nqo1, mpo, cyp2e1, gstt1 and gstm1 polymorphisms and biological effects of benzene exposure—a...
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Toxicology Letters 182 (2008) 7–17
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Mini review
NQO1, MPO, CYP2E1, GSTT1 and GSTM1 polymorphisms and biologicaleffects of benzene exposure—A literature review
Diana Doughertya, Seymour Garteb, Aaron Barchowskyb, Joe Zmudac, Emanuela Taioli a,∗
a Department of Epidemiology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USAb Department of Environmental Occupational Health, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USAc Department of Human Genetics, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
a r t i c l e i n f o
Article history:Received 20 July 2008Received in revised form13 September 2008Accepted 14 September 2008Available online 20 September 2008
Keywords:BiomarkersEnvironmental exposureEpidemiology
a b s t r a c t
Background: Benzene is a ubiquitous toxic environmental pollutant. Biological effects have been detectedas a result of low-level environmental exposures, suggesting that a large proportion of the population maypotentially suffer ill health effects. Polymorphisms in genes involved in benzene metabolism are thoughtto influence individual susceptibility to various levels of benzene exposure.Methods: Medline literature database search for articles relating to benzene exposure and polymorphismsin genes known to be involved in benzene metabolism (NQO1, CYP2E1, GSTT1, GSTM1 and MPO). Twenty-two reports were included in this review.Results: A modest effect of the studied gene polymorphisms on the analyzed biomarkers was observed.GSTM1 and GSTT1 showed some consistent associations with both biomarkers of exposure and effect.Conclusion: Genetic polymorphisms on the benzene metabolism pathway should be taken into accountwhen studying the biological effects of benzene exposure. Unique combinations of genetic polymorphisms
may increase susceptibility of individuals and/or population subgroups. However, gene–gene interactions,and the biological effects of long-term and low-level exposure to benzene are not yet analyzed withC
f
0d
well-designed studies that incorporate multiple biological end-points and multiple genes.© 2008 Elsevier Ireland Ltd. All rights reserved.
ontents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81.1. Occupational exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81.2. Environmental exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81.3. Health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81.4. Biomarkers of exposure to benzene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81.5. Biomarkers of biological effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91.6. Susceptibility gene polymorphisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.1. NQO1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.1.1. Biomarkers of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.1.2. Biomarkers of effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.1.3. Benzene poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.2. CYP2E1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.2.1. Biomarkers of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.2.2. Biomarkers of effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author at: University of Pittsburgh Cancer Institute, UPMC Cancer Pavax: +1 412 623 3878.
E-mail address: [email protected] (E. Taioli).
378-4274/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.toxlet.2008.09.008
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
ilion, 5150 Centre Avenue, Pittsburgh, PA 15232, USA. Tel.: +1 412 623 2217
8 D. Dougherty et al. / Toxicology Letters 182 (2008) 7–17
3.3. GSTT1 and GSTM1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143.3.1. Biomarkers of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143.3.2. Biomarkers of effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.4. MPO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. Introduction
Subjects exposed to benzene have been found to display a rangef variations in levels of biomarker of exposure, suggesting thatolymorphisms in genes involved in benzene metabolism may sig-ificantly influence one’s susceptibility to benzene toxicity (Bolufert al., 2006). It is of public health importance to fully understandhe health implications of various levels of exposure in both occu-ation and environmental settings, and to identify any subgroupsith increased susceptibility to such exposure. This review sum-arizes the literature evaluating the influence of polymorphisms
n selected metabolic genes on biological indicators of benzenexposure and toxicity.
.1. Occupational exposure
Benzene has long been recognized as a carcinogen, and has beentrictly regulated in the workplace in the US and European Union,ith a current limit of 1 ppm (EU, 1997). Occupational exposure
o benzene usually occurs in industrial settings that heavily utilizeetroleum, petroleum fuel or other solvents. This includes factories,efineries and industrial structures involved in the production ofaint or organic chemicals (Wiwanitkit, 2006). Another category oforkers exposed to benzene are those in the shoemaking industry
Wang et al., 2006). Most exposure occurs due to use of chemicalsn an unregulated workplace (Snyder et al., 1993).
.2. Environmental exposure
Benzene is a ubiquitous environmental pollutant. Outdoor aironcentrations in select cities across the US ranged from 0.0005 to.006 ppm, and personal exposure to benzene in five US cities wasound to range from 0.0021 to 0.010 ppm (Wallace, 1989). A moreecent paper (Capleton and Levy, 2005) states that occupationalxposures to benzene have decreased, while environmental expo-ures are generally below 0.015 ppm. Ambient benzene exposures derived from a variety of sources including petroleum productsnd cigarette smoke. Ingestion of benzene through food or water issecondary source of exposure (Wallace, 1996).
Petroleum products are a major source of ambient benzeneSnyder et al., 1993) through emissions from gasoline vehicles andvaporative loss from gasoline filling stations (Fishbein, 1998; Bond,986). The benzene level in gasoline ranges from 5% in the US to0% in other countries. Traffic policemen, parking attendants, andas station attendants have been included in a number of stud-es (Fustinoni et al., 2005; Rossi et al., 1999; Verdina et al., 2001;hanvaivit et al., 2007; Manini et al., 2006; Carere et al., 2002;eopardi et al., 2003; Avogbe et al., 2005) due to their exposure
uring work hours.The other major source of environmental benzene exposure isigarette smoking (Best et al., 2001), for both first and second-and smokers. Median measured air benzene concentration was
ound to be 0.0023 ppm in homes without smokers, but this value
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ncreased 50% to 0.0034 ppm (Wallace, 1989) in homes with at leastne smoker. It has been estimated that smokers receive 90% of theirotal benzene exposure from smoking, and that their average bodyurden is 6–10 times that of non-smokers (Wallace, 1996).
It has been suggested that household items also contribute toumulative benzene concentrations in the indoor environment.aints, adhesives, marking pens, rubber products and tapes haveeen estimated to contribute overall 0.1–140 ppm (NASA, 1999).
.3. Health effects
Benzene exposure has been associated with a variety of healthffects, including hematological diseases. Benzene has been rec-gnized as a class I carcinogenic agent (WHO, 1993). Long-termccupational exposure has been associated with anemia, pancy-openia, aplasia (ASTDR, 1997), acute myeloid leukemia (Lan et al.,004; Chen et al., 2007; Yin et al., 1996; Verma and Tombe, 1999),yelodysplastic syndromes and non-Hodgkin’s lymphoma (Hayes
t al., 1997; Sorhan et al., 2005).A study on workers exposed to less than 1 ppm air benzene
howed a significant decrease in the number of white blood cellsWBC) (Lan et al., 2004). Another study showed that in some of theenzene-exposed workers who have developed chronic benzeneoisoning (CBP), WBC count remains below 4 × 109/l even yearsfter the workers have been removed from the source of exposureWan et al., 2006) suggesting that the biological effects of benzenexposure can be long lasting.
Benzene exposure typically occurs through inhalation; the mea-ure of benzene in blood or urine (Weisel et al., 1996; Brugnonet al., 1989; Perbellini et al., 1988) is utilized as a biomarker ofecent exposures (Weisel et al., 1996; Ashley et al., 1994). Detec-ion of either benzene or the products of its metabolism in bloodr urine can be used as markers of individual exposure. The healthffects of benzene may be mediated by intermediate genotoxic andytotoxic metabolites that induce DNA damage, including chro-osomal aberrations (CA), sister chromatid exchanges (SCE) andicronuclei (MN) formation (Erexson et al., 1985; Yager et al., 1990;
hang et al., 1993; Kim et al., 2004). The occurrence of benzeneetabolism within the bone marrow makes it particularly toxic to
he haematopoietic progenitor cells (Irons and Neptun, 1980; Ross,996; Snyder and Hedli, 1996).
.4. Biomarkers of exposure to benzene
Benzene metabolism begins in the liver where several enzymesonvert it into various metabolites including phenol, hydroquinoneHQ), catechol, s-phenylmercapturic acid (s-PMA), and trans,trans-
uconic acid (tt-MA). Since Both s-PMA and tt-MA are excreted in
he urine, they are the commonly measured biomarkers of exposureWeisel et al., 1996).Phenol has been found to be proportional to levels of exposure,hen the latter exceeds 1 ppm, up to 190 ppm (Weisel et al., 1996;
noue et al., 1986; Roush and Ott, 1985; Drummond et al., 1988).
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rinary tt-MA and s-PMA have been considered suitable biomark-rs for exposures in the range of 0.1–1 ppm (Ducos et al., 1990; Hotzt al., 1997). However, tt-MA is also produced from the metabolismf sorbic acid present in food, therefore its specificity is limited. Thealue of either of these urinary biomarkers to detect low levels ofnvironmental exposure is questionable (Weisel et al., 1996).
.5. Biomarkers of biological effect
Some benzene metabolites, including HQ, phenol and catechol,ccumulate in the bone marrow (Rickert et al., 1979) where theyndergo autoxidation or activation to toxic quinones (Greenleet al., 1981; Thomas et al., 1990; Levay et al., 1993; Irons, 1985).hrough redox cycling, quinones produce highly reactive oxygenpecies (ROS) (Sorensen et al., 2003; Halliwell and Gutteridge, 1999)hich may be responsible for cell damage.
Biomarkers of the biological effect of benzene include chromo-omal aberrations (CA) and aneuploidy, sister chromatid exchangesSCE), micronuclei (MN), and DNA strand breaks (SB). CA may be
easurable for many years after exposure, thus representing a pos-ible indicator of historical exposure (Forni, 1996). MN, DNA singletrand breaks (SSB) (Garte et al., 2005; Nilsson et al., 1996) andouble strand breaks (DSB) (Winn, 2003) can be produced by ben-ene metabolites (Robertson et al., 1991), however, their occurrences not specific to benzene (Au et al., 2005). SCE has been associ-ted with occupational exposure to benzene, but not with smokingCelik and Akbas, 2005), suggesting that this biomarker may note sensitive at lower benzene exposure, and that it does not occurpecifically as a result of benzene toxicity (Au et al., 2005).
.6. Susceptibility gene polymorphisms
Benzene metabolism occurs in two phases, first it is activatedy phase I enzyme, mainly cytochrome P450 2E1 (CYP2E1) intontermediate metabolites including phenol, HQ, catechol and 1,2,4-enzenetriol (Seaton et al., 1994); there is wide individual variation
n the activity of this liver enzyme (Seaton et al., 1994). Polymor-hisms have been reported in the RsaI and PstI restriction sites inhe promoter region of the gene, and in the DraI restriction site. Theariant types have been associated with both increased (Hayashit al., 1991) and decreased (LeMarchand et al., 1999) enzymaticctivity, thus making unclear what the overall effect of the poly-orphisms is on the enzymatic function of CYP2E1 (Qu et al., 2005).96-base-pair insertion in the 5′ flanking region has been associ-
ted with increased activity, but only when stimulated by alcoholr obesity (McCarver et al., 1998).
Intermediate metabolites reach the bone marrow whereyeloperoxidase (MPO) converts them into toxic quinones; 1,4-
enzoquinone in particular induces protein and DNA adducts androduces reactive oxygen species (Zhang et al., 2007). A G > A poly-orphism at the 463 locus decreases enzyme activity through loss
f a transcription binding site (Kiyohara et al., 2005; Piedrafita etl., 1996; Williams, 2001). The MPO 463G > A variant genotype haseen associated with a reduced risk of acute leukemia and thisas been attributed to the diminished activation of carcinogensroduced by this variant (Zhang et al., 2007).
Detoxification of the quinones can occur via NAD(P)H: quininexidoreductase-1 (NQO1) or via Glutathione s-transferases (GSTs).QO1 is responsible for the reduction of benzoquinones to less toxicihydroquinones (Ross et al., 2000), thus preventing oxidative dam-
ge (Nebert et al., 2000; Dalton et al., 1999), while the conjugationith glutathione operated by GSTs is responsible for the productionf less toxic compounds (Snyder et al., 1993; Ross, 1996). On thether hand, conjugation of benzene metabolites with glutathionean also give rise to toxic compounds (Bratton et al., 2000).
CQ2cT
Letters 182 (2008) 7–17 9
The NQO1 609C > T polymorphism is associated with loss ofnzyme activity in the TT homozygous variant (Traver et al., 1992),hile heterozygotes exhibit an intermediate activity. The NQO1
65C > T polymorphism is also thought to cause a reduction ofnzyme activity (Krajinovic, 2005).
Both Glutathione s-transferase TI (GSTT1) and Glutathione s-ransferase M1 (GSTM1) are involved in the detoxification ofenzene oxide to s-PMA (Snyder et al., 1993; Ross, 1996). A vari-tion consisting in the complete deletion of the gene obtains theoss of enzymatic activity (Alves et al., 2002; Seidegard et al., 1988;prenger et al., 2000). These deletions have been previously asso-iated with various forms of leukemia including acute myeloideukemia (Bolufer et al., 2006).
There are differences in the frequencies of variant allelesetween different geographic populations (Garte et al., 2001). Therequencies of these polymorphisms in healthy populations haveeen described for CYP2E1, GSTM1 and GSTT1 (Garte et al., 2001),or NQO1 (Zhang et al., 2003), and for MPO (Manuguerra et al., 2007;hen et al., 2007).
. Methods
A MEDLINE search was conducted up to September 2007, and articles on theole of the genes involved in benzene metabolism were identified. The followingenes were included in the search: NQO1, GSTT1, GSTM1, CYP2E1 and MPO. Theollowing search terms were used: “benzene AND (NQO1 OR NAD(P)H: quinonexidoreductase) OR (GSTT1 OR GSTM1 OR GST OR glutathione s-transferase) ORCYP2E1 OR cytochrome P450) OR (MPO OR myeloperoxidase)”.
Abstracts were reviewed to determine eligibility for inclusion. Only studiesonducted on adult healthy human subjects exposed to benzene which includedne or more genetic polymorphisms in on or more of the genes listed above wereelected. The studies must have also included the effect of the gene polymorphismn biomarkers of benzene exposure or effect. Studies that evaluated the effects ofpolymorphism on leukemia or other cancer endpoints were not included. Case-
eports and review articles were also excluded.Eight identified studies (Wang et al., 2002; Xu et al., 2003; Wan et al., 2002a,b;
hang et al., 2004; Sun et al., 2007; Chen et al., 2004, 2005; Gu et al., 2006) were notublished in English. When available, English-language abstracts were reviewed forhese publications. In six instances (Xu et al., 2003; Wan et al., 2002a,b; Zhang etl., 2004; Chen et al., 2004, 2005; Gu et al., 2006) the information provided in thebstract was sufficient to determine that the populations and/or results overlappedstudy published in an English-language journal. Therefore the English version wassed for this review. Two studies (Sorensen et al., 2004; Scheepers et al., 2002)ere conducted on the same population in Estonia, but reported results on different
ndpoints and different genes; the same was true for two studies conducted in ChinaHayes et al., 1997; Kim et al., 2007), and three studies conducted in Italy (Verdinat al., 2001; Carere et al., 2002; Leopardi et al., 2003). In all these instances, theopulation under study was described once, but all the various endpoints wereonsidered in the review.
The number of studies following the inclusion criteria was 22, with the majorityaving been conducted in China (n = 7, 31.8%) and Italy (n = 8, 36.7%). Populationharacteristics of the studies reviewed are summarized in Table 1. Exposure levelsre reported in part per million (ppm); when data were available as microgram/m3,he value was converted in ppm by dividing it by 3190.
. Results
.1. NQO1
Table 2summarizes the studies that have investigated NQO1.
.1.1. Biomarkers of exposureNine publications evaluated the relationship between the
QO1 609C > T polymorphism and the urinary metabolite tt-MAFustinoni et al., 2005; Rossi et al., 1999; Verdina et al., 2001;
hanvaivit et al., 2007; Sorensen et al., 2003; Garte et al., 2005;u et al., 2005; Kim et al., 2007). In one study (Sorensen et al.,003), subjects with the variant TT or CT genotypes had signifi-antly higher levels of tt-MA than subjects with the CC genotype.his population had particularly low levels of benzene environmen-
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Letters182
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Table 1Description of the studies included in this review.
Author (year) Country Number exposed Exposure level (ppm) Number unexposed Exposure level (ppm) Type of measure
Qu et al. (2005) China 130 Factory workers 0.06–122 (median 3.2) 51 Frequency matched by age, sex,smoking and drinking histories
Personal air monitor
Kim et al. (2004) China 82 Coke-oven employees TWA: 0.014–0.743 (geometric mean:0.557)
79, Matched by age and sex Individual monitor
Kim et al. (2007) and Lan etal. (2004)
China 250 Shoe workers <1: n = 119; 1–10: n = 110; >eq 10: n = 31 140 Clothing workers, frequencymatched by sex
<0.04, 0.512 (0.002–6.40)a Individual monitor
Hsieh et al. (1999) China 159 Caprolactam workers High exposure workers 149 Caprolactam workers Low exposure workers Job classificationXu et al. (1998) China 23 Painters in glass factory 0.71 ± 0.6 22 Machine shop workers 0.03 ± 0.02 Personal samplingChanvaivit et al. (2007) Thailand 31 Factory laboratory workers;
31 gas station attendants0.0024 ± 0.0058; 0.112 + 0.0139; lab:0.0266 + 0.0054; gas: 0.0468 + 0.0051
34 Mail sorters 0.00139 ± 0.00017;0.00073 + 0.000007
Personal air monitorambient air measures
Manini et al. (2006) Italy 37 Taxi drivers 1.85 ± 0.53; 2.41 + 0.63 Personal monitoring cabmonitoring
Testa et al. (2005) Italy 25 male car-painters 0.0031 ± 0.0055 (0.00047–0.0167) 37 Males usual blood donorsmatched by age
Ambient air measures
Fustinoni et al. (2005) Italy 78 Gas-station attendants; 77urban policemen; 152 busdrivers
0.0197 (0.0035–0.1542); 0.0071(0.0029–0.1019); 0.0068(0.0019–0.0297)
Office workers; 58 from Milan, 49from Genova matched by gender,age, and smoking
0.0019 (<0.0019–0.0371);0.0029 (0.0019–0.0148)
Personal air sampling
Avogbe et al. (2005) Africa 29 Taxi drivers; 37 roadsideresidents; 42 suburbanresidents
0.039 (0.0216–0.0706); 0.0129(0.0084–0.02); 0.0042 (0.0023–0.0087)
27 Rural controls 0.0006 (0.0001–0.0013) Estimated from urinarys-PMA
Garte et al. (2005) and Garteet al. (2008)
Bulgaria 158 Petrochemical workers 1.75 ± 3.6 50, Matched by gender, age, andsmoking
0.02 ± 0.09 Personal monitoring
Sorensen et al. (2004) andScheepers et al. (2002)
Estonia 50 Male underground oil shaleminers
0.0613 ± 0.0161; 0.091 + 0.004 50 Male surface workers 0.037 ± 0.0113;0.041 + 0.008;0.0091 + 0.00094
Personal samplingfixed-location samplingambient-air
Leopardi et al. (2003), Carereet al. (2002)b and Verdinaet al. (2001)c
Italy 134 Traffic policemen TWA: 0.0031 ± 0.0035 58 Office policemen TWA: 0.0012 ± 0.00047 Personal monitor
Sorensen et al. (2003) Denmark 40 Volunteers 0.0008 Personal samplingPitarque et al. (2002) Bulgaria 52 Shoe factory workers N/A 36 Controls N/A Job classificationBergamaschi et al. (1999) Italy 24 Cyclists Rural routes: 0.002 (0.0012–0.004);
urban routes: 0.0155 (0.0073–0.027)Personal sampling
Rossi et al. (1999) Italy 59 Bus drivers 0.0265 (0.0105–0.0471) Personal sampling
a Overall median.b 133 Traffic policemen, 57 office policemen.c 118 Traffic policemen, 51 office policemen.
D. Dougherty et al. / Toxicology Letters 182 (2008) 7–17 11
Table 2Summary of the results on the effect of metabolic gene polymorphisms on biomarkers levels.
Polymorphic site Ref. Outcome analyzed Analysis performed Effect of genotypeon outcome
Genotypes associated withchanges in biomarker levels
Biomarkers of exposureMPO
642G > A 92 tt-MA, s-PMA, phenol, CA, HQ – Not discussed –
NQO1609C > T 11 tt-MA-baseline (�g/l) – No –609C > T 12 tt-MA (log/U-benzene) – No –609C > T 51 tt-MA (�g/24 h) – Yes CT vs. CC609C > T 92 tt-MA (�mol/l) Multivariate No –609C > T 13 Average ln (TMA)/blood benzene – No –
609C > T 14 EOS tt-MA (mg/g creatinine) Non-exposed No –Lab workers NoGas attendants No
609C > T 63 EOS tt-MA (mg/g creatinine) – No –609C > T 54 EOS tt-MA (mg/g creatinine) – No –609C > T 11 EOS tt-MA (�g/l) – No –609C > T 92 s-PMA (�mol/l) Multivariate Yes CC vs. CT/TT609C > T 13 Average ln (s-PMA)/blood benzene – No –609C > T 63 s-PMA (�g/g creatinine) – No –609C > T 12 s-PMA (log*1000/U-benzene) – Yes TT vs. CT/CC609C > T 51 s-PMA (�g/24 h) – Yes CT vs. CC609C > T 15 EOS s-PMA (�g/g creat.) – Not discussed –609C > T 11 EOS s-PMA (�g/l) – No –609C > T 54 EOS s-PMA (�g/g creat.) – No –609C > T 11 U-benzene-baseline (ng/l) – No –609C > T 92 Phenol (�mol/l) Multivariate Yes CC vs. CT/TT609C > T 63 Phenol – No –
CYP2E1CYP2E1*5 11 tt-MA-baseline (�g/l) – Yes WV/VV vs. WW
Multivariate Yes WV/VV vs. WW
CYP2E1*6 11 tt-MA-baseline (�g/l) – Yes WV/VV vs. WWCYP2E1*5 92 tt-MA (�mol/l) Multivariate Yes WW vs. WV/VVCYP2E1*5 13 Average ln (TMA)/blood benzene – No –CYP2E1*6 11 EOS tt-MA (�g/l) – No –CYP2E1*6 63 EOS tt-MA (mg/g creatinine) – No –CYP2E1*5 11 EOS tt-MA (�g/l) Adjusted No –
CYP2E1*5 14 EOS tt-MA (mg/g creatinine) Non-exposed No –Lab workers NoGas attendants No
CYP2E1*5 63 EOS tt-MA (mg/g creatinine) – No –CYP2E1*5 63 s-PMA (�g/g creatinine) – No –CYP2E1*6 63 s-PMA (�g/g creatinine) – No –CYP2E1*5 92 s-PMA (�mol/l) Multivariate No –CYP2E1*5 13 Average ln (s-PMA)/blood benzene – No –CYP2E1*6 11 EOS s-PMA (�g/l) – No –CYP2E1*5 11 EOS s-PMA (�g/l) Adjusted No –
CYP2E1*5 14 Blood benzene (ppt) Non-exposed No –Lab workers NoGas attendants No
CYP2E1*6 11 U-benzene-baseline (ng/l) – No –CYP2E1*5 11 U-benzene-baseline (ng/l) Multivariate Yes WW vs. WVCYP2E1*6 11 EOS U-benzene (ng/l) – No –CYP2E1*5 11 EOS U-benzene (ng/l) Multivariate Yes WW vs. WVCYP2E1*6 63 Phenol – No –CYP2E1*5 63 Phenol – No –CYP2E1*5 92 Phenol (�mol/l) Multivariate Yes WW/WV vs. VV
GSTT1GSTT1 13 Average ln (TMA)/blood benzene – No –GSTT1 90 tt-MA (mg/mol creat.) – No –GSTT1 51 tt-MA (�g/24 h) – No –GSTT1 12 tt-MA (log/U-benzene) – Yes Null vs. non-nullGSTT1 14 EOS tt-MA (mg/g creatinine) – No –GSTT1 63 EOS tt-MA (mg/g creatinine) – No –GSTT1 13 Average ln (s-PMA)/blood benzene – No –
GSTT1 18 s-PMA Taxi-drivers Yes Non-null vs. nullRoadside Yes Non-null vs. nullSuburban Yes Non-null vs. nullRural Yes Non-null vs. null
12 D. Dougherty et al. / Toxicology Letters 182 (2008) 7–17
Table 2 (Continued )
Polymorphic site Ref. Outcome analyzed Analysis performed Effect of genotypeon outcome
Genotypes associated withchanges in biomarker levels
GSTT1 91 s-PMA – Yes Non-null vs. nullGSTT1 63 s-PMA (�g/g creatinine) – Yes Non-null vs. nullGSTT1 90 s-PMA (�g/mol creatinine) – No –GSTT1 51 s-PMA (�g/24 h) – No –GSTT1 92 s-PMA (�mol/l) Multivariate Yes Non-null vs. nullGSTT1 12 s-PMA (log*1000/U-benzene) – No –GSTT1 15 EOS s-PMA (�g/g creatinine) – Not discussed –GSTT1 63 Phenol – No –
GSTM1GSTM1 13 Average ln (TMA)/blood benzene – No –GSTM1 90 tt-MA (mg/mol creat.) – Not discussed –GSTM1 51 tt-MA (�g/24 h) – No –GSTM1 12 tt-MA (log/U-benzene) – No –
GSTM1 96 tt-MA (�g/g creat.) Pre-run No –Post-run Yes
GSTM1 13 Average ln (s-PMA)/blood benzene – No –GSTM1 91 s-PMA – Not discussed –GSTM1 90 s-PMA (�g/mol creatinine) – Not discussed –GSTM1 51 s-PMA (�g/24 h) – No –GSTM1 92 s-PMA (�mol/l) Multivariate No –GSTM1 12 s-PMA (log*1000/U-benzene) – No –
GSTM1 15 EOS s-PMA (�g/g creatinine) – Yes Non-null vs. nullSmokers No –Non-smokers No –
Biomarkers of effectMPO
463G > A 23 WBC count Non-exposed No –Exposed Yes AG/AA vs. GG
463G > A 93 SSB No
NQO1609C > T 23 WBC count Non-exposed No –
Exposed Yes CT vs. CC
465C > T 23 WBC count Non-exposed No –Exposed No –
609C > T 16 SCE (mean, per cell) – Not discussed –609C > T 54, 93 SSB – Yes CT/TT vs. CC609C > T 17 MN – Not discussed –609C > T 92 Catechol (�mol/l) Multivariate Yes CC vs. CT/TT609C > T 92 HQ (�mol/l) Multivariate Yes CC vs. CT/TT
CYP2E1CYP2E1*5 23 WBC count Non-exposed No –
Exposed No –
CYP2E1*5 17 MN – Not discussed –
CYP2E1*5 16 SCE (mean, per cell) Non-exposed No –Non-exposed No –Smokers No –Non-smokers Yes WW vs. WV
CYP2E1*5 92 Catechol (�mol/l) Multivariate No –CYP2E1*5 92 HQ (�mol/l) Multivariate Yes WW vs. WV/VVCYP2E1*5 93 SSB No
GSTT1GSTT1 100 Low WBC count (<5 × 103/�l) – No –GSTT1 97 CA (%) – Not discussed –GSTT1 17 MN – Not discussed –GSTT1 97 MN (%) – Not discussed –GSTT1 16 SCE (mean, per cell) – Not discussed –GSTT1 97 SCE (mean, per cell) – Not discussed –
GSTT1 98 SCE (mean, per cell) Exposed No –Unexposed No –Regression, all sample No –Regression, smokers No –Regression, non-smokers No –
GSTT1 98 DEB-induced SCE Exposed Yes Null vs. non-nullUnexposed Yes Null vs. non-nullRegression, all sample Yes Null vs. non-null
D. Dougherty et al. / Toxicology Letters 182 (2008) 7–17 13
Table 2 (Continued )
Regression, smokers Yes Null vs. non-nullRegression, non-smokers Yes Null vs. non-null
GSTT1 93 SSB Yes Null vs. non-null
GSTM1GSTM1 100 Low WBC count (<5 × 103/�l) – No –GSTM1 97 CA (%) – Not discussed –GSTM1 17 MN Multivariate Yes Non-null vs. nullGSTM1 97 MN (%) – No –
GSTM1 99 MN (per 1000 cells) Non-smokers Yes Exposed vs. non-exposed, innulls
Smokers Yes Exposed vs. non-exposed, innulls
GSTM1 97 SCE (mean, per cell) – Not discussed –GSTM1 16 SCE (mean, per cell) – Not discussed –
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al exposure (0.0008 ppm); this was also the only study to evaluatet-MA excretion over a period of 24 h.
Eight studies quantified the effect of the NQO1 genotype on s-MA excretion (Fustinoni et al., 2005; Rossi et al., 1999; Verdinat al., 2001; Manini et al., 2006; Sorensen et al., 2003; Garte etl., 2005; LeMarchand et al., 1999; Kim et al., 2007). Two of themRossi et al., 1999; Kim et al., 2007) reported that the CT and TTenotypes were associated with significant decreases in s-PMA inomparison to the CC wild-type subjects. However, another studyeported a significant increase in s-PMA excretion in CT heterozy-otes relative to CC subjects (Sorensen et al., 2003), a result thatoes not follow the prediction of a reduction in the urinary excre-ion of metabolites in the presence of an NQO1 polymorphism thateduces the gene activity. The population under study was smalln = 40), and exposed to very low levels of benzene (0.0008 ppm).owever, another study conducted on a population exposed touch higher benzene levels (1.8 ppm) did not report any effect of
he NQO1 polymorphism on s-PMA levels (Garte et al., 2005). Ithould be noted that NQO1 is not directly involved in the pathwayseading to production of these urinary metabolites, which mightxplain the diverse findings from different laboratories.
The influence of NQO1 polymorphisms on phenol was evaluatedn two studies (Qu et al., 2005; Kim et al., 2007). Kim et al. observed aecrease in phenol excretion with the CT and TT genotypes, whereasu et al. reported no effect of these genotypes on the metabolite.nly the analysis by Kim et al. involved adjustment for sex, age,
moking and body mass index (BMI).Two studies (Manini et al., 2006; Fustinoni et al., 2005) consid-
red the effect of NQO1 609C > T on urinary benzene, but neitherbserved a significant influence of the CT heterozygous nor TTomozygous genotype relative to CC wild type individuals on uri-ary benzene. Both populations were exposed to very low levels ofenzene (<0.02 ppm).
.1.2. Biomarkers of effectHeterozygosity for the NQO1 609C > T polymorphism has also
een associated with a reduction in peripheral WBC count in com-arison to CC wild-type subjects upon exposure to benzene in onetudy (Lan et al., 2004). However, no effect on WBC was observedith the 465C > polymorphism.
The T variant of the NQO1 609C > T polymorphism has beenssociated with a significant increased frequency of SSB (Garte etl., 2005, 2008). Kim et al. (2004) observed a greater likelihood ofranslocations in TT subjects compared to CC, and a significantlyncreased rate of monosomy 8 and 21 in a multivariate model. This
oihi
s No –No –
No
opulation was exposed to an average of 0.512 ppm benzene. In aultivariate model, the TT homozygotes had a reduced excretion ofQ (Kim et al., 2007) relative to other genotypes. Studies on popu-
ations with much lower benzene exposure (0.0031 ppm), reportedo effect of the NQO1 609C > T polymorphism on SCE or MN (Careret al., 2002; Leopardi et al., 2003).
.1.3. Benzene poisoningAlthough not strictly a biomarker, benzene poisoning has been
sed as a clinical endpoint to investigate the role of metabolic geneolymorphisms in mediating the toxic effects of benzene. Threetudies found a significant increase in the odds for chronic ben-ene poisoning for the NQO1 TT homozygotes (Chen et al., 2007;othman et al., 1997; Wan et al., 2002a,b).
.2. CYP2E1
.2.1. Biomarkers of exposureFustinoni et al. (2005) (Table 2) reported a significantly
ncreased excretion of tt-MA in heterozygous subjects relative toild-type homozygotes for the CYP2E1*5 allele. This association
emained significant after adjustment for several covariates. Theame study also reported a significantly increased tt-MA excretionmong CYP2E1*6 variant homozygotes and heterozygotes relativeo the wild-type homozygotes. However, *5/*5 variant homozy-otes for the CYP2E1*5 polymorphism were found to have reducedt-MA excretion relative to the homozygous wild-type subjects innother study (Kim et al., 2007). Additional publications on otherYP2E1 polymorphic variants did not report any significant effectf the gene variants on tt-MA (Fustinoni et al., 2005; Verdina et al.,001; Chanvaivit et al., 2007; Qu et al., 2005).
No associations were detected between CYP2E1*5 or CYP2E1*6olymorphisms and s-PMA excretion (Fustinoni et al., 2005;erdina et al., 2001; Qu et al., 2005; Kim et al., 2007) or bloodenzene (Chanvaivit et al., 2007). Significantly decreased levelsf urinary benzene were detected in one study (Fustinoni et al.,005) and were associated with the heterozygous CYP2E1*5 vari-nt polymorphism relative to the wild-type homozygous subjects.owever, this effect was only detected in end-of-shift (EOS) urinaryenzene; no effect was found with the CYP2E1*6 variant allele.
Two studies (Qu et al., 2005; Kim et al., 2007) evaluated the effectf the polymorphism CYP2E1*5 on phenol. One reported a signif-cant decrease in phenol with the TT genotype relative to the CComozygous wild-type genotype after adjusting for sex, age, smok-
ng and BMI (Kim et al., 2007). The CYP2E1 DraI polymorphism was
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ot found to be associated with phenol levels in another publica-ion (Qu et al., 2005). The CYP2E1 RsaI 1054 C > T polymorphism wasssociated with a reduced level of HQ in TT homozygous subjectselative to the CC homozygotes.
.2.2. Biomarkers of effectNo associations were reported between CYP2E1 polymorphisms
nd WBC count, MN, SCE, catechol or SSB (Carere et al., 2002;eopardi et al., 2003; Lan et al., 2004; Kim et al., 2007; Garte etl., 2008).
.3. GSTT1 and GSTM1
Nineteen of the 22 (86.4%) studies reviewed have investigatedhe effects of the GSTT1 or GSTM1 deletion on a variety of endpoints.hese have been summarized in Table 2.
.3.1. Biomarkers of exposureEight studies (Rossi et al., 1999; Verdina et al., 2001; Manini et
l., 2006; Avogbe et al., 2005; Sorensen et al., 2003; Qu et al., 2005;orensen et al., 2004; Scheepers et al., 2002) evaluated the effectf the GSTT1 null on the excretion of s-PMA. Four of them (Avogbet al., 2005; Qu et al., 2005; Sorensen et al., 2004; Kim et al., 2007)etected a significant reduction in the excretion of s-PMA in sub-
ects with the null genotype. One did not report specific results onSTT1 (Manini et al., 2006), the remaining failed to detect any effectf the GSTT1 deletion on s-PMA. The ability to detect a change in s-MA levels with the GSTT1 deletion does not seem to be dependentn the level of exposure. The exposure of the populations in whichn effect of GSTT1 deletion was observed ranged from 0.0006 to22 ppm; among those that did not detect an effect, the highestxposure level was 0.0613 ppm. However, most of the studies hadmall sample sizes. Three of the four studies showing a significantffect of GSTT1 null genotype on the urinary endpoint includeddjustment for potential confounders such as age, sex, exposureevel, and BMI. None of the studies that failed to detect an effecteported adjusted measures of association.
Seven studies evaluated the effect of GSTM1 null on s-PMARossi et al., 1999; Verdina et al., 2001; Manini et al., 2006; Sorensent al., 2003, 2004; Scheepers et al., 2002; Kim et al., 2007). Twof them (Manini et al., 2006; Kim et al., 2007) showed significanteductions in s-PMA levels to be associated with the GSTM1 nullenotype using multivariate models. Studies that failed to detect anffect of the GSTM1 null genotype on s-PMA levels did not utilizeither stratification or multivariate models.
Six studies evaluated the association between GSTT1 null andt-MA (Rossi et al., 1999; Verdina et al., 2001; Chanvaivit et al.,007; Qu et al., 2005; Sorensen et al., 2004; Kim et al., 2007). Kim etl. (2007) evaluated various polymorphisms, including the GSTT1eletion, and tt-MA levels using a multivariate approach. However,o results were reported on this gene. Of the remaining studies,nly one reported a significant increase in tt-MA excretion associ-ted with the GSTT1 homozygous null genotype when compared tohe heterozygous or wild-type genotypes (Rossi et al., 1999). Thistudy included a relatively small sample of 59 bus drivers exposedo levels of benzene that were intermediate to that of the other
tudies being compared.The effect of the GSTM1 null on tt-MA was evaluated in six stud-es (Rossi et al., 1999; Verdina et al., 2001; Sorensen et al., 2003,004; Kim et al., 2007; Bergamaschi et al., 1999). Kim et al. (2007)eported no effect of the deletion on tt-MA; Bergamaschi et al.1999) reported the only significant effect of GSTM1 on tt-MA forpost-exercise” measurements in a group of 29 urban cyclists.
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Letters 182 (2008) 7–17
.3.2. Biomarkers of effectVarious intermediate end-points have been studied in relation
o GST enzymes. The effect of GSTT1 on SCE was evaluated in threeopulations (Carere et al., 2002; Testa et al., 2005; Xu et al., 1998).STT1 null was not associated with the frequency of SCE in anyf the studies. However, the frequency of diepoxybutane (DEB)-nduced SCE was significantly increased in GSTT1 null subjects, andhis association did not change when the population was strati-ed by smoking or exposure status (Xu et al., 1998). No significantffects on SCE frequency were found with the GSTM1 deletionCarere et al., 2002; Testa et al., 2005; Pitarque et al., 2002).
No associations were detected between either the GSTM1 orSTT1 null and WBC count (Hsieh et al., 1999). Testa et al. (2005)id not find an effect of either of these variant genotypes on CA,owever, Kim et al. (2004) reported an increased occurrence of CA
n subjects carrying the null genotype of both GSTM1 and GSTT1elative to the heterozygotes or non-null individuals.
GSTT1 deletion was not reported to be associated with the fre-uency of MN (Chanvaivit et al., 2007; Chen et al., 2004). GSTM1ull subjects who were occupationally exposed to benzene were
ound to have a higher frequency of MN than controls (Pitarquet al., 2002). However, in another study (Leopardi et al., 2003) theSTM1 null genotype was associated with a decreased frequencyf MN. One further study reporting on this association found noffect of the genotype on MN (Testa et al., 2005). The GSTT1 dele-ion was reported to be associated with increased SSB, whereas noffect was seen with GSTM1 genotype (Garte et al., 2008).
.4. MPO
Only three studies have examined the role of MPO polymor-hisms on biomarkers of benzene exposure or toxicity (Table 2).im et al. (2007) analyzed the effects of the MPO 624G > A poly-orphism on tt-MA, s-PMA, phenol levels, catechol and HQ levels,
nd did not find any significant association.The 463G > A polymorphism was found to be protective against
reduction of white blood cell (WBC) count resulting from ben-ene exposure. In the exposed population the WBC reduction wasess severe in subjects with the AG or AA genotypes than in GGomozygous subjects (p = .04) (Lan et al., 2004). It has to be notedhat benzene exposure was fairly low in this population, with 109ubjects exposed to less than 1 ppm, and 110 exposed to valuesetween 1 and 10 ppm. Only 31 individuals experienced exposuresreater than 10 ppm. No effect was seen for MPO gene variants onSB (Garte et al., 2008).
. Discussion
The results of the current review seem to indicate a modest effectf the studied gene polymorphisms on the analyzed biomarkers.he only genes that showed some consistent associations with bothiomarkers of exposure and effect are GSTM1 and GSTT1.
The majority of studies showing an association between GSTsnd biomarkers of exposure are consistent with the biological func-ion of these enzymes, which are thought to act in the pathwayesulting in the production of s-PMA; lack of the GSTT1 or GSTM1nzymes would prevent completion of this pathway. Similarly,iomarkers of effect tend to be higher in subjects with the reducedSTs function, confirming the hypothesis that subjects with the null
enotype for GSTT1 or GSTM1 would be less resistant to benzeneoxicity.The effects of CYP2E1 polymorphisms on benzene biomarkersre not completely clear. Most studies failed to find any effect ofYP2E1 on biomarkers of exposure or effect. Among the studies
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hat did report positive results, the findings were somewhat con-radictory. This may be due, in part, to the highly polymorphicature of this gene, which leads to a wide range of enzyme activity
evels between individuals. In addition, several environmental fac-ors influence CYP2E1 transcription (LeMarchand et al., 1999), thusompeting with benzene exposure.
Some of the observed results are inconsistent with what pre-icted by the known changes in gene activity introduced by aertain polymorphism. For example, a reduced NQO1 activityroduced by the polymorphism should be accompanied by theeduction in the urinary excretion of metabolites, but this was notonfirmed by a study that measured s-PMA (Sorensen et al., 2003).owever, the very small sample size, the very low levels of ben-ene exposure (0.0008 ppm), and the threshold of sensitivity of theiomarker could be responsible for this unexpected result. Sim-
larly, studies involving biomarkers of benzene effect and NQO1olymorphisms report contradictory results in the few analyseshat showed a role of this gene on benzene toxicity.
There are very few studies on MPO polymorphisms and benzenexposure. The results are consistent with the predicted reducednzymatic activity of the MPO 463G > A polymorphism, whichould result in fewer toxic metabolites being produced in the bonearrow, and ultimately less damage to WBCs.Among the limitations of the current literature is the fact that
tudies utilize a small population size, thereby limiting the abil-ty to accurately detect associations, and to compare the findings
ith larger studies. The ability to detect a significant effect is alsoffected by the sensitivity of the biomarker. For instance, it is knownhat s-PMA is not particularly sensitive at exposures of less than1 ppm, and that biomarkers resulting from DNA damage are subjecto background levels.
A significant barrier to drawing conclusions from these studiess the lack of comparison among study designs, among the methodstilized for biomarker detection, and among the cut offs used forata analysis. Another important issue is that benzene exposuref the individual study populations spans a wide range, as doesumulative exposure time and polymorphism frequencies. Addi-ionally, the methodologies for defining exposure are inconsistentetween studies, and in some populations exposure has not beeneasured at all, but has been indirectly derived by job classification.
his information is critical in order to perform meaningful compar-sons between populations with similar exposure levels, especiallyn light of the fact that different metabolic mechanisms may existt high and low benzene exposure (Weisel et al., 1996).
A wide range of benzene exposure in occupational setting iseported in the studies reviewed here. In a study involving workersrom various factories, exposures ranged from 0.06 to 122 ppm (Qut al., 2005). The median exposure in a group of coke-oven employ-es was 0.557 ppm (Kim et al., 2004). Among shoe factory workers,4% of them had a personal exposure of <1 ppm, while another 44%as exposed to values between 1 and 10 ppm, and the remainingas exposed to more than 10 ppm (Lan et al., 2004). A group ofetrochemical workers was exposed to an average of 1.8 ppm ben-ene, with a maximum exposure of 22 ppm (Garte et al., 2005); aopulation of underground oil shale miners was exposed to lesshan 1 ppm (Sorensen et al., 2004), painters in a glass factory werexposed to 0.71 ppm (Xu et al., 1998).
Some studies were able to detect associations only after adjust-ent for covariates such as age, sex, smoking status; these baseline
haracteristics of the population should be available from all the
tudies. Smoking, in particular, can significantly increase personalxposure to benzene; if this variable is not considered, then signif-cant effects of gene polymorphisms may be masked.Behavioral factors may also play a role in benzene exposurend/or metabolism. For instance, Bergamaschi et al. (1999) detected
A
A
Letters 182 (2008) 7–17 15
hanges in tt-MA levels with GSMT1 deletion only after the cyclists’un. Although this may be the result of exposure to benzene dur-ng bicycling, it may also be due to the influence of exercise on
etabolic gene transcription/enzyme activity. Similarly, lifestyleactors such as obesity can also influence the effects of benzenexposure, possibly through changes in transcription levels of genesnvolved in benzene metabolism (Kim et al., 2007). Therefore theseariables should also be considered in future studies.
Another limitation of the current published literature is thenalysis of one SNP at a time, while the final amount of toxicetabolites produced as result of exposure is likely to be affected by
ll the enzymes in the metabolic pathways. For instance, CYP2E1ontributes to the production of toxic compounds, and NQO1 isnvolved in detoxification; polymorphisms which render CYP2E1
ore active and NQO1 less active would be expected to result inxcessive accumulation of toxic products and in detectable changesn biomarker levels accordingly. Studies involving multiple genesesting in relation to biomarkers of benzene exposure or effectould be very useful at this point.
Another important issue is the inclusion of populations withery different ethnic backgrounds; some of the differences in find-ngs can be attributed to ethnic differences in the distribution ofolymorphisms that influence the benzene metabolism.
. Summary
Overall, this review shows that multiple genetic polymorphismsn the benzene metabolism pathway should be taken into accounthen studying the biological effects of benzene exposure. While it
s possible to predict the effects that certain polymorphisms mayave on the biological effects of a certain level of benzene exposure,he literature is inconsistent and sparse. Future research shouldake care of collecting and reporting all relevant information onersonal life style behavior and environmental exposure. This is ofarticular importance for evaluating the effects of long-term and
ow-level exposure to benzene to which the population at large isxposed. The existing literature suggests that this type of exposureay have a significant public health impact, and that unique com-
inations of genetic polymorphisms may increase susceptibility ofndividuals and/or population subgroups. However, the relation-hips are as yet unclear and must be confirmed with well-designedtudies that incorporate multiple biological end-points and multi-le genes.
onflict of interest
None.
cknowledgments
This work was partially supported by grant number 2430 fromhe ACC.
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