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Human & Experimental Toxicology http://het.sagepub.com Short Review: Benzene's toxicity: a consolidated short review of human and animal studies Haseeb Ahmad Khan Hum Exp Toxicol 2007; 26; 677 DOI: 10.1177/0960327107083974 The online version of this article can be found at: http://het.sagepub.com/cgi/content/abstract/26/9/677 Published by: http://www.sagepublications.com Additional services and information for Human & Experimental Toxicology can be found at: Email Alerts: http://het.sagepub.com/cgi/alerts Subscriptions: http://het.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.co.uk/journalsPermissions.nav Citations http://het.sagepub.com/cgi/content/refs/26/9/677 Downloaded from http://het.sagepub.com at HAM/TMC LIBRARY on November 10, 2009 Human & Experimental Toxicology (2007) 26: 677685 http:// het.sagepub.com SHORT REVIEW Benzene's toxicity: a consolidated short review of human and animal studies Haseeb Ahmad Khan* Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia A large population of humans is exposed to benzene from various occupational and environmental sources. Benzene is an established human and animal carcinogen. Exposure to benzene has been associated with leukaemia in humans and several types of malignancies in animals. The exact mechanism of benzene-induced toxicity is poorly understood. It is believed that benzene exerts its adverse effects by metabolic activation to toxic metabolites. Certain benzene metabolites are genotoxic and mutagenic. This consolidated short-review is composed of human and animal studies to summarize the adverse effects of benzene with special reference to molecular mechanisms involved in benzene-induced toxicity. Human & Experimental Toxicology (2007) 26, 677685 Key words: benzene; chromosomal aberrations; cytotoxicity; genotoxicity; health hazards; mutations; sister chromatid exchange Introduction Benzene is commonly used as a starting material for the synthesis of several other chemicals of industrial and medicinal importance. It is used as an excellent solvent in various industries including dyes, varnish, lacquer, leather and so on. Benzene is also a component of cigarette smoke and gasoline. Huge numbers of population from entire globe are exposed to benzene either occupationally or due to environmental contamination. Benzene has been confirmed to be a human and animal carcinogen. Chronic exposure to low dose of benzene is associated with aplastic anaemia and leukaemia. Acute effects of benzene exposure include irritation of mucous membranes, restlessness, convulsions, excitement, depression and even death due to respiratory failure. The major toxic effect of benzene is its haematopoietic toxicity. This concise review is *Correspondence: Haseeb Ahmad Khan, Department of Biochemistry, College of Science, Bld 5, Room 2A68, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia E-mail: khan_haseeb@yahoo.com Received 26 August 2006; accepted 6 August 2007 aimed to compile various aspects of benzene toxicity in humans and experimental animals by incorporating the relevant studies beginning from the decades old historical contributions to current insights on benzene toxicity. Human toxicological studies Occupational and environmental exposure A large number of industrial workers from petroleum, rubber, paint, shoe making, printing, solvent and other chemical industries are occupationally exposed to benzene14 Moreover, the individuals working at the petrol filling stations, tanker crew, motor mechanic and traffic policemen are also at a potential risk to benzene exposure occupationally.59 The major sources of environmental exposure to benzene include active and passive smoking, auto exhaust and driving or riding in automobiles.1012 Jermann et al.13 found high levels of benzene in the blood of children from the urban areas with high traffic density as compared with the children from rural areas. Although inhalation is the main route 2007 SAGE Publications Downloaded from http://het.sagepub.com at HAM/TMC LIBRARY on November 10, 2009 10.1177/0960327107083974 678 Benzene's toxicity HA Khan of benzene exposure because of its appreciable vapour pressure at ambient temperature it may also get a route through contaminated drinking water14,15 and dermal absorption.16,17 Nakai et al.18 have suggested that use of sunscreens may significantly enhance the absorption of benzene into the skin. Accidents like oil fires may also significantly enhance the environmental exposure of benzene.19 Benzene contamination of soil may also occur due to oil production facilities and coastal refineries.20,21 Human health hazards Chronic exposure of humans to benzene is associated with blood disorders including aplastic anaemia2224 and leukaemia.2528 Aplastic anaemia results from bone marrow toxicity of benzene causing progressive decrease in erythrocytes, thrombocytes and each of the various types of leukocytes. The incidence of aplastic anaemia at high level of benzene exposure (100 ppm) has been reported to be 1/100, which drops to around 1/10 000 at an exposure level of 1020 ppm.22 Working atmospheric concentrations of more than 5 ppm of benzene significantly reduced the haemoglobin level and mean corpuscular haemoglobin concentration in occupationally exposed workers.29 However, even low levels of benzene exposure (5 ppm) may also result in haematological suppression.4 Molinini et al.3 have suggested that synergistic effects of other environmental contaminants may promote myelotoxic effect of low level of benzene exposure. Baak et al.24 also reported a case of aplastic anaemia induced by low-level benzene exposure. On the other hand, Collins et al.30 found the benzene exposure of 0.55 ppm to be safe without any indication of haematotoxicity. Leukaemia is a neoplastic type of blood dyscrasia associated with benzene exposure.31,32 The benzeneinduced leukaemia is acute myeloid leukaemia that is characterized by increased number of cells morphologically similar with myeloblasts. Aksoy et al.28 reported high incidence of leukaemia in shoe workers occupationally exposed to benzene, whereas Hunting et al.33 observed high haematopoietic cancer mortality in motor vehicle mechanics. Nordlinder and Jarvholm34 found a close association between leukaemia and the density of motor vehicles (20 cars/km2). The duration of exposure to benzene was found to be closely related with the risk of leukaemia in petroleum distribution workers.35 A minimum critical concentration of 5060 ppm of benzene may be required for the risk of leukaemia in pliofilm workers.36 Xu et al.37 reported an increased risk of spontaneous abortion for the woman frequently exposed to petrochemicals including benzene. As an acute poison, benzene produces narcotic effects comparable to those of toluene. The human oral lethal dose would probably be between 50 to 500 mg/kg.38 Human inhalation of about 20 000 ppm (2% in air) was fatal in 510 min.39 The acute symptoms of benzene exposure may include headache, nausea, vertigo, fatigue and dizziness.6 Cytotoxicity Snyder et al.40 pointed out that benzene and its metabolites do not function well as mutagens, but are highly clastogenic, producing chromosomal aberrations, sister chromatid exchange (SCE) and micronuclei. An increased incidence of chromosomal aberrations has been reported in workers exposed to 25150 ppm benzene for 125 years as compared with general population.41 Killian and Daniel42 observed that long-term exposure to even below 10 ppm levels of benzene caused about two-fold increase in chromosomal breaks and a three-fold increase in rings and dicentric chromosomes as compared with controls. Sarto et al.43 found an increase in chromosome aberrations, but no increase in SCE among 22 workers exposed to 0.2 12.4 ppm benzene for about 11 years, as compared with controls matched for sex, age, smoking habits and site of residence. Yardley-Jones et al.44 observed a significant increase in chromosomal aberrations, whereas no significant change in SCE frequencies was noticed in 60 workers exposed to 100 ppm benzene. Erexson et al.45 studied the effect of benzene and its metabolites on SCE induction in human lymphocytes. They observed that catechol was highly potent for inducing SCE, follow by 1,4-benzoquinone hydroquinone 1,2,4-benzenetriol phenol benzene. On the other hand, benzene exposure at 19 ppm for 120 years or 350 ppm for 212 years failed to produce any significant effect on chromosomal aberrations and SCE in female workers.46 The occupational exposure of benzene failed to increase SCE frequency in 36 workers employed in shoe industry.47 Bukvic et al.48 concluded that the occurrence of SCE was significantly associated with age and smoking habits and not with the length of employment at gasoline station. There was no significant difference in the frequency of SCE between traffic wardens and office workers; whereas the same study revealed highly significant increase in SCE among smokers.49 On the contrary Celi and Akbas50 observed significant difference in SCE in gasoline station workers as compared with control individuals; there was no interaction between cigarette smoking and benzene exposure for SCE values. Downloaded from http://het.sagepub.com at HAM/TMC LIBRARY on November 10, 2009 Benzene's toxicity HA Khan Ding et al.51 reported a significant increase in hypodiploid and hyperdiploid cells in benzeneexposed patients of either sex. The chromosome deletions in the hypodiploid cells involved groups C, E and G chromosomes whereas chromosome gains in the hyperdiploid cells involved groups C and E. Although high concentrations of benzene are associated with increased levels of cytogenic indices of genotoxicity in exposed workers, the concentrations below TLV do not produce any measurable cytogenic damage in humans. The incidence of dicentric chromosomes in the shoe industry workers has been found to be significantly higher than control group.47 Benzene decreases peripheral white blood cell and platelet counts and specifically lowers T-cells, B-cells, NK-cells and granulocytes; however, benzene's lymphotoxicity is not mediated by diminished thymus function.52 On the other hand, human bone marrow CD34() haematopoietic progenitor cells are sensitive targets for benzoquinone (a metabolite of benzene) toxicity that utilizes the p53 pathway for protection against benzoquinoneinduced DNA damage.53 The inhibition of topoisomerase II (a key enzyme of DNA replication) has also been linked to benzene-induced cytotoxicity and leukemogenesis.54 Chung and Kim55 have reported that treatment with benzene metabolites resulted in the induction of monosomy in human lymphocytes in a concentration-dependent manner. Rothman et al.56 used glycophorin A (GPA) gene loss mutation assay to evaluate the nature of DNA damage produced by benzene exposed workers. A significant increase in GPA variant cell frequency was observed in benzene exposed workers as compared with control subjects, suggesting the role of chromosomal damage and mitotic recombination in benzene-induced leukaemia. Polymorphisms in the genes involved in benzene metabolism influence the susceptibility of individuals to chromosomal aberrations in relation to benzene exposure.57 NADPH:quinone oxidoreductase 1 (NQO1) performs multiple functions including cellular redox balance, scavenging of ODFR, stabilization of p53 and stabilization of microtubules; the NQO1*2 polymorphism predisposes to benzene toxicity and to various forms of leukaemia.58 Animal toxicological studies Subchronic toxicity Data from animal models are frequently used in risk assessment of benzene. Animal studies have shown that mice are more sensitive to benzene toxicity than rats59,60 hence, they are preferred for toxicological studies. Faiola et al.61 observed that male mice were more susceptible to benzene toxicity following the exposure of up to 100 ppm benzene for 6 h/day, five days/week for two weeks. Haematotoxity was evident in all male mice but not seen in female mice.61 It is plausible that the enzymes that activate and detoxify benzene are likely the genetic determinants of benzene's toxicity. Bauer et al.62 found that the male mice deficient in microsomal epoxide hydrolase (mEH -/-) did not show any significant haematotoxicity or myelotoxicity at the highest benzene exposure (100 ppm). On the other hand, deficiency of NQO1 (-/- genotype) predisposes both male and female mice to benzeneinduced toxicity.63 Although cytochrome P450 2E1 (CYP2E1) dependent metabolic activation has been implicated in benzene's toxicity64 this pathway failed to define the strain-specific differences in tumour response of the haematopoietic system of mice.65 Ward et al.66 reported that exposure of 300 ppm benzene, 6 h/day, five days/week for 13 weeks produced significant haematological changes including decreased haematocrit, total haemoglobin, erythrocyte/leukocyte count, platelet count and myeloid:erythrocyte ratio in CD-1 mice. However, the rats exposed to the similar doses of benzene showed only a decrease in lymphocyte count and increase in neutrophil count. Exposure of mice to 300 ppm benzene (6 h/day for 10 days) produced long-lasting haematotoxic effects.67 Farris et al.68 observed that mice exposed to 100200 ppm benzene for eight weeks showed persistent reductions in femoral B-, splenic T- and B- and Thymic T- lymphocytes. The target cells for benzene haematopoietic toxicity include pluripotent stem cells, the colony-forming cell units in the spleen and the progenitor cells for granulocytes and macrophages. Rozen and Snyder69 reported a significant decrease in B-lymphocytes in bone marrow and spleen and T-lymphocytes in thymus and spleen of C57BL mice exposed to 300 ppm benzene, 6 h/day, five day/week for 115 exposures. The exposure of 50200 ppm benzene, 6 h/day for 7 to 14 days depressed the ratios and absolute numbers of T- and B-lymphocytes in blood and spleen of BALB/C mice.70 A significant depression in colony-forming units in B-lymphocytes was observed in C57 BL mice after inhalation of 10 ppm of benzene 6 h/day for six days, whereas the dose of 31 ppm also resulted in depressed blastogenesis of T-lymphocytes.71 Cronkite et al.72 reported significant reduction in bone marrow cellularity in CBA/CA mice following benzene exposure at 100 ppm or greater, 6 h/day, five day/week for two weeks. Downloaded from http://het.sagepub.com at HAM/TMC LIBRARY on November 10, 2009 679 680 Benzene's toxicity HA Khan Carcinogenicity Maltoni and Scarnato73 clearly demonstrated the carcinogenicity of benzene in experimental animals. Benzene is a potent carcinogen in rodents when administered by inhalation or ingestion, producing carcinomas of the Zymbal gland, oral cavity, nasal cavities, skin, stomach, mammary glands, lungs and liver. Thus, benzene is considered as a multipotential carcinogen that produces cancers in several organs of various species of animals by different routes of administration.7376 Various concentrations of benzene, route and duration of exposure have been used in long-term studies on benzeneinduced carcinogenesis in mice.7779 Snyder et al.80 reported significantly higher incidence of tumours in C57BL mice inhaled 300 ppm benzene for 6 h/day, five days/week for two years. Oral administration of benzene in the doses of 50 and 250 mg/kg, 4 to 5 days/week for 52 weeks caused a dosedependent increase in total cancers in rats. Cronkite and coworkers77,81 reported comparatively high incidence of benzene-induced leukemia in male C57BL/6 and CBA/CA mice than females following the exposure of 100300 ppm benzene, 6 h/day, five days/week for 16 weeks. Developmental toxicity Kuna and Kapp82 observed significant reduction in fetal body weight and crown-to-sump distance as well as developmental delay following the exposure of benzene (10, 50 and 500 ppm 7 h/day) to pregnant rats during 615 days of gestation. They suggested benzene-induced fetotoxicity in rats at 50 and 500 ppm, and teratogenecity at 500 ppm. Coate et al.83 also reported reduction in fetal body weight due to maternal exposure of benzene (100 ppm, 6 h/day) on days 615 of gestation, however, no teratogenecity was observed. Twenty-four hours exposure to 308 ppm benzene during 615 days of gestation has been shown to retard skeletal development in mouse fetus and spontaneous abortions in rabbits.84 Whereas, administration of benzene to pregnant experimental animals at concentrations, which did not cause maternal toxicity also failed to produce any remarkable developmental effects in the fetus.85 Genotoxicity Mutations Several investigators have observed negative findings for benzene-induced mutagenesis using Salmonella typhimurium gene mutation assay.86,87 However, McCarroll et al.88 reported positive result using a microsuspension assay with hepatic microsomal activation resulting in an increase in the number of revertants in S. typhimurium strain TA100. The growth of DNA repair deficient Escherichia coli strain WP100 was inhibited by benzene exposure, but no such effect was observed in repair proficient strains.89 Rossman et al.90 examined the mutagenic potential of several metabolites of benzene using E. coli WP2s (lambda) as a target and concluded that only t,t-muconic acid, which is metabolized to a diepoxide may be the ultimate mutagen and possibly the ultimate carcinogen. Benzene was reported to be negative in Saccharomyces cerevisiae gene conversion and mitotic crossing-over assays,91 however, it was considered mutagenic for S. cerevisiae strains D61M and D6.92 Recently, p-benzoquinone-induced deletion recombination in S. cerevisiae at a dose of 300-fold lower than any of the other metabolites of benzene suggested that it might be responsible for much of benzene's genotoxicity.93 The metabolite of benzene, p-benzoquinone readily forms adducts with the nucleotides leading to deletions in the transcription products at the site of damage.94 Whereas DNA adducts subject to excision repair were not formed by benzene or its metabolites, as demonstrated using excision repair deficient strain of S. cerevisiae.93 Studies on Drosophila have shown no evidence for mutagenic response to benzene exposure.95,96 Moreover, studies on cultured mammalian cells have also been inconclusive regarding an association between point mutation and benzene exposure.97 Ward et al.98 noticed that subchronic exposure to benzene at levels below the occupational safety permitted exposure limit may induce gene mutations in lymphocytes of CD-1 mice. Significant increases in lacI mutations were observed in the spleen and bone marrow of benzene treated mice using the standardized lambda/lacI transgenic mouse mutation assay.99 Chromosomal aberrations Benzene exposure has been shown to induce chromosomal structural changes and aneuploidy in cultured mammalian cells. Howard et al.100 reported chromosomal aberrations in cultured human lymphocytes after 3 h incubation with 988 g benzene/mL, with or without S9 activation. Benzene concentrations of 100 and 1100 g/mL, with S9 activation produced aberrations in Chinese hamster ovary cells and lung fibroblasts, respectively.101 Eastmond102 suggested that the chromosomal aberrations induced by the quinone metabolites of benzene may play a role in the carcinogenic effects of the parent compound. The metabolic activation of benzene is necessary for the induction of sister-chromatid exchange (SCE) in cultured human lymphocytes, whereas its metabolites cathecol and hydroquinone are potent SCE inducers.103 Glutathione has been suggested to play Downloaded from http://het.sagepub.com at HAM/TMC LIBRARY on November 10, 2009 an important role in protecting against benzeneinduced SCE formation by conjugating with toxic metabolites.104 Tice et al.105 reported a dose-dependent increase in SCE following benzene exposure where the mice with male sex and younger age were more sensitive to SCE formation. DNA damage Although benzene failed to exhibit genotoxicity in tests for unscheduled DNA synthesis (UDS) in cultured primary rat hepatocytes, an association between benzene exposure and increased UDS has been reported by Glauert et al.106 Cell transforming and genotoxic effects of benzene and its metabolites using cultured mammalian cells have been reported.107 Pellack-Walker and Blumer108 observed that exposure to 1.0 mmol of benzene, phenol or catechol or 0.1 mmol of hydroquinone failed to show any single-strand breaks in the DNA of mouse lymphoma cells, however, 70% DNA breakage was observed with p-benzoquinone or 1,2,4-benzenetriol at a concentration of 6 mol exposed for 3 and 60 min, respectively. Benzene metabolites, hydroquinone and benzoquinone are highly potent to induce DNA strand breakage in chinese hamster ovary cells.109 The enhanced production of oxygen-derived free radicals (ODFR) by redox-cycling of phenoxy radicals has been implicated in the oxidative damage of DNA.110 Rao111 suggested glutationyl hydroquinone to be a possible toxic metabolite of benzene with pro-oxidant property for the degradation of DNA. The involvement of ODFR in benzoquinone-induced DNA damage has been observed using the comet assay of peripheral blood mononuclear cells.112 Recent studies have shown that modulation of topoisomerase II enzyme by benzene's metabolites play a key role in benzeneinduced DNA damage.113,114 Neoplasia Although benzene was not found to be mutagenic in cultured Balb/C 3T3 mouse fibroblasts Benzene's toxicity HA Khan and in simian adenovirus-transformed Syrian hamster embryo (SHE) cells, it was considered to be mutagenic in SHE cells using morphologically transformed colonies as a marker.115 Alteration in gene expression in Swiss mouse spleen lymphocytes exposed to benzene or its metabolites hydroquinone and p-benzoquinone has been reported.116 The concentration of 1020 mol of both hydroquinone and p-benzoquinone caused 50% inhibition in RNA synthesis. The inhibition of T-cell proliferation and reduced production of interleukin2 by p-benzoquinone was suggested to be a possible cause of benzene-induced aplastic anemia.116 Bioactivation of benzene causes increased generation of ODFR, which in turn activates the oncogene c-myb leading to the formation of leukemic cells.117 Studies on C57BL/6 normal and p53 knockout mice have shown that benzene suppresses the cell cycle by p53 mediated overexpression of p21, a cyclindependent kinase inhibitor, resulting in dynamic change of haemopoiesis during and after benzene exposure.118 Gene expression profiles in bone marrow cells from C57BL/6 p53 / and isogenic p53 /- mice chronically exposed for 15 weeks to 100 ppm of inhaled benzene revealed that p53 homozygous mice expressed significantly higher levels of a majority of key genes involved in p53regulated DNA damage response pathway compared with p53 heterozygous bone marrow cells.119 The mice lacking expression of NQO1 and NQO2 protein showed myelogenous hyperplasia of the bone marrow and increased granulocytes in the peripheral blood accompanied by decreased apoptosis.120 Short-term exposure of NQO1-/- mice to benzene demonstrated substantially greater benzene-induced toxicity as compared with wild type mice.120 Nitric oxide has also been suggested to be an important mediator of benzene-induced bone marrow suppression and haematopoietic impairment in mice.121 681 References 1 Tompa A, Jakab MG, Major J. 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