich MJ. Theriauk G. A ret- rospective mortality study among Canadian petroleum marketing and distribution workers. Environ Health Perspect IOllsuppl 6):8599 (1993). 18 Stern M 4 Eckman J, Offerman MK. Aplastic anemia alter exposure to burning oil [lenerl. N EnglJ Med 331:s (19941. 19. Molinini R. Mera E. Pavone V, Liso V. Aplastic anemia in a young coke plant worker. Int Arch Occup Environ Health69:1UI4661997l. 20. Bechtold WE, Lucier G, Birnbaum LS. Yin SN. Li GL, Henderson RF. Muconic acid determinations in urine as a biological exposure index for workers occupationally exposed to benzene. Am Ind Hyg Assoc J 52111):473-478 11991). 21. Bwgard PJ. van Sinert NJ. Suitability of S-Phenyl mer. CapturiC acid and trans-trans-muconic acid as biomarkers for exposure to low concentrations of benzene. Enwron Health Perspect lM(suppl6I:1151-1157 115961. 22. Weisel C, Yu R, Roy A, Georgopoulos P. Biomarkers of environmental benzene exposure. Environ Health Perspect lWsuppl6l:1141-1146 119961. 23. Lauwerys RR. Buchet JP. Andrien F. Muconic acid in urine: a reliable indicator of occupational exposure to benzene. Am J Ind Med 2297-300 11994). 24. lnoue 0, Seiji K. Nakatsuka H.Watanabe T, Yin SN. Li GL Cai SX. Jin C, Ikeda M. Urinary t.t-muconic acid as an indicator of exposure to benzene. Br J Ind Med 46:122-127 119891. EnvironmentalHealth Perspectives Volume 107, Number IO. October 1999 853