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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Chemical Agents and Related Occupations. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 100F.)

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Chemical Agents and Related Occupations.

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Benzene was considered by previous IARC Working Groups in 1981 and 1987 (IARC, 1982, 1987). Since that time new data have become available, which have been incorporated in this Monograph, and taken into consideration in the present evaluation.

1. Exposure Data

1.1. Identification of the agent

  • Chem. Abstr. Serv. Reg. No.: 71–43–2
  • Chem. Abstr. Serv. Name: Benzene
  • IUPAC Systematic Name: Benzene
  • Image 978-9283201380-C024-F001.jpg
  • C6H6
  • Relative molecular mass: 78.1
  • From O’Neil (2006) and Lide (2008), unless otherwise stated
  • Description: Clear, colourless, volatile, highly flammable liquid
  • Solubility: Slightly soluble in water; miscible with acetone, chloroform, diethyl ether and ethanol; soluble in carbon tetrachloride
  • Octanol/water partition coefficient: log Kow, 2.13 (Hansch et al., 1995)
  • Conversion factor: ppm = 0.313 × mg/m3

1.2. Uses

Historically, benzene has been used as a component of inks in the printing industry, as a solvent for organic materials, as starting material and intermediate in the chemical and drug industries (e.g. to manufacture rubbers, lubricants, dyes, detergents, pesticides), and as an additive to unleaded gasoline (NTP, 2005; ATSDR, 2007; Williams et al., 2008).

The primary use of benzene today is in the manufacture of organic chemicals. In Europe, benzene is mainly used to make styrene, phenol, cyclohexane, aniline, maleic anhydride, alkylbenzenes and chlorobenzenes. It is an intermediate in the production of anthraquinone, hydroquinone, benzene hexachloride, benzene sulfonic acid and other products used in drugs, dyes, insecticides and plastics (Burridge, 2007). In the United States of America, the primary use of benzene is in the production of ethylbenzene, accounting for 52% of the total benzene demand in 2008. Most ethylbenzene is consumed in the manufacture of styrene, which is used in turn in polystyrene and various styrene copolymers, latexes and resins. The second-largest use of benzene in the United States of America (accounting for 22% of demand) is in the manufacture of cumene (isopropylbenzene), nearly all of which is consumed in phenol production. Benzene is also used to make chemical intermediates: cyclohexane, used in making certain nylon monomers (15%); nitrobenzene, an intermediate for aniline and other products (7%); alkylbenzene, used in detergents (2%); chlorobenzenes, used in engineering polymers (1%); and miscellaneous other uses (1%) (Kirschner, 2009). Benzene occurs naturally in petroleum products (e.g. crude oil and gasoline) and is also added to unleaded gasoline for its octane-enhancing and anti-knock properties. Typically, the concentration of benzene in these fuels is 1–2% by volume (ATSDR, 2007).

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).

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 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 Americaa.

Table 1.3

Typical benzene exposure levels in different occupational groups/areas in Europe and North Americaa.

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.

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.

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 benzenea.

Table 1.5

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

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.]

2.1. Leukemias and lymphomas

2.1.1. Acute non-lymphocytic leukaemia/acute myelogenous leukaemia

Since 1987, additional analyses of previously published cohort studies (e.g. results in Crump (1994) and Wong (1995), based on the cohort study described in Infante et al. (1977) and Rinsky et al. (1981, 1987), which reported an excess risk for combined (mostly acute) myelogenous and monocytic leukaemia) and new cohort studies with quantitative data on benzene exposure have shown evidence of a dose–response relationship between exposure to benzene and risk for ANLL/AML in various industries and in several countries (Hayes et al., 1997; Rushton & Romaniuk, 1997; Divine et al., 1999b; Guénel et al., 2002; Collins et al., 2003; Glass et al., 2003; Bloemen et al., 2004; Gun et al., 2006; Kirkeleit et al., 2008; see Table 2.1 available at It was also noted that the NCI-CAPM cohort study found evidence of an increased risk for the combined category of ANLL and myelodysplastic syndromes (Hayes et al., 1997). Case–control studies do not add substantively to these conclusions (see Table 2.2 available at In one case–control study an increased risk for childhood ANLL was found for maternal self-reported occupational exposure to benzene (Shu et al., 1988; see Table 2.1 online). One case–control study of childhood cancer in Denmark did not find an association of estimates of environmental benzene exposure from air pollution with an increased risk for ANLL (Raaschou-Nielsen et al., 2001).

2.1.2. Acute lymphocytic leukaemia

Acute Lymphocytic Leukaemia (ALL) is now considered one subtype of NHL in the WHO-classification of lymphomas. In multiple cohorts there was a non-significantly increased risk for ALL, but the numbers of cases were small (Rushton, 1993; Wong et al., 1993; Satin et al., 1996; Divine et al., 1999b; Lewis et al., 2003; Kirkeleit et al., 2008; Yin et al., 1996; Guénel et al., 2002; Gun et al., 2006; see Table 2.3 available at [The Working Group noted that the magnitude of the risk-estimate in the NCI-CAPM cohort (Yin et al., 1996) was similar to the risk observed for ANLL in the same study, which was statistically significant. This approach has been suggested when attempting to interpret the association between occupational exposure to benzene and hematological subtypes that are less common than AML (Savitz & Andrews, 1997).]

In one case–control study in adults in Shanghai, a significant increased risk for ALL was found for the group with 15 or more years of self-reported occupational exposure to benzene (Adegoke et al., 2003); another study in the USA had only three exposed cases (Blair et al., 2001; Table 2.4 available at In a case–control study of childhood ALL no association was found with maternal self-reported occupational exposure to benzene, but a borderline significant association was noted with exposure to gasoline (Shu et al., 1988; see Table 2.4 online). No association with self-reported maternal exposure to benzene was found in a large study of childhood ALL in the USA (Shu et al., 1999; see Table 2.4 online). A case-control study of childhood cancer in Denmark did not find an association of estimated environmental exposure to benzene from air pollution with ALL (Raaschou-Nielsen et al., 2001).

2.1.3. Chronic myelogenous leukaemia

Several studies in the petroleum industry and in other settings show non-significantly increased risks for CML, whereas other studies show no evidence of an association, including two that had quantitative estimates of exposure to benzene but no dose–response relationship (Rushton & Romaniuk, 1997; Guénel et al., 2002; see Table 2.5 available at Case–control studies have shown inconsistent results, with both increased risks (exposure for > 15 years was associated with an OR of 5.0 (1.8–13.9; Adegoke et al., 2003) and no increase in risk (Björk et al., 2001) reported (see Table 2.6 available at

2.1.4. Chronic lymphocytic leukaemia

Chronic Lymphocytic Leukaemia (CLL) – also referred to as small lymphocytic lymphoma (SLL) – is now considered as a subtype of NHL in the WHO-classification of lymphomas. CLL can be an indolent disease of the elderly, which raises questions about cohorts that are not followed up until the study population is relatively old and about studies that use mortality instead of incident data. In addition, the diagnosis of CLL was less frequently made in the past, until complete blood counts were routinely obtained in recent decades.

Several cohort studies in the petroleum industry showed mixed results, with some non-significantly increased risks reported and other studies showing no association (see Table 2.7 available at In a nested case–control study in the Australian petroleum industry an increasing risk for CLL was detected with increasing exposure to benzene over a relatively small range of ppm–years, but the increase was not significant (Glass et al., 2003). Similarly, in a nested case–control study within a cohort of French gas and electrical utility workers, a non-significant increase in risk with increasing years of benzene exposure was detected (Guénel et al., 2002). Some evidence of risk with increasing benzene exposure was also found in a cohort study among petroleum workers in the United Kingdom, but the trends were not clear and interpretation is difficult as white- and blue-collar workers were mixed in the analysis and interactions may have been present (Rushton & Romaniuk, 1997). Updates of two cohort studies in the Southern US found an increased risk for CLL, which was significant in one cohort for workers hired before 1950, but not in the other (Huebner et al., 2004).

A case–control study in Italy showed evidence of a dose–response relationship between the extent of benzene exposure with the number of years worked with benzene (Costantini et al., 2008) and in a large multicentre international study in Europe a significant excess in risk for CLL was found with increasing exposure to benzene, but the dose–response was not significant (Cocco et al., 2010; see Table 2.8 available at Blair et al. (2001) conducted a study in the Midwestern USA and found no association with benzene exposure although there were only three cases in the high-exposure category. In a study of women in Connecticut, a non-significantly increased risk for CLL was found with increasing exposure to benzene (Wang et al., 2009; see Table 2.8 online).

2.1.5. Non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of histological subtypes, and the definition of both NHL and its subtypes has evolved over the last several decades with the application and discontinuation of several classification schemes, which complicates the assessment of exposure to benzene and risk for NHL. For example, CLL – now classified by the WHO as a subtype of NHL – has generally not been combined with other types of NHL in reports from cohort studies of benzene-exposed workers or in earlier case–control studies of NHL. Further, given the indolent nature of some NHL subtypes, cohorts with only mortality data may underestimate associations with NHL. In most cohort studies an increased risk for NHL was not detected, one particular exception being the NCI-CAPM cohort study in China (Hayes et al., 1997; Table 2.9 available at An excess of NHL was not detected in the Pilofilm cohort (Rinsky et al., 2002) or in the Australian Health Watch study in an analysis of NHL combined with multiple myeloma (two-thirds of which were NHL cases) (Glass et al., 2003).

Of 14 independent case–control studies that were considered informative, five showed evidence of increased risk with benzene exposure, two (Fabbro-Peray et al., 2001; Dryver et al., 2004) for NHL as a whole (Table 2.10 available at Data on histological subtypes of NHL have generally not been reported in publications of occupational cohort studies of benzene-exposed workers, but they have been mentioned in some case–control studies. For various benzene-exposure metrics, slightly increased, but non-significant risks for NHL were found in a case–control study among women in Connecticut, as well as higher risks – also non-significant – for follicular lymphoma and diffuse large B-cell lymphoma (DLBCL), two common NHL subtypes (Wang et al., 2009). Cocco et al. (2010) conducted an analysis of a large multicentre case–control study of NHL in Europe and found no significant increase in risk for B-cell NHL or DLBCL, but an elevated risk, albeit not statistically significant, for follicular lymphoma associated with exposure to benzene (see Table 2.10 online), and a significant association between combined exposure to benzene/toluene/xylene and follicular lymphoma. Other case–control studies showed increased, non-significant risks for one or both of these histological subtypes, and in one study in Italy a significant association was found between medium/high exposure to benzene and the risk for diffuse lymphoma (Miligi et al., 2006; OR = 2.4, 95%CI: 1.3–1.5).

2.1.6. Multiple myeloma

Most cohort studies showed no association with multiple myeloma (MM) (Table 2.11 available at However, there was a statistically significant excess of MM reported for the Pliofilm cohort (SMR 4.1; 95%CI: 1.1–10.5, based upon four deaths) (Rinsky et al., 1987), which did not persist in the most recent update (Rinsky et al., 2002; see Table 2.11 online). In a cohort study among chemical workers at the Monsanto chemical company suggestive evidence was found of a dose–response relationship (Collins et al., 2003), while in a cohort study of Norwegian workers in the upstream petroleum industry (i.e. the phases of oil extraction and initial transportion, which entail extensive exposure to crude oil) a significant increased risk for MM was found (Kirkeleit et al., 2008).

Case–control studies of MM with estimates of exposure to benzene largely show no association (Table 2.12 available at An exception was an early study in which a significant association was found between risk for MM and the proportion of cases and controls with “solvent/benzene” exposure (La Vecchia et al., 1989). In another study, borderline significant effects were detected (Costantini et al., 2008). In a large multicentre case–control study of NHL in Europe there was no association of benzene exposure with MM (Cocco et al., 2010).

A meta-analysis by Infante (2006) analysed data from seven well defined “benzene cohorts” outside of petroleum refining and found a statistically significant increase in risk for MM (RR 2.1; 95%CI: 1.3–3.5).

2.1.7. Hodgkin disease

There are sparse data on Hodgkin disease in studies of benzene-exposed cohorts, with most studies having very small numbers of cases and showing no association (see Table 2.13 available at Overall, there is no evidence of an increased risk. The relatively few case–control studies in adults also show no association (see Table 2.14 available at In a case–control study of childhood cancer in Denmark, an increased risk for Hodgkin disease was detected in association with estimated environmental exposures to benzene (Raaschou-Nielsen et al. (2001) (see Table 2.14 online).

2.2. Cancer of the lung

Cohort studies with information on potential or estimated benzene exposure and lung cancer are shown in Table 2.15 (available at Although most studies show no association, in two cohorts with quantitative exposure-assessment evidence of a dose–response relationship was found (Hayes et al., 1996; Collins et al., 2003) and in two others statistically significant increases in risk were observed (Lynge et al., 1997; Sorahan et al., 2005). A case–control study from Canada showed no association of exposure to benzene with lung cancer overall or with the major histological subtypes (Gérin et al., 1998; see Table 2.16 available at

2.3. Cancer of the kidney

Cohort studies with results on kidney cancer are shown in Table 2.17 (available at Results generally do not show any association. In a case–control study among males in Germany an association was found between exposure to benzene and an increased risk for kidney cancer (Pesch et al., 2000), but in a study in Montreal, Canada, there was little evidence of an association (Gérin et al., 1998) (see Table 2.18 available at

2.4. Other cancers

In the evaluation of the cohort studies that provided data on the cancer sites considered above, it was apparent that associations have occasionally been found with other cancer sites including malignant melanoma (Schnatter et al., 1996; Consonni et al., 1999; Lewis et al., 2003), nose and stomach cancer (Fu et al., 1996) and prostate cancer (Collingwood et al., 1996), but overall there was no consistency across the cohorts.

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 3.1

Carcinogenicity studies in experimental animals exposed to benzene by inhalation.

Table 3.2. Carcinogenicity studies in experimental animals exposed to benzene by gavage.

Table 3.2

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 3.3

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 .

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

4.1. Genetic and related effects

Benzene induced chromosomal aberrations, micronuclei and sister chromatid exchange in bone-marrow cells of mice, chromosomal aberrations in bone-marrow cells of rats and Chinese hamsters and sperm-head anomalies in mice treated in vivo. It induced chromosomal aberrations and mutation in human cells in vitro but did not induce sister chromatid exchange in cultured human lymphocytes, except in one study in which high concentrations of an exogenous metabolic system were used. In some test systems, benzene induced cell transformation. It did not induce sister chromatid exchange in rodent cells in vitro, but it did induce aneuploidy and, in some studies, chromosomal aberrations in cultured Chinese hamster ovary cells. Benzene induced mutation and DNA damage in some studies in rodent cells in vitro. In Drosophila, benzene was reported to be weakly positive in assays for somatic mutation and for crossing-over in spermatogonia; in single studies, it did not induce sex-linked recessive lethal mutations or translocations. It induced aneuploidy, mutation and gene conversion in fungi. Benzene was not mutagenic to bacteria (IARC, 1982, 1987). Chromosomal aberrations in human peripheral lymphocytes have been associated with occupational exposure to benzene for decades (Forni, 1979; IARC, 1982; Eastmond, 1993; Zhang et al., 2002; Holecková et al., 2004).

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.

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

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-ABLP210) oncogene – demonstrated that young bone-marrow cells transformed with BCR-ABLP210 initiated both MPD and B-lymphoid leukaemia, whereas BCR-ABLP210-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).


  • Abdulkarim K, Girodon F, Johansson P, et al. AML transformation in 56 patients with Ph- MPD in two well defined populations. Eur J Haematol. 2009;82:106–111. [PubMed: 19134023] [CrossRef]
  • Adegoke OJ, Blair A, Shu XO, et al. Occupational history and exposure and the risk of adult leukemia in Shanghai. Ann Epidemiol. 2003;13:485–494. [PubMed: 12932623] [CrossRef]
  • Andersen MK, Larson RA, Mauritzson N, et al. Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002;33:395–400. [PubMed: 11921273] [CrossRef]
  • ATSDR (1997). Toxicological Profile for Benzene. Update (Final Report), (NTIS Accession No. PB98–101157). Atlanta, GA: Agency for Toxic Substances and Disease Registry, pp. 459 .
  • ATSDR (2007). Toxicological Profile for Benzene. Atlanta, GA: Agency for Toxic Substances and Disease Registry, pp. 438 .
  • Badham HJ, Winn LM. In utero exposure to benzene disrupts fetal hematopoietic progenitor cell growth via reactive oxygen species. Toxicol Sci. 2010;113:207–215. [PubMed: 19812361] [CrossRef]
  • Baker RK, Kurz EU, Pyatt DW, et al. Benzene metabolites antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase IIalpha. Blood. 2001;98:830–833. [PubMed: 11468185] [CrossRef]
  • Bandele OJ, Osheroff N. Cleavage of plasmid DNA by eukaryotic topoisomerase II. Methods Mol Biol. 2009;582:39–47. [PMC free article: PMC2893727] [PubMed: 19763940] [CrossRef]
  • Bechtold WE, Willis JK, Sun JD, et al. Biological markers of exposure to benzene: S-phenylcysteine in albumin. Carcinogenesis. 1992;13:1217–1220. [PubMed: 1638689] [CrossRef]
  • Björk J, Albin M, Welinder H, et al. Are occupational, hobby, or lifestyle exposures associated with Philadelphia chromosome positive chronic myeloid leukaemia? Occup Environ Med. 2001;58:722–727. [PMC free article: PMC1740065] [PubMed: 11600728] [CrossRef]
  • Blair A, Zheng T, Linos A, et al. Occupation and leukemia: a population-based case-control study in Iowa and Minnesota. Am J Ind Med. 2001;40:3–14. [PubMed: 11439392] [CrossRef]
  • Blanchard KT, Ball DJ, Holden HE, et al. Dermal carcinogenicity in transgenic mice: relative responsiveness of male and female hemizygous and homozygous Tg.AC mice to 12-O-tetradecanoylphorbol 13-acetate (TPA) and benzene. Toxicol Pathol. 1998;26:541–547. [PubMed: 9715513] [CrossRef]
  • Bloemen LJ, Youk A, Bradley TD, et al. Lymphohaematopoietic cancer risk among chemical workers exposed to benzene. Occup Environ Med. 2004;61:270–274. [PMC free article: PMC1740730] [PubMed: 14985523] [CrossRef]
  • Bodell WJ, Pathak DN, Lévay G, et al. Investigation of the DNA adducts formed in B6C3F1 mice treated with benzene: implications for molecular dosimetry. Environ Health Perspect. 1996;104 Suppl 6:1189–1193. [PMC free article: PMC1469766] [PubMed: 9118892]
  • Bollati V, Baccarelli A, Hou L, et al. Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res. 2007;67:876–880. [PubMed: 17283117] [CrossRef]
  • Bolstad-Johnson DM, Burgess JL, Crutchfield CD, et al. Characterization of firefighter exposures during fire overhaul. AIHAJ. 2000;61:636–641. [PubMed: 11071414] [CrossRef]
  • Brugnone F, Perbellini L, Romeo L, et al. Benzene in environmental air and human blood. Int Arch Occup Environ Health. 1998;71:554–559. [PubMed: 9860165] [CrossRef]
  • Burridge E (2007). Chemical Profile: Benzene. ICIS Chemical Business (Europe/Middle East/Asia), 2(57): 36 .
  • Calabretta B, Perrotti D. The biology of CML blast crisis. Blood. 2004;103:4010–4022. [PubMed: 14982876] [CrossRef]
  • Capleton AC, Levy LS. An overview of occupational benzene exposures and occupational exposure limits in Europe and North America. Chem Biol Interact. 2005;153-154:43–53. [PubMed: 15935799] [CrossRef]
  • CAREX (1999). Carex: industry specific estimates – Summary. Available at http://www​​/chemical_safety/carex​/Documents/5_exposures​_by_agent_and_industry.pdf.
  • Carrer P, Maroni M, Alcini D, et al. Assessment through environmental and biological measurements of total daily exposure to volatile organic compounds of office workers in Milan, Italy. Indoor Air. 2000;10:258–268. [PubMed: 11089330] [CrossRef]
  • Caux C, O’Brien C, Viau C. Determination of firefighter exposure to polycyclic aromatic hydrocarbons and benzene during fire fighting using measurement of biological indicators. Appl Occup Environ Hyg. 2002;17:379–386. [PubMed: 12018402] [CrossRef]
  • Chen H, Eastmond DA. Topoisomerase inhibition by phenolic metabolites: a potential mechanism for benzene’s clastogenic effects. Carcinogenesis. 1995;16:2301–2307. [PubMed: 7586126] [CrossRef]
  • Cho JY. Suppressive effect of hydroquinone, a benzene metabolite, on in vitro inflammatory responses mediated by macrophages, monocytes, and lymphocytes. Mediators Inflamm. 2008;2008:298010. [PMC free article: PMC2625402] [PubMed: 19148301] [CrossRef]
  • Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005;102:13944–13949. [PMC free article: PMC1236577] [PubMed: 16166262] [CrossRef]
  • Cocco P, t’Mannetje A, Fadda D, et al. Occupational exposure to solvents and risk of lymphoma subtypes: results from the Epilymph case-control study. Occup Environ Med. 2010;67:341–347. [PubMed: 20447988] [CrossRef]
  • Collingwood KW, Raabe GK, Wong O. An updated cohort mortality study of workers at a northeastern United States petroleum refinery. Int Arch Occup Environ Health. 1996;68:277–288. [PubMed: 8832292] [CrossRef]
  • Collins JJ, Ireland B, Buckley CF, Shepperly D. Lymphohaematopoeitic cancer mortality among workers with benzene exposure. Occup Environ Med. 2003;60:676–679. [PMC free article: PMC1740628] [PubMed: 12937190] [CrossRef]
  • CONCAWE (1986). Review of the European Oil Industry Benzene Exposure Data, Report 3/86. Den Haag, The Netherlands: CONCAWE .
  • CONCAWE (2000). A Review of European Gasoline Exposure Data for the Period 1993–1998, Report 2/00. Brussels, Belgium: CONCAWE .
  • CONCAWE (2002). A Survey of European Gasoline Exposures for the Period 1999–2001, Report 9/02. Brussels, Belgium: CONCAWE.
  • Consonni D, Pesatori AC, Tironi A, et al. Mortality study in an Italian oil refinery: extension of the follow-up. Am J Ind Med. 1999;35:287–294. [PubMed: 9987562] [CrossRef]
  • Costantini AS, Benvenuti A, Vineis P, et al. Risk of leukemia and multiple myeloma associated with exposure to benzene and other organic solvents: evidence from the Italian Multicenter Case-control study. Am J Ind Med. 2008;51:803–811. [PubMed: 18651579] [CrossRef]
  • Crebelli R, Tomei F, Zijno A, et al. Exposure to benzene in urban workers: environmental and biological monitoring of traffic police in Rome. Occup Environ Med. 2001;58:165–171. [PMC free article: PMC1740101] [PubMed: 11171929] [CrossRef]
  • Cronkite EP, Bullis JE, Inoue T, Drew RT. Benzene inhalation produces leukemia in mice. Toxicol Appl Pharmacol. 1984;75:358–361. [PubMed: 6474468] [CrossRef]
  • Cronkite EP, Drew RT, Inoue T, et al. Hematotoxicity and carcinogenicity of inhaled benzene. Environ Health Perspect. 1989;82:97–108. [PMC free article: PMC1568102] [PubMed: 2792054]
  • Crump KS. Risk of benzene-induced leukemia: a sensitivity analysis of the pliofilm cohort with additional follow-up and new exposure estimates. J Toxicol Environ Health. 1994;42:219–242. [PubMed: 8207757] [CrossRef]
  • Cuneo A, Bigoni R, Cavazzini F, et al. Incidence and significance of cryptic chromosome aberrations detected by fluorescence in situ hybridization in acute myeloid leukemia with normal karyotype. Leukemia. 2002;16:1745–1751. [PubMed: 12200689] [CrossRef]
  • Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–2301. [PubMed: 19474426] [CrossRef]
  • Deweese JE, Osheroff N. The DNA cleavage reaction of topoisomerase II: wolf in sheep’s clothing. Nucleic Acids Res. 2009;37:738–748. [PMC free article: PMC2647315] [PubMed: 19042970] [CrossRef]
  • Divine BJ, Hartman CM, Wendt JK. Update of the Texaco mortality study 1947–93: part II. Analysis of specific causes of death for white men employed in refining, research and petrochemicals. Occup Environ Med. 1999;56:174–180. b. [PMC free article: PMC1757716] [PubMed: 10448326] [CrossRef]
  • Dixon-McIver A, East P, Mein CA, et al. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia. PLoS ONE. 2008;3:e2141. [PMC free article: PMC2373886] [PubMed: 18478077] [CrossRef]
  • Dryver E, Brandt L, Kauppinen T, Olsson H. Occupational exposures and non-Hodgkin’s lymphoma in Southern Sweden. Int J Occup Environ Health. 2004;10:13–21. [PubMed: 15070021]
  • Duarte-Davidson R, Courage C, Rushton L, Levy L. Benzene in the environment: an assessment of the potential risks to the health of the population. Occup Environ Med. 2001;58:2–13. [PMC free article: PMC1740026] [PubMed: 11119628] [CrossRef]
  • Eastmond DA. Induction of micronuclei and aneuploidy by the quinone-forming agents benzene and o-phenylphenol. Toxicol Lett. 1993;67:105–118. [PubMed: 8451753] [CrossRef]
  • Eastmond DA, Mondrala ST, Hasegawa L. Topoisomerase II inhibition by myeloperoxidase-activated hydroquinone: a potential mechanism underlying the genotoxic and carcinogenic effects of benzene. Chem Biol Interact. 2005;153-154:207–216. [PubMed: 15935818] [CrossRef]
  • Eastmond DA, Schuler M, Frantz C, et al. Characterization and mechanisms of chromosomal alterations induced by benzene in mice and humans. Res Rep Health Eff Inst. 2001;103:1–68, discussion 69–80. [PubMed: 11504146]
  • Egeghy PP, Hauf-Cabalo L, Gibson R, Rappaport SM. Benzene and naphthalene in air and breath as indicators of exposure to jet fuel. Occup Environ Med. 2003;60:969–976. [PMC free article: PMC1740428] [PubMed: 14634191] [CrossRef]
  • Fabbro-Peray P, Daures JP, Rossi JF. Environmental risk factors for non-Hodgkin’s lymphoma: a population-based case-control study in Languedoc-Roussillon, France. Cancer Causes Control. 2001;12:201–212. [PubMed: 11405325] [CrossRef]
  • Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2007;109:874–885. [PubMed: 17008539] [CrossRef]
  • Farris GM, Everitt JI, Irons RD, Popp JA. Carcinogenicity of inhaled benzene in CBA mice. Fundam Appl Toxicol. 1993;20:503–507. [PubMed: 8314465] [CrossRef]
  • Fazi F, Rosa A, Fatica A, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell. 2005;123:819–831. [PubMed: 16325577] [CrossRef]
  • Felix CA. Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol. 2001;36:525–535. [PubMed: 11340607] [CrossRef]
  • Forni A. Chromosome studies in workers exposed to benzene or toluene or both. Arch Environ Health. 1971;22:373–378. [PubMed: 5162138]
  • Forni A. Chromosome changes and benzene exposure. A review. Rev Environ Health. 1979;3:5–17. [PubMed: 395589]
  • Frantz CE, Chen H, Eastmond DA. Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites. Environ Health Perspect. 1996;104 Suppl 6:1319–1323. [PMC free article: PMC1469756] [PubMed: 9118913]
  • French JE, Saulnier M. Benzene leukemogenesis: an environmental carcinogen-induced tissue-specific model of neoplasia using genetically altered mouse models. J Toxicol Environ Health A. 2000;61:377–379. [PubMed: 11086942] [CrossRef]
  • Fröhling S, Döhner H. Disruption of C/EBPalpha function in acute myeloid leukemia. N Engl J Med. 2004;351:2370–2372. [PubMed: 15575052] [CrossRef]
  • Fu H, Demers PA, Costantini AS, et al. Cancer mortality among shoe manufacturing workers: an analysis of two cohorts. Occup Environ Med. 1996;53:394–398. [PMC free article: PMC1128495] [PubMed: 8758034] [CrossRef]
  • Fung J, Hoffmann MJ, Kim DD, Snyder R. Inhibition of topoisomerase II in 32D.3(G) cells by hydroquinone is associated with cell death. J Appl Toxicol. 2004;24:183–188. [PubMed: 15211611] [CrossRef]
  • Fustinoni S, Buratti M, Giampiccolo R, Colombi A. Biological and environmental monitoring of exposure to airborne benzene and other aromatic hydrocarbons in Milan traffic wardens. Toxicol Lett. 1995;77:387–392. [PubMed: 7618166] [CrossRef]
  • Gaskell M, McLuckie KI, Farmer PB. Genotoxicity of the benzene metabolites para-benzoquinone and hydroquinone. Chem Biol Interact. 2005;153-154:267–270. [PubMed: 15935826] [CrossRef]
  • Gérin M, Siemiatycki J, Désy M, Krewski D. Associations between several sites of cancer and occupational exposure to benzene, toluene, xylene, and styrene: results of a case-control study in Montreal. Am J Ind Med. 1998;34:144–156. [PubMed: 9651624] [CrossRef]
  • Glass DC, Gray CN, Jolley DJ, et al. Leukemia risk associated with low-level benzene exposure. Epidemiology. 2003;14:569–577. [PubMed: 14501272] [CrossRef]
  • Gobba F, Rovesti S, Borella P, et al. Inter-individual variability of benzene metabolism to trans,trans-muconic acid and its implications in the biological monitoring of occupational exposure. Sci Total Environ. 1997;199:41–48. [PubMed: 9200846] [CrossRef]
  • Goldstein BD, Snyder CA, Laskin S, et al. Myelogenous leukemia in rodents inhaling benzene. Toxicol Lett. 1982;13:169–173. [PubMed: 6959383] [CrossRef]
  • Gowans ID, Lorimore SA, McIlrath JM, Wright EG. Genotype-dependent induction of transmissible chromosomal instability by gamma-radiation and the benzene metabolite hydroquinone. Cancer Res. 2005;65:3527–3530. [PubMed: 15867342] [CrossRef]
  • Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Natl Rev. 2003;3:639–649. [PubMed: 12951583]
  • Grulich AE, Vajdic CM, Cozen W. Altered immunity as a risk factor for non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007;16:405–408. [PubMed: 17337643] [CrossRef]
  • Guénel P, Imbernon E, Chevalier A, et al. Leukemia in relation to occupational exposures to benzene and other agents: a case-control study nested in a cohort of gas and electric utility workers. Am J Ind Med. 2002;42:87–97. [PubMed: 12125084] [CrossRef]
  • Gun RT, Pratt N, Ryan P, Roder D. Update of mortality and cancer incidence in the Australian petroleum industry cohort. Occup Environ Med. 2006;63:476–481. [PMC free article: PMC2092518] [PubMed: 16698808] [CrossRef]
  • Guo W, Lasky JL, Chang CJ, et al. Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature. 2008;453:529–533. [PMC free article: PMC2840044] [PubMed: 18463637] [CrossRef]
  • Hackanson B, Bennett KL, Brena RM, et al. Epigenetic modification of CCAAT/enhancer binding protein alpha expression in acute myeloid leukemia. Cancer Res. 2008;68:3142–3151. [PubMed: 18451139] [CrossRef]
  • Hansch C, Leo A, Hoekman D (1995). Exploring QSAR: Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society, p. 18.
  • Hartge P, Smith MT. Environmental and behavioral factors and the risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007;16:367–368. [PubMed: 17344463] [CrossRef]
  • Hayes RB, Yin SN, Dosemeci M, et al. Mortality among benzene-exposed workers in China. Environ Health Perspect. 1996;104 Suppl 6:1349–1352. [PMC free article: PMC1469764] [PubMed: 9118919]
  • Hayes RB, Yin SN, Dosemeci M, et al. Chinese Academy of Preventive Medicine–National Cancer Institute Benzene Study Group. Benzene and the dose-related incidence of hematologic neoplasms in China. J Natl Cancer Inst. 1997;89:1065–1071. [PubMed: 9230889] [CrossRef]
  • Henderson AP, Bleasdale C, Delaney K, et al. Evidence for the formation of Michael adducts from reactions of (E,E)-muconaldehyde with glutathione and other thiols. Bioorg Chem. 2005;33:363–373. [PubMed: 16005934] [CrossRef]
  • Hirabayashi Y, Inoue T. Aryl hydrocarbon receptor biology and xenobiotic responses in hematopoietic progenitor cells. Biochem Pharmacol. 2009;77:521–535. [PubMed: 18940184] [CrossRef]
  • Hirabayashi Y, Yoon BI, Li GX, et al. Benzene-induced hematopoietic toxicity transmitted by AhR in wild-type mouse and nullified by repopulation with AhR-deficient bone marrow cells: time after benzene treatment and recovery. Chemosphere. 2008;73 Suppl:S290–S294. [PubMed: 18514254] [CrossRef]
  • Holden HE, Stoll RE, Spalding JW, Tennant RW. Hemizygous Tg.AC transgenic mouse as a potential alternative to the two-year mouse carcinogenicity bioassay: evaluation of husbandry and housing factors. J Appl Toxicol. 1998;18:19–24. [PubMed: 9526830] [CrossRef]
  • Holecková B, Piesová E, Sivikova K. Dianovskỳ J. Chromosomal aberrations in humans induced by benzene. Ann Agric Environ Med. 2004;11:175–179. [PubMed: 15627321]
  • Hotz P, Carbonnelle P, Haufroid V, et al. Biological monitoring of vehicle mechanics and other workers exposed to low concentrations of benzene. Int Arch Occup Environ Health. 1997;70:29–40. [PubMed: 9258705] [CrossRef]
  • Huebner WW, Wojcik NC, Rosamilia K, et al. Mortality updates (1970–1997) of two refinery/petrochemical plant cohorts at Baton Rouge, Louisiana, and Baytown, Texas. J Occup Environ Med. 2004;46:1229–1245. [PubMed: 15591975]
  • Huff JE, Haseman JK, DeMarini DM, et al. Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice. Environ Health Perspect. 1989;82:125–163. [PMC free article: PMC1568117] [PubMed: 2676495]
  • Hutt AM, Kalf GF. Inhibition of human DNA topoisomerase II by hydroquinone and p-benzoquinone, reactive metabolites of benzene. Environ Health Perspect. 1996;104 Suppl 6:1265–1269. [PMC free article: PMC1469763] [PubMed: 9118903]
  • IARC. Some industrial chemicals and dyestuffs. IARC Monogr Eval Carcinog Risk Chem Hum. 1982;29:1–398. [PubMed: 6957379]
  • IARC. Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum Suppl. 1987;7:1–440. [PubMed: 3482203]
  • Infante PF. Benzene exposure and multiple myeloma: a detailed meta-analysis of benzene cohort studies. Ann N Y Acad Sci. 2006;1076:90–109. [PubMed: 17119195] [CrossRef]
  • Infante PF, Rinsky RA, Wagoner JK, Young RJ. Leukaemia in benzene workers. Lancet. 1977;2:76–78. [PubMed: 69157] [CrossRef]
  • Irons RD, Stillman WS. The process of leukemogenesis. Environ Health Perspect. 1996;104 Suppl 6:1239–1246. [PMC free article: PMC1469736] [PubMed: 9118899]
  • Irons RD, Stillman WS, Colagiovanni DB, Henry VA. Synergistic action of the benzene metabolite hydroquinone on myelopoietic stimulating activity of granulocyte/macrophage colony-stimulating factor in vitro. Proc Natl Acad Sci USA. 1992;89:3691–3695. [PMC free article: PMC525556] [PubMed: 1570288] [CrossRef]
  • Iskander K, Jaiswal AK. Quinone oxidoreductases in protection against myelogenous hyperplasia and benzene toxicity. Chem Biol Interact. 2005;153-154:147–157. [PubMed: 15935811] [CrossRef]
  • Jankovic J, Jones W, Burkhart J, Noonan G. Environmental study of firefighters. Ann Occup Hyg. 1991;35:581–602. [PubMed: 1768008] [CrossRef]
  • Javelaud B, Vian L, Molle R, et al. Benzene exposure in car mechanics and road tanker drivers. Int Arch Occup Environ Health. 1998;71:277–283. [PubMed: 9638485] [CrossRef]
  • Johnson ES, Langård S, Lin Y-S. A critique of benzene exposure in the general population. Sci Total Environ. 2007;374:183–198. [PubMed: 17261327] [CrossRef]
  • Kauppinen T, Toikkanen J, Pedersen D, et al. Occupational exposure to carcinogens in the European Union. Occup Environ Med. 2000;57:10–18. [PMC free article: PMC1739859] [PubMed: 10711264] [CrossRef]
  • Kawasaki Y, Hirabayashi Y, Kaneko T, et al. Benzene-induced hematopoietic neoplasms including myeloid leukemia in Trp53-deficient C57BL/6 and C3H/He mice. Toxicol Sci. 2009;110:293–306. [PMC free article: PMC2708599] [PubMed: 19478238] [CrossRef]
  • Kearney L, Gonzalez De Castro D, Yeung J, et al. Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood. 2009;113:646–648. [PubMed: 18927438] [CrossRef]
  • Kim S, Vermeulen R, Waidyanatha S, et al. Using urinary biomarkers to elucidate dose-related patterns of human benzene metabolism. Carcinogenesis. 2006;27:772–781. a. [PubMed: 16339183] [CrossRef]
  • Kim S, Vermeulen R, Waidyanatha S, et al. Modeling human metabolism of benzene following occupational and environmental exposures. Cancer Epidemiol Biomarkers Prev. 2006;15:2246–2252. b. [PubMed: 17119053] [CrossRef]
  • Kim SY, Choi JK, Cho YH, et al. Chromosomal aberrations in workers exposed to low levels of benzene: association with genetic polymorphisms. Pharmacogenetics. 2004;14:453–463. [PubMed: 15226677] [CrossRef]
  • Kirkeleit J, Riise T, Bråtveit M, Moen BE. Increased risk of acute myelogenous leukemia and multiple myeloma in a historical cohort of upstream petroleum workers exposed to crude oil. Cancer Causes Control. 2008;19:13–23. [PubMed: 17906934] [CrossRef]
  • Kirschner M. 2009Chemical Profile: Benzene. ICIS Chemical Businessavailable at
  • Kivistö H, Pekari K, Peltonen K, et al. Biological monitoring of exposure to benzene in the production of benzene and in a cokery. Sci Total Environ. 1997;199:49–63. [PubMed: 9200847] [CrossRef]
  • La Vecchia C, Negri E, D’Avanzo B, Franceschi S. Occupation and lymphoid neoplasms. Br J Cancer. 1989;60:385–388. [PMC free article: PMC2247171] [PubMed: 2789947] [CrossRef]
  • Lamm SH, Engel A, Byrd DM. Non-Hodgkin lymphoma and benzene exposure: a systematic literature review. Chem Biol Interact. 2005;153-154:231–237. [PubMed: 15885679] [CrossRef]
  • Lan Q, Zhang L, Li G, et al. Hematotoxicity in workers exposed to low levels of benzene. Science. 2004;306:1774–1776. [PMC free article: PMC1256034] [PubMed: 15576619] [CrossRef]
  • Lan Q, Zhang L, Shen M, et al. Large-scale evaluation of candidate genes identifies associations between DNA repair and genomic maintenance and development of benzene hematotoxicity. Carcinogenesis. 2009;30:50–58. [PMC free article: PMC2639030] [PubMed: 18978339] [CrossRef]
  • Larson RA, Le Beau MM. Therapy-related myeloid leukaemia: a model for leukemogenesis in humans. Chem Biol Interact. 2005;153-154:187–195. [PubMed: 15935816] [CrossRef]
  • Lau A, Belanger CL, Winn LM. In utero and acute exposure to benzene: investigation of DNA double-strand breaks and DNA recombination in mice. Mutat Res. 2009;676:74–82. [PubMed: 19486867]
  • Lee SG, Choi JR, Kim JS, et al. Therapy-related acute lymphoblastic leukemia with t(9;22)(q34;q11.2):a case study and review of the literature. Cancer Genet Cytogenet. 2009;191:51–54. [PubMed: 19389510] [CrossRef]
  • Lewis RJ, Schnatter AR, Drummond I, et al. Mortality and cancer morbidity in a cohort of Canadian petroleum workers. Occup Environ Med. 2003;60:918–928. [PMC free article: PMC1740448] [PubMed: 14634182] [CrossRef]
  • Ley TJ, Mardis ER, Ding L, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008;456:66–72. [PMC free article: PMC2603574] [PubMed: 18987736] [CrossRef]
  • Li B, Li YQ, Yang LJ, et al. Decreased T-cell receptor excision DNA circles in peripheral blood mononuclear cells among benzene-exposed workers. Int J Immunogenet. 2009;36:107–111. [PubMed: 19228219] [CrossRef]
  • Liang Y-X, Wong O, Armstrong T, et al. An overview of published benzene exposure data by industry in China, 1960–2003. Chem Biol Interact. 2005;153-154:55–64. [PubMed: 15935800] [CrossRef]
  • Lide DR, editor (2008). CRC Handbook of Chemistry and Physics, 89th ed. Boca Raton, FL: CRC Press, pp. 3–32.
  • Lindsey RH Jr, Bender RP, Osheroff N. Effects of benzene metabolites on DNA cleavage mediated by human topoisomerase II alpha: 1,4-hydroquinone is a topoisomerase II poison. Chem Res Toxicol. 2005;18:761–770. [PubMed: 15833037] [CrossRef]
  • Lindsey RH Jr, Bromberg KD, Felix CA, Osheroff N. 1,4-Benzoquinone is a topoisomerase II poison. Biochemistry. 2004;43:7563–7574. [PubMed: 15182198] [CrossRef]
  • Lobato MN, Metzler M, Drynan L, et al. Modeling chromosomal translocations using conditional alleles to recapitulate initiating events in human leukemias. J Natl Cancer Inst Monogr. 2008;39:58–63. [PubMed: 18648005] [CrossRef]
  • Long DJ 2nd, Gaikwad A, Multani A, et al. Disruption of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia. Cancer Res. 2002;62:3030–3036. [PubMed: 12036909]
  • Lynge E, Andersen A, Nilsson R, et al. Risk of cancer and exposure to gasoline vapors. Am J Epidemiol. 1997;145:449–458. [PubMed: 9048519]
  • Maltoni C, Ciliberti A, Cotti G, et al. Benzene, an experimental multipotential carcinogen: results of the long-term bioassays performed at the Bologna Institute of Oncology. Environ Health Perspect. 1989;82:109–124. [PMC free article: PMC1568122] [PubMed: 2792037] [CrossRef]
  • Maltoni C, Conti B, Cotti G. Benzene: a multipotential carcinogen. Results of long-term bioassays performed at the Bologna Institute of Oncology. Am J Ind Med. 1983;4:589–630. [PubMed: 6353911] [CrossRef]
  • Maltoni C, Conti B, Cotti G, Belpoggi F. Experimental studies on benzene carcinogenicity at the Bologna Institute of Oncology: current results and ongoing research. Am J Ind Med. 1985;7:415–446. [PubMed: 4003403] [CrossRef]
  • Maltoni C, Conti B, Perino G, Di Maio V. Further evidence of benzene carcinogenicity. Results on Wistar rats and Swiss mice treated by ingestion. Ann N Y Acad Sci. 1988;534 1 Living in a C:412–426. [PubMed: 3389671] [CrossRef]
  • Maltoni C, Conti B, Scarnato C. Squamous cell carcinomas of the oral cavity in Sprague-Dawley rats, following exposure to benzene by ingestion. First experimental demonstration. Med Lav. 1982;73:441–445. b. [PubMed: 7177031]
  • Maltoni C, Cotti G, Valgimigli L, Mandrioli A. Zymbal gland carcinomas in rats following exposure to benzene by inhalation. Am J Ind Med. 1982;3:11–16. a. [PubMed: 7124739] [CrossRef]
  • Maltoni C, Cotti G, Valgimigli L, Mandrioli A. Hepatocarcinomas in Sprague-Dawley rats, following exposure to benzene by inhalation. First experimental demonstration. Med Lav. 1982;73:446–450. c. [PubMed: 7177032]
  • Maltoni C, Scarnato C. First experimental demonstration of the carcinogenic effects of benzene; long-term bioassays on Sprague-Dawley rats by oral administration. Med Lav. 1979;70:352–357. [PubMed: 554913]
  • Marcucci G, Radmacher MD, Maharry K, et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1919–1928. [PubMed: 18450603] [CrossRef]
  • Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–1066. [PMC free article: PMC3201812] [PubMed: 19657110] [CrossRef]
  • Maronpot RR. Ovarian toxicity and carcinogenicity in eight recent National Toxicology Program studies. Environ Health Perspect. 1987;73:125–130. [PMC free article: PMC1474570] [PubMed: 3665857] [CrossRef]
  • McClendon AK, Osheroff N. DNA topoisomerase II, genotoxicity, and cancer. Mutat Res. 2007;623:83–97. [PMC free article: PMC2679583] [PubMed: 17681352]
  • McDonald TA, Waidyanatha S, Rappaport SM. Production of benzoquinone adducts with hemoglobin and bone-marrow proteins following administration of [13C6]benzene to rats. Carcinogenesis. 1993;14:1921–1925. [PubMed: 8403219] [CrossRef]
  • McHale CM, Lan Q, Corso C, et al. Chromosome translocations in workers exposed to benzene. J Natl Cancer Inst Monogr. 2008;39:74–77. [PubMed: 18648008] [CrossRef]
  • McHale CM, Wiemels JL, Zhang L, et al. Prenatal origin of childhood acute myeloid leukemias harboring chromosomal rearrangements t(15;17) and inv(16). Blood. 2003;101:4640–4641. [PubMed: 12756163] [CrossRef]
  • McKinney PA, Alexander FE, Cartwright RA, Parker L. Parental occupations of children with leukaemia in west Cumbria, north Humberside, and Gateshead. BMJ. 1991;302:681–687. [PMC free article: PMC1669138] [PubMed: 2021741]
  • Mehlman MA. Carcinogenic effects of benzene: Cesare Maltoni’s contributions. Ann N Y Acad Sci. 2002;982:137–148. [PubMed: 12562633] [CrossRef]
  • Merlo DF, Bertazzi PA, Bolognesi C et al. (2001). Exposure to Low Levels of Benzene, Interindividual Biological Variability and Cancer Risk: A Multicentre European Study. Milan, Italy: Istituto Nazionale per la Ricerca sul Cancro.
  • Miligi L, Costantini AS, Benvenuti A, et al. Occupational exposure to solvents and the risk of lymphomas. Epidemiology. 2006;17:552–561. [PubMed: 16878041] [CrossRef]
  • Mistry AR, Felix CA, Whitmarsh RJ, et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med. 2005;352:1529–1538. [PubMed: 15829534] [CrossRef]
  • Morgan GJ, Alvares CL. Benzene and the hemopoietic stem cell. Chem Biol Interact. 2005;153-154:217–222. [PubMed: 15935819] [CrossRef]
  • Mrózek K, Bloomfield CD. Clinical significance of the most common chromosome translocations in adult acute myeloid leukemia. J Natl Cancer Inst Monogr. 2008;39:52–57. [PubMed: 18648004] [CrossRef]
  • Navasumrit P, Chanvaivit S, Intarasunanont P, et al. Environmental and occupational exposure to benzene in Thailand. Chem Biol Interact. 2005;153-154:75–83. [PubMed: 15935802] [CrossRef]
  • Nedelcheva V, Gut I, Soucek P, et al. Metabolism of benzene in human liver microsomes: individual variations in relation to CYP2E1 expression. Arch Toxicol. 1999;73:33–40. [PubMed: 10207612] [CrossRef]
  • NIOSH (1990). National Occupational Exposure Survey (1981–83). Cincinnati, OH: US Department of Health and Human Services, Public Health Service, National Institute for Occupational Safety and Health []
  • Nordlinder R, Ramnäs O. Exposure to benzene at different work places in Sweden. Ann Occup Hyg. 1987;31:345–355. [PubMed: 3426034] [CrossRef]
  • NTP. NTP toxicology and carcinogenesis studies of benzene (CAS NO. 71–43–2) in F344/N rats and B6C3F1 mice (Gavage studies). Natl Toxicol Program Tech Rep Ser. 1986;289:1–277. [PubMed: 12748714]
  • NTP. 2005BenzeneNTP 11th Report on Carcinogens. Rep Carcinog 111–A32. [PubMed: 19826456]
  • NTP. NTP report on the toxicology and carcinogenesis study of benzene (CAS No. 71–43–2) in genetically modified haploinsufficient p16 Ink4a/p19 Arf mice (gavage study). Natl Toxicol Program Genet Modif Model Rep. 2007;8:1–81. [PubMed: 18784769]
  • O’Neil MJ, editor (2006). The Merck Index, 14th ed. Whitehouse Station, NJ: Merck & Co., p. 177.
  • Ong CN, Kok PW, Lee BL, et al. Evaluation of biomarkers for occupational exposure to benzene. Occup Environ Med. 1995;52:528–533. [PMC free article: PMC1128288] [PubMed: 7663638] [CrossRef]
  • Ong CN, Kok PW, Ong HY, et al. Biomarkers of exposure to low concentrations of benzene: a field assessment. Occup Environ Med. 1996;53:328–333. [PMC free article: PMC1128475] [PubMed: 8673180] [CrossRef]
  • Passegué E, Weisman IL. Leukemic stem cells: where do they come from? Stem Cell Rev. 2005;1:181–188. [PubMed: 17142854] [CrossRef]
  • Patel AS, Talbott EO, Zborowski JV, et al. Risk of cancer as a result of community exposure to gasoline vapors. Arch Environ Health. 2004;59:497–503. [PubMed: 16425659] [CrossRef]
  • Pedersen-Bjergaard J, Andersen MK, Andersen MT, Christiansen DH. Genetics of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2008;22:240–248. [PubMed: 18200041] [CrossRef]
  • Pedersen-Bjergaard J, Andersen MT, Andersen MK. Genetic pathways in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2007:392–397. [PubMed: 18024656]
  • Pedersen-Bjergaard J, Christiansen DH, Desta F, Andersen MK. Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2006;20:1943–1949. [PubMed: 16990778] [CrossRef]
  • Pesch B, Haerting J, Ranft U, et al. Occupational risk factors for renal cell carcinoma: agent-specific results from a case-control study in Germany. MURC Study Group. Multicenter urothelial and renal cancer study. Int J Epidemiol. 2000;29:1014–1024. [PubMed: 11101542] [CrossRef]
  • Picciano D. Cytogenetic study of workers exposed to benzene. Environ Res. 1979;19:33–38. [PubMed: 510268] [CrossRef]
  • Popp W, Rauscher D, Müller G, et al. Concentrations of benzene in blood and S-phenylmercapturic and t,t-muconic acid in urine in car mechanics. Int Arch Occup Environ Health. 1994;66:1–6. [PubMed: 7523309] [CrossRef]
  • Powley MW, Carlson GP. Cytochromes P450 involved with benzene metabolism in hepatic and pulmonary microsomes. J Biochem Mol Toxicol. 2000;14:303–309. [PubMed: 11083083] [CrossRef]
  • Qu Q, Shore R, Li G, et al. Biomarkers of benzene: urinary metabolites in relation to individual genotype and personal exposure. Chem Biol Interact. 2005;153-154:85–95. [PubMed: 15935803] [CrossRef]
  • Raaschou-Nielsen O, Hertel O, Thomsen BL, Olsen JH. Air pollution from traffic at the residence of children with cancer. Am J Epidemiol. 2001;153:433–443. [PubMed: 11226975] [CrossRef]
  • Rappaport SM, Kim S, Lan Q, et al. Evidence that humans metabolize benzene via two pathways. Environ Health Perspect. 2009;117:946–952. [PMC free article: PMC2702411] [PubMed: 19590688]
  • Ravandi F, Kebriaei P. Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2009;23:1043–1063, vi. [vi.] [PMC free article: PMC4091825] [PubMed: 19825452] [CrossRef]
  • Ren X, Lim S, Smith MT, Zhang L. Werner syndrome protein, WRN, protects cells from DNA damage induced by the benzene metabolite hydroquinone. Toxicol Sci. 2009;107:367–375. [PMC free article: PMC2639759] [PubMed: 19064679]
  • Rinsky RA, Hornung RW, Silver SR, Tseng CY. Benzene exposure and hematopoietic mortality: A long-term epidemiologic risk assessment. Am J Ind Med. 2002;42:474–480. [PubMed: 12439870] [CrossRef]
  • Rinsky RA, Smith AB, Hornung R, et al. Benzene and leukemia. An epidemiologic risk assessment. N Engl J Med. 1987;316:1044–1050. [PubMed: 3561457] [CrossRef]
  • Rinsky RA, Young RJ, Smith AB. Leukemia in benzene workers. Am J Ind Med. 1981;2:217–245. [PubMed: 7345926] [CrossRef]
  • Rivedal E, Witz G. Metabolites of benzene are potent inhibitors of gap-junction intercellular communication. Arch Toxicol. 2005;79:303–311. [PubMed: 15690152] [CrossRef]
  • Romieu I, Ramirez M, Meneses F, et al. Environmental exposure to volatile organic compounds among workers in Mexico City as assessed by personal monitors and blood concentrations. Environ Health Perspect. 1999;107:511–515. [PMC free article: PMC1566663] [PubMed: 10378996] [CrossRef]
  • Ross D. The role of metabolism and specific metabolites in benzene-induced toxicity: evidence and issues. J Toxicol Environ Health A. 2000;61:357–372. [PubMed: 11086940] [CrossRef]
  • Rothman N, Smith MT, Hayes RB, et al. Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C–>T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res. 1997;57:2839–2842. [PubMed: 9230185]
  • Rushton L. A 39-year follow-up of the U.K. oil refinery and distribution center studies: results for kidney cancer and leukemia. Environ Health Perspect. 1993;101 Suppl 6:77–84. [PMC free article: PMC1520001] [PubMed: 8020451] [CrossRef]
  • Rushton L, Romaniuk H. A case-control study to investigate the risk of leukaemia associated with exposure to benzene in petroleum marketing and distribution workers in the United Kingdom. Occup Environ Med. 1997;54:152–166. [PMC free article: PMC1128678] [PubMed: 9155776] [CrossRef]
  • Satin KP, Wong O, Yuan LA, et al. A 50-year mortality follow-up of a large cohort of oil refinery workers in Texas. J Occup Environ Med. 1996;38:492–506. [PubMed: 8733641] [CrossRef]
  • Savitz DA, Andrews KW. Review of epidemiologic evidence on benzene and lymphatic and hematopoietic cancers. Am J Ind Med. 1997;31:287–295. [PubMed: 9055951] [CrossRef]
  • Scélo G, Metayer C, Zhang L, et al. Household exposure to paint and petroleum solvents, chromosomal translocations, and the risk of childhood leukemia. Environ Health Perspect. 2009;117:133–139. [PMC free article: PMC2627857] [PubMed: 19165400]
  • Schnatter AR, Armstrong TW, Nicolich MJ, et al. Lymphohaematopoietic malignancies and quantitative estimates of exposure to benzene in Canadian petroleum distribution workers. Occup Environ Med. 1996;53:773–781. [PMC free article: PMC1128597] [PubMed: 9038803] [CrossRef]
  • Sheets PL, Yost GS, Carlson GP. Benzene metabolism in human lung cell lines BEAS-2B and A549 and cells overexpressing CYP2F1. J Biochem Mol Toxicol. 2004;18:92–99. [PubMed: 15122651] [CrossRef]
  • Shen M, Lan Q, Zhang L, et al. Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity. Carcinogenesis. 2006;27:2083–2089. [PubMed: 16728435] [CrossRef]
  • Shu XO, Gao YT, Brinton LA, et al. A population-based case-control study of childhood leukemia in Shanghai. Cancer. 1988;62:635–644. [PubMed: 3164642] [CrossRef]
  • Shu XO, Stewart P, Wen WQ, et al. Parental occupational exposure to hydrocarbons and risk of acute lymphocytic leukemia in offspring. Cancer Epidemiol Biomarkers Prev. 1999;8:783–791. [PubMed: 10498397]
  • Signer RA, Montecino-Rodriguez E, Witte ON, et al. Age-related defects in B lymphopoiesis underlie the myeloid dominance of adult leukemia. Blood. 2007;110:1831–1839. [PMC free article: PMC1976345] [PubMed: 17554060] [CrossRef]
  • Singh KP, Casado FL, Opanashuk LA, Gasiewicz TA. The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol. 2009;77:577–587. [PMC free article: PMC2665706] [PubMed: 18983985] [CrossRef]
  • Smith MT. The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect. 1996;104 Suppl 6:1219–1225. [PMC free article: PMC1469721] [PubMed: 9118896]
  • Smith MT, Skibola CF, Allan JM, Morgan GJ. Causal models of leukaemia and lymphoma. IARC Sci Publ. 2004;157:373–392. [PubMed: 15055307]
  • Smith MT, Zhang L. Biomarkers of leukemia risk: benzene as a model. Environ Health Perspect. 1998;106 Suppl 4:937–946. [PMC free article: PMC1533331] [PubMed: 9703476]
  • Smith MT, Zhang L, Jeng M, et al. Hydroquinone, a benzene metabolite, increases the level of aneusomy of chromosomes 7 and 8 in human CD34-positive blood progenitor cells. Carcinogenesis. 2000;21:1485–1490. [PubMed: 10910948] [CrossRef]
  • Smith MT, Zhang L, Wang Y, et al. Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene. Cancer Res. 1998;58:2176–2181. [PubMed: 9605763]
  • Snyder CA, Goldstein BD, Sellakumar AR, et al. The inhalation toxicology of benzene: incidence of hematopoietic neoplasms and hematotoxicity in ARK/J and C57BL/6J mice. Toxicol Appl Pharmacol. 1980;54:323–331. [PubMed: 6893503] [CrossRef]
  • Snyder CA, Sellakumar AR, James DJ, Albert RE. The carcinogenicity of discontinuous inhaled benzene exposures in CD-1 and C57Bl/6 mice. Arch Toxicol. 1988;62:331–335. [PubMed: 3242441] [CrossRef]
  • Snyder R. Xenobiotic metabolism and the mechanism(s) of benzene toxicity. Drug Metab Rev. 2004;36:531–547. [PubMed: 15554234] [CrossRef]
  • Sorahan T, Kinlen LJ, Doll R. Cancer risks in a historical UK cohort of benzene exposed workers. Occup Environ Med. 2005;62:231–236. [PMC free article: PMC1740992] [PubMed: 15778255] [CrossRef]
  • Steinmaus C, Smith AH, Jones RM, Smith MT. Meta-analysis of benzene exposure and non-Hodgkin lymphoma: biases could mask an important association. Occup Environ Med. 2008;65:371–378. [PMC free article: PMC4353490] [PubMed: 18417556] [CrossRef]
  • Stillman WS, Varella-Garcia M, Irons RD. The benzene metabolite, hydroquinone, selectively induces 5q31- and -7 in human CD34+CD19- bone marrow cells. Exp Hematol. 2000;28:169–176. [PubMed: 10706073] [CrossRef]
  • Stoner GD, Conran PB, Greisiger EA, et al. Comparison of two routes of chemical administration on the lung adenoma response in strain A/J mice. Toxicol Appl Pharmacol. 1986;82:19–31. [PubMed: 3945940] [CrossRef]
  • Swerdlow SH, Campo E, Lee Harris N (2008). WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edition. Lyon, France: IARC.
  • Thomadaki H, Scorilas A. BCL2 family of apoptosis-related genes: functions and clinical implications in cancer. Crit Rev Clin Lab Sci. 2006;43:1–67. [PubMed: 16531274] [CrossRef]
  • Tough IM, Brown WM. Chromosome Aberrations and Exposure to Ambient Benzene. Lancet. 1965;1:684. [PubMed: 14258551] [CrossRef]
  • Valentine JL, Lee SS, Seaton MJ, et al. Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression. Toxicol Appl Pharmacol. 1996;141:205–213. [PubMed: 8917693]
  • van Steensel-Moll HA, Valkenburg HA, van Zanen GE. Childhood leukemia and parental occupation. A register-based case-control study. Am J Epidemiol. 1985;121:216–224. [PubMed: 3860001]
  • van Wijngaarden E, Stewart PA. Critical literature review of determinants and levels of occupational benzene exposure for United States community-based case-control studies. Appl Occup Environ Hyg. 2003;18:678–693. [PubMed: 12909536] [CrossRef]
  • Vaughan AT, Betti CJ, Villalobos MJ, et al. Surviving apoptosis: a possible mechanism of benzene-induced leukemia. Chem Biol Interact. 2005;153-154:179–185. [PubMed: 15935815] [CrossRef]
  • Verma DK, Johnson DM, McLean JD. Benzene and total hydrocarbon exposures in the upstream petroleum oil and gas industry. AIHAJ. 2000;61:225–263. [PubMed: 10782197]
  • Voltz R, Starck M, Zingler V, et al. Mitoxantrone therapy in multiple sclerosis and acute leukaemia: a case report out of 644 treated patients. Mult Scler. 2004;10:472–474. [PubMed: 15327049] [CrossRef]
  • Waidyanatha S, Rothman N, Fustinoni S, et al. Urinary benzene as a biomarker of exposure among occupationally exposed and unexposed subjects. Carcinogenesis. 2001;22:279–286. [PubMed: 11181449] [CrossRef]
  • Waidyanatha S, Rappaport SM. Investigation of cysteinyl protein adducts of benzene diolepoxide. Chem Biol Interact. 2005;153-154:261–266. [PubMed: 15935825] [CrossRef]
  • Walter MJ, Payton JE, Ries RE, et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci USA. 2009;106:12950–12955. [PMC free article: PMC2716381] [PubMed: 19651600] [CrossRef]
  • Wang L, Roy SK, Eastmond DA. Differential cell cycle-specificity for chromosomal damage induced by merbarone and etoposide in V79 cells. Mutat Res. 2007;616:70–82. [PubMed: 17174356]
  • Wang R, Zhang Y, Lan Q, et al. Occupational exposure to solvents and risk of non-Hodgkin lymphoma in Connecticut women. Am J Epidemiol. 2009;169:176–185. [PMC free article: PMC2727253] [PubMed: 19056833] [CrossRef]
  • Whysner J, Reddy MV, Ross PM, et al. Genotoxicity of benzene and its metabolites. Mutat Res. 2004;566:99–130. [PubMed: 15164977] [CrossRef]
  • Wiemels JL, Cazzaniga G, Daniotti M, et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet. 1999;354:1499–1503. [PubMed: 10551495] [CrossRef]
  • Wiemels JL, Xiao Z, Buffler PA, et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood. 2002;99:3801–3805. [PubMed: 11986239] [CrossRef]
  • Williams PRD, Panko JM, Unice K, et al. Occupational exposures associated with petroleum-derived products containing trace levels of benzene. J Occup Environ Hyg. 2008;5:565–574. [PubMed: 18615290] [CrossRef]
  • Williams PRD, Robinson K, Paustenbach DJ. Benzene exposures associated with tasks performed on marine vessels (circa 1975 to 2000). J Occup Environ Hyg. 2005;2:586–599. [PubMed: 16234219] [CrossRef]
  • Wong O. Risk of acute myeloid leukaemia and multiple myeloma in workers exposed to benzene. Occup Environ Med. 1995;52:380–384. [PMC free article: PMC1128241] [PubMed: 7627314] [CrossRef]
  • Wong O, Harris F, Smith TJ. Health effects of gasoline exposure. II. Mortality patterns of distribution workers in the United States. Environ Health Perspect. 1993;101 Suppl 6:63–76. [PMC free article: PMC1520018] [PubMed: 8020450] [CrossRef]
  • Wong O, Raabe GK. Cell-type-specific leukemia analyses in a combined cohort of more than 208,000 petroleum workers in the United States and the United Kingdom, 1937–1989. Regul Toxicol Pharmacol. 1995;21:307–321. [PubMed: 7644720] [CrossRef]
  • Wong O, Raabe GK. Multiple myeloma and benzene exposure in a multinational cohort of more than 250,000 petroleum workers. Regul Toxicol Pharmacol. 1997;26:188–199. [PubMed: 9356282] [CrossRef]
  • Wong O, Raabe GK. A critical review of cancer epidemiology in the petroleum industry, with a meta-analysis of a combined database of more than 350,000 workers. Regul Toxicol Pharmacol. 2000;32:78–98. a. [PubMed: 11029272] [CrossRef]
  • Wong O, Raabe GK. Non-Hodgkin’s lymphoma and exposure to benzene in a multinational cohort of more than 308,000 petroleum workers, 1937 to 1996. J Occup Environ Med. 2000;42:554–568. b. [PubMed: 10824308] [CrossRef]
  • Xu X, Wiencke JK, Niu M, et al. benzene exposure, GSTT homozygous deletion and SCE. Am J Ind Med. 1998;33:157–163. [PubMed: 9438048] [CrossRef]
  • Yin SN, Hayes RB, Linet MS, et al. A cohort study of cancer among benzene-exposed workers in China: overall results. Am J Ind Med. 1996;29:227–235. [PubMed: 8833775] [CrossRef]
  • Yoon BI, Hirabayashi Y, Kawasaki Y, et al. Aryl hydrocarbon receptor mediates benzene-induced hematotoxicity. Toxicol Sci. 2002;70:150–156. [PubMed: 12388843] [CrossRef]
  • Zhang L, Eastmond DA, Smith MT. The nature of chromosomal aberrations detected in humans exposed to benzene. Crit Rev Toxicol. 2002;32:1–42. [PubMed: 11846214] [CrossRef]
  • Zhang L, Rothman N, Li G, et al. Aberrations in chromosomes associated with lymphoma and therapy-related leukemia in benzene-exposed workers. Environ Mol Mutagen. 2007;48:467–474. [PubMed: 17584886] [CrossRef]
  • Zhang L, Rothman N, Wang Y, et al. Benzene increases aneuploidy in the lymphocytes of exposed workers: a comparison of data obtained by fluorescence in situ hybridization in interphase and metaphase cells. Environ Mol Mutagen. 1999;34:260–268. [PubMed: 10618174] [CrossRef]
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