| Backgroup:Toluene diisocyanate (TDI), as the most common isocyanate compound, were used for the production of polyurethane foam, which applied in many fields such as furniture manufacturing, transportation and construction etc. TDI annually domestic production and usage had increased rapidly, as a rusult, exposed populations gradually expanded. TDI caused occupational asthma had been included in the catalogs of occupational diseases, in addition, TDI could also cause a variety of adverse effects, for example, allergic dermatitis, pneumonia, liver damage, DNA damage. Besides the international agency for research on cancer(IARC) had categorized TDI into group 2B carcinogen. However, the domestic researches about TDI toxicity were based on the in-vitro assaies and animal experiments, less population studies were used. TDI exposure caused inflammatory injury, appeard as activation of a large number of lymphocyte and release of inflammatory cytokines, for example, a large numbers of T lymphocyte activation and eosinophil accumulation were found in the bronchial biopsies of patients with TDI asthma. Further, inflammatory injuries were risk factors of chronic obstructive pulmonary disease (COPD), bronchial asthma, cancer and other diseases, but inflammatory injury caused by TDI did not attract enough attentions.Objective:Study the effect of TDI occupational exposure on workers’ respiratory function and immune system, and to explore the role of inflammatory cells and inflammatory mediators in TDI-induced respiratory system diseases.Methods:In October 2014, by cluster sampling, we conducted a cross-sectional study in a TDI production factory located in China’s western region.62 exposed workers were recruited from workers engaged in packing, operating and checking.61 factory managers, matching age and agent, were selected as controls, having same work intense and not contacting the TDI or other allergens. Allergies, patients with immune disease, those taken medicine in one week and patients with respiratory illness were excluded. The questionnaire surveys were used to obtain the agent, age, work age, smoking and drinking, personal and family allergic history, occupational history and the recent health conditions. The time weighted average concentrations (8h-TWA) were used to describe the levels of TDI air exposure in working environment. Gas Chromatography were used to evaluate the levels of 2,4-toluenediamine (2,4-TDA) and 2,6-toluene diamine (2,6-TDA) in urinary, the total TDA concentrations by adding were internal exposure concentrations. The detection system of portable lung function device measured the levels of forced vital capacity (FVC), forced expiratory volume in one second (FEV1.0). The percentage of peripheral blood lymphocyte subsets in peripheral blood and the concentrations of cytokine and chemokine in serum were determined by Flow cytometry. The levels of MMP-9 and TIMP-1 in serum of subjects were measured by ELISA.Results:1. Assessment of TDI occupational exposure and its effect on pulmonary function8-hour time weighted allowable concentration (8h-TWA) mean of TDI air levels in exposed group was 0.39 mg/m3. The lung function FVC, FEV1.0, FEV1.0/FVC in exposed group [(89.37 ± 11.29), (83.86 ± 14.03), (110.48 ± 13.51)%], respectively, reduced 29%,39%,14%(all P<0.01), compared with the control group [(125.62 ± 20.79), (137.72 ± 23.43), (129.02 ± 5.57)%].52 workers from the exposed group were selected, and compared with controls matched for age, body mass index (BMI), smoking, and alcohol consumption. According to concentrations of total TDA in urine, the selected exposed group was divided into high exposure and low exposure group, with the controls, multiple linear regression trend analysis was used to test effects of exposure concentration on lung function. The levels of FVC, FEV1.0, FEV1.0/FVC all decreased with increasing concentrations. According to exposure-time, the exposed group was divided into short-term and long-term exposure groups, with the control group; multiple linear regression trend analysis was also used to test effects of exposure-time on lung function. The levels of FVC, FEV1.0, FEV1.0/FVC decreased with increasing exposure-time (all P< 0.05).2. inflammatory response in toluene dissocyanate occupational exposure workers and its correlation with lung functionAfter adjustment for age, BMI, smoking, alcohol consumption by linear regression analysis, in exposed group, the levels of NK cells, T lymphocytes, CD4+ T lymphocyte percentage [(25.89±9.04),(65.36 ± 12.04), (35.3 ± 6.81)%], respectivly, increased 24%,13%,27%, compared with that in controls [(20.84±9.01, 58.04±14.1,27.81±11.23)%] (P< 0.01, P= 0.03, P< 0.01). The levels of IL-8 and TNF-α in serum in exposed group [16.09 (11.17-22.96),6.07 (5.27-11.1)], respectivly, decreased 81%,40%, compared with controls [83.2(11.74-387.02),10.13(5.26-28.7) pg/ml] (P< 0.05, respectively). The concentrions of MMP-9 and MMP-9/TIMP-1 in exposed group, respectively, were 516.14(178.29-1175.91) ng/ml,2.24(0.75-5.02), significantly decreased 32% and 52% (P< 0.05, respectively), compared with controls [758.32 (378.6-1328.32) ng/ml,4.64 (1.78-12.11)]. The concentritions of TIMP-1 in exposed group [236.43 (152.89-334.55) ng/ml] were significantly 32% higher than that in controls (P< 0.01). Correlation analysis showed, the percentages of NK cells were negatively associated with lung function FVC, FEV1.0, FEV1.0/ FVC(r--0.24,-0.19,-0.26, P< 0.05), the percentage of T cells were negatively associated with lung function FEV1.0/FVC (r=-0.21, P< 0.05), that of the CD4+T cells were negatively associated with lung function FVC, FEV1.0, FEV1.0/FVC (r=-0.28,-0.31,-0.22, all P< 0.01), that of CD8+T lymphocyte were negatively associated with lung function, FEV1.0, FEV1.0/FVC(r=-0.2, P=0.03; r=-0.24, P< 0.01). The levels of IL-8 in serum were positively associated with lung function FVC, FEV1.0, FEV1.0/FVC (r= 0.52,0.49,0.56, all P< 0.01), the levels of TNF-α in serum were positively associated with lung function FVC, FEV1.0, FEV1.0/FVC (r = 0.39,0.41,0.33, all P< 0.01). The concentritions of MMP-9 were positively associated with lung function FEV1.0, FEV1.0/FVC (r=0.27,0.25, P< 0.01, respectively), that of MMP-9/TIMP-1 were positively associated with lung function FEV1.0, FEV1.0/FVC (r= 0.34,0.44,0.40, all P< 0.01), the levels of TIMP-lwere negatively associated with lung functionFVC, FEV1.0, FEV1.0/FVC (r=-0.33,-0.40,-0.39, all P< 0.01).52 workers from the exposed group were selected, and compared with controls matched for age, body mass index (BMI), smoking, and alcohol consumption. According to concentrations of total TDA in urine, the seleced exposed group was divided into high exposure and low exposure group, with the controls, multiple linear regression trend analysis was used to test effects of exposure concentration on immunity indexes. Levels of immune cells percentage (T, CD4+T, CD8+T cells) and TIMP-1 rised with increasing concentrations. The concentrations of cytokines (IL-8 and TNF-α) and metalloproteinases (MMP-9 and MMP-9/TIMP-1) decreased with increasing concentrations. According to exposure-time, the exposed group was divided into short-term and long-term exposure groups, with the control group; multiple linear regression trend analysis was also used to test effects of exposure-time on immunity indexes. Levels of immune cells percentage (T, CD4+T, CD8+T cells) and levels of TIMP-1 rised with increasing exposure-time. The concentrations of cytokines (IL-8 and TNF-α) and metalloproteinases (MMP-9 and MMP-9/TIMP-1) decreased with increasing exposure-time (all P< 0.05).Stratified according to smoking, in smokers, the levels of NK and CD4+T cells in exposed group significantly higher than that in controls (all P< 0.01), and the concentrions of TNF-β in exposed group were lower than that in controls (P< 0.01). On the other hand, in nonsmokers, the level of CD4+T cells in exposed group was much higher than that in controls (P< 0.01).Conclusion:Occupational exposure to TDI can cause respiratory dysfunction and trigger immune response in the body. There is a correlation between immune response and lung function,suggesting that levels of IL-8, TNF-α, MMP-9/TIMP-1 in serum could response respiratory inflammatory injury, and could be used as biomarkers of pulmonary injury. |
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