1. Exposure Data

1.3. Human exposure

1.3.1 Occupational exposure

Occupational exposure to benzene occurs via inhalation or dermal absorption of solvents in the rubber, paint (including paint applications) and parts-manufacturing industries. It also occurs during crude-oil refining and chemical manufacturing, a large component of which entails exposure to gasoline. Workers involved in the transport of crude oil and gasoline and in the dispensing of gasoline at service stations, as well as street workers, taxi drivers and others employed at workplaces with exposure to exhaust gases from motor vehicles also experience exposure to benzene (Nordlinder & Ramnäs, 1987).

CAREX (CARcinogen EXposure) is an international information system on occupational exposure to known and suspected carcinogens, based on data collected in the European Union (EU) from 1990 to 1993. The CAREX database provides selected exposure data and documented estimates of the number of exposed workers by country, carcinogen, and industry (Kauppinen et al., 2000). Table 1.1 presents the results for benzene in the EU by industry for the top-10 industries (CAREX, 1999). Exposure to benzene is defined as inhalation or dermal exposure at work to benzene likely to exceed significantly non-occupational exposure due to inhaling urban air or filling in gasoline stations (long-term exposure usually below 0.01 ppm)].

Table 1.1

Estimated numbers of workers exposed to benzene in the European Union (top 10 industries).

From the US National Occupational Exposure Survey (1981–1983), it was estimated that approximately 272300 workers (including 143000 women) were potentially exposed to benzene in the United States of America. Industries where potential exposure occurred included agricultural services, oil and gas extraction, construction (includes general building and special trades contractors), food products, tobacco manufacturing, textile mills, lumber and wood, printing and publishing, chemical and allied products, petroleum and coal products, rubber manufacturing, leather manufacturing, transportation, and health services (NIOSH, 1990).

van Wijngaarden & Stewart (2003) conducted a critical review of the literature on occupational exposures to benzene in the 1980s in the USA and Canada. The data indicated that workers in most industries experienced exposure levels below the regulatory limit (1 ppm) of the US Occupational Safety and Health Administration (OSHA), with a weighted arithmetic mean of 0.33 ppm across all industries. It was noted that little information was available on exposure levels and their determinants for many industries with potential exposure.

Williams et al. (2008) summarized the values of the benzene content of selected petroleum-derived products based on published literature between 1956 and 2003. A total of 22 studies were identified, which contained 46 individual data sets and evaluated potential occupational exposure to benzene in the USA during the handling or use of these petroleum-derived products. All mean (or median) airborne concentrations were less than 1 ppm, and most were < 0.1 ppm. Table 1.2 (available at http://monographs.iarc.fr/ENG/Monographs/vol100F/100F-19-Table1.2.pdf) summarizes airborne benzene concentrations from studies and governmental reports published between 1981 and 2006.

Capleton & Levy (2005) tabulated typical benzene-exposure levels in different occupational groups in various areas in Europe and North America (Table 1.3). The values are similar to those reported by van Wijngaarden & Stewart (2003) and Williams et al. (2008) for exposures of 1 hour or more.

Table 1.3

Typical benzene exposure levels in different occupational groups/areas in Europe and North America^a.

Williams et al. (2005) reviewed available industrial-hygiene data describing exposure during the marine transport of benzene-containing products. Although there were differences in sampling strategies and in benzene content of the liquids being transported, typical benzene concentrations in air (personal time-weighted average) were in the range of 0.2–2.0 ppm during closed loading and 2–10 ppm during open loading-operations.

Liang et al. (2005) reviewed and tabulated benzene exposures by industry in the People’s Republic of China, using data published between 1960 and 2003. The five industries with the highest reported exposures were those producing leather products, electronic devices, machinery, shoes, and office supplies and sports equipment. Median ambient concentrations in these industries were, respectively: 124.8 mg/m³, 98.7 mg/m³, 75.4 mg/m³, 50.4 mg/m³, and 50.3 mg/m³. [The Working Group noted that all data were collected with sampling methods of very short duration (1–20-minute time-weighted averages). In addition, a considerable part of the surveys were follow-up studies of benzene poisonings. Therefore, these data cannot be considered as representative and cannot be compared with the information reported from the USA.] Levels of short-term exposure to benzene varied considerably between industries (Table 1.4) and showed generally a downward trend over time (Fig. 1.1).

Table 1.4

Comparison of the average benzene concentrations (mg/m³) by industry.

Fig. 1.1

Overall trend in median benzene exposure in Chinese industry, 1979–2001. The star indicates the number of measurement sets in the database

Urinary trans,trans-muconic acid (t,t-MA) and S-phenylmercapturic acid (S-PMA) are sensitive markers for recent exposure to benzene at low levels (Qu et al., 2005).

1.3.2 Non-occupational exposure

The major sources of benzene in the atmosphere are anthropogenic and include fixed industrial sources, fuel evaporation from gasoline filling-stations and automobile exhaust. Benzene has been measured in outdoor air at various locations in the USA at concentrations ranging from 0.02 ppb (0.06 μg/m³) in a rural area, to 112 ppb (356 μg/m³) in an urban area. Exposure to benzene is highest in areas of heavy motor-vehicle traffic and around gasoline filling-stations. Based on an average benzene concentration of 12.5 ppb (40 μg/m³) in the air and an exposure of 1 hour per day, the daily intake of benzene from driving or riding in a motor vehicle is estimated to be 40 μg. Exposure is higher for people who spend significant time in motor vehicles in areas of congested traffic (NTP, 2005; ATSDR, 2007).

The primary sources of exposure to benzene for the general population are ambient air containing tobacco smoke, air contaminated with benzene (for example, in areas with heavy traffic, around gasoline filling-stations), drinking contaminated water, or eating contaminated food. The median level of benzene was 2.2 ppb (7 μg/m³) in 185 homes without smokers and 3.3 ppb (10.5 μg/m³) in 343 homes with one or more smokers. Amounts of benzene measured per cigarette ranged from 5.9 to 75 μg in mainstream smoke and from 345 to 653 μg in sidestream smoke. Benzene intake from ingestion of water and foods is very low, compared with intake from ambient air (ATSDR, 1997; NTP, 2005). Residential exposure to benzene can also occur from leaking underground gasoline-storage tanks. Benzene concentrations in homes from such exposures have been estimated to range from 0–42 ppm (1–136 mg/m³) (Patel et al., 2004).

Duarte-Davidson et al. (2001) assessed human exposure to benzene in the general population of the United Kingdom. It was estimated that infants (< 1 year old), the average child (11 years old), and non-occupationally exposed adults receive average daily doses of benzene in the range of 15–26 μg, 29–50 μg, and 75–522 μg, respectively. These values correspond to average airborne benzene concentrations in the range of 3.40–5.76 μg/m³, 3.37–5.67 μg/m³, and 3.7–41 μg/m³ for these three groups, respectively.

Benzene concentrations in breath, blood and urine samples collected among the general populations (without occupational or known exposure to benzene) in Asia, Europe and North America are presented in Table 1.5 (Johnson et al., 2007).

Table 1.5

Benzene in breath, blood and urine samples in the general population without occupational or known exposure to benzene^a.

2. Cancer in Humans

In IARC Monographs Volume 29 (IARC, 1982) the Working Group concluded there was sufficient evidence in humans for the carcinogenicity of benzene, noting that a series of cohort and case–control studies showed statistically significant associations between occupational exposure to benzene and benzene-containing solvents and leukaemia (predominantly myelogenous leukaemia). In IARC Monographs Supplement 7 (IARC, 1987) benzene was classified as a Group-1 carcinogen, citing additional evidence of an increased incidence of acute nonlymphocytic leukaemia (ANLL) in workers exposed to benzene in three cohort studies, including an update of a cohort cited in Volume 29 (IARC, 1982). Since 1987, there have been numerous reports from cohort studies in populations exposed to benzene, including updates of earlier reports, and new case–control studies of leukaemia or its subtypes, non-Hodgkin lymphoma (NHL), multiple myeloma, and to a lesser extent other tumours in adults. There have also been several case–control studies of childhood leukaemia with data on benzene, solvents, gasoline, and other related exposures. In addition, several meta-analyses have been published of one or more tumour sites.

[The Working Group decided to restrict its review to those case–control studies of paediatric cancers that included estimates of environmental benzene exposure, rather than surrogate exposures such as proximity to petrol stations or traffic. Also, the Working Group weighed more heavily the findings from studies with estimates of occupational exposure to benzene rather than broader measures (e.g. to solvents) in case–control studies. It was also decided not to rely in general on case–control studies where exposure assessment was limited to asking study subjects directly if they had been exposed to particular chemicals. Furthermore, the Working Group did not consider cohort studies of workers in synthetic rubber-manufacturing due to the difficulty of separating out effects from benzene vs those of other chemicals that may cause haematological malignancies. The Working Group decided not to take into consideration a series of meta-analyses of studies of petroleum workers (Wong & Raabe, 1995, 1997, 2000a, b). There were methodological concerns about the expansion from paper to paper of additional studies, cohorts, and countries, and the overall approach may dilute out the risks associated with relatively highly exposed subgroups of these populations that in general were not identified. In addition, an increased risk of ANLL – or the alternative classification, Acute Myelogenous Leukaemia (AML), which is more restrictive but still constitutes most of ANLL – was not detected in the initial meta-analysis by Wong & Raabe (1995), this body of work was not considered relevant for assessing what additional cancers may be associated with exposure to benzene beyond ANLL/AML. Abd finally, the Working Group noted that some meta-analyses of the same tumour came to opposite conclusions, which could be due to different inclusion/exclusion criteria, focusing on different subgroups of the study populations, or to different approaches to selecting risk estimates for inclusion (e.g. Lamm et al., 2005; Steinmaus et al., 2008), thus complicating the overall assessment of the literature. The Working Group therefore decided not to rely in general on results of meta-analyses in its evaluations.]

3. Cancer in Experimental Animals

Studies on the carcinogenesis of benzene in rats and mice after exposure by inhalation, intragastric gavage, skin application, and by intraperitoneal or subcutaneous injection have been reviewed in IARC Monographs Volume 29 and in Supplement 7 (IARC, 1982, 1987). In Supplement 7 it was concluded that there is sufficient evidence in experimental animals for the carcinogenicity of benzene. Results of adequately conducted carcinogenicity studies reported before and after 1987 are summarized in Tables 3.1, 3.2, 3.3, 3.4.

Table 3.1

Carcinogenicity studies in experimental animals exposed to benzene by inhalation.

Table 3.2

Carcinogenicity studies in experimental animals exposed to benzene by gavage.

Table 3.3

Carcinogenicity studies in experimental animals exposed to benzene by intraperitoneal injection.

Table 3.4

Carcinogenicity studies in experimental animals exposed to benzene via skin application .

Exposure to benzene by inhalation increased the incidence of Zymbal gland carcinomas, liver adenomas, and forestomach and oral cavity carcinomas in female rats (Maltoni et al., 1982a, c, 1983, 1985, 1989). It also increased the incidence of lymphohaematopoietic (lymphoma, myelogenous) neoplasms in male and female mice (Snyder et al., 1980; Cronkite et al., 1984, 1989; Farris et al., 1993), and Zymbal gland carcinomas, squamous cell carcinomas of the preputial gland, and lung adenomas in male mice (Snyder et al., 1988; Farris et al., 1993).

Oral administration of benzene increased the incidence of Zymbal gland carcinomas and oral-cavity papillomas and carcinomas in rats of both sexes, of carcinomas of the tongue, papillomas and carcinomas of the skin and of the lip and papillomas of the palate in male rats, of forestomach acanthomas in both sexes of the rat, and of forestomach carcinomas in female rats (Maltoni & Scarnato, 1979; Maltoni et al.,1982b, 1983, 1988, 1989; NTP, 1986; Maronpot, 1987; Huff et al., 1989; Mehlman, 2002). Given by the oral route, benzene also increased the incidence of Zymbal gland carcinomas, forestomach papillomas, lymphomas, and lung adenomas and carcinomas in mice of both sexes, of liver carcinomas, adrenal gland pheochromocytomas, Harderian gland adenomas and preputial gland squamous cell carcinomas in male mice, and of benign and malignant ovarian tumours, mammary gland carcinomas and carcinosarcomas, and Harderian gland carcinomas in female mice (NTP, 1986; Stoner et al., 1986; Maronpot, 1987; Maltoni et al., 1988, 1989; Huff et al., 1989; Mehlman, 2002).

Increased multiplicity of lung adenomas was observed in male mice after intraperitoneal injection of benzene (Stoner et al., 1986).

Exposure of genetically altered, tumour-prone mice to benzene by oral administration, skin application, or inhalation resulted in increased incidences of skin tumours (Blanchard et al. 1998; Holden et al., 1998; French & Saulnier, 2000) and lymphohaematopoietic malignancies (French & Saulnier, 2000; NTP, 2007; Kawasaki et al., 2009).

4. Other Relevant Data

4.2. Leukaemogenic potential of benzene

Benzene is carcinogenic to the bone marrow causing leukaemia and myelodysplastic syndromes (MDS) and probably also to the lymphatic system causing non-Hodgkin lymphoma. Its carcinogenic mechanism of action is likely to be different for these two target tissues and probably multifactorial in nature. The metabolism of benzene will be summarized below and a review is presented of the current state of knowledge on the mechanisms of leukaemia and lymphoma induction by benzene. With regard to leukaemia, probable mechanisms of leukaemogenesis in the myeloid series, mainly acute myeloid leukaemia (AML) and MDS are discussed. Then, potential mechanisms by which benzene could cause acute lymphocytic leukaemia (ALL) in both adults and children are reviewed. Finally, mechanisms for the benzene-induced development of non-Hodgkin lymphoma are summarized, including that of chronic lymphocytic leukaemia (CLL), as it is now classified as a form of lymphoma.

4.2.1. Metabolism of benzene and its relevance to carcinogenicity

Benzene must be metabolized to become carcinogenic (Ross, 2000; Snyder, 2004). Its metabolism is summarized in Fig. 4.1. The initial metabolic step involves cytochrome P450 (CYP)-dependent oxidation to benzene oxide, which exists in equilibrium with its tautomer oxepin. Most benzene oxide spontaneously rearranges to phenol, which is either excreted or further metabolized to hydroquinone and 1,4-benzoquinone. The remaining benzene oxide is either hydrolysed to produce benzene 1,2-dihydrodiol (catechol), which is further oxidized to 1,2-benzoquinone, or it reacts with glutathione to produce S-phenylmercapturic acid. Metabolism of oxepin is thought to open the aromatic ring, to yield the reactive muconaldehydes and E,E-muconic acid. Human exposure to benzene at concentrations in air between 0.1 and 10 ppm, results in urinary metabolite profiles with 70–85% phenol, 5–10% each of hydroquinone, E,E-muconic acid and catechol, and less than 1% of S-phenylmercapturic acid (Kim et al., 2006b). Benzene oxide, the benzoquinones, muconaldehydes, and benzene dihydrodiol epoxides (formed from CYP-mediated oxidation of benzene dihydrodiol) are electrophiles that readily react with peptides, proteins and DNA (Bechtold et al., 1992; McDonald et al., 1993; Bodell et al., 1996; Gaskell et al., 2005; Henderson et al., 2005; Waidyanatha & Rappaport, 2005) and can thereby interfere with cellular function (Smith, 1996). It remains unclear what role these different metabolites play in the carcinogenicity of benzene, but benzoquinone formation from hydroquinone via myeloperoxidase in the bone marrow has been suggested as being a key step (Smith, 1996). There is considerable evidence for an important role of this metabolic pathway that leads to benzoquinone formation, as the benzoquinone-detoxifying enzyme NAD(P)H:quinone oxidoreductase1 (NQO1) protects mice against benzene-induced myelodysplasia (Long et al., 2002; Iskander & Jaiswal, 2005) and humans against the hematotoxicity of benzene (Rothman et al., 1997). However, this does not rule out adverse effects from other metabolites.

Fig. 4.1

Simplified metabolic scheme for benzene showing major pathways and metabolizing enzymes leading to toxicity. CYP2E1, cytochrome P450 2E1; GST, glutathione-S-transferase; NQO1, NAD(P)H:quinone oxidoreductase 1; MPO, myeloperoxidase; UDPGT, Uridine diphosphate (more...)

Increased susceptibility to the toxic effects of benzene has been linked to genetic polymorphisms that increase the rate of metabolism of benzene to active intermediates, or decrease the rate of detoxification of these active intermediates (Rothman et al., 1997; Xu et al., 1998; Kim et al., 2004).

Recently it has been shown that benzene is most likely metabolized initially to phenol and E,E-muconic acid via two enzymes rather than just one CYP enzyme, and that the putative, high-affinity enzyme is active primarily at benzene concentrations below 1 ppm (Rappaport et al., 2009). CYP2E1 is the primary enzyme responsible for mammalian metabolism of benzene at higher levels of exposure (Valentine et al., 1996; Nedelcheva et al., 1999). CYP2F1 and CYP2A13 are reasonable candidate enzymes that are active at environmental levels of exposure below 1 ppm (Powley & Carlson, 2000; Sheets et al., 2004; Rappaport et al., 2009). These CYPs are highly expressed in the human lung. Despite much research, more work is needed to elucidate the different roles of multiple metabolites in the toxicity of benzene and the pathways that lead to their formation.

A role for the aryl-hydrocarbon receptor (AhR) is also emerging in the haematotoxicity of benzene. AhR is known mainly as the mediator for the toxicity of certain xenobiotics (Hirabayashi & Inoue, 2009). However, this transcription factor has many important biological functions and evidence is emerging that it has a significant role in the regulation of haematopoietic stem cells (Hirabayashi & Inoue, 2009; Singh et al., 2009). It has been hypothesized that AhR expression is necessary for the proper maintenance of quiescence in these cells, and that AhR downregulation is essential for their “escape” from quiescence and subsequent proliferation (Singh et al., 2009). It has been demonstrated that AhR-knockout (KO) (AhR^−/−) mice do not show any haematotoxicity after exposure to benzene (Yoon et al., 2002). Follow-up studies have shown that mice that had been lethally irradiated and repopulated with marrow cells from AhR-KO mice did not display any sign of benzene-induced haematotoxicity (Hirabayashi et al., 2008). The most likely explanation for these findings is that the absence of AhR removes haematopoietic stem cells from their quiescent state and makes them susceptible to DNA damage from benzene exposure and subsequent cell death through apoptosis. Further research is needed to examine the effects of benzene and its metabolites on cycling and quiescent haematopoietic stem cells.

4.2.2. Mechanisms of myeloid leukaemia development

(a) General

AML and MDS are closely-related diseases of the bone marrow that arise de novo (without an obvious cause) in the general population or following therapy with alkylating agents, topoisomerase II inhibitors, or ionizing radiation (therapy-related AML and MDS, i.e. t-AML and t-MDS) (Pedersen-Bjergaard et al., 2006, 2008). Occupational exposure to benzene is widely thought to cause leukaemias that are similar to various forms of t-AML and t-MDS (Irons & Stillman, 1996; Larson & Le Beau, 2005; Zhang et al., 2007). AML and MDS both arise from genetically altered CD34+ stem cells or progenitor cells in the bone marrow (Morgan & Alvares, 2005; Passegué & Weisman, 2005) and are characterized by many different types of recurrent chromosome aberrations (Pedersen-Bjergaard et al., 2006; Mrózek & Bloomfield, 2008). These aberrations have been shown to often develop into the genetic mutations that produce leukaemia. Cytogenetic analysis of chromosome number and structure has therefore become important in diagnosis and treatment of MDS and AML (Pedersen-Bjergaard et al., 2006; Mrózek & Bloomfield, 2008). Recent research has shown that the chromosome aberrations and gene mutations detected in therapy-related and de novo MDS and AML are identical, although the frequencies with which they are observed in different subtypes may differ (Pedersen-Bjergaard et al., 2008). Hence, therapy-related and de novo MDS and AML are considered identical diseases (Pedersen-Bjergaard et al., 2008).

At least three cytogenetic categories of AML and MDS are commonly observed: those with unbalanced aberrations, with balanced rearrangements, and with normal karyotype:

Unbalanced chromosome aberrations comprise primarily the loss of various parts of the long arm or loss of the whole chromosome 5 or 7 (5q–/–5 or 7q–/–7) and gain of a whole chromosome 8 (+8) (Pedersen-Bjergaard et al., 2006, 2007, 2008). These cases often have a complex karyotype and carry point mutations of TP53 or AML1. Unbalanced chromosome aberrations are common after therapy with alkylating agents.

Balanced rearrangements are recurrent balanced translocations [e.g. t(11q23), t(8;21) and t(15;17)] or inversions [e.g. inv(16)], which arise, at least in the therapy-related subset of cases, as illegitimate gene recombinations related to functional inhibition of topoisomerase II (Pedersen-Bjergaard et al., 2006, 2008). Among the most important rearranged transcription-factor genes are the mixed-lineage leukaemia (MLL) at 11q23, the AML1 at 21q22, the retinoic-acid receptor-α RARA at 17q21 and the core-binding factor subunit-β (CBFB) at 16q22 (Pedersen-Bjergaard et al., 2007).

Cases with a normal karyotype often harbour mutations of the NPM1 gene (which encodes nucleophosmin), internal tandem duplications of the FLT3 gene (which encodes fms-related tyrosine kinase), and/or point mutations or an altered methylation status of the C/EBPα gene (which encodes CCAAT/enhancer binding protein α) (Cuneo et al., 2002; Pedersen-Bjergaard et al., 2006, 2007, 2008; Hackanson et al., 2008).

Within these three cytogenetic categories there are at least eight different genetic pathways that lead to MDS and AML, as defined by the specific chromosome aberrations present in each (Pathways I –VIII in Fig. 4.2). As more becomes clear about the molecular cytogenetics of leukaemia, it seems likely that many other pathways to AML and MDS will be discovered. For example, recent unbiased high-resolution genomic screens have identified many genes not previously implicated in AML that may be relevant for pathogenesis, along with many known oncogenes and tumour-suppressor genes (Ley et al., 2008; Mardis et al., 2009; Walter et al., 2009).

Fig. 4.2

Genetic Pathways to Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia

Another classical pathway to AML is through the transformation of a myeloproliferative disorder (MPD) (Abdulkarim et al., 2009), although there is less evidence for this pathway as a relevant mechanism to benzene-induced AML. MPDs include Philadelphia chromosome (Ph)-positive chronic myelogenous leukaemia (CML) and the Ph-negative conditions polycythemia vera, essential trombocythemia and idiopathic myelofibrosis. It is well established that AML may occur as a late complication in all these disorders. Over the first ten years after diagnosis, the incidence of leukaemic transformation is reported to be higher in patients with idiopathic myelofibrosis (8–23%) compared with patients with essential trombocythemia (0.5–1%) and polycythemia vera (1–4%) (Abdulkarim et al., 2009). Thus, benzene may first produce an MPD, which later transforms into AML.

An important role for epigenetic changes is also emerging in association with the development of leukaemia. Functional loss of the CCAAT/enhancer binding protein α (C/EBPα) (also known as CEBPA), a central regulatory transcription factor in the haematopoietic system, can result in a differentiation block in granulopoiesis and thus contribute to leukaemic transformation (Fröhling & Döhner, 2004). Recent work has shown that epigenetic alterations of C/EBPα occur frequently in AML and that C/EBPα mRNA is a target for miRNA-124a (Hackanson et al., 2008). This miRNA is frequently silenced by epigenetic mechanisms in leukaemia cell lines. C/EBPα is also capable of controlling miRNA-223 expression, which is vital in granulocytic differentiation (Fazi et al., 2005). Altered expression of several miRNAs is also observed in some forms of AML (Dixon-McIver et al., 2008; Marcucci et al., 2008).

(b) Mechanisms of benzene-induced myeloid leukaemia development

There is strong evidence that benzene can induce AML via pathways I, II and IV, considerable supporting evidence for pathway V, some evidence for pathway III, but little information regarding pathways VI–VIII (see Fig. 4.2). Exposure to benzene has been associated with higher levels of the chromosomal changes commonly observed in AML, including 5q–/–5 or 7q–/–7, +8, and t(8;21) in the blood cells of highly exposed workers (Smith et al., 1998; Zhang et al., 1999, 2002). The benzene metabolite hydroquinone produces these same changes in cultured human cells, including cultures of CD34+ progenitor cells (Smith et al., 2000; Stillman et al., 2000). This provides strong evidence for the induction by benzene of AML via pathways I, II and IV (see Fig. 4.2).

Pathways III, IV and V are related to the inhibition of the DNA-related enzyme topoisomerase II, which is essential for the maintenance of proper chromosome structure and segregation; it removes knots and tangles from the genetic material by passing an intact double helix through a transient double-stranded break that it creates in a separate segment of DNA (McClendon & Osheroff, 2007; Bandele & Osheroff, 2009). To maintain genomic integrity during its catalytic cycle, topoisomerase II forms covalent bonds between active-site tyrosyl residues and the 5′-DNA termini created by cleavage of the double helix (Bandele & Osheroff, 2009). Normally, these covalent topoisomerase II-cleaved DNA complexes (known as cleavable complexes) are fleeting intermediates and are tolerated by the cell. However, when the concentration or longevity of cleavage complexes increases significantly, DNA double-strand breaks occur (Lindsey et al., 2004). If topoisomerase II–induced double-strand breaks are incorrectly repaired, two unrelated (nonhomologous) chromosomes are fused together to produce translocations or inversions (Deweese & Osheroff, 2009).

There are different types of topoisomerase-II inhibitors. Epidophyllotoxins, such as etoposide, cause chromosome damage and kill cells by increasing physiological levels of topoisomerase II-DNA cleavage complexes (Baker et al., 2001; Felix, 2001; Deweese & Osheroff, 2009). These drugs are referred to as topoisomerase-II poisons to distinguish them from catalytic inhibitors of the enzyme because they convert this essential enzyme to a potent cellular toxin. Other drugs, such as merbarone, act as inhibitors of topo-II activity but, in contrast to etoposide they do not stabilize topoisomerase II-DNA cleavable complexes. Nevertheless, they are potent clastogens both in vitro and in vivo (Wang et al., 2007).

Several studies have shown that benzene in vivo, and its reactive metabolites hydroquinone and 1,4-benzoquinone in vitro, inhibit the functionality of topoisomerase II and enhance DNA cleavage (Chen & Eastmond, 1995; Frantz et al., 1996; Hutt & Kalf, 1996; Eastmond et al., 2001; Fung et al., 2004; Lindsey et al., 2004, 2005; Whysner et al., 2004). Bioactivation of hydroquinone by myeloperoxydase to 1,4-benzoquinone enhances topoisomerase-II inhibition (Eastmond et al., 2005). Indeed, 1,4-benzoquinone was shown to be a more potent topoisomerase-II inhibitor than hydroquinone in a cell-free assay system (Hutt & Kalf, 1996; Baker et al., 2001). These findings demonstrate that benzene through its reactive quinone metabolites can inhibit topoisomerase II and probably cause leukaemias with chromosome translocations and inversions known to be generated by topoisomerase-II inhibitors, including AMLs harbouring t(21q22), t(15;17) and inv(16) in a manner consistent with pathways IV and V (Andersen et al., 2002; Voltz et al. 2004; Mistry et al., 2005; Pedersen-Bjergaard et al., 2007, 2008). The evidence for rearrangements of the mixed lineage leukaemia (MLL) gene through t(11q23) via pathway III in benzene-induced leukaemia is less convincing but may occur through an apoptotic pathway (Vaughan et al., 2005).

AML can arise de novo via pathways VII and VIII without apparent chromosome abnormalities, but molecular analysis has revealed many genetic changes in these apparently normal leukemias, including mutations of NPM1, AML1, FLT3, RAS and C/EBPα. (Fig. 4.2; Cuneo et al., 2002; Falini et al., 2007; Mardis et al., 2009). More work is needed to clarify the ability of benzene and its metabolites to produce mutations of the type found in these leukaemias, along with those found in Ph-negative MPDs such as Janus kinase 2 (JAK2), and somatic mutations in the ten-eleven translocation 2 (TET2) oncogene, which are found in about 15% of patients with various myeloid cancers (Delhommeau et al., 2009). One potential mechanism for the induction of such mutations is through the generation of reactive oxygen species.

The ability of benzene and/or its metabolites to induce epigenetic changes related to the development of leukaemia, such as altered methylation status of C/EBPα, is unclear at this time. Bollati et al. (2007) reported that hypermethylation in p15 (+0.35%; P = 0.018) and hypomethylation in the MAGE-1 gene (encoding the human melanoma antigen) (−0.49%; P = 0.049) were associated with very low exposures to benzene (~22 ppb) in healthy subjects including gas-station attendants and traffic-police officers, although the corresponding effects on methylation were very low. Further study of the role epigenetics in the haematotoxicity and carcinogenicity of benzene is warranted, including studies of aberrant DNA methylation and altered microRNA expression.

While benzene and its metabolites are clearly capable of producing multiple forms of chromosomal mutation, including various translocations, deletions and aneuploidies, these are usually insufficient as a single event to explain the induction of leukaemia (Guo et al., 2008; Lobato et al., 2008). Other secondary events, such as specific gene mutations and/or other chromosome changes, are usually required (Guo et al., 2008; Lobato et al., 2008). Thus, benzene-induced leukaemia probably begins as a mutagenic event in the stem cell or progenitor cell and subsequent genomic instability allows for sufficient mutations to be acquired in a relatively short time. Studies have shown that the benzene metabolite hydroquinone is similar to ionizing radiation in that it induces genomic instability in the bone marrow of susceptible mice (Gowans et al., 2005). Recent findings showing the importance of genes involved in DNA repair and maintenance – such as the WRN gene encoding the Werner syndrome protein – in determining genetic susceptibility to the toxicity of benzene also support this mechanism (Shen et al., 2006; Lan et al., 2009; Ren et al., 2009).

Haematotoxic effects may also contribute to leukaemogenesis from benzene. Haematopoietic stem cells occupy an ordered environment in the bone marrow and interact with supportive stromal cells and mature lymphocytes. Haematotoxic damage to this ordered stem-cell microenvironment most likely allows for the clonal expansion of the leukaemic stem cells. This dual mode of action for benzene fits with the known ability of benzene metabolites to induce chromosomal mutations and genomic instability in blood stem cells and progenitor cells, and with the fact that haematotoxicity is associated with an increased risk for benzene-induced haematopoietic malignancies (Rothman et al., 1997).

Thus, exposure to benzene can lead to multiple alterations that contribute to the leukaemogenic process. Benzene may act by causing chromosomal damage (aneuploidy, deletions and translocations) through inhibition of topoisomerase II, disruption of microtubules and other mechanisms; by generating oxygen radicals that lead to point mutations, strand breaks and oxidative stress; by causing immune system dysfunction that leads to decreased immunosurveillance (Cho, 2008; Li et al., 2009); by altering stem-cell pool sizes through haematotoxic effects (Irons et al., 1992); by inhibiting gap-junction intercellular communication (Rivedal & Witz, 2005); and by altering DNA methylation and perhaps specific microRNAs. This multimodal mechanism of action for benzene suggests that the effects of benzene on the leukaemogenic process are not singular and can occur throughout the process.

4.2.3. Potential mechanisms of benzene-induced acute lymphocytic leukaemia (ALL) development

Evidence of an association between exposure to benzene from air pollution and childhood leukaemia is growing. The most common form of childhood leukaemia is ALL, with AML being less common at around 15% of the incidence of ALL. The opposite is true for adults where the ratio is reversed, with AML being predominant. Reasons for this difference were suggested to be age-related defects in lymphopoiesis (Signer et al., 2007). Studies with a murine model of chronic myeloid leukaemia – an adult-onset malignancy that arises from transformation of haematopoietic stem cells by the breakpoint cluster region-Ableson (BCR-ABL^P210) oncogene – demonstrated that young bone-marrow cells transformed with BCR-ABL^P210 initiated both MPD and B-lymphoid leukaemia, whereas BCR-ABL^P210-transformed old bone-marrow cells recapitulated the human disease by inducing MPD with rare lymphoid involvement (Signer et al., 2007). Thus, if benzene were to induce a leukaemia-related oncogenic mutation in young bone-marrow cells, it could produce either an MPD that transformed to AML, or a B-cell ALL, whereas exposure in an adult would have only a very limited chance of producing ALL.

The long-standing distinction between AML and ALL also has become somewhat blurred in recent years. Both forms of leukaemia arise in pluripotential stem cells or early progenitor cells in the bone marrow. Either disease can occur under conditions that formerly seemed restricted to AML. These include ALL occurring in the acute leukaemia seen in Down Syndrome (Kearney et al., 2009); in secondary leukaemias related to chemotherapy (Lee et al., 2009); and in the blast crisis of chronic myelogenous leukaemia (Calabretta & Perrotti, 2004). Similarly, the Philadelphia chromosome, long considered to be specific to chronic myelogenous leukaemia, is also the most common chromosome rearrangement in adult ALL (Ravandi & Kebriaei, 2009).

Since the genotoxic action of benzene metabolites on pluripotent precursor cells in the bone marrow appears promiscuous, producing multiple genetic abnormalities, it seems probable that exposure to benzene can initiate both AML and ALL by causing the chromosomal rearrangements and mutations that are on the causal pathway to these malignancies. For childhood ALL and AML it has been shown that the disease is usually initiated in utero, since leukaemic translocations and other genetic changes have been detected in blood spots collected at birth (Wiemels et al., 1999; Wiemels et al., 2002; Greaves & Wiemels, 2003; McHale et al., 2003). Thus, exposure of the mother, and perhaps even the father, to benzene could be just as important as exposure of the child in producing childhood AML and ALL, as has been suggested in several epidemiological studies (van Steensel-Moll et al., 1985; McKinney et al., 1991; Shu et al., 1999; Scélo et al., 2009). Supporting this hypothesis is an animal study demonstrating that in utero exposure to benzene increases the frequency of micronuclei and DNA recombination events in haematopoietic tissue of fetal and post-natal mice (Lau et al., 2009). Another study showed that oxygen radicals play a key role in the development of in utero-initiated benzene toxicity through disruption of haematopoietic cell-signalling pathways (Badham & Winn, 2010). These studies support the idea that genotoxic and non-genotoxic events following exposure to benzene may be initiators of childhood leukaemia in utero.

4.2.4. Mechanisms of lymphoma development

(a) General

Lymphoma is a cancer of the immune system that includes over 40 malignant diseases originating from B- and T-lymphocytes and natural killer (NK) cells (Swerdlow et al., 2008). It is therefore not surprising that functional disorders of immune-system cells are associated with a risk for malignant transformation. Immune deficiency is one of the strongest known risk factors for non-Hodgkin lymphoma (NHL) (Hartge & Smith, 2007). The risk for NHL increases with the degree of immune deficiency, and there is no evidence of a threshold (Grulich et al., 2007). Thus, even modest immunosuppression, especially at the local level, may increase the risk for lymphoma.

It is well recognized that lymphomas, like other tumours, develop according to a multistep pathogenic process (Smith et al., 2004). Clonal progression of an initiated cell to a clone of highly malignant cells is well documented. Natural selection of clones already present within oligoclonal expansions gives rise to true monoclonal lymphomas. Thus, it is possible to make generalizations about the type of molecular mechanism responsible for each of the stages involved in lymphomagenesis. For example, a cell may become initiated and genetically unstable through errors in recombination and DNA repair, which could be spontaneous or induced by an exogenous chemical agent. Other early molecular events often inhibit apoptosis and lead to the expansion of an intrinsically genetically unstable population of cells, which is at risk for additional genetic events and tumour progression. An example is the t(14;18) chromosome translocation associated with B-cell lymphoma 2 gene BCL2 dysregulation, which inhibits apoptosis (Cimmino et al., 2005; Thomadaki & Scorilas, 2006). Normally, one of the key protectors against the selection and progression of malignant clones of cells into full-blown lymphoma is local immunosurveillance in which activated T-cells kill the mutated clones. It is generally accepted that if this immunosurveillance is no longer intact, e.g. in immuno-suppressed individuals, then the malignant cells divide and grow rapidly, collecting more mutations to become aggressive, rapidly growing tumours.

(b) Mechanisms of benzene-induced lymphoma development

From the discussion above, there are at least two probable mechanisms by which exposure to benzene could enhance the incidence of lymphoma, i.e. by inducing chromosome rearrangements associated with NHL, and through immunosuppression leading to decreased immunosurveillance.

Benzene is well known to produce multiple cytogenetic abnormalities in lymphocytes (Tough & Brown, 1965; Forni, 1971, 1979; Picciano, 1979; Smith & Zhang, 1998; Zhang et al., 2002). Further, benzene induces specific chromosomal changes associated with NHL in human lymphocytes (Zhang et al., 2007). Fluorescence in situ hybridization (FISH) analysis showed increased levels of t(14;18) and del(6q) in benzene-exposed workers, but the higher levels of t(14;18) could not be confirmed in a follow-up study by use of real time-PCR (polymerase chain reaction) (McHale et al., 2008). This may be because the PCR method only detected 50% of t(14;18) translocations or that the FISH method detects non-functional as well as functional translocations. Reduced immunosurveillance is another potential mechanism of NHL induction by benzene. The importance of T-cell immunosurveillance in preventing B-cell neoplasia is well established and is carried out by activated cytotoxic T lymphocytes. The toxic effects of benzene on T-cells is well documented and there appears to be a selective effect on CD4⁺ T-lymphocytes resulting in a lowering of the CD4⁺/CD8⁺ ratio (Lan et al., 2004). This immunosuppressive pattern is similar to the early onset of acquired immuno-deficiency syndrome (AIDS), and although it is not as severe it may be associated with an increased risk for NHL (Grulich et al., 2007). Thus, benzene, like other leukaemogens including alkylating agents, topoisomerase inhibitors, and ionizing radiation, may cause NHL through a combination of immunosuppression and DNA double-strand break induction that leads to illegitimate recombination and chromosome rearrangements in lymphoid cells.

Thus, the biological plausibility of benzene as a cause of lymphoproliferative disorders has been strengthened in recent years. There are additional studies demonstrating that benzene produces lymphomas in laboratory animals, and a recent study showing that it does so simultaneously with AML in Tp53-deficient mice (Kawasaki et al., 2009). Multiple studies show that it produces genotoxicity in the lymphocytes of exposed humans. Accordingly, there is considerable support for the notion that it is biologically plausible for benzene to cause human lymphatic tumours.

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of benzene. Benzene causes acute myeloid leukaemia/acute non-lymphocytic leukaemia.

Also, a positive association has been observed between exposure to benzene and acute lymphocytic leukaemia, chronic lymphocytic leukaemia, multiple myeloma, and non-Hodgkin lymphoma.

There is sufficient evidence for the carcinogenicity of benzene in experimental animals.

There is strong evidence that benzene metabolites, acting alone or in concert, produce multiple genotoxic effects at the level of the pluripotent haematopoietic stem cell resulting in chromosomal changes in humans consistent with those seen in haematopoietic cancer. In multiple studies in different occupational populations in many countries over more than three decades a variety of genotoxic changes, including chromosomal abnormalities, have been found in the lymphocytes of workers exposed to benzene.

Benzene is carcinogenic to humans (Group 1).

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