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hpa_benzene_toxicological_overview_v2.pdf

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Benzene Toxicological overview

Key Points
Kinetics and metabolism • • The primary route of entry is via inhalation. Dermal absorption is poor. Reactive metabolites such as benzene oxide have been implicated in the mechanism(s) of benzene toxicity.

Health effects of acute exposure • Acute exposure may resemble solvent intoxication, clinically manifest as drowsiness, dizziness, delirium, loss of consciousness, respiratory arrest and death.

Health effects of chronic exposure • • Two, well documented adverse health effects of chronic benzene exposure are anaemia and leukaemia. Benzene is a known human carcinogen and clastogen but is not considered to be a reproductive toxicant.

Prepared by R P Chilcott CHAPD HQ, HPA 2007 Version 2

It is mutagenic and a genotoxic carcinogen. dizziness. resulting from suppression of bone marrow tissue [2]. The assumption is made that there is no threshold to such effects and that any exposure results in some increase in risk.BENZENE – TOXICOLOGICAL OVERVIEW Toxicological Overview Summary of Health Effects Acute exposure to relatively high concentrations of benzene (benzol) may result in CNS disturbances consistent with solvent exposure. tremor. with a substantial number of case reports and epidemiological studies providing evidence of a causal relationship between occupational (chronic) exposure and various types of leukaemia [3]. respiratory arrest and death [1]. albeit this may be very small. ataxia.. Benzene is a known human carcinogen. Toxicological overview: Page 2 of 14 . loss of consciousness. delirium. drowsiness. A characteristic effect of chronic benzene exposure is aplastic anaemia. It is currently hypothesised that the carcinogenic effects of benzene are predominantly mediated via metabolites such as benzene oxide [4]. viz. headache.

respectively ([18. 16]. Systemic absorption of benzene after ingestion is likely to be high. susceptibility to benzene toxicity is augmented in human individuals and animals lacking NQ01 [21. Although the actual metabolite that is responsible for the carcinogenic effects of benzene has not been definitively identified [16]. 22]. Legislation to decrease the benzene content of engine fuels to less than 1% [6] and the compulsory introduction of catalytic converters on vehicle exhausts have significantly reduced this source of pollution. especially when dissolved in water and case reports of poisoning indicate that benzene is extensively absorbed by the oral route [11]. Absence of CYP2E1 leads to a reduction of the cytotoxic and genotoxic effects of benzene in transgenic mice [20]. principally through the combustion of fuels for cooking and heating and the operation of garden appliances such as lawn mowers and patio heaters [5] . in 2004. road traffic vehicles have represented the major source of benzene in the UK and accounted for ~ 60% of total emissions in 1990 [5]. However. However. 99. there is evidence that this is mediated by benzene oxide.9% of an applied dose may vaporise from the skin surface before being absorbed [13]. The metabolism of benzene has been widely studied in human and animal models due to its putative role in carcinogenesis (metabolic activation) [15. excessive dermal contamination may make a substantial contribution to the daily intake and so skin contact with benzene should be avoided [14]. 19] as reviewed by [1]). Domestic sources currently contribute the greatest proportion (33%) of benzene emissions. When applied as a discrete droplet. Toxicological overview: Page 3 of 14 . there are significant species-specific differences in the extent to which benzene is metabolised by each pathway [17].BENZENE – TOXICOLOGICAL OVERVIEW Kinetics and metabolism Benzene is well absorbed by inhalation [11]: systemic absorption of benzene from the lungs is greatest over the first few minutes of exposure (70 – 80% of inhaled dose) and decreases thereafter to approximately 50% of the inhaled dose after one hour [12]. the proportion of benzene metabolised by each pathway appears to be dose-dependent. road vehicles accounted for less than 20% of UK benzene emissions [5]. Historically. Sources and route of human exposure Benzene is a ubiquitous air pollutant which can vary widely in concentration according to location (Figure 1). The metabolic pathways implicated in benzene toxicity are broadly comparable across species. with hydroquinone and phenyl conjugation pathways predominating at lower (<10ppm) and higher (>10ppm) concentrations. Conversely. Furthermore. a reactive metabolite of CYP2E1 [4] which is sufficiently stable (t½ ~ 7 – 9 minutes) to ensure distribution throughout the body. Dermal absorption of benzene is generally considered to be poor. Two enzymes have been particularly implicated in the mechanism of benzene toxicity: cytochrome P450 2E1 (CYP2E1) and quinone oxidoreductase (NQ01).

“ppb” = parts per billion.1 73 92 400 Toxicological overview: Page 4 of 14 . For the majority of the population. Ambient air concentrations of benzene within dwellings tend to be around twice as high as comparable outdoor concentrations (Figure 1) and smoking indoors can make a significant contribution to the concentration of benzene [9]. Source Diet Air Smoking Food Water Rural (non smoker) Urban (non-smoker) 20 cigarettes per day Total Benzene (µg day-1) 1. Table 1: Current estimated (average) daily intake of benzene in adults. Table 1). although contaminated groundwater may potentially represent a significant source of benzene exposure [8]. 16 traffic 14 12 Benzene Concentration (ppb) 10 8 indoors 6 4 outdoors 2 0 rural urban rural NS urban NS urban S roadside in vehicle Contributions to the daily intake of benzene from food and water are relatively low (less than 1½ to 2% of total. smoking and propinquity to road traffic are the predominant factors affecting daily exposure (Table 1). “S” = smoker.5 < 0. data from [7]. “NS” = non-smoker. data from [10].BENZENE – TOXICOLOGICAL OVERVIEW Figure 1: Approximate concentrations of benzene in ambient air.

acute lethal dose of benzene in humans is estimated to be 125 mg kg-1.000 Duration of exposure (min) 480 300 60 60 30 30 5-10 Effect(s) No observable effect Headache. Recovery from an acute exposure is dose-dependent. shallow and rapid pulse. Signs of intoxication following ingestion include staggered gait. weakness Symptoms of illness Serious symptoms Endurable Dangerous to life Fatal Inhalation The commonly quoted “lethal dose” of benzene (20. Fatal exposures have been associated with asphyxiation. Benzene is irritating to the nose and respiratory tract at “high” concentrations [24]. Toxicological overview: Page 5 of 14 . Concentration ppm 25 50-150 500 1500 3000 7500 19000-20000 mg m-3 80 160-480 1. vomiting. characterised by euphoria. It has been observed that aspiration of benzene directly onto the lungs causes “immediate pulmonary oedema and haemorrhage at the site of contact with the pulmonary tissue” [24]. Overt signs of exposure have previously been referred to as “benzol jag”. asphyxiation or respiratory or circulatory arrest. coma and death [11]. Ingestion The single. nervous irritability and unsteadiness in gait persisting in severe cases for two to three weeks [24]. unsteady gait and confusion [23]. central nervous system depression. central nervous system depression and possibly cardiac arrhythmias [26]. delirium. Death may be due to CNS depression. lassitude. pnuemonitis. respiratory arrest.000 ppm) is an estimate based on a review of a single case report following 5 – 10 minutes’ exposure [25]. Table 2: Summary of acute benzene vapour toxicity [11].BENZENE – TOXICOLOGICAL OVERVIEW Health Effects of Acute / Single Exposure Human Data General toxicity Benzene is not generally regarded as an acutely toxic material and there are correspondingly few reports pertaining to the (human) health effects of a single exposure. In general.600 4.800-64.600 24.000 60. somnolence.800 9. acute exposure to concentrations of benzene in excess of 500 ppm may illicit signs and symptoms consistent with solvent intoxication (Table 2). equivalent to 10 ml per 70 kg man-1. with breathlessness.

Toxicological overview: Page 6 of 14 . vesiculation and dermatitis [27]. transient injury to the epithelial cells [28].BENZENE – TOXICOLOGICAL OVERVIEW Dermal / ocular exposure Whilst benzene is poorly absorbed through the skin. erythema. Eye contamination with droplets of benzene may cause a moderate burning sensation with only slight. viz. prolonged or excessive contact may cause signs consistent with the defatting (delipidising) effects of organic solvents.. Benzene vapour may cause a smarting effect on the eyes at high concentrations. Delayed effects following an acute exposure Most cases of acute benzene intoxication resolve spontaneously or with supportive care in the absence of long-term sequelae [29].

Genotoxicity Benzene is a human clastogen [3]: chronic exposure results in consistent structural and numerical chromosomal aberrations in lymphocytes and bone marrow cells which may be observed for at least five years after cessation of (occupational) exposure [11]. with bone marrow depression leading to aplastic anaemia being the most common clinical manifestation (occurring in approximately 1% of individuals exposed to > 100 ppm benzene) [11. In addition to effects on the haematopoietic system. one study has suggested that chronic benzene exposure to less than 1 ppm may induce haematotoxic effects in such genetically susceptible populations. Indeed. 30]. immune dysfunction [11] and cancer [3]. any exposure is associated with some increase in risk. pancytopenia and myelodysplastic syndrome [31]. 26. Further. Although the actual metabolite that is responsible for the carcinogenic effects of benzene has not been definitively identified [16]. However. Benzene is also established as being leukaemogenic in humans [3. although it was recognised that more data were required before any definite conclusions could be drawn [52].BENZENE – TOXICOLOGICAL OVERVIEW Health Effects of Chronic / Repeated Exposure Human Data General toxicity The adverse health effects of chronic benzene exposure have been extensively documented and primarily relate to impairment of the haemopoietic system [23-34]. although this may be very small [4]. altered differentiation of early progenitor cells and depletion of the stem cell pool [30]. an excess of CYP2E1 [46-48] or deficiency of quinone oxidoreductase (NQO) [4951] may enhance benzene toxicity. 36. Other effects on the haemopoietic system include leukopenia. 32-38]. since benzene is a genotoxic carcinogen (see below) the assumption is made that there is no threshold for its effect. agranulocytosis. benzene exposures have been implicated in neurological disorders [53]. Susceptibility to benzene toxicity has been related to genetic polymorphisms [40-45]. I. anaemia. Toxicological overview: Page 7 of 14 . induction of apoptosis. detailed information on the general toxicity of benzene can be obtained from a number of comprehensive reviews [11. Other factors that influence the toxicity of benzene include the systemic distribution rates of metabolites and consequent events within bone marrow tissue such as secondary metabolic activation. 54]. 39]. Exposures to 1 ppm benzene for 40 working years has been considered not to be associated with any increase in leukaemia or any other haematological abnormality [11.e. a metabolite of CYP2E1 which is sufficiently stable (t½ ~ 7 – 9 minutes) to ensure distribution throughout the body [9]. For example. there is evidence that it is mediated by benzene oxide.

However. multiple myeloma 956 Leukaemia. WBC (white Toxicological overview: Page 8 of 14 . Study Type¶ “n” 44 63 94 1 6 1 28.500 Putative disease outcome Original Reference [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] Leukaemia Leukaemia.460 Acute and chronic leukaemia 391 Leukaemia Leukaemia Reproductive and developmental toxicity Benzene diffuses across the placenta and is considered to be fetotoxic in the presence of maternal toxicity [27]. leukaemia 28. malignant lymphoma Hodgkin’s disease Case Subacute granulocytic leukaemia Haemocytoblastic leukaemia Acute myelogenous leukaemia Aplastic anaemia. General toxicity Numerous repeated dose studies in animals have shown that benzene produces bone marrow depression leading to a range of haematological effects including reduction in haematocrit. Putative disease outcome = disease state associated/correlated with occupational benzene exposure. multiple myeloma. acute myelogenous leukaemia 3636 Leukaemia Epidemiology 259 Lymphatic and haemopoietic neoplasms 2013 Aplastic anaemia.BENZENE – TOXICOLOGICAL OVERVIEW Carcinogenicity Benzene is classified by the IARC as Group 1 human carcinogen [3] and its role as a leukaemogen has been clearly established through a number of epidemiological studies (Table 3). Animal Data Animal studies are largely in accordance with the known toxicity of benzene in humans. Data derived from IPCS [11]. Table 3: Empirical summary of studies pertaining to chronic (occupational) benzene exposure and putative disease outcomes. the carcinogenic effects of benzene in animals is primarily associated with epithelial tissue rather than leukaemia [11]. decreased haemoglobin and a reduction in RBC (red blood cell). acute leukaemia Myeloid and monocytic leukaemia Leukaemia. Benzene is not considered to be a teratogen and there is currently no evidence that it causes reproductive effects in humans [71].

Some adverse effects on the foetus (reduced birth weight and/or minor skeletal variants) were seen at relatively high exposure levels (~ 150 mg m-3 and above). in studies with transgenic mice (using lac1 as a reporter gene). None has detected any teratogenic potential even at exposure levels that produced some evidence of toxicity in the maternal animals. Genotoxicity Although assays for the ability of benzene to induce gene mutations in bacteria were negative. Carcinogenicity Benzene has been shown to produce several types of neoplasms in both rats and mice after either oral dosing or inhalation exposure. Benzene is clearly an in-vivo mutagen. Thus. benzene clearly has mutagenic potential. benzene has consistently given positive results from in-vitro assays for clastogenicity [72]. These include various types of epithelial neoplasms and a few lymphomas and leukaemias [11]. There is in-vivo evidence to demonstrate that benzene is both clastogenic and induces gene mutations in animals. Toxicological overview: Page 9 of 14 .BENZENE – TOXICOLOGICAL OVERVIEW blood cell) and platelet counts. Decreased proliferation of B and T lymphocytes and resistance to infection has also been demonstrated [11]. benzene induced gene mutations in the lung and spleen [11]. Some haematopoietic changes were observed in offspring from adults exposed to lower levels (16 mg m-3 and above) [11]. For example. Reproductive Toxicity A number of studies have been carried out to investigate the effect of exposure to benzene during pregnancy.

265 . 522 . D. D. J. Ross. J. CRC Critical Reviews in Toxicology 3. Environmental Health Perspectives Supplements 101 S6. 1972-1992. Courage. Journal MSc Thesis. IPCS (1993) Environmental Health Criteria 150: BenzeneInternational Programme on Chemical Safety. R. Srbova. J. S. Duarte-Davidson. D.526. L. 111-118. Archives of Industrial Hygiene and Occupational Medicine 2. Lindstrom. Eighth joint annual report. 1998 Annual report of the committees on toxicity mutagenicity carcinogenicity of chemicals in food.200. and McAuliffe. (1985). Buckley. Penetration of benzene through human skin. Environmental accounts Spring 2006. and Levy. (2001). and Michael. Directive 98/70/EC of the European Parliament and of the Council of 13 octob er 1998 relating to the quality of petrol and diesel fuels and amending Council Directive 93/12/EEC. Blank. [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] Toxicological overview: Page 10 of 14 . (1950).BENZENE – TOXICOLOGICAL OVERVIEW References [1] Paustenbach. ISBN 92 4 1571500. European Journal of Haematology 57. Snyder. Absorption and elimination of inhaled benzene in man. 74. D. (1996). IARC Monographs on the evaluation of carcinogenic risks to humans. (1993). L. Skin absorption of benzene in vitro. R. Benzene in the environment: an assessment of the potential risks to the health of the population. 183-95.. EC (1998). J. Occupational and Environmental Medicine 58. DH (1998). H. 1-8. Journal of Investigative Dermatology 85.. R. COMEAP (2004). and Price. (1975). L. P.. World Health Organisation. T. J. Pate. Committee on the Medical Effects of Air Pollutants guidance on the effects on health of indoor air pollutants. Metabolic basis of benzene toxicity. V. Highsmith. C. Current concepts of chronic benzene toxicity. R. Benzene toxicity and risk assessment. Department for Environment Food and Rural Affairs and Environment Agency (DEFRA) (2003). (2002). J. Implications for future regulation. IARC (1987). consumer products and the environment. W. Rushton. (1994).288.13. J Expo Anal Environ Epidemiol 4. J. C. Overall evaluations of carcinogenicity: An updating of IARC Monographs Volumes 1 to 42. B. Contaminants in soil: collation of toxicological data and intake values for humans. Office for National Statistics (2006). I. and Kocsis. Supplement 7. Gasoline-contaminated ground water as a source of residential benzene exposure: a case study. A. 177 . J. and Skamovsky. Teisinger. Official Journal of the European Communities. Hattersley. 2 .... S. Bass. J.. I. Benzene.

A. Toxicology and Applied Pharmacology 141. M. Grant. (1996). Wilbur. Clinical analysis of 43 cases of chronic benzene poisoning. and Henderson. Valentine.. J. Experimental Pathology 37.. Ross. F. Elsevier Publishing Company. J. (1996).. S. A toxicokinetic model for simulation of benzene metabolism... F. (1996). J. (2005).. Smith. 137-146. B. F. (1993) Toxicology of the eyeCharles Thomas. Lee. Faroon. A. Bristol. and Henderson. M. J. J. A. 1-12.. Quinone oxidoreductase in protection against myelogenous hyperplasia and benzene toxicity. P. W. 531-547. P. Henderson. Lucier. Iskander. Chemico-Biological Interactions 153-154. H. G. Aromatic hydrocarbons . Toxicology and Applied Pharmacology 87. Corton. L. Eur J Haematol Suppl 60. 231-301.. T. K. G. C. Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression. M. D. F. S.. Poisons Information Monograph (PIM) 63. UK. Keith.. Asgharian. F. J. Elsevier monographs on toxic agents. (1987). Species differences in the metabolism of benzene. A. L. Sabourin. and Hardy. Springfield. K. S. Lucier. T. F. (1983) Hamilton and hardy's Industrial Toxicology. R.. Gonzalez. Overview of benzene-induced aplastic anaemia. [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] Toxicological overview: Page 11 of 14 . Chen. (2001). Farris. Fisher. 1173-1175. G. E. W. (1928). Xenobiotic metabolism and the mechanism(s) of benzene toxicity. R. Journal 4. S. M. 147-157. Environmental Health Perspectives 104. 65-82. 107-10. B.... and Quinones-Rivera. Effect of dose on the absorption and excretion of [14C]benzene administered orally or by inhalation in rats and mice. (1960) Toxicology and biochemistry of armoatic hydrocarbons.. Chemico-Biological Interactions 153154. R. 150-154. Stickney. S. A. 205-213. S. Agency for Toxic Substances and Disease Registry. O. Functions and distribution of NQ01 in human bone marrow: potential clues to benzene toxicity. IL IPCS (1999). London Flury. M. R. (1989). Draft toxicological profile for benzene. Birnbaum. Drug Metabolism Reviews 36. and Liang.. (2004). J. L. S. A. Sabourin. Kuang.. Seaton. Henderson. Moderne gewerbliche vergiftungen in pharmakologischtoxikologischer hinsicht. PSG Inc. (2004). Paikoff.. Arch Exp Pathol Pharmakol 138. Hamilton. S. W. and Schuman.. (2005). Diamond. Gerarde. 129-35. and Medinsky. W.. J.John Wright. L. S. S. Finkel. D.. R. Chem Biol Interact 153-154. Wohlers. Medinsky. H.benzene and other alkylbenzenes. (2005).BENZENE – TOXICOLOGICAL OVERVIEW [16] [17] [18] Snyder.E. G. Browning. J. Birnbaum. and Jaisal.

W. Gist. R. (2006). T. Shields. M.HMSO. (2005). Snyder. Schnatter. and Morgan. G. Chem Biol Interact 153-154. G. Savitz. and Fu. Manno. T.. O. R. Mutat Res 463. 81-7. Pharmacogenetics: detecting sensitive populations. 33-41. and role in pathology]. [Cytochrome P4502E1. and Wojcik. L. 287-95. 130-2. D. (2005). R.. Engel. Chem Biol Interact 153-154.. 285-308. Rosamilia. K. (2002). A. Exposure to benzene and non-Hodgkin lymphoma. P. D. (2002). H. C. W. 71-81. Metabolic enzyme polymorphisms and susceptibility to acute leukemia in adults. S. 661-714. Toxicol Lett 124. (1993). Gonzales. physiological function.. London Chen. Ferrara. A. Causal models of leukaemia and lymphoma. Polymorphism. (2001). Inherited factors and environmental exposures in cancer risk. an epidemiologic overview and an ongoing case-control study in Shanghai. A. G. J. (2005). S. 329-35. F. Toxicol Ind Health 13. Ukr Biokhim Zh 76. O. D. (1997). Vasiliou. M. (2004). J. R.. 34-41. C. 531-47. and Burg. Xenobiotic metabolism and the mechanism(s) of benzene toxicity. T. G. J Occup Med 35. (2000). Wei Sheng Yan Jiu 31. Review of the literature on benzene exposure and leukemia subtypes. Biological indicators of genotoxic risk and metabolic polymorphisms. M. and Berthou. Ross. IARC Sci Publ. D. 155-210. Shields. regulation. A. and Yin. P. Benzene--a review of the literature from a health effects perspective. (1997). H. K. Pentiuk. D. Benzene and leukemia... Drug Metab Rev 36. Kachula. Skibola. (2004). M. Li. Smith. Lamm. Expert Panel on Air Quality Standard (EPAQS) (1994) Benzene. Environ Health Perspect 102 Suppl 11. The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. M.. Morgan. Crit Rev Toxicol 32. Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family. O. (2004). E. O. N. F. Albores. Environ Health Perspect 104 Suppl 6. (1994). 16-28. Review of epidemiologic evidence on benzene and lymphatic and hematopoietic cancers. S. Chem Biol Interact 153-154. M. Hum Genomics 2. G. E. back cover. [Individual susceptibility to hematotoxicity from benzene exposure and the genetic polymorphism of metabolic enzymes]. R. 373-92. S. Smith. J. and Andrews.BENZENE – TOXICOLOGICAL OVERVIEW [32] Wong. J. and Nebert. 9-21. V. G. Cytochrome CYP2E1 phenotyping and genotyping in the evaluation of health risks from exposure to polluted environments. (2002). Non-Hodgkin lymphoma and benzene exposure: a systematic literature review. Y. Am J Ind Med 31. Am J Pharmacogenomics 2. Snyder.. [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] Toxicological overview: Page 12 of 14 . 231-7. (1996).. 121925. and Herych. Lucas. and Clonfero.. O. and Smith. and Byrd. Allan. Pavanello. 79-92.

. M. N. E. 1774-6. T. Waidyanatha. M.. Kopp. Aksoy. 685-91. L. M. R. Aksoy. B. M. P. Q. and Smith. M. J. R. Young. E. and Cook.. S. R....BENZENE – TOXICOLOGICAL OVERVIEW [50] [51] [52] Ross. G. R. S. S.. P. A. Guo... Different types of malignancies due to occupational exposure to benzene: a review of recent observations in Turkey. Dose response analyses. Arch Environ Health 33. T. R. Smith. Kim. Mortality among individuals occupationally exposed to benzene. (1987). C. Leukaemia in benzene workers. M. and Aksoy. R. Blut 28. 8726. G. K.. R. 181-90. (1978).. 7624-6. Alter. Chromosome study in a case of granulocytic leukaemia with 'Pelgerisation' 7 years after benzene pancytopenia. Shen. and genetic susceptibility to cancer. S. (1974). Chronic exposure to benzene as a possible contributary etiologic factor in Hodgkin's disease. M. M. Dincol. NQO1.. G. A. 83-5. Okun. J Toxicol Environ Health A 61. Baslo. Townsend. Neurological abnormalities in chronic benzene poisoning. R. S. Rothman.. Lancet 2. S. Blood 44. C.. 1044-50. M. M.. C. [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] Toxicological overview: Page 13 of 14 . S. Rinsky. D. Linet. A. Hornung. Smith.. Infante.. Rabkin. An update of mortality among chemical workers exposed to benzene. (1971). Wong. A. (1974). M. Rappaport. G. Br J Ind Med 44.. (2004). Rinsky. Eur J Cancer 7. and Langner. A. M. S. and Keleman. W. 837-41. Erdem. Sellyei. G. 382-95. (1987). Bond. and Saita. A. N Engl J Med 271.. Ott. Lan. R. (2000). Chem Biol Interact 153-154.. J. J. Zhang. Wagoner.... G. (1980). (2005). McLaren. O. K. Hayes. and Landrigan. M. A. Br J Ind Med 43. Vigliani. Filloon. J. Science 306.. Environ Res 23. and Young. 137-46. Wu. 76-8.. Hematotoxicity in workers exposed to low levels of benzene. Environ Res 27. Li. W. Aksoy. (1999). Blood 52. Functions and distribution of NQO1 in human bone marrow: potential clues to benzene toxicity. T. C. Proc Natl Acad Sci U S A 96. L. and DinCol. Aksoy. R. Yin. Snyder. 285-92.. Baldwin. B.. W. Vermeulen. Chanock. Overview of the toxicology of benzene. A. B. (1986). (1964). P.. G. and Erdem. R. J. T. (1982). Erdem. Followup study on the mortality and the development of leukemia in 44 pancytopenic patients with chronic exposure to benzene. and Dincol. N Engl J Med 316. E. H. Benzene and leukemia. Benzene. 339-46.. (1978). 3-10. R. Benzene and Leukemia.. Dosemeci. Leukemia in shoe-workers exposed chronically to benzene. An industry wide mortality study of chemical workers occupationally exposed to benzene. G. 293-8. II.. Weinberg. Hepyuksel... 457-65. A study of six patients with aplastic anemia and two with preleukemia. F. An epidemiologic risk assessment. S. (1977).. Y. Fishbeck.

502-3.. [68] [69] [70] [71] [72] This document will be reviewed not later than 3 years or sooner if substantive evidence becomes available. Yin. (2000).. ISBN 92 4 1571500. L.. S. Buiatti.. Miligi. E. and Blair. leukemia and other cancer mortality in a cohort of shoe workers exposed to benzene.. M. P. G. and Sim.. Fu. D. and Kaldor.. 124-8. (2006). J. Y. G. J. Environ Res 30. Pucci. and Maclaren. W. (1987).. A. 347-51. J. S. Mortality among chemical workers exposed to benzene and other agents. The health watch case-control study of leukemia and benzene: the story so far. Zhang.. E. I. Ann N Y Acad Sci 1076. 16-25. J. Aplastic anemia. Br J Ind Med 48. 80-9. Simonato.. Luo. Jolley. C. (1983). Z. D. R. J. A... Environmental Health Criteria 150: Benzene. J. Scarpelli. E.. P. McConnell. Exposure to benzene and mortality from leukaemia: results from coke oven and other coal product workers. Jin.. Whysner. N. A. 313-8. Ye. Li. W.. Scand J Work Environ Health 15. S. J. Benzene-induced genotoxicity. Hurley. R. C. Paci. W. (1989). Z. G. (1991). C.. International Programme on Chemical Safety. Seniori Costantini. J Toxicol Environ Health A 61. Wang.. L. N. Br J Ind Med 44. C. Toxicological overview: Page 14 of 14 . World Health Organisation.BENZENE – TOXICOLOGICAL OVERVIEW [66] [67] Decoufle. L.. and et al. Cherrie. Z. C. Blattner. F. N. E. Petrioli. J.. Winkelmann. (1993). A. F. Gibbons. Leukaemia in benzene workers: a retrospective cohort study.. Tain. D. Gray. Chen.. Glass.. M.

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