|Year : 2017 | Volume
| Issue : 4 | Page : 161-168
Phenotype analysis of lymphocytes in workers with chronic benzene exposure
Hanan M Fayed1, Sanaa S Aly1, Samira M Saleh2, Mohamed El-Shahat Ebeid3, Yasser A Ahmed3
1 Department of Clinical and Chemical Pathology, Faculty of Medicine, South Valley University, Qena University Hospital, Qena, Egypt
2 Department of Toxicology and Forensic Medicine, Faculty of Medicine, South Valley University, Qena University Hospital, Qena, Egypt
3 Department of Biochemistry, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Menoufia, Egypt
|Date of Submission||06-Feb-2017|
|Date of Acceptance||22-Feb-2018|
|Date of Web Publication||9-Feb-2018|
Hanan M Fayed
Department of Clinical and Chemical Pathology, Faculty of Medicine, South Valley University, Qena University Hospital, Mabber El-Shbab Street, Qena, 83523
Source of Support: None, Conflict of Interest: None
Background Automobile service station workers are at high risk of benzene toxicity because they neither take protective measures to prevent inhalation of petroleum products nor undergo regular medical checkup.
Objective The aim of this paper was to study the effects of long-term benzene exposure on blood cells and liver function.
Patients and methods The study was a controlled trial, which included 30 automobile service station workers investigated for alterations in blood cells, hepatic functions, and lymphocyte phenotype.
Results When compared with controls, benzene-exposed workers had significant increase in alanine aminotransferase (47.80±3.19 vs. 28.50±4.35), aspartate aminotransferase (41.20±2.62 vs. 23.60±4.58), and alkaline phosphatase (305.13± 16.39 vs. 174.40±26.69) levels and significant decrease in total proteins (6.39±0.11 vs. 6.79±0.12), albumin (3.57±0.14 vs. 4.5±0.48), hemoglobin (10.77±0.49 vs. 13.97±0.69), platelets count (146.8±4.9 vs. 217.8±37.4), mean platelet volume (7.68±0.4; 8.83±0.8), white blood cells (3459±444 vs. 6171±1482), monocytes (188±64 vs. 338±190), neutrophils (2095±267 vs. 3487±998), lymphocytes (1177±265 vs. 2138±439) and its subsets [CD3 cells (948±217 vs. 1686±337), CD4 cells (321±81 vs. 1101±222), B cells (228±70 vs. 45.1±13.22), and CD4 : CD8 ratio (0.51±0.04 vs. 1.88±0.08)], with significant increase in CD8 cells (627±138 vs. 585±117) and platelet-lymphocyte ratio (PLR) (130.7±26.66 vs. 104.96±22.49).
The duration of exposure positively correlated with PLR and negatively correlated with hemoglobin, platelets, mean platelet volume, white blood cells, neutrophil, lymphocyte (B cells, helper cells, and suppressor cells), and serum albumin. PLR had a negative correlation with CD4, CD8, and CD19 absolute counts.
Conclusion Benzene exposure is detrimental to the liver and bone marrow and results in the reduction of all blood and lymphocyte series, intiating immune suppression which may predispose to carcinogenesis. PLR is a valuable, inexpensive, and reproducible index that is closely associated with impaired immune system in benzene-exposed workers.
Keywords: automobile service stations, benzene occupational exposure, flow cytometry, lymphocyte phenotype, platelet-lymphocyte ratio
|How to cite this article:|
Fayed HM, Aly SS, Saleh SM, El-Shahat Ebeid M, Ahmed YA. Phenotype analysis of lymphocytes in workers with chronic benzene exposure. Egypt J Haematol 2017;42:161-8
|How to cite this URL:|
Fayed HM, Aly SS, Saleh SM, El-Shahat Ebeid M, Ahmed YA. Phenotype analysis of lymphocytes in workers with chronic benzene exposure. Egypt J Haematol [serial online] 2017 [cited 2020 Feb 20];42:161-8. Available from: http://www.ehj.eg.net/text.asp?2017/42/4/161/225090
| Introduction|| |
Benzene, an aromatic hydrocarbon, is a common component of gasoline, with known hematotoxic  and carcinogenic effects . Benzene by itself is not regarded as a toxic substance; however, its toxicity involves biological interactions of multiple reactive benzene intermediates with various cellular targets within the bone marrow resulting in bone marrow suppression and increasing susceptibility to infections .
Benzene physiochemical properties include low evaporation temperature and vapor pressure, which allows its direct incorporation into the environment . Inhalation is the main route of absorption of benzene, and the liver is the main site of its metabolism. Humans absorb 30-52% of inhaled benzene, depending on the benzene concentration, length of exposure, and pulmonary ventilation . Moreover, the secondary metabolism of benzene occurs in the bone marrow, which plays an important role in benzene’s myelotoxicity . Toxins induce hepatic damage, which is observed by increased serum liver cytoplasmic enzymes because of enzymes leakage owing to altered membrane permeability .
Lymphocyte subpopulations are proposed to be the most sensitive target cells for the immune-toxic effect of benzene . Moreover, benzene induces depression and alteration of both cell-mediated and humoral immune system, with decrease in the T and B cell proliferative response and inhibition of the activity of T cytotoxic cells .
Benzene exposure has been linked to acute myeloid leukemia. However, some studies related to other subtypes including chronic lymphocytic leukemia ,. Relatively low-level exposure to benzene was associated with an increased risk of myelodysplastic syndrome, which is recognized as a precursor to acute myeloid leukemia .
Individual variations depend on the age, physical activity, smoking, pre-existing medical condition of the exposed person, amount of adipose tissue, genetic variation in benzene-activating and detoxifying enzymes, DNA healing capacity, and several growth-regulatory soluble mediators ,,.
| Aim|| |
It was to study the effects of occupational long-term exposure to benzene in automobile service station workers on blood cells series, liver functions, and lymphocyte subsets and its correlation with duration of exposure, peripheral systemic inflammatory response markers [neutrophil-to-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and mean platelet volume (MPV)].
| Patients and methods|| |
Study design and patients
A controlled clinical trial was conducted including 30 participants working in automobile service stations with long-term benzene occupational exposure (group 1) and 30 healthy age-matched, sex-matched, and socioeconomic status-matched unexposed workers who served as control (group 2). The study was conducted after approval by ethical committee in Qena Faculty of Medicine, South Valley University, and an informed consent was obtained from all the participants.
The participants’ selection criteria were as follows: (a) at least 1 year of occupational exposure and (b) no medical or family history of liver diseases or exposure to hepatotoxic agents and no job history of exposure to other chemical materials. Exposed participants were the employees of eight different automobile service stations: three from Qena City, Qena Governorate, and five from Hurgada City, Red Sea Governorate.
Patients with poor nutrition; acute illness; acute infection; under immune-suppressant drugs, radiotherapy, or chemotherapy; or with any disease that can alter immune status such as immune-deficiency disease, autoimmune disease, and malignancy were excluded from the study.
All participants were subjected to questionnaire and blood sampling.
The individuals were asked to answer a questionnaire, structured specifically for the assessment of exposure, personal data, and determination of lifestyle factors like smoking, alcohol, and use of medications. The following characteristics were observed or calculated: age, weight, height, and BMI.
A 5-ml venous blood was collected after work shift under aseptic precautions. In addition, two direct peripheral smears were made.
A 3-ml blood was taken in plain glass tube, and after clotting, the tube was centrifuged at 2000 rpm for 3 min and then the serum was separated to be used for estimation of liver function tests.
Rest of the blood was placed in EDTA-containing vacutainer tube for complete blood count and flow cytometric determination of lymphocyte subsets.
Complete blood count was done using Cell Dyne 3500 Automated Cell Counter (Abbott CD 3500, Abbott Diagnostics Division, Mountain View, CA, USA). Neutrophil, lymphocyte, and platelets counts were retrieved separately and used for calculation of NLR and PLR (both derived from inflammation-induced derangements in blood cell count). In our laboratory, thrombocytopenia exists if platelets are less than 150 000 (×106/l), leukopenia exists if white blood cells (WBCs) are less than 4000 (×106/l), and lymphopenia exists if lymphocytes are less than 1500 (×106/l).
Liver function [total proteins, albumin, and liver enzymes − alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP)] was assessed using Cobas c311 automated chemistry analyzer (Roche Diagnostics GmbH D-68298 Mannheim, Germany).
Lymphocyte subpopulations enumeration and calculation of CD4 : CD8 ratio were done using FACSCalibur flow cytometry (FCM) (BD Biosciences, San Jose, California, USA). Briefly (100 µl), whole blood was labeled with respective antibodies (BD Biosciences) per manufacturer’s instructions. After 30 min of incubation in dark at room temperature with monoclonal antibodies, red blood cells (RBCs) were lysed using FACS lysing solution and washed with PBS. After proper setting, calibration, and compensation, labeled lymphocytes were acquired on FCM and analyzes by Cell Quest Pro software (v5.2) (Becton Dickinson, BD Biosciences, 2350 Qume Drive, San Jose, CA, USA); the absolute counts for each cell subset were calculated using the specific subset percentages obtained by FCM, and lymphocyte counts were obtained from hematology analyzer. Those gated lymphocytes were analyzed for CD3 (T cells), CD19 (B cells), CD4 (T-helper/inducer cells), and CD8 (T cytotoxic/suppressor cells). All antibodies were obtained from Becton Dickinson (Becton Dickenson, San Jose, California, USA).
Data analysis was performed using statistical package for the social science (SPSS, version 22) software (IBM SPSS Statistics for Windows, Version 22.0, IBM Corp, Armonk, NY, USA). For quantitative data, paired-sample and independent-sample Mann–Whitney U tests were used, and χ2-test was applied for qualitative categorical data. Data were statistically described in terms of mean and SD for quantitative data and numbers and percentage for qualitative data. Spearman’s rank correlation coefficient was used to explore the relationship between quantitative variables. A P-value of less than 0.05 was considered significant. All tests were two sided.
| Results|| |
This study involved 30 male patients working in automobile service stations, with age of 39.4±4.2 years and length of exposure of 14±1.46 years, and all of them were current smokers. Moreover, 30 healthy age-matched (37.1±6 years), sex- matched, socioeconomic status-matched unexposed workers were selected as control group. Of all workers, 100% showed microcytic hypochromic red cells [mean corpuscular volume (MCV)=68.47±3.9 fl and mean corpuscular hemoglobin (MCH)=21.94±1.40 pg], of whom 6.67% had anemia and thrombocytopenia, 13.33% had anemia and leukopenia, 6.67% had anemia and lymphopenia, and 73.33% had pancytopenia.
When compared with controls, exposed group showed significant reduction in the hematological parameters: RBCs count, hemoglobin (Hb) and indices, platelet count (PLT), total WBCs (P<0.00001), neutrophils (P=0.00003), MPV (P=0.00006), lymphocytes count (P<0.00001), and monocyte count (P=0.009); moreover, the percentage reductions in the cell count in the exposed group were 44% for WBCs, 45% for lymphocytes, 40% for neutrophils, 44% for monocytes, and 33% for platelets, but with significant increase in PLR of 25% (P=0.0224) ([Table 1]).
|Table 1 Full blood count parameters among the control group and the study group|
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Compared with controls, exposed group showed significant reduction in CD19 cells (P=0.00007), CD4 (P<0.00001), CD4 : CD8 ratio (P<0.00001), and serum proteins (P<0.00001), with significant increase of 7% for CD8 cells (P<0.00001) and increase of 66–75% for liver enzymes (P<0.00001) ([Table 2]).
|Table 2 Lymphocyte phenotypes and liver function among the control group and the study group|
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Spearman’s rank correlation between absolute count of CD3, CD4, and CD8; CD4 : CD8; and duration of benzene exposure with other laboratory parameters in the study group is as follows ([Table 3]):
- CD3 absolute counts have significant positive correlation with Hb, platelets, MPV, WBCs, lymphocyte, PLR, total protein, and albumin but significant negative correlation with NLR, AST, and ALP.
- CD4 absolute counts have significant positive correlation with Hb, WBCs, lymphocyte, CD3, CD8, CD19, total protein, and albumin but significant negative correlation with NLR, PLR, and liver enzymes.
- CD8 absolute counts have significant positive correlation with Hb, MPV, WBCs, lymphocyte, CD3, CD4, total protein, albumin, and globulin but significant negative correlation with NLR, PLR, CD19, and liver enzymes.
- CD4 : CD8 ratio has significant positive correlation with monocyte count and serum total proteins levels.
- CD19 absolute counts have significant positive correlation with Hb, platelets, MPV, WBCs, neutrophil, lymphocyte, CD3, CD4, and albumin but significant negative correlation with PLR, and liver enzymes (AST and ALP).
- Platelet count has significant positive correlation with Hb (r=0.6002; P=0.018) and with WBCs count (r=0.52292; P=0.0455).
|Table 3 Spearman’s rank correlation between absolute count of CD3, CD4, CD8 CD19, and CD4 : CD8 with other laboratory parameters in the study group|
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Spearman’s rank correlation between percentage of CD3, CD4, CD8, and CD19 and duration of benzene exposure with other laboratory parameters in the study group is as follows ([Table 4]):
- CD3 percentage has significant negative correlation with Hb, MPV, WBCs, neutrophils, CD19 lymphocytes, and ALT.
- CD4 percentage has significant positive correlation with CD4 : CD8 ratio, monocytes count, and CD19 count but significant negative correlation with neutrophil count and ALT liver enzymes.
- CD8 percentage has significant negative correlation with Hb, platelets, MPV, WBCs count, and CD19 absolute count.
- CD19 percentage has significant positive correlation with neutrophil count.
- The duration of exposure has significant positive correlation with PLR but significant negative correlation with hematological parameter (Hb, platelets, MPV, WBCs count, neutrophil count, lymphocyte counts and subsets B, total T cells T-helper and T-suppressor cells) and serum albumin.
|Table 4 Spearman rank correlation between CD3, CD4, CD8, and CD19 percentages and duration of benzene exposure with other laboratory parameters in the study group|
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| Discussion|| |
Benzeneexposure isassociated with hematotoxicity and hematopoietic dysfunction, with progression to either aplastic anemia or leukemia . Benzene affects the immune system, both innate and adaptive constituents .
Moreover, benzene exposure was demonstrated to alter telomere length as an outcome from oxidative stress . In addition, smoking, a known source of nonoccupational benzene exposure, was reported to affect lymphocyte subpopulations , owing to the synergistic influence of solvents’ immunesuppressive effect , and a significant correlation between smoking and the level of lymphocyte subsets was reported by Biro et al. .
Despite the small sample size, we found statistical significant associations between benzene exposure and the suppression of all blood cells types. In this study, we reveals significant reduction in Hb and RBCs count in benzene-exposed group with the presence of microcytic hypochromic cells in blood smear; this was in line with other studies ,,,,. In addition, Ray et al.  informed the presence of RBC anisopoikilocytosis and target cells.
In contrast, Uzma et al.  found gradual increase in RBC count and Hb among workers exposed to benzene and air pollutants.
This study reveals significant reduction in WBC count; this was in line with other studies ,,,,,,,,. However, Brandão et al.  reported increase in monocyte count. Snyder et al.  reported neutropenia and thrombocytopenia, and Ray et al.  found that exposed patients had decreased lymphocyte and platelet counts, but showed increase in neutrophil and band cells.
In this study, we revealed that nearly 73% of workers had pancytopenia and 27% had bicytopenia.
However, several studies did not detect adverse hematological effects after exposure to benzene ,,,,,. However, Tunsaringkarn et al.  found reduction of eosinophil counts with no changes in WBCs or platelets counts.
This study reveals significant reduction in CD3, CD4, and CD19 cells by 44, 47, and 50% respectively, and CD 4: CD8 ratio by 73% but with significant increase in CD8 cells of 7%. This was in line with other studies ,,.Our results partially agree with the studies by Lan et al. , Moszczynsky et al. , Biro et al. , and Wiwanitkit et al. ; they found reduction in all cell types in benzene-exposed patients. However, Ray et al.  found decreases in CD4, CD8, and CD19 cells by 37, 20, and 47% respectively; however, they reported 20% increase in natural killer cells.
Our results also partially agree with Luan  and Moszczynski and Lisiewicz  as they reported a reduction in the percentages and absolute counts of total T lymphocytes, lymphocytes CD4, CD8, and natural killer cells and an increase in the monocytes count.
In this study, platelets count had significant positive correlation with Hb level and WBCs count signifying that benzene has hematotoxicity affecting cell types derived from myeloid progenitor cells, including granulocytes and platelets together with alterations in lymphoid cell types, including B cells and T cells.
In contrast, Bogadi-Sare et al.  found reduction in lymphocyte subsets, immunoglobulin, and complements factors C3 and C4.
In this study, we observed significant decrease in MPV and platelets counts in benzene-exposed group; this is supposed to be because of the release of bioactive molecules of proinflammatory platelets in the presence of inflammation .
The present study reveals that benzene exposure caused a significant increase in serum levels of ALT and AST; this is in line with the findings of other studies ,,,,,.
In this study, the duration of occupational exposure to benzene showed significant negative correlation with Hb level, platelets counts, and WBCs counts, including all lymphocyte subtypes and neutrophil, and serum albumin level, and positive correlation with PLR.
In this study, NLR had significant negative correlation with CD4, CD8, and CD3 absolute cell counts but with insignificant difference between benzene-exposed patients and controls.
In this study, PLR had significant negative correlation with CD4, CD8, and CD19 absolute cell counts, with significant increase of PLR in benzene-exposed patients than controls; this may be because of the selective benzene toxicity to lymphocytes.
In this study, MPV was positively correlated with CD8 and CD19 cells but negatively correlated with the benzene duration of exposure. Moreover, platelets count was positively correlated with CD19 and CD3 cell counts but negatively correlated with CD8 cell count and benzene duration of exposure.
In the present study, no serious systemic dysfunction was identified in benzene-exposed patients. It is well accepted that a correlation exists concerning qualitative and quantitative changes in the immune function with the appearance of clinical signs of immune deficiencies.
Many factors, including age and nutritional status, have considerable influence on the immunological competence and injury to the immune system. In the present study, the characteristics of the benzene-exposed group and control were similar, and there were insignificant differences regarding age; therefore, the reduction in the numbers of lymphocytes and subpopulations did not occur because of immune system aging, but probably because of exposure to benzene.
Therefore, benzene exposure results in depressive effects on both myeloid and lymphoid cell types with decrease in CD4 and increase in CD8 T cells which may lead to immunosuppression and decreased body capability to respond to antigens or carcinogen, thereby possibly leading to hematological malignancies.
Inherent limitations of low sample size and cross-sectional design cannot establish the relationships. However, circumstantial evidence indicates that these finding are likely to be the direct consequences of exposure to benzene.
Additional longitudinal epidemiological studies with larger sample sizes, sufficient long follow-up time together with the assessment of cell functions are required to verify these findings and explore the mechanisms underlying these effects.
| Conclusion|| |
Occupational benzene exposure results in liver toxicity, hematotoxicity, and impaired immune system, which may results in the long term to carcinogenesis process. PLR, an inexpensive, valuable, and reproducible index, is closely associated with impaired immune system in benzene-exposed patients.
Strict medical follow-up with full blood count and PLR calculation can be used to figure out the high-risk person for early detection of reversible effects, and stopping smoking and obeying occupational guidelines are a must for allowable exposure limits which is related to WBC count reduction.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]