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not ,, ly. reot, and iGlaser sucep:under I in the ,o steep ly sug:sponse N valuq ntration ators of Tubular ,"moda which icoming y somet limit). on risk S. der, and ,-3 a. In Hiscock . Research y r R (eds) : Cadmium "Cadmium 120-126. ihort of US Imium. Am American Journal of Industrial Medicine 20:707-711 (1991) - COMMENTARY -= Benzene Health Effects: Unanswered Questions Still Not Addressed - -. Myron A. Mehlman, PhD I 1 Key words. benzene exposure, occupational cancers, leukemia, lymphoma, regulatory threshold limits INTRODUCTION In 1985 the American Journal of Industrial Medicine reviewed then-available information on the health effects of benzene (Volume 7). It was clear that our knowledge of benzene's effects in a number of significant areas of investigations was still incomplete. We did not know at what level of exposure benzene became overtly hazardous in terms of human disease. Data were lacking concerning a potential "practical threshold dose" below which overt adverse effects do not occur in exposed individuals. This critical information could be obtained from a series of long-term* chronic, low-level benzene exposure studies in experimental animals, using a wide dose distribution between 0.1 and 50 ppm which could, in conjunction with biochemical mechanistic studies, be used to help evaluate a "no effects'' level. Such a "practical threshold level" could be used as a basis for consideration of regulation. At the time, I recommended to the benzene-manufacturing industry that research be undertaken to answer questions relative to bone marrow damage, Le.. is such a phenomenon a necessary precondition for the development of human leukemias, a malignancy known to be caused by benzene. If this were the case, could it then serve as a means for early detection and prevention of harmful effects, namely, leukemias and other cancers due to benzene exposure? Eight years later, the issues are still largely unaddressed. Benzene, a significant component of gasoline, has been shown to be a carcinogen in both animals and humans (Mehlman. 1990; EPA, 1984, 1986; Tironi et 31.. 1986; Westberg and Lamb, 1985;Machle, 1941; Poklis and Burkett, 19771. At one time, benzene was widely used as a solvent, present in inks, rubber, lacquers. paint remover, and many other products. Total benzene usage today is approximately 1 I Department of Environmental and Community Medicine UMDNJ-Robert Wood Johnson Medical k b l . Piscataway. NJ. .Address reprint requests to Dr. M.A. Mehlman. Department of Environmental and Community Medicine. UMDNJ-RobertWood JohnsonMedical School. 675 Hoes Lane. Piscataway NJ 08854-5635. Accepted for publication March 28. 1991. 0 1991 Wiley-Lis, Inc. .- . . - . . .. 708 Mehlman billion gallons per year [ACGIH, 19901and it has been estimated that 238,000 people are occupationally exposed to benzene in petrochemical plants, petroleum refineries, and other operations. Benzene is currently classified by EPA and IARC as a human carcinogen. 1 EXPERIMENTAL CARCINOGENESIS In numerous studies, Maltoni et al. [Maltoni, 1982a.b. 1983; Maltoni and Scarnato, 1977, 1979; Maltoni et al., 1982a,b,c,d, 1983a,b, 1985. 19871 demonstrated that benzene caused tumors in rats and mice including cancer of the zymbal gland, cancer of the oral cavity, lymphoma, cancer of the lung, cancer of the skin, cancer of the nasal cavity, cancer of the forestomach, cancer of the harderian gland, cancers of mammary gland, ovary, and uterus, hemolymphoreticular neoplasia, and all types of leukemias. Huff et al. [ 19891expanded these studies, using a broader dose range, and reported numerous cancers, occurring at a lower dosage, in various organs and tissues. Infante and White [I9851 calculated the excess of death from leukemia per 1,OOO workers exposed to benzene for an occupational lifetime. The relative risk of death from leukemia was calculated from 3.75 to 25, depending on the level and duration of exposure. EARLIER KNOWLEDGE Earlier data on benzene-caused carcinogenicity in humans were based on a number of clinical cases of leukemias in humans occupationally exposed to benzene. The 1928 report by Delore and Borgomano and the 1932 report by Lignac were followed by a variety of reports from Italy [Vigliani, 1976;Vigliani and Saita. 19641. France [Goguel et al.. 1967; Girard et al., 1968, 1970, 1971a,b; Girard and Revol. 19701, and Turkey [Aksoy et al., 1972. 19741. Goldstein in 1977, in a comprehensive review of the literature on benzene, compiled case reports on benzene-exposed individuals with hemolymphoreticular cancers. The types of leukemias found in these individuals were acute myelogenous leukemia. erythroleukemia, acute myelomonocytic leukemia, chronic myelogenous leukemia. myelofibrosis, and myeloid metaplasia, thrombocytopenia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphomas, and other related cancers. While there is larger prevalence of acute myelogenous leukemias, it has been found that all forms of leukemia can be caused by benzene. In 1971. lshimaru et al. reported leukemia in adult survivors of Hiroshima and Nagasaki. This report noted that the risk of leukemia was two and a half times greater among individuals who. in addition to radiation, had also been occupationally exposed to benzene. HUMAN NEOPLASMS The types of leukemias caused from exposure to benzene include acute myelogenous leukemia, acute lymphocytic leukemia, acute erythroleukemia, leukemia. acute myelomonocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, hairy cell leukemia, chronic myelogenous leukemia, chronic lympho- :ople :ties, iman i and. monimbal skin, ;land, I, and r dose rgans ia per -isk of 21 and f on a nzene. 2 were 19641. Revol. iensive .d indin these )monoI metatic leu- 3s been -u et al. t noted who, in e myelgkemia. fferentiympho- Benzene Health Effects 709 cytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple my- eloma. In 1939 Hunter reported that benzene causes human cancers. Recently Yin et al. [ 19891 reported significant increases `in human cancers from exposure to benzene. Benzene caused leukemia and cancer1 of the lung, liver, lymphosarcoma, stomach, esophagus nasopharynx, and intestine. REGULATION -- The threshold limit value-time weighted average (TLV-TWA) for benzene in 1946 was 100 ppm; in 1947, 50 pprn; 1948-1956, 35 ppm; 1957-1962, 25 ppm; 1977-1987, 10 ppm; and it is currently I ppm. In July of 1990, the American Conference of Governmental Industrial Hygienists (ACGIH) recommended that the TLV-TWA for benzene be reduced to 0.1 ppm. The American Petroleum Institute (API) in September of 1948, issued a document entitled "API Toxicology Review: Benzene," prepared by P. Drinker and widely circulated to oil companies. This report states, "Inasmuch as the body develops no tolerance to benzene and there is a wide variation in individual susceptibility, it is generally considered that the only absolutely safe concentration for benzene is zero.'' The API document further stated that "a limit of 50 pprn or less is strongly recommended, particularly where exposures are recurrent. Skin contact should be avoided." This API document recommended level was 500-fold greater than that recently recommended by ACGIH. Thus, in spite of scientific evidence and general knowledge of the carcinogenicity of benzene, it is disconcerting that warning labels are not utilized to identify the carcinogenicity of benzene in products containing this chemical, especially gasoline. The current benzene content of gasoline is between 1.5% and 6%. - SUMMARY Data which could have helped answer many of the scientific questions posed in 1983 concerning the carcinogenicity of benzene are not yet available. Since we do not know of any safe level above zero, the problems that have been plaguing the health protection process relative to benzene can perhaps be best resolved by setting current recommended maximum levels of exposure to 0.004 to 0. I ppm, and, to the extent possible, avoiding any exposure at all to benzene and benzene-containing products. REFERENCES ACGIH (1990).Notice of intended changes-benzene. Appl &cup Environ Hyg 5:453-463. Aksoy M. Dincol K. Erdem S, Dincol G ( 1972): Acute kukemia due to chronic exposure 10 benzene. Am 1 Med 52:160-166. Aksoy M. Erdem S, Dincol G (1974): Leukemia in shoe workers exposed chronically to benzene. Blood 44:837-841. Delore P. Borgomano C (1928): Leuce`mie aigue au cours de I'intoxication benzenique: Sur I'origine toxique de certaine IeucCmies aigues et lcurs relations avec les anCmies graves. J Med Lyon 9:227-233. 710 Mehlnian Girard R. Revol L (1970): La frtquence d'une exposition benzinique au cours des hemopathies graves. Nouv Rev Fr Hematol 10477-484. Girard R. Prost G. Tdot F ( 1971a): Comments on indemnification for benzene induced leukemia and aplasia. Arch Mal Prof Med Trav Secur Soc 3258 1-583. Girard R. Rigaut P. Bertholon J. Tolot F, Bourret J ( 1968):Les expositions benziniques meconnues: Leur . recherche systematique au cours des hemopathies graves. Enquete chez 200 hemopatiques hospiMal Prof Med Trav Secur Soc 29:723-726. Girard R. Tolot F Bwrret J (1970): Hydrocarbures benziniques et himopathies graves. Arch Mal Prof Med Trav Secur Soc 31:625-636. Girard R. Tolot F, Boumt J (1971b). Malignant hemopathiesand benzene poisoning. Med-Lav 62:71-76. Goguel A. Cavigneaux A. Bernard J (1967): Les leucimies benzkniques de la &$ion parisienne entre 1950 et 1965. (Etude de 50 observations). Nouv Rev Fr Hematol 7:465-480. Goldstein BD (1977): Hematotoxicity in humans. J Toxicol Environ Health 2:69-105. Huff JE. Haseman JK. De Marini DM, Eustes S . Maronpot RR. Peters AC, Pershing RL. Chrisp CC. Jacobs AC (1989): Multiple site carcinogenicityof benzene in Fisher 344 rats and B6C3FI Mice. Environmental Health Perspectives, Volume 82. Hunter FH (1939): Chronic exposure to benzene-11. The clinical effects. J Ind Hyg Toxicol 21:331. Infante P. White M (1985): Projections of leukemia risk associated with occupational exposure to benzene. Am J hied 7403-413. Ishimaru T,Okada H, Torniyasu T. TsuchimotoT, Hoshino T. Ishimaru M (197I):Occupational factors in the epidemiology of leukemia in Hiroshima and Nagasaki. Am J Epidemiol 93:157-165. Lignac GOE (1982): Die Benzallekamie bei Menschen und weissen Mausen. Ill. Zweite Benzolversuchsreihe-von 54 Mausen gehen 8 an leukamie oder Lymphoblastoma infiltrans aleucaemicum zugrunde-fruhere. Teerbenzolversuche. Krankeitsforsch 9926-453. Machle W (1941): Gas intoxication. JAMA 177:1965-1971. Maltoni C (1982a): Benzene: A multipotential carcinogen. Acta Oncol 3:1. Maltoni C ( l982b): La cancerogenicitadel benzene: Le piu recenti acquisizioni. Conference at the Carlo Erba Foundation, 1-1 1. Maltoni C (1983): Myths and facts in the history of benzene carcinogenicity. In M. A. Mehlman (ed): "Advances in Modern Environmental Toxicology," Vol. 4. Princeton. NJ: Princeton Scientific Publishers. pp 1-15. Maltoni C. Scarnato C (1977): Le prime prove sperimcntali del I'azione cancerogeno del benzene. Gli Ospedali delta Vita 4:l 11-1 13. Maltoni C. ScarnatoC (1979): First experimental demonstration of the carcinogenic effects of benzene. Long-term bioassays on Sprague-Dawley rats by oral administration. Med Lav 70:352-357. Maltoni C. Conti B. Cotti G (1983a): Benzene: A multipotential carcinogen. Results of long-term bioassays performed at the Bologna Institute of Oncology. Am J Ind Med 4589-630. Maltoni C. Conti B, Scarnato C (1982al: Squamous cell carcinomasof the oral cavity in Sprague-Dawley rats. following exposure to benzene by ingestion. First experimental demonstration. Med Lav 731441 - 4 5 . Maltoni C.Conti B. Colti G. Belpoggi F (1983b): Benzene as an experimental carcinogen: Up-to-date evidence. Acta Oncol 4:141-164. Maltoni C. Conti B. Cotti G. Belpoggi F ( 1985): Experimental studies on benzene Carcinogenicity at the Bologna Institute of Oncology: Current results and ongoing research. Am J Ind Med 7:415-4-46. Maltoni C. Conti B. Cotti G, Mandrioli A. Scarnato C. Valgimigli L tl98Zb): Benzene. An Experimental Multipotential Carcinogen. The Up-to-Date Results of the Long-term Bioassays. Performed at thc Bologna Institute of Oncology. Istituto Supcriore di Sanita. Repon No. ISSN-0391-1675: 1-55. Maltoni C. Conti 6.Perino G. DiMaio V (1987): Further evidence of benzene carcinogenicity. Results on Wistar rats and Swiss mice, treated by ingestion. Ann NY Acad Sci 534:41?-426. Maltoni C. Cotti G, Valgimigli L. Mandrioli A ( 1983): Hepatocarcinomas in Sprague-Dawley rats. following exposure to benzene by inhalation. First experimental demonstration. Med Lav 73: 448-450. Maltoni C. Cotti G, Valgimigli L. Mandrioli A (19824): Zymbal gland carcinomas in rats following exposure to benzene by inhalation. Am J Ind Med 3:l 1-16. Mehlman MA (1990):Dangerous properties of petroleum refining producrs: Carcinogenicity of motor fuels (gasoline). Teratogenesis Carcinog Mutagen 10:399-408. Poklis A. Burkett C (1977): Gasoline sniffing: A review. 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N Engl J Med-271:%72-876; 271:1-43-1- 5. Westberg H. Lamb B (1985):"Human Exposures to Gasoline Vapor." Health Effects Institute Report. Yin SN, Li GL, Tain FD. Fu ZI,Jin C. Chen YJ.Luo SJ,Ye F Z ZhangIZ. Wang GC. Zhang XC,Wu HN. Zhong QC (1989):A retrospective study of leukemia and other cancers in benzene workers. Environ Health Prosp 82:207-214.