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EFFECT OF THE GSTM1 GENOTYPE ON THE BIOMARKERS OF EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS: META-ANALYSIS.

INTRODUCTION

There is much evidence showing that exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with an increase in the incidence of respiratory and cardiovascular diseases and lung cancer in populations from occupational [1,2] as well as non-occupational environments [3-6]. Polycyclic aromatic hydrocarbons are formed during incomplete combustion processes and are released into ambient air due to industrial emissions, vehicle exhaust, domestic heating and cigarette smoking which emit a wide variety of genotoxic agents [7-9]. Occupationally exposed populations, such as coke oven workers, chimney sweeps, traffic police, professional drivers, street vendors and ecological operators, have more opportunities for exposure to PAHs. As a family of semi-volatile organic compounds, PAHs concurrently have both aerosol particulate and gas phases and may be cumulated in the house dust. Therefore, PAH exposure is very common for the general population, especially for young children [10].

Biomarkers of internal exposure to PAHs include urinary 1-hydroxypyrene (1-OHP) [11,12], and PAH-DNA (deoxyribonucleic acid) and PAH-protein adducts, and in effect biomarkers include DNA damage, chromosomal aberrations, sister chromatid exchanges and micronuclei. 1-Hydroxypyrene, a metabolite of the PAH pyrene [13], is considered the main biomarker currently available for measuring exposure to PAHs. This is because pyrene is present in high amounts in all mixtures of PAHs, and the correlation between external pyrene exposure and internal 1-OHP levels has been shown [14].

After metabolic activation catalyzed by a series of enzymes, some PAHs bind covalently to DNA to form the damaging DNA-PAH adducts [15]. Deoxyribonucleic acid adduct is considered to be a biomarker of carcinogen exposure, and to some extent, reflects individual susceptibility [16-18]. The measurement of bulky DNA adducts in white blood cells have been shown in human to correlate with the level of PAHs in lung tissue [19,20].

Activated PAHs in the human body are detoxified by phase II enzymes such as glutathione S-transferase M1 (GSTM1), which makes PAH metabolites, such as 1-OHP, more water soluble and suitable for excretion [21]. Glutathione S-transferase M1 has well-defined null and active genotypes, and it has been reported that the null GSTM1 genotype causes a homozygous deletion that could result in functional loss of this enzyme [22]. Hence, the ability of null GSTM1 carriers to eliminate PAH metabolites is reduced; therefore, for individuals with this genotype, the PAH biomarker levels are generally higher [23].

Liu et al. [24] were the first to conduct a meta-analysis to investigate the influence of the GSTM1 genotype on the formation of DNA adducts. Their results showed that the DNA adduct levels in null GSTM1 carriers were significantly higher than those in active GSTM1 carriers among workers who were occupationally exposed to PAHs. However, in this meta-analysis, 2 important occupational field studies [25,26] that met the inclusion criteria were not included. Moreover, one of the studies included did not investigate the bulky adduct but the benzo[a]pyrene diol epoxide adduct. The detection methods for these 2 kinds of adducts are completely different, and it has concurrently been shown that the bulky adduct is a better biomarker when both environmental exposure and exposure as a result of lifestyle habits, such as smoking, are considered [27]. Polycyclic aromatic hydrocarbons exposure causes DNA adduct formation and DNA oxidation, which eventually leads to DNA damage [28] and may result in chromosome loss or chromosome breakage, and genetic instability, and might eventually trigger cancer. Micronucleus frequency in peripheral blood lymphocytes has been used as a sensitive biomarker of chromosomal damage, genetic instability and even cancer risk [29,30]. Therefore, the micronucleus frequency in peripheral blood lymphocytes is a potential effect biomarker of PAH exposure.

Given that there clearly is the need for better measures of exposure in both occupational workers and non-occupationally exposed general population for improving the quantitative risk assessment of PAHs, in this study we have performed a meta-analysis on the level of bulky adducts present in white blood cells as a biomarker of PAHs. As stated before, the previous meta-analysis by Liu et al. [24] did not include 2 important occupational field studies. Moreover, as reports on the influence of the GSTM1 status on the 1-OHP level and micronucleus frequency have been inconsistent, our other aim has been to determine the robustness of 1-OHP and micronucleus frequency as biomarkers in active GSTM1 as well as null carriers.

METHODS

Because of the heterogeneity of the included studies, both the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) were used [31,32].

Search strategy and data collection

Relevant publications were searched for in 2 frequently-used on-line databases--PubMed and Web of Science --from January 1994 to March 2015. The literature search was conducted in April 2015 and the search terms used were "1-OHP" (or "1-hydroxypyrene"), "DNA adducts" (or "aromatic DNA adducts"), "micronucleus frequency", "GSTM1 polymorphism" (or "glutathione S-transferase M1"), and "PAH" (or 'polycyclic aromatic hydrocarbons"). Only papers published in English were collected. All the literature was reviewed by 2 independent reviewers. Then, articles that met the following specific inclusion and exclusion criteria were included in the meta-analysis.

Inclusion and exclusion criteria

Inclusion criteria:

--the study must compare the 1-OHP in urine, DNA adduct levels and micronucleus frequency in peripheral blood lymphocytes of subjects with active GSTM1 and null GSTM1 carriers between occupationally exposed workers and the non-occupationally exposed population;

--the study must clearly describe the GSTM1 genotyping method and equipment and the method and equipment for the measurement of 1-OHP, DNA adduct, and micronucleus frequency.

Exclusion criteria:

--family-based studies, reviews, abstracts, comments, editorials and letters were excluded;

--studies with incomplete or overlapping data were excluded;

--finally, studies that did not use high-pressure liquid chromatograph (HPLC), 32P-post-labeling assay, and cytokinesis-block micronucleus (CBMN) assay for the detection of 1-OHP, DNA adduct and micronuclei frequency, respectively, were also excluded.

Statistical analysis

The meta-analysis was performed using the RevMan software (version 5.3, Cochrane Community, London, UK) and STATA software (version 11.0, STATA Corp., College Station, USA). The 1-OHP and DNA adduct levels and micronuclei frequency were used in the analysis only in the mean and standard deviation form. For articles that provided the median and range values, the mean and standard deviation were calculated using the formula provided by Hozo et al. [33]. The transferring method provided by Higgins et al. [34] for the geometric mean or related parameters was applied.

The random-effects model and fixed-effects model were used for combining the results of the meta-analysis. The standardized mean difference (SMD) in the groups of each study and the overall SMD were calculated. The corresponding 95% confidence intervals (CIs) were also computed. Heterogeneity and variance among studies were evaluated using the [Chi.sup.2] test (with a significance level set at p < 0.10), and the inconsistency index ([I.sup.2]) was also calculated ([I.sup.2] > 50% suggesting substantial heterogeneity). Then, the appropriate effect model was chosen according to the results of the heterogeneity test, and the publication bias was determined using Egger's test and the funnel plot analysis.

RESULTS

Study selection

We obtained 78 studies that met the study criteria of 1-OHP. An additional article was found by a hand search. After reviewing the full texts, we only included articles that used HPLC for detecting 1-OHP. Eleven studies were finally included in the meta-analysis [35-45]. Table 1 lists these studies and their main features.

We found 155 articles on the DNA adduct levels, GSTM1 polymorphisms and PAH exposure, including 2 papers that were found after a hand search. After all the articles were reviewed, the measurement of bulky PAH-DNA adduct levels in white blood cells using the 32P-Postlabeling assay was additionally included as an inclusion criterion. Finally, 9 eligible studies were included in this meta-analysis (Table 2) [25,26,38,46-51]. In total, 56 papers that investigated the micronucleus frequency, GSTM1 polymorphisms and exposure to PAHs were found. The CBMN assay measures all cells including necrotic and apoptotic cells as well as the number of nuclei per cell to provide a measure of cytotoxicity and mitotic activity. The CBMN assay has in fact evolved into a "cytome" method for comprehensive measurement of chromosomal instability and altered cellular viability caused by genetic defects or exogenous genotoxins [52]. The use of the CBMN assay and binucleated cells for determining the micronucleus frequency [53] were also considered as inclusion criteria. Finally, 5 papers were selected after the screening (Table 3) [42,54-57].

Effect of the GSTM1 genotype on urinary 1-OHP

Twenty study groups were extracted. Subjects with the active GSTM1 genotype had significantly lower 1-OHP levels than those with the null GSTM1 genotype. The heterogeneity was so high that random-effect model was used ([Chi.sup.2] coefficient = 90.27, p < 0.001, [I.sup.2] = 79%). After 1 subgroup was removed, the effect of the GSTM1 was remained, and the fixed-effects model was used according to the heterogeneity ([Chi.sup.2] coefficient = 26.44, p > 0.05, [I.sup.2] = 32%). The overall SMD between the subjects with active GSTM1 and null GSTM1 carriers was -0.16 (95% CI: -0.28-(-0.04), Z = 2.53, p = 0.01) (Table 4). No significant publication bias was found by Egger's test (p = 0.132) or the funnel plot analysis (Figure 1a.1).

The 19 study groups comprised 11 occupational and 8 non-occupational groups that were separated for the further meta-analysis (Tables 5 and 6). A remarkably significant difference was found in the 1-OHP levels between subjects with the active GSTM1 genotype and those with the null GSTM1 genotype only in the non-occupational populations with a SMD = -0.29 (95% CI: -0.48-(-0.1)). The heterogeneity test indicated a low level of inconsistency in both groups, with a p value of 0.23 ([I.sup.2] = 27%) and 0.13 ([I.sup.2] = 29%), respectively. The funnel plots also showed only a small publication bias (Figure 1a.2 and 1a.3).

Effect of the GSTM1 genotype on the DNA adduct levels

Combining the results of the 9 selected studies showed that there was no significant difference in the adduct levels between the subjects with the active GSTM1 genotype and those with the null GSTM1 genotype, even after the study groups were divided into the occupational workers and non-occupational groups (Tables 7-9). The heterogeneity test showed low level of inconsistency in all groups, with p values all > 0.3 and [I.sup.2] < 15%. No significant publication bias was found according to the result of Egger's test (p > 0.05), or from the funnel plot (Figure 1b.1-3).

Effect of the GSTM1 genotype on the micronucleus frequency

In the articles in which the micronucleus frequency was considered, the subjects who had an active GSTM1 genotype seemed to have a remarkably lower micronucleus frequency than the null GSTM1 carriers, with an [I.sup.2] value of 93%. Because of the high heterogeneity, 3 articles [58-60] were excluded from the analysis, after which the heterogeneity decreased significantly to 41% (p = 0.1) for the remaining studies. However, the effect of the GSTM1 genotype on the micronucleus frequency was still evident, with a SMD = -0.33 (95% CI: -0.5-(-0.17), p < 0.0001) (Table 10). Moreover, there was no remarkable evidence of a publication bias according to the funnel plot (Figure 1c.1). In the 4 occupational groups, a significant difference was found in the micronucleus frequency between the workers who carried active GSTM1 and null GSTM1 carriers (Table 11). Subjects with the active GSTM1 genotype had a lower micronucleus frequency (SMD = -0.27, 95% CI: -0.48-(-0.05), p = 0.01) as compared with the null GSTM1 carriers,. The [I.sup.2] value was 59%, which indicated moderate heterogeneity, but the [Chi.sup.2] test showed that the p value was 0.06. In the 4 non-occupational groups, GSTM1 was found to have similar effects on the micronucleus frequency as in the occupational groups (SMD = -0.43, 95% CI: -0.68(-0.18), p = 0.0008), but the [I.sup.2] value was 19% (Table 12). Funnel plots for both groups showed only a small publication bias (Figure 1c.2 and 1c.3).

DISCUSSION

Our study presents a comprehensive evaluation of the influence of GSTM1 genotypes on the biological markers commonly used for PAH exposure. Our meta-analysis results indicate that GSTM1 genotypes may affect 1-OHP level and micronucleus frequency. None of GSTM1 carriers showed significantly higher 1-OHP levels in the non-occupational general population and significantly higher micronucleus frequency in both occupational workers and non-occupational exposed general population. Bulky DNA adduct levels seemed no significant association with GSTM1 genotypes.

Our findings that the null GSTM1 genotype was associated with significantly higher levels of 1-OHP in non-occupational environments indicate that the GSTM1 genotype of the individual should be considered when 1-OHP is used for evaluating low levels of PAH exposure. Ciarrocca et al. [12] reviewed that 1-OHP was a reliable biomarker for studying outdoor occupational exposure to PAHs from urban pollution, and the combined concentration of 1-OHP tended to be higher in those with the null GSTM1 than the active GSTM1. The studies included in our analysis indicated that the urinary 1-OHP concentrations in workers with exposure to urban air pollution were all lower than 1 [micro]g/ml, which was different from the indoor occupational PAH exposure. Therefore, their results from the meta-analysis were the same as ours for the non-occupational general population.

Our results indicated that in both occupationally exposed workers and non-occupationally exposed general population, the null GSTM1 genotype could not affect the bulky DNA adduct levels, which was inconsistent with another recently published meta-analysis by Liu et al. [24]. For the subgroups of occupational workers, Liu et al. [24] missed 2 studies, and for the non-occupational subgroups, 2 studies were excluded from our analysis and 2 other studies that met the inclusion criteria were included instead. The study by Pavanello et al. [61] was excluded because it measured the level of the benzo[a]pyrene diol epoxide adduct and not the bulky adduct. The other study excluded was the one by Viezzer et al. [48] because it showed high heterogeneity with the other studies, based on the [I.sup.2] values.

The largest difference in our analysis was that bulky adduct but not benzo[a]pyrene diol epoxide adduct was used. A multicenter European study showed that bulky DNA adducts were positively associated with environmental factors, such as occupational exposure and smoking, while benzo[a]pyrene diol epoxide adducts were more strongly associated with smoking than with the environmental exposure. The multivariate analyses concurrently indicate that GSTM1 genotypes mainly contribute not to bulky DNA adduct but benzo[a]pyrene diol epoxide adduct [27]. To cope with the DNA adduct formation caused by PAH exposure, the human body has developed numerous defensive mechanisms, including DNA repair pathways, such as nucleotide excision repair, that faithfully remove the DNA lesions, including the PAH-DNA adducts [62,63]. This may be one of the confounding factors for the unclear difference in the DNA adduct levels between the 2 genotypes of GSTM1.

Our results confirmed the correlation between the different genotypes of GSTM1 and micronucleus frequency. As observed for 1-OHP, the null GSTM1 genotype was associated with a significantly higher micronucleus frequency in both the occupational and non-occupational populations. However, the correlation between internal 1-OHP concentrations and micronucleus frequency was still inconsistent, although occupational PAH exposure was associated with higher micronucleus frequency [64,65]. DNA-adduct levels, but not 1-OHP, concurrently showed dose-response relationship with micronucleus frequency [65]. This may be explained by that 1-OHP is a specific biomarker reflecting exposure to PAH mixtures containing pyrene; however, pyrene itself and its metabolites are not genotoxic; micronuclei on the other hand may be formed after exposure to diverse genotoxic agents and not only PAHs.

We tried our best to set strict inclusion criteria for the included studies and concurrently conduct as comprehensive an analysis as possible. Firstly, the articles were chosen from 2 open comprehensive public databases: PubMed and Web of Science. A reasonable search strategy was designed; the language and the period covered by the publications were limited. Most importantly, the detection methods for the biomarkers were restricted for the selected articles. There was no evidence of significant heterogeneity but this meta-analysis may have certain limitations. Since it has been based on published data, the results would be unreliable if a publication bias exists. However, it has been difficult to estimate the extent of a publication bias. Only a low number of subgroups (N < 10) fitted for our final subgroup analysis. Then Egger's test was not used for these subgroup studies. Although there was no evident bias, the possibility of a bias cannot be disregarded.

CONCLUSIONS

Our results suggest that, as the biomarker of PAH exposure, the 1-OHP level in non-occupationally exposed general population, and micronucleus frequency in both occupational and non-occupational population could be affected by GSTM1 genotypes, while no significant association was found for the level of bulky DNA adducts. None of GSTM1 carriers have seemed more susceptible to PAH damage as it has been indicated by the elevated level of 1-OHP in low levels of PAH exposed population and by high micronucleus frequency observed in both occupational and non-occupational population.

https://doi.org/10.13075/ijomeh.1896.01054

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[48.] Viezzer C, Norppa H, Clonfero E, Gabbani G, Mastrangelo G, Hirvonen A, et al. Influence of GSTM1, GSTT1, GSTP1, and EPHX gene polymorphisms on DNA adduct level and HPRT mutant frequency in coke-oven workers. Mutat Res. 1999;431:259-69, https://doi.org/10.1016/S00275107(99)00169-4.

[49.] Lee J, Kang D, Lee KH, Ichiba M, Zhang J, Tomokuni K, et al. Influence of GSTM1 genotype on association between aromatic DNA adducts and urinary PAH metabolites in incineration workers. Mutat Res. 2002;514:213-21, https://doi. org/10.1016/S1383-5718(01)00340-0.

[50.] Binkova B, Chvatalova I, Lnenickova Z, Milcova A, Tulupova E, Farmer PB, et al. PAH-DNA adducts in environmentally exposed population in relation to metabolic and DNA repair gene polymorphisms. Mutat Res. 2007;620:49-61, https://doi.org/10.1016/j.mrfmmm.2007.02.022.

[51.] Molina E, Perez-Morales R, Rubio J, Petrosyan P, Cadena LH, Arlt VM, et al. The GSTM1null (deletion) and MGMT84 rs12917 (Phe/Phe) haplotype are associated with bulky DNA adduct levels in human leukocytes. Mutat Res. 2013;758:62-8, https://doi.org/10.1016/j.mrgentox. 2013.09.007.

[52.] Fenech M. Cytokinesis-block micronucleus assay evolves into a "cytome" assay of chromosomal instability, mitotic dysfunction and cell death. Mutat Res. 2006;600:58-66, https://doi.org/10.1016/j.mrfmmm.2006.05.028.

[53.] Thomas P, Umegaki K, Fenech M. Nucleoplasmic bridges are a sensitive measure of chromosome rearrangement in the cytokinesis-block micronucleus assay. Mutagenesis. 2003;18:187-94, https://doi.org/10.1093/mutage/18.2.187.

[54.] Leng S, Dai Y, Niu Y, Pan Z, Li X, Cheng J, et al. Effects of genetic polymorphisms of metabolic enzymes on cytokinesis-block micronucleus in peripheral blood lymphocyte among coke-oven workers. Cancer Epidemiol Biomarkers Prev. 2004;13:1631-9.

[55.] Palma S, Cornetta T, Padua L, Cozzi R, Appolloni M, Ievoli E, et al. Influence of glutathione S-transferase polymorphisms on genotoxic effects induced by tobacco smoke. Mutat Res. 2007;633:1-12, https://doi.org/10.1016/j.mrgentox.2007.03.014.

[56.] Kumar A, Yadav A, Giri SK, Dev K, Gautam SK, Gupta R, et al. Effect of genetic polymorphism of GSTM1 and GSTT1 genotypes on cytogenetic biomarkers among coaltar workers. Environ Toxicol Pharmacol. 2011;32:128-35, https://doi. org/10.1016/j.etap.2011.04.002.

[57.] Eshkoor S, Ismail P, Rahman S, Moin S, Adon M. Role of the CYP1A2 gene polymorphism on early ageing from occupational exposure. Balkan J Med Genet. 2013;16:45-52, https://doi.org/10.2478/bjmg-2013-0031.

[58.] Villarini M, Moretti M, Fatigoni C, Agea E, Dominici L, Mattioli A, et al. Evaluation of primary DNA damage, cytogenetic biomarkers and genetic polymorphisms for CYP1A1 and GSTM1 in road tunnel construction workers. J Toxicol Environ Health A. 2008;71:1430-9, https://doi. org/10.1080/15287390802328580.

[59.] Masetti S, Botto N, Manfredi S, Colombo MG, Rizza A, Vassalle C, et al. Interactive effect of the glutathione S-transferase genes and cigarette smoking on occurrence and severity of coronary artery risk. J Mol Med (Berl). 2003;81:488-94, https://doi.org/10.1007/s00109-003-0448-5.

[60.] Testa A, Festa F, Ranaldi R, Giachelia M, Tirindelli D, de Marco A, et al. A multi-biomarker analysis of DNA damage in automobile painters. Environ Mol Mutagen. 2005;46: 182-8, https://doi.org/10.1002/em.20147.

[61.] Pavanello S, Pulliero A, Clonfero E. Influence of GSTM1 null and low repair XPC PAT+ on anti-B[a]PDE-DNA adduct in mononuclear white blood cells of subjects low exposed to PAHs through smoking and diet. Mutat Res. 2008;638: 195-204, https://doi.org/10.1016/j.mrfmmm.2007.10.004.

[62.] Xu G, Spivak G, Mitchell DL, Mori T, McCarrey JR, McMahan CA, et al. Nucleotide excision repair activity varies among murine spermatogenic cell types. Biol Reprod. 2005;73:12330, https://doi.org/10.1095/biolreprod.104.039123.

[63.] Crew KD, Gammon MD, Terry MB, Zhang FF, Zablotska LB, Agrawal M, et al. Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-DNA adducts, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2007;16:2033-41, https://doi.org/10.1158/1055-99 65.EPI-07-0096.

[64.] Liu AL, Lu WQ, Wang ZZ, Chen WH, Lu WH, Yuan J, et al. Elevated levels of urinary 8-hydroxy-2-deoxyguanosine, lymphocytic micronuclei, and serum glutathione S-transferase in workers exposed to coke oven emissions. Environ Health Perspect. 2006;114:673-7, https://doi.org/10.1289/ehp.8562.

[65.] Pavanello S, Kapka L, Siwinska E, Mielzynska D, Bolognesi C, Clonfero E. Micronuclei related to anti-B[a]PDE-DNA adduct in peripheral blood lymphocytes of heavily polycyclic aromatic hydrocarbon-exposed nonsmoking coke-oven workers and controls. Cancer Epidemiol Biomarkers Prev. 2008;17: 2795-9, https://doi.org/10.1158/1055-9965.EPI-08-0346.

DANDAN LI (1), BINGLING WANG (1), GUOCHANG FENG (1), MENG XIE (2), LIJUAN WANG (1), and RUQIN GAO (1)

(1) Qingdao Centers for Disease Control and Prevention, Qingdao, China

(2) Qingdao University, Qingdao, China

School of Public Health, Department of Epidemiology and Health Statistics

Funding: this study was partly supported by grants from the National Natural Science Foundation of China ("Effects of postnatal exposure to polycyclic aromatic compounds in settled house dust on the neurodevelopment of urban toddlers" No. 81372955). Project manager: Bingling Wang, Ph.D.

Received: June 25, 2016. Accepted: September 23, 2016.

Dandan Li, Bingling Wang, and Guochang Feng contributed equally to this work and should be all considered as 1st authors.

Corresponding author: R. Gao, Qingdao Centers for Disease Control and Prevention, 175 Shandong Road, Qingdao 266033, China (e-mail: gaoruqin@yeah.net).

Caption: Fig. 1. Funnel plots for studies on influence of GSTM1 genotypes on a) urinary 1-OHP, b) bulky DNA adducts, c) micronucleus frequency, for 1) both occupational and non-occupational populations, 2) only occupational workers, 3) only non- occupational populations
Table 1. Characteristics of the articles on influence of GSTM1
genotypes on urinary 1-OHP included in the review

Study                                Country

Merlo et al., 1998 [35]               Italy

Ovrebo et al., 1998 [36]              Norway

Alexandrie et al., 2000 [37]          Sweden

Kuljukka-Rabb et al., 2002 [38]      Estonia

Pavanello et al., 2005 [39]           Poland

Chuang and Chang, 2007 [40]           Taiwan

Ruchirawat et al., 2007 [41]         Thailand

Mielzynska-Svach et al., 2013 [42]    Poland

Gabbani et al., 1996 [43]             Sweden

Ada et al., 2007 [44]                 Turkey

Zare et al., 2013 [45]                 Iran

                                                Respondents

Study
                                            study group           n

Merlo et al., 1998 [35]               traffic police officers     89
                                         general officers         43

Ovrebo et al., 1998 [36]                 coke oven workers        66
                                        examined in January
                                         coke oven workers        46
                                         examined in June

Alexandrie et al., 2000 [37]              potroom workers         97
                                     postmen and city council     54
                                             employees

Kuljukka-Rabb et al., 2002 [38]      coke oven workers in fall    23
                                      countryside population      10

Pavanello et al., 2005 [39]              coke oven workers        67

Chuang and Chang, 2007 [40]                taxi drivers           95
                                         office employees         75

Ruchirawat et al., 2007 [41]            school children in        60
                                             Chonburi
                                     school children in Bangkok   99

Mielzynska-Svach et al., 2013 [42]           children             64

Gabbani et al., 1996 [43]                coke oven workers        27

Ada et al., 2007 [44]                 iron and steel workers      50
                                          packing workers         50

Zare et al., 2013 [45]                  carbon anode plant        42
                                              workers
                                          office workers          43

Study                                                        age
                                          sex             [years]
                                                       (M[+ or -]SD)

Merlo et al., 1998 [35]              males/females   35.8 [+ or -] 5.0
                                     males/females   35.0 [+ or -] 4.5

Ovrebo et al., 1998 [36]                unknown           unknown
                                        unknown           unknown

Alexandrie et al., 2000 [37]             males            unknown
                                         males            unknown

Kuljukka-Rabb et al., 2002 [38]      males/females        unknown
                                     males/females        unknown

Pavanello et al., 2005 [39]              males       40.0 [+ or -] 15.0

Chuang and Chang, 2007 [40]              males       39.7 [+ or -] 3.9
                                         males       44.3 [+ or -] 7.2

Ruchirawat et al., 2007 [41]             males       11.0 [+ or -] 2.0
                                         males            unknown

Mielzynska-Svach et al., 2013 [42]   males/females    9.5 [+ or -] 4.5

Gabbani et al., 1996 [43]               unknown           unknown

Ada et al., 2007 [44]                    males       37.0 [+ or -] 12.0
                                         males       37.5 [+ or -] 15.5

Zare et al., 2013 [45]                  unknown      30.4 [+ or -] 4.5
                                        unknown      32.5 [+ or -] 5.7

                                                 GSTM1
                                                          active
                                                         1-OHP in
Study                                                   respondents'
                                     respondents          urine
                                         [n]         [[micro]mol/mol
                                                       creatinine]
                                                      (M[+ or -]SD)

Merlo et al., 1998 [35]                  46        0.143 [+ or -] 0.153
                                         20        0.121 [+ or -] 0.124

Ovrebo et al., 1998 [36]                 32         2.45 [+ or -] 2.55
                                         24         3.07 [+ or -] 3.95

Alexandrie et al., 2000 [37]             45        4.22 [+ or -] 2.628
                                         22         0.10 [+ or -] 0.04

Kuljukka-Rabb et al., 2002 [38]          16        6.008 [+ or -] 5.338
                                          5        0.31 [+ or -] 0.157

Pavanello et al., 2005 [39]              47         9.14 [+ or -] 6.87

Chuang and Chang, 2007 [40]              44        0.16 [+ or -] 0.007
                                         35         0.08 [+ or -] 0.05

Ruchirawat et al., 2007 [41]             23        0.11 [+ or -] 0.002
                                         41        0.22 [+ or -] 0.003

Mielzynska-Svach et al., 2013 [42]       37         0.51 [+ or -] 0.36

Gabbani et al., 1996 [43]                 7         1.71 [+ or -] 1.48

Ada et al., 2007 [44]                    25         1.71 [+ or -] 2.90
                                         26         0.25 [+ or -] 0.18

Zare et al., 2013 [45]                   20         4.05 [+ or -] 3.66
                                         18         0.50 [+ or -] 0.43

                                                  GSTM1

                                                           null
                                                         1-OHP in
Study                                                   respondents'
                                     respondents          urine
                                         [n]          [[micro]ol/mol
                                                       creatinine]
                                                      (M[+ or -]SD)

Merlo et al., 1998 [35]                  43        0.136 [+ or -] 0.154
                                         23        0.083 [+ or -] 0.054

Ovrebo et al., 1998 [36]                 34         1.95 [+ or -] 1.60
                                         22         2.20 [+ or -] 2.22

Alexandrie et al., 2000 [37]             52        4.51 [+ or -] 4.395
                                         32        0.12 [+ or -] 0.235

Kuljukka-Rabb et al., 2002 [38]           7        4.108 [+ or -] 4.306
                                          5        0.65 [+ or -] 0.469

Pavanello et al., 2005 [39]              20         9.78 [+ or -] 8.50

Chuang and Chang, 2007 [40]              51         0.18 [+ or -] 0.12
                                         40         0.12 [+ or -] 0.07

Ruchirawat et al., 2007 [41]             37        0.12 [+ or -] 0.003
                                         58         0.23 [+ or -] 0.03

Mielzynska-Svach et al., 2013 [42]       27         0.56 [+ or -] 0.25

Gabbani et al., 1996 [43]                20         1.61 [+ or -] 1.30

Ada et al., 2007 [44]                    25         1.65 [+ or -] 1.81
                                         24         0.45 [+ or -] 0.56

Zare et al., 2013 [45]                   22         8.38 [+ or -] 5.05
                                         25         0.57 [+ or -] 0.53

GSTM1--glutathione S-transferase Mu 1:1-OHP--1-hydroxypyrene.
M--mean: SD--standard deviation.

Table 2. Characteristics of the articles on influence of GSTM1
genotypes on bulky DNA adducts in peripheral blood lymphocytes
included in the review

                                                      Respondents

Study               Country
                                       study group           n

Hu et al.,           China         all study subjects       194
2008 [25]                           exposure <0.1 |ig       160
                                benzo [a]pyrene/[m.sup.3]

Schoket et al.,     Hungary          potroom workers        161
2001 [26]

Kuljukka-Rabb       Finland              control             9
et al., 2002 [38]

                                    coke oven workers       17
Ichibaet al.,        Sweden          chimney sweeps         69
1994 [46]                        electricity maintenance    34

Binkova et al.,    Slovak and     workers in a battery      68
1995 [47]            Czech                plant
                                     machine workers        55

Viezzer et al.,      Italy             high 1-OHP           37
1999 [48]                               low 1-OHP           45

Lee et al.,          South         incinerator workers      25
2002 [49]            Korea               control            20

Binkova et al.,      Czech              policemen           53
2007 [50]                                control            51

Molina et al.,       Mexico          general people         93
2013 [51]

Study                                     age
                        sex             [years]         respondents
                                     (M (min.-max)          [n]
                                    or M[+ or -]SD))

Hu et al.,         males/females        unknown             82
2008 [25]          males/females        unknown             73

Schoket et al.,       unknown           unknown             79
2001 [26]

Kuljukka-Rabb          males            unknown              4
et al., 2002 [38]

                       males            unknown             12
Ichibaet al.,          males           37(20-65)            36
1994 [46]              males           42(19-62)            16

Binkova et al.,        males           40(27-55)            40
1995 [47]
                       males           39(23-58)            29

Viezzer et al.,       unknown           unknown             17
1999 [48]                                                   18

Lee et al.,        males/females        unknown             14
2002 [49]          males/females        unknown              7

Binkova et al.,        males            unknown             22
2007 [50]              males            unknown             22

Molina et al.,     males/females   36.7 [+ or -] 10.8       63
2013 [51]

                                   GSTM1

                         active
Study                  DNA adducts
                      in respondents      respondents
                         [n] (a)              [n]
                      (M[+ or -]SD)

Hu et al.,          1.02 [+ or -] 1.29        112
2008 [25]           0.91 [+ or -] 1.02        87

Schoket et al.,      3.2 [+ or -] 1.8         82
2001 [26]

Kuljukka-Rabb       1.05 [+ or -] 0.55         5
et al., 2002 [38]

                     1.3 [+ or -] 0.7          5
Ichibaet al.,       0.65 [+ or -] 0.21        33
1994 [46]           0.63 [+ or -] 0.28        18

Binkova et al.,     2.64 [+ or -] 1.42        28
1995 [47]           1.83 [+ or -] 0.71        26

Viezzer et al.,     1.36 [+ or -] 1.46        20
1999 [48]           1.05 [+ or -] 1.00        27

Lee et al.,         0.49 [+ or -] 0.16        11
2002 [49]           0.62 [+ or -] 0.22        13

Binkova et al.,    0.823 [+ or -] 0.228       31
2007 [50]           0.79 [+ or -] 0.14        29

Molina et al.,     2.106 [+ or -] 0.411       30
2013 [51]

                           GSTM1
                           null
Study                  DNA adducts
                      in respondents
                         [n] (a)
                      (M[+ or -]SD)

Hu et al.,          1.37 [+ or -] 2.31
2008 [25]           1.13 [+ or -] 2.44

Schoket et al.,      2.9 [+ or -] 1.7
2001 [26]

Kuljukka-Rabb       1.03 [+ or -] 0.55
et al., 2002 [38]

                    1.43 [+ or -] 0.49
Ichibaet al.,       0.72 [+ or -] 0.25
1994 [46]           0.59 [+ or -] 0.3

Binkova et al.,     2.58 [+ or -] 0.67
1995 [47]           1.9 [+ or -] 0.8

Viezzer et al.,     1.99 [+ or -] 1.83
1999 [48]           1.26 [+ or -] 1.70

Lee et al.,         0.54 [+ or -] 0.23
2002 [49]           0.51 [+ or -] 0.23

Binkova et al.,     0.99 [+ or -] 0.328
2007 [50]           0.82 [+ or -] 0.25

Molina et al.,     1.922 [+ or -] 0.401
2013 [51]

Abbreviations as in lable 1.

(a) Aromatic DNA adducts/108 nucleotides.

Table 3. Characteristics of the articles on influence of GSTM1
genotypes on micronuclei frequency in peripheral blood lymphocytes
included in the review

                                                 Respondents
Study             Country

                                study group       n         sex

Mielzynska-        Poland        children        74    males/females
Svach et al.,
2013 [42]

Leng et al.,       China      nonoccupational    66    males/females
2004 [54]                    coke oven workers   141   males/females

Palma et al.,      Italy        non-smokers      47    males/females
2007 [55]                         smokers        25    males/females

Kumar et al.,      India     road construction   115   males/females
2011 [56]                         workers

                              nonoccupational    105   males/females
Eshkoor et al.,   Malaysia    nonoccupational    120      unknown
2013 [57]

                                                   GSTM1

                                          active
Study                    age                          micronuclei in
                       [years]        respondents       respondents
                      (range or           [n]         [n/1000 cells]
                    M[+ or -]SD)                       (M[+ or -]SD)

Mielzynska-             5-14              40        4.82 [+ or -] 3.44
Svach et al.,
2013 [42]

Leng et al.,      38.0 [+ or -] 8.0       41         3.7 [+ or -] 3.4
2004 [54]         39.0 [+ or -] 7.0       74         8.9 [+ or -] 6.8

Palma et al.,     38.9 [+ or -] 8.7       23        5.77 [+ or -] 3.85
2007 [55]         34.3 [+ or -] 8.1       10         6.2 [+ or -] 4.24

Kumar et al.,     35.7 [+ or -] 9.9       67        6.58 [+ or -] 2.16
2011 [56]

                  37.3 [+ or -] 10.0      63        2.96 [+ or -] 0.966
Eshkoor et al.,         > 18              109        2.3 [+ or -] 1.72
2013 [57]

                                GSTM1

                         null
Study                                micronuclei in
                     respondents      respondents
                         [n]         [n/1000 cells]
                                     (M[+ or -]SD)

Mielzynska-              29        4.13 [+ or -] 3.44
Svach et al.,
2013 [42]

Leng et al.,             25         4.4 [+ or -] 4.0
2004 [54]                67        10.2 [+ or -] 6.3

Palma et al.,            24        6.45 [+ or -] 4.09
2007 [55]                15        9.64 [+ or -] 4.08

Kumar et al.,            48        7.66 [+ or -] 1.80
2011 [56]

                         42        3.50 [+ or -] 1.04
Eshkoor et al.,          11        3.82 [+ or -] 2.23
2013 [57]

Abbreviations as in Table 1.

Table 4. Studies on influence of GSTM1 genotypes on urinary 1-OHP for
occupational workers and the non-occupational general population

                                   GSTM1 active

                                   1-OHP in
                                   respondents'
Study and study group              urine             respondents
                                   [[micro]mol/mol     [n]
                                   creatinine]

                                     M      SD

Ada et al., 2007 [44]
packing workers                    0.25    0.18        26
iron and steel workers             1.71     2.9        25
Alexandrie et al., 2000 [37]
control                             0.1    0.04        22
potroom workers                    4.22    2.628       45
Chuang and Chang, 2007 [40]
office employees                   0.08    0.05        35
taxi drivers                       0.16    0.007       44
Gabbani et al., 1996 [43]
coke oven workers                  1.71    1.48        7
Kuljukka-Rabb et al., 2002 [38]
coke oven 1 workers                8.958   9.127       13
coke oven 2 workers                6.008   5.338       16
control workers                    0.31    0.157       5
Zare et al, 2013 [45]
carbon anode plant workers         4.05    3.66        20
office employees                    0.5    0.43        18
Merlo et al., 1998 [35]
general officers                   0.121   0.124       20
traffic police officers            0.143   0.153       46
Melzynska-Svach et al., 2013 [42]
children                           0.51    0.36        37
Ovrebo et al., 1998 [36]
coke oven workers in January       2.45    2.55        32
coke oven workers in June          3.07    3.95        24
Pavanello et al., 2005 [39]
coke oven workers                  9.14    6.87        47
Ruchirawat et al., 2007 [41]
school children                    0.22    0.003       41
Total                                                 523
Heterogeneity
Test for overall effect

                                       GSTM1 null

                                       1-OHP in
                                      respondents'
 Study and study group                  urine          respondents
                                     [[micro]mol/mol     [n]
                                      creatinine]

                                      M        SD

 Ada et al., 2007 [44]
 packing workers                     0.45     0.56      24
 iron and steel workers              1.65     1.81      25
 Alexandrie et al., 2000 [37]
 control                             0.12     0.235     32
 potroom workers                     4.51     4.395     52
 Chuang and Chang, 2007 [40]
 office employees                    0.12     0.07      40
 taxi drivers                        0.18     0.12      51
 Gabbani et al., 1996 [43]
 coke oven workers                   1.61     1.3       20
 Kuljukka-Rabb et al., 2002 [38]
 coke oven 1 workers                19.318   21.863      7
 coke oven 2 workers                 4.108    4.306      7
 control workers                     0.65     0.469      5
 Zare et al, 2013 [45]
 carbon anode plant workers          8.38     5.05      22
 office employees                    0.57     0.53      25
 Merlo et al., 1998 [35]
 general officers                   0.083     0.054     23
 traffic police officers            0.136     0.154     43
 Melzynska-Svach et al., 2013 [42]
 children                           0.56      0.25      27
 Ovrebo et al., 1998 [36]
 coke oven workers in January       1.95      1.6       34
 coke oven workers in June          2.2       2.22      22
 Pavanello et al., 2005 [39]
 coke oven workers                  9.78      8.5       20
 Ruchirawat et al., 2007 [41]
 school children                    0.23      0.03      58
 Total                                                 537
 Heterogeneity                      [Chi.sup.2] = 26.44, df = 18
                                    (p = 0.09), [I.sup.2] = 32%
 Test for overall effect            Z = 2.53 (p = 0.01)

                                                Standardized mean
                                                  difference

Study and study group                weight         IV fixed
                                     [%]           (95% CI)

Ada et al., 2007 [44]
packing workers                      4.8      -0.48 (-1.04-0.08)
iron and steel workers               4.9       0.02 (-0.53-0.58)
Alexandrie et al., 2000 [37]
control                              5.2      -0.11 (-0.65-0.44)
potroom workers                      9.5      -0.08 (-0.48-0.32)
Chuang and Chang, 2007 [40]
office employees                     7.0      -0.64 (--1.11--(--0.18))
taxi drivers                         9.3      -0.23 (-0.63-0.18)
Gabbani et al., 1996 [43]
coke oven workers                    2.1       0.07 (-0.79-0.93)
Kuljukka-Rabb et al., 2002 [38]
coke oven 1 workers                  1.7      -0.68 (-1.63-0.27)
coke oven 2 workers                  1.9       0.36 (-0.53-1.26)
control workers                      0.9      -0.88 (-2.21-0.46)
Zare et al, 2013 [45]
carbon anode plant workers           3.7      -0.96 (--1.60--(--0.31))
office employees                     4.1      -0.14 (-0.75-0.47)
Merlo et al., 1998 [35]
general officers                     4.1       0.40 (-0.21-1.01)
traffic police officers              8.8       0.05 (-0.37-0.46)
Melzynska-Svach et al., 2013 [42]
children                             6.2      -0.16 (-0.65-0.34)
Ovrebo et al., 1998 [36]
coke oven workers in January         6.5       0.23 (-0.25-0.72)
coke oven workers in June            4.5       0.26 (-0.32-0.85)
Pavanello et al., 2005 [39]
coke oven workers                    5.6      -0.09 (-0.61-0.44)
Ruchirawat et al., 2007 [41]
school children                      9.3      -0.43 (--0.83--(--0.03))
Total                              100.0      -0.16 (--0.28--(--0.04))
Heterogeneity
Test for overall effect

IV--inverse variance: df--degree of freedom; 12--heterogeneity index
(0-100): Z--score of Z-test.

Other abbreviations as in Table 1.

Table 5. Studies on influence of GSTM1 genotypes on urinary 1-OHP
for only occupational workers

                                   GSTM1 active

                                  1-OHP in
Study and study group             respondents' urine
                                  [[micro]mol/mol      respondents
                                  creatinine]             [n]

                                    M      SD

Ada et al., 2007 [44]
iron and steel workers            1.71     2.9            25
Alexandrie et al., 2000 [37]
potroom workers                   4.22    2.628           45
Chuang and Chang, 2007 [40]
taxi drivers                      0.16    0.007           44
Gabbani et al., 1996 [43]
coke oven workers                 1.71    1.48             7
Kuljukka-Rabb et al., 2002 [38]
coke oven 1 workers               8.958   9.127           13
coke oven 2 workers               6.008   5.338           16
Zare et al., 2013 [45]
carbon anode plant workers        4.05    3.66            20
Merlo et al., 1998 [35]
traffic police officers           0.143   0.153           46
Ovrebo et al., 1998 [36]
coke oven workers in January      2.45    2.55            32
coke oven workers in June         3.07    3.95            24
Pavanello et al., 2005 [39]
coke oven workers                 9.14    6.87            47
Total                                                    319
Heterogeneity
Test for overall effect

                                     GSTM1 null

                                      1-OHP in
Study and study group              respondents' urine
                                   [[micro]mol/mol      respondents
                                   creatinine]              [n]

                                     M       SD

Ada et al., 2007 [44]
iron and steel workers             1.65    1.810          25
Alexandrie et al., 2000 [37]
potroom workers                    4.51    4.395          52
Chuang and Chang, 2007 [40]
taxi drivers                       0.18    0.120          51
Gabbani et al., 1996 [43]
coke oven workers                  1.61    1.300          20
Kuljukka-Rabb et al., 2002 [38]
coke oven 1 workers               19.318   21.863          7
coke oven 2 workers                4.108    4.306          7
Zare et al., 2013 [45]
carbon anode plant workers         8.38    5.050          22
Merlo et al., 1998 [35]
traffic police officers            0.136   0.154          43
Ovrebo et al., 1998 [36]
coke oven workers in January       1.95    1.600          34
coke oven workers in June          2.2     2.220          22
Pavanello et al., 2005 [39]
coke oven workers                  9.78    8.500          20
Total                                                    303
Heterogeneity                     [Chi.sup.2] = 13.63, df = 10
                                  (p = 0.19), [I.sup.2] = 27%
Test for overall effect           Z = 0.82 (p = 0.41)

                                              Standardized mean
                                                 difference

Study and study group
                                    weight       IV fixed
                                     [%]         (95% CI)

Ada et al., 2007 [44]
iron and steel workers              8.5      0.02 (-0.53-0.58)
Alexandrie et al., 2000 [37]
potroom workers                    16.3     -0.08 (-0.48-0.32)
Chuang and Chang, 2007 [40]
taxi drivers                       15.9     -0.23 (-0.63-0.18)
Gabbani et al., 1996 [43]
coke oven workers                   3.5      0.07 (-0.79-0.93)
Kuljukka-Rabb et al., 2002 [38]
coke oven 1 workers                 2.9     -0.68 (-1.63-0.27)
coke oven 2 workers                 3.2      0.36 (-0.53-1.26)
Zare et al., 2013 [45]
carbon anode plant workers          6.3     -0.96 (--1.60--(--0.31))
Merlo et al., 1998 [35]
traffic police officers            15.1      0.05 (-0.37-0.46)
Ovrebo et al., 1998 [36]
coke oven workers in January       11.1      0.23 (-0.25-0.72)
coke oven workers in June           7.7      0.26 (-0.32-0.85)
Pavanello et al., 2005 [39]
coke oven workers                   9.5     -0.09 (-0.61-0.44)
Total                             100.0     -0.07 (-0.23-0.09)
Heterogeneity
Test for overall effect

IV--inverse variance: df--degree of freedom: 12--heterogeneity index
(0-100): Z--score of Z-test.

Other abbreviations as in Table 1.

Table 6. Studies on influence of GSTM1 genotypes on urinary 1-OHP
for only the general population

                                    GSTM1 active

                                    1-OHP in
Study and study group               respondents' urine
                                    [[micro]mol/mo]      respondents
                                    creatinine]             [n]

                                      M      SD

Ada et al., 2007 [44]
packing workers                     0.25    0.18           26
Alexandrie et al., 2000 [37]
control workers                      0.1    0.04           22
Chuang and Chang, 2007 [40]
office employees                    0.08    0.05           35
Kuljukka-Rabb et al., 2002 [38]
control workers                     0.31    0.157           5
Zare et al., 2013 [45]
office workers                       0.5    0.43           18
Merlo et al., 1998 [35]
general officers                    0.121   0.124          20
Mielzynska-Svach et al.,
2013 [42]
children                            0.51    0.36           37
Ruchirawat et al., 2007 [41]
school children                     0.22    0.003          41
Total                                                     204
Heterogeneity
Test for overall effect

                                      GSTM1 null

                                     1-OHP in
Study and study group               respondents' urine
                                    [[micro]mol/mol      respondents
                                     creatinine]           [n]

                                     M       SD

Ada et al., 2007 [44]
packing workers                     0.45     0.56           24
Alexandrie et al., 2000 [37]
control workers                     0.12     0.235          32
Chuang and Chang, 2007 [40]
office employees                    0.12     0.07           40
Kuljukka-Rabb et al., 2002 [38]
control workers                     0.65     0.469           5
Zare et al., 2013 [45]
office workers                      0.57     0.53           25
Merlo et al., 1998 [35]
general officers                    0.083    0.054          23
Mielzynska-Svach et al.,
2013 [42]
children                            0.56     0.25           27
Ruchirawat et al., 2007 [41]
school children                     0.23     0.03           58
Total                                                      234
Heterogeneity                      [Chi.sup.2] = 9.80, df = 7
                                   (p = 0.2), [I.sup.2] = 29%
Test for overall effect            Z = 2.96 (p = 0.003)

                                                Standardized mean
                                                   difference

Study and study group
                                     weight        IV fixed
                                      [%]          (95% CI)

Ada et al., 2007 [44]
packing workers                      11.5      -0.48 (-1.04-0.08)
Alexandrie et al., 2000 [37]
control workers                      12.4      -0.11 (-0.65-0.44)
Chuang and Chang, 2007 [40]
office employees                     16.9      -0.64 (--1.11--(--0.18))
Kuljukka-Rabb et al., 2002 [38]
control workers                       2.1      -0.88 (-2.21-0.46)
Zare et al., 2013 [45]
office workers                        9.9      -0.14 (-0.75-0.47)
Merlo et al., 1998 [35]
general officers                     10.0       0.40 (-0.21-1.01)
Mielzynska-Svach et al.,
2013 [42]
children                             14.8      -0.16 (-0.65-0.34)
Ruchirawat et al., 2007 [41]
school children                      22.4      -0.43 (--0.83--(--0.03))
Total                               100.0      -0.29 (--0.48--(--0.10))
Heterogeneity
Test for overall effect

IV--inverse variance; df--degree of freedom; [I.sup.2]--heterogeneity
index (0-100): Z--score of Z-test.

Other abbreviations as in Table 1.

Table 7. Studies on influence of GSTM1 genotypes on bulky DNA adduct
levels for occupational workers and the non-occupational general
population

                                  GSTM1 active

                                  bulky DNA adduct
                                  in respondents
Study and study group             [aromatic DNA        respondents
                                  adducts/[10.sup.8]     [n]
                                  nucleotides]

                                    M      SD

Binkova et al., 1995 [47]
machine workers                   1.83    0.71           29
battery plant workers             2.64    1.42           40
Binkova et al., 2007 [50]
control                           0.79    0.14           22
policemen                         0.823   0.228          22
Hu et al., 2008 [25]
general                           1.02    1.29           82
low exposure with <0.1 [micro]g   0.91    1.02           73
benzo [a]pyrene/[m.sup.3]
Ichibaet al., 1994 [46]
chimney sweeps                    0.65    0.21           36
electricity maintenance           0.63    0.28           16
Kuljukka-Rabb et al., 2002 [38]
coke oven workers                 1.3     0.7            12
control workers                   1.05    0.55            4
Lee et al., 2002 [49]
control workers                   0.62    0.22            7
incinerator workers               0.49    0.16           14
Molina et al, 2013 [51]
general people                    2.106   0.411          63
Schoket et al., 2001 [26]
potroom workrs                    3.2     1.8            79
Viezzer et al., 1999 [48]
coke oven workers with high       1.36    1.46           17
1-OHP levels
coke oven workers with low        1.05    1              18
1-OHP levels
Total                                                   534
Heterogeneity
Test for overall effect

                                    GSTM1 null

                                   bulky DNA adduct
                                   in respondents
Study and study group              [aromatic DNA        respondents
                                   adducts/[10.sup.8]     [n]
                                   nucleotides]

                                    M       SD

Binkova et al., 1995 [47]
machine workers                    1.9     0.8            26
battery plant workers              2.58    0.67           28
Binkova et al., 2007 [50]
control                            0.82    0.25           29
policemen                          0.99    0.328          31
Hu et al., 2008 [25]
general                            1.37    2.31          112
low exposure with <0.1 [micro]g    1.13    2.44           87
benzo [a]pyrene/[m.sup.3]
Ichibaet al., 1994 [46]
chimney sweeps                     0.72    0.25           33
electricity maintenance            0.59    0.3            18
Kuljukka-Rabb et al., 2002 [38]
coke oven workers                  1.43    0.49            5
control workers                    1.03    0.55            5
Lee et al., 2002 [49]
control workers                    0.51    0.23           13
incinerator workers                0.54    0.23           11
Molina et al, 2013 [51]
general people                     1.922   0.401          30
Schoket et al., 2001 [26]
potroom workrs                     2.9     1.7            82
Viezzer et al., 1999 [48]
coke oven workers with high        1.99    1.83           20
1-OHP levels
coke oven workers with low         1.26    1.7            27
1-OHP levels
Total                                                    557
Heterogeneity                     [Chi.sup.2] = 15.23, df = 15
                                  (p = 0.43), [I.sup.2] = 2%
Test for overall effect           Z = 0.94 (p = 0.35)

                                                Standardized mean
                                                    difference

Study and study group              weight         IV fixed
                                     [%]          (95% CI)

Binkova et al., 1995 [47]
machine workers                     5.2      -0.09 (-0.62-0.44)
battery plant workers               6.3       0.05 (-0.43-0.53)
Binkova et al., 2007 [50]
control                             4.7      -0.14 (-0.70-0.41)
policemen                           4.7      -0.57 (--1.12--(--0.01))
Hu et al., 2008 [25]
general                            17.9      -0.18 (-0.46-0.11)
low exposure with <0.1 [micro]g    15.1      -0.11 (-0.42-0.20)
benzo [a]pyrene/[m.sup.3]
Ichibaet al., 1994 [46]
chimney sweeps                      6.5      -0.30 (-0.78-0.17)
electricity maintenance             3.2       0.13 (-0.54-0.81)
Kuljukka-Rabb et al., 2002 [38]
coke oven workers                   1.3      -0.19 (-1.24-0.86)
control workers                     0.8       0.03 (-1.28-1.35)
Lee et al., 2002 [49]
control workers                     1.7       0.46 (-0.47-1.40)
incinerator workers                 2.3      -0.25 (-1.04-0.54)
Molina et al, 2013 [51]
general people                      7.5       0.45 (0.01-0.89)
Schoket et al., 2001 [26]
potroom workrs                     15.2       0.17 (-0.14-0.48)
Viezzer et al., 1999 [48]
coke oven workers with high         3.4      -0.37 (-1.02-0.28)
1-OHP levels
coke oven workers with low          4.1      -0.14 (-0.74-0.46)
1-OHP levels
Total                             100.0      -0.06 (-0.18-0.06)
Heterogeneity
Test for overall effect

Abbreviations as in Table 1.

Table 8. Studies on influence of GSTM1 genotypes on bulky DNA
adduct levels for only occupational workers

                                  GSTM1 active

                                  bulky DNA adduct
                                  in respondents
Study and study group             [aromatic DNA        respondents
                                  adducts/[10.sup.8]     [n]
                                  nucleotides]

                                    M      SD

Binkova et al., 1995 [47]
battery plant workers             2.64    1.42           40
Binkova et al., 2007 [50]
policemen                         0.823   0.228          22
Hu et al., 2008 [25]
low exposure with <0.1 [micro]g   0.91    1.02           73
benzo [a]pyrene/[m.sup.3]
Ichibaet al., 1994 [46]
chimney sweeps                    0.65    0.21           36
Kuljukka-Rabb et al., 2002 [38]
coke oven workers                 1.3     0.7            12
Lee et al., 2002 [49]
incinerator workers               0.49    0.16           14
Schoket et al., 2001 [26]
potroom workers                   3.2     1.8            79
Viezzer et al, 1999 [48]
coke ovenworkers with high        1.36    1.46           17
1-OHP levels
coke oven workers with low        1.05    1              18
1-OHP levels
Total                                                   311
Heterogeneity
Test for overall effect

                                     GSTM1 null

                                   bulky DNA adduct
                                   in respondents
Study and study group              [aromatic DNA        respondents
                                   adducts/[10.sup.8]      [n]
                                   nucleotides]

                                     M     SD

Binkova et al., 1995 [47]
battery plant workers              2.58   0.67            28
Binkova et al., 2007 [50]
policemen                          0.99   0.328           31
Hu et al., 2008 [25]
low exposure with <0.1 [micro]g    1.13   2.44            87
benzo [a]pyrene/[m.sup.3]
Ichibaet al., 1994 [46]
chimney sweeps                     0.72   0.25            33
Kuljukka-Rabb et al., 2002 [38]
coke oven workers                  1.43   0.49             5
Lee et al., 2002 [49]
incinerator workers                0.54   0.23            11
Schoket et al., 2001 [26]
potroom workers                    2.9    1.7             82
Viezzer et al, 1999 [48]
coke ovenworkers with high         1.99   1.83            20
1-OHP levels
coke oven workers with low         1.26   1.7             27
1-OHP levels
Total                                                    324
Heterogeneity                     [Chi.sup.2] = 7.51, df = 8
                                  (p = 0.48), [I.sup.2] = 0%
Test for overall effect           Z = 1.28 (p = 0.2)

                                               Standardized mean
                                                  difference

Study and study group               weight       IV fixed
                                     [%]         (95% CI)

Binkova et al., 1995 [47]
battery plant workers               10.6      0.05 (-0.43-0.53)
Binkova et al., 2007 [50]
policemen                            8.0     -0.57 (--1.12--(--0.01))
Hu et al., 2008 [25]
low exposure with <0.1 [micro]g     25.6     -0.11 (-0.42-0.20)
benzo [a]pyrene/[m.sup.3]
Ichibaet al., 1994 [46]
chimney sweeps                      11.0     -0.30 (-0.78-0.17)
Kuljukka-Rabb et al., 2002 [38]
coke oven workers                    2.3     -0.19 (-1.24-0.86)
Lee et al., 2002 [49]
incinerator workers                  3.9     -0.25 (-1.04-0.54)
Schoket et al., 2001 [26]
potroom workers                     25.9      0.17 (-0.14-0.48)
Viezzer et al, 1999 [48]
coke ovenworkers with high           5.8     -0.37 (-1.02-0.28)
1-OHP levels
coke oven workers with low           7.0     -0.14 (-0.74-0.46)
1-OHP levels
Total                              100.0     -0.10 (-0.26-0.05)
Heterogeneity
Test for overall effect

Abbreviations as in Table 1.

Table 9. Studies on influence of GSTM1 genotypes on bulky DNA
adduct levels for only the general population

                                  GSTM1 active

                                  bulky DNA adduct
                                  in respondents
Study and study group             [aromatic DNA        respondents
                                  adducts/[10.sup.8]     [n]
                                  nucleotides]

                                    M      SD

Binkova et al., 1995 [47]
control (workers)                 1.83    0.71           29
Binkova et al., 2007 [50]
control (general people)          0.79    0.14           22
Hu et al., 2008 [25]
general                           1.02    1.29           82
Ichibaet al., 1994 [46]
electricity maintenance           0.63    0.28           16
Kuljukka-Rabb et al., 2002 [38]
control (workers)                 1.05    0.55            4
Lee et al., 2002 [49]
control                           0.62    0.22            7
Molina et al., 2013 [51]
general people                    2.106   0.411          63
Total                                                   223
Heterogeneity
Test for overall effect

                                     GSTMl null

                                   bulky DNA adduct
                                   in respondents
Study and study group              [aromatic DNA        respondents
                                   adducts/[10.sup.8]      [n]
                                   nucleotides]

                                     M      SD

Binkova et al., 1995 [47]
control (workers)                   1.9     0.8             26
Binkova et al., 2007 [50]
control (general people)            0.82    0.25            29
Hu et al., 2008 [25]
general                             1.37    2.31           112
Ichibaet al., 1994 [46]
electricity maintenance             0.59    0.3             18
Kuljukka-Rabb et al., 2002 [38]
control (workers)                   1.03    0.55             5
Lee et al., 2002 [49]
control                             0.51    0.23            13
Molina et al., 2013 [51]
general people                      1.922   0.401           30
Total                                                      233
Heterogeneity                       [Chi.sup.2] = 6.96, df = 6
                                    (p = 0.32), [I.sup.2] = 14%
Test for overall effect             Z = 0.07 (p = 0.95)

                                               Standardized mean
                                                  difference

Study and study group               weight       IV fixed
                                     [%]         (95% CI)

Binkova et al., 1995 [47]
control (workers)                    12.6     -0.09 (-0.62-0.44)
Binkova et al., 2007 [50]
control (general people)             11.5     -0.14 (-0.70-0.41)
Hu et al., 2008 [25]
general                              43.5     -0.18 (-0.46-0.11)
Ichibaet al., 1994 [46]
electricity maintenance               7.8      0.13 (-0.54-0.81)
Kuljukka-Rabb et al., 2002 [38]
control (workers)                     2.1      0.03 (-1.28-1.35)
Lee et al., 2002 [49]
control                               4.1      0.46 (-0.47-1.40)
Molina et al., 2013 [51]
general people                       18.3      0.45 (0.01-0.89)
Total                               100.0      0.01 (-0.18-0.19)
Heterogeneity
Test for overall effect

Abbreviations as in Table 1.

Table 10. Studies on influence of GSTM1 genotypes on the
micronucleus frequency for both occupational workers and
the non-occupational general population

                            GSTM1 active

                            micronuclei in
Study and study group       respondents      respondents
                            [n/1000 cells]      [n]

                             M      SD

Eshkoor et al., 2013 [57]
nonoccupational             2.3    1.72        109
Kumar et al., 2011 [56]
road construction workers   6.58   2.16         67
nonoccupational             2.96   0.968        63
Leng et al., 2004 [54]
coke oven workers           8.9    6.8          74
nonoccupational             3.7    3.4          41
Mielzynska-Svach et al,
2013 [42]
children                    4.82   3.44         40
Palma et al, 2007 [55]
nonsmokers                  5.77   3.85         23
smokers                     6.2    4.24         10
Total                                          427
Heterogeneity
Test for overall effect

                              GSTM1 null

                             micronuclei in
Study and study group         respondents     respondents
                             [n/1000 cells]     [n]

                              M      SD

Eshkoor et al., 2013 [57]
nonoccupational             3.82    2.23        11
Kumar et al., 2011 [56]
road construction workers   7.66    1.8         48
nonoccupational             3.5     1.04        42
Leng et al., 2004 [54]
coke oven workers           10.2    6.3         67
nonoccupational              4.4    4           25
Mielzynska-Svach et al,
2013 [42]
children                    4.13    3.44        29
Palma et al, 2007 [55]
nonsmokers                  6.45    4.09        24
smokers                     9.64    4.08        15
Total                                          261
Heterogeneity               [Chi.sup.2] = 11.93, df = 7
                            (p = 0.1), [I.sup.2] = 41%
Test for overall effect     Z = 4.03 (p < 0.0001)

                                          Standardized mean
                                             difference

Study and study group         weight         IV fixed
                               [%]          (95% CI)

Eshkoor et al., 2013 [57]
nonoccupational                6.7     -0.85 (--1.48--(--0.22))
Kumar et al., 2011 [56]
road construction workers     18.6     -0.53 (--0.91--(--0.15))
nonoccupational               16.7     -0.54 (--0.93--(--0.14))
Leng et al., 2004 [54]
coke oven workers             24.1     -0.20 (-0.53-0.13)
nonoccupational               10.6     -0.19 (-0.69-0.31)
Mielzynska-Svach et al,
2013 [42]
children                      11.5      0.20 (-0.28-0.68)
Palma et al, 2007 [55]
nonsmokers                    8.0      -0.17 (-0.74-0.40)
smokers                       3.8      -0.80 (-1.64-0.03)
Total                       100.0      -0.33 (--0.50--(--0.17))
Heterogeneity
Test for overall effect

Abbreviations as in Table 1.

Table 11. Studies on influence of GSTM1 genotypes on the
micronucleus frequency for only occupational workers

                            GSTM1 active

                            micronuclei in
Study and study group       respondents      respondents
                            [n/1000 cells]     [n]

                              M      SD

Kumar et al., 2011 [56]
road construction workers   6.58    2.16       67
Leng et al., 2004 [54]
coke oven workers            8.9    6.8        74
Mielzynska-Svach et al.,
2013 [42]
children                    4.82    3.44       40
Palma et al., 2007 [55]
smokers                      6.2    4.24       10
Total                                         191
Heterogeneity
Test for overall effect

                              GSTM1 null

                            micronuclei in
Study and study group       respondents      respondents
                            [n/1000 cells]      [n]

                              M      SD

Kumar et al., 2011 [56]
road construction workers    7.66    1.8        48
Leng et al., 2004 [54]
coke oven workers           10.2     6.3        67
Mielzynska-Svach et al.,
2013 [42]
children                    4.13     3.44       29
Palma et al., 2007 [55]
smokers                     9.64     4.08       15
Total                                          159
Heterogeneity               [Chi.sup.2] = 7.26, df = 3
                            (p = 0.06), [I.sup.2] = 59%
Test for overall effect     Z = 2.43 (p = 0.01)

                                         Standardized mean
                                             difference

Study and study group        weight          IV fixed
                              [%]           (95% CI)

Kumar et al., 2011 [56]
road construction workers    32.1     -0.53 (--0.91--(--0.15))
Leng et al., 2004 [54]
coke oven workers            41.5     -0.20 (-0.53-0.13)
Mielzynska-Svach et al.,
2013 [42]
children                     19.9      0.20 (-0.28-0.68)
Palma et al., 2007 [55]
smokers                       6.5     -0.80 (-1.64-0.03)
Total                       100.0     -0.27 (--0.48--(--0.05))
Heterogeneity
Test for overall effect

Abbreviations as in Table 1.

Table 12. Studies on influence of GSTM1 genotypes on the
micronucleus frequency for only the general population

                            GSTM1 active

                            micronuclei in
Study and study group       respondents      respondents
                            [n/1000 cells]      [n]

                              M      SD

Eshkoor et al., 2013 [57]
nonoccupational              2.3    1.72        109
Kumar et al., 2011 [56]
nonoccupational              2.96   0.968       63
Leng et al., 2004 [54]
nonoccupational              3.7    3.4         41
Palma et al., 2007 [55]
nonsmokers                   5.77   3.85        23
Total                                          236
Heterogeneity
Test for overall effect

                              GSTM1 null

                             micronuclei in
Study and study group        respondents      respondents   weight
                             [n/1000 cells]      [n]         [%]

                              M      SD

Eshkoor et al., 2013 [57]
nonoccupational              3.82   2.23        11          15.8
Kumar et al., 2011 [56]
nonoccupational              3.5    1.04        42          39.8
Leng et al., 2004 [54]
nonoccupational              4.4    4           25          25.3
Palma et al., 2007 [55]
nonsmokers                   6.45   4.09        24          19.1
Total                                          102         100.0
Heterogeneity                [Chi.sup.2] = 3= 0.29), [I.sup.2] = 19%
Test for overall effect       Z =    3.36 (p  : 0.0008)

                              Standardized mean
                                  difference

Study and study group             IV fixed
                                  (95% CI)

Eshkoor et al., 2013 [57]
nonoccupational              -0.85 (--1.48--(--0.22))
Kumar et al., 2011 [56]
nonoccupational              -0.54 (--0.93--(--0.14))
Leng et al., 2004 [54]
nonoccupational              -0.19 (-0.69-0.31)
Palma et al., 2007 [55]
nonsmokers                   -0.17 (-0.74-0.40)
Total                        -0.43 (--0.68--(--0.18))
Heterogeneity
Test for overall effect

Abbreviations as in Table 1.
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Title Annotation:REVIEW PAPER
Author:Li, Dandan; Wang, Bingling; Feng, Guochang; Xie, Meng; Wang, Lijuan; Gao, Ruqin
Publication:International Journal of Occupational Medicine and Environmental Health
Date:Mar 1, 2017
Words:11542
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