Association Between Metabolic-enzyme Gene Polymorphisms And Susceptibility Of Benzene-induced Adverse Effects Among Benzene-exposed Workers

Benzene is an important organic chemical and a confirmed human carcinogen. Chronic benzene exposure can cause hematotoxicity, including drop of blood cell counts in peripheral blood, aplastic anemia, MDS and leukemia. At present, the occupational exposure limit (OEL) of benzene in developed countries is1ppm (3.25mg/m3), while the PC-TWA in China is6mg/m3. However there were several researches suggesting that hematotoxicity still could be observed when concentration of benzene in air was below1ppm. Hence it is necessary to study benzene-induced hematotoxicity and gene-toxicity at current OELs. Susceptibility to these toxicities can affect by age, sex, health-and-nutrition level, especially the activity of metabolic enzymes and ability of DNA repair of individual, all of which can be attributed to gene polymorphisms. A pile of studies have been done to investigate the relationship between benzene-induced hematotoxicity and metabolic gene polymorphisms, but only a few studies paid attention to the gene-toxicity in early stage exposure and its relationship with hematotoxicity and metabolic gene polymorphisms, so by studying these it may lead us to the further understanding of the mechanisms of benzene-induced toxicity.This study used questionnaire and blood test to investigate the exposure and hematic damages of737benzene-exposed workers and88controls; then sampled461exposed to get CBMN assay with all controls, evaluating their chromosomal damages; at last, PCR-RFLP was taken to exam their metabolic genotype, in order to analyze their modifications to benzene-induced adverse effects.As the indication of hematotoxicity, blood test showed the average means of RBC counts, WBC counts and Hb in exposed group were significantly lower than those in control group(P<0.01), except plaque counts. And the abnormality rates of WBC, RBC and Hb scaled up with increment of exposed chance. However, the difference of abnormality rate of Hb was not significant among groups(P=0.35), and WBC-abnormality rate’s increment showed more consistency with the increment of exposed chance than RBC. Multiple-factor analysis suggested that individual BMI index, sex, working duration and bath after work are statistically related to the change of WBC counts besides the exposure to the benzene. But there was no evidence to prove that age, smoking or drinking related to WBC-count change.Both of t-test and Poisson regression showed benzene-exposed workers got higher MN frequency than controls (P<0.01). Under the same exposed duration, MN frequencies of middle and highly-exposed groups were significantly higher than low-exposed ones, which suggested the MN frequency is related to the exposed chances. Similarly, the abnormality rate of MN in exposed group was higher than that in control, and middle-exposed was significantly higher than the low-exposed. Age was suggested to be related to the MN rate by single-factor Poisson regression, and multiple-factor analysis prompted that personal prevention, sex and age can be influential factors. Statistics between the hematic and genetic damages showed that with the decline of WBC counts, the MN frequency rose significantly, which meant they were strongly connected.Next, PCR-RFLP were used to detect polymorphism of6polymorphisms of4genes, including GSTT1、GSTM1、CY2E1、mEH113、mEHl39and NQO1609. Liner and Poisson regression were used to analyze the relationship between polymorphisms and susceptibilities to toxicities. Means of WBC counts of NQO1609heterozygotes (CT) was0.34×109/L higher than that of wide homozygotes (CC), and mutant homozygotes (TT) were0.56*109/L higher than wide homozygotes by single-factor analysis. Sex and NQO1609polys were enrolled in the formula while using step backward selection to establish multiple-factor liner regression, and results were: female workers had higher WBC counts than males; The interaction effects between exposure ad NQO1609polys were statistically significant. NQO1609CT and TT genotypes got higher WBC counts than CC genotypes (P<0.05) in control and mid-exposed group after adjusting. MN frequency of NQO1609mutant homozygotes (TT) was lower than that of wide homozygotes (CC)(Irr=0.79,95%CI:0.66-0.99, P<0.05) by single factor analysis. Multiple-factor Poisson regression enrolled exposure, age and NQO1609polys as final variants. After adjusting, MN frequencies in exposed group were higher than control (Irr=1.78,95%CI:1.45-2.18, P<0.01), NQO1609TTs were lower than CCs (Irr=0.8395%CI:0.69-0.99, P<0.05), and those who were older got higher MN than who were younger(P<0.05). NQO1609genotype and smoking were found to be able to modify the relationship between benzene-induced hematotoxicity and gene-toxicity. Supposing having the same WBC count, NQO1609TTs had lower MN frequency than CCs, and those who smoked more than5pack year had higher than who were not (Irr=1.46,95%CI:1.46-2.04, P<0.05). All those results above showed that NQO1609wide homozygotes were more venerable to benzene-induced toxicities.So, under current OELs of benzene in China, hematotoxicity and gene-toxicity still cound be observed. WBC counts of peripheral blood can indicate the hematotoxicity and MN can be used to measure the early-stage chromosomal damages, hence both of them can be used to monitor the health of benzene-exposed worker. Benzene-induced toxicities can be modulated by factors as sex, age, personal prevention and gene polymorphism, and NQO1609wide homozygotes were more venerable. Those factors should be considered when health monitors were taken. This study suggested further study should be helpful to explain the mechanisms of toxicities. and provide solid evidence to protect worker.