Cross-sectional and longitudinal relationships between urinary 1-bromopropane metabolite and pulmonary function and underlying role of oxidative damage among urban adults in the Wuhan-Zhuhai cohort in China.

1-bromopropane is a US Environmental Protection Agency-identified significant hazardous air pollutant with concerned adverse respiratory effect. We aimed to investigate the relationship between 1-bromopropane exposure and pulmonary function and the underlying role of oxidative damage, which all remain unknown. Pulmonary function and urinary biomarkers of 1-bromopropane exposure (N-Acetyl-S-(n-propyl)-L-cysteine, BPMA) and oxidative damage to DNA (8-hydroxy-deoxyguanosine, 8-OHdG) and lipid (8-iso-prostaglandin-F2α, 8-iso-PGF2α) were measured for 3259 Chinese urban adults from the Wuhan-Zhuhai cohort. The cross-sectional relationship of BPMA with pulmonary function and the joint relationship of BPMA and 8-OHdG or 8-iso-PGF2α with pulmonary function were investigated by linear mixed models. The mediating roles of 8-OHdG and 8-iso-PGF2α were evaluated by mediation analysis. Additionally, a panel of 138 subjects was randomly convened from the same cohort to evaluate the stability of BPMA repeatedly measured in urine samples collected over consecutive three days and intervals of one, two, and three years, and to estimate the longitudinal relationship of BPMA with pulmonary function change in three years. We found each 3-fold increase in BPMA was cross-sectionally related to FVC and FEV1 reductions by 29.88-mL and 25.67-mL, respectively (all P < 0.05). Joint relationship of BPMA and 8-OHdG rather than 8-iso-PGF2α with reduced pulmonary function was observed. Moreover, 8-OHdG significantly mediated 9.44% of the BPMA-related FVC reduction. Findings from the panel revealed a fair to excellent stability (intraclass correlation coefficient: 0.43-0.79) of BPMA in repeated urines collected over a period of three years. Besides, BPMA was longitudinally related to pulmonary function reduction in three years: compared with subjects with persistently low BPMA level, those with persistently high BPMA level had 79.08-mL/year and 49.80-mL/year declines in FVC and FEV1, respectively (all P < 0.05). Conclusively, 1-bromopropane exposure might impair pulmonary function of urban adult population, and oxidative DNA damage might be a potential mechanism underlying 1-bromopropane impairing pulmonary function especially FVC.

Association of silica dust exposure with mortality among never smokers: A 44-year cohort study.

The association of silica dust exposure with mortality among never smokers has not been well established. We aimed to evaluate the association of silica dust exposure with mortality among never smokers. We studied 17,130 workers employed for at least 1 year between January 1, 1960 and December 31, 1974, with follow-up until the end of 2013. Cumulative respirable silica dust exposure (CDE) was estimated by linking a job-exposure matrix to personal work history. We observed 3937 deaths during 589,357.26 person-years of follow-up. Significant positive exposure-response relationships were found between CDE and mortality from all cause (HR = 1.01, 95%CI = 1.01-1.02), respiratory tuberculosis (HR = 1.04, 95%CI = 1.02-1.06), CVDs (HR = 1.03, 95%CI = 1.02-1.04), and diseases of the respiratory system (HR = 1.06, 95%CI = 1.04-1.07). We found higher standardized mortality ratios for respiratory tuberculosis (2.62, 2.32-2.95), CVDs (1.43, 1.32-1.54), and pneumoconiosis (77.75, 68.21-88.25) among silica dust exposed workers. In addition, we estimated that 4.19%, 20.69%, 7.48% and 34.06% of deaths for all cause, respiratory tuberculosis, CVDs, and diseases of the respiratory system among Chinese workers were attributed to silica, after adjusting for other covariates. With regard to lung cancer, compared with unexposed group, the HRs and 95% CI were 0.94 (0.52-1.71), 1.86 (1.15-3.00), 1.65 (0.95-2.86) for low, medium, and high exposed workers, respectively. Long-term silica dust exposure is associated with increased mortality in the absence of cigarette smoking.

Exogenous Clara cell protein 16 attenuates silica particles-induced inflammation in THP-1 macrophages by down-regulating NF-κB and caspase-1 activation.

Inhalation of silica particles leads to pulmonary inflammatory responses. Clara cell protein 16 (CC16) has been reported to played a protective role in inflammatory lung diseases. However, its role on silica particles-induced inflammation has not been fully clarified. In this study, THP-1 macrophages were exposed to 75 µg/cm2 silica particles with or without 2 µg/mL exogenous CC16 (recombinant CC16, rCC16) for 24 hr. The production of inflammatory cytokines, including interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and IL-6, in the cell supernatants of different groups was detected through ELISA kits and real-time RT-PCR, respectively. The nuclear translocation of nuclear factor (NF)-κB, protein levels of pro-IL-1ß, the nucleotide-binding domain-like receptor protein 3 (NLRP3) and caspase-1 were evaluated via immunofluorescence or western blot. Results showed that, at 75 µg/cm2 silica particle concentration, the treatment of rCC16 significantly decreased IL-1ß, TNF-α and IL-6 protein release and mRNA levels in THP-1 macrophages. Compared to those only exposed to silica particles, THP-1 macrophages exposed to both silica particles and rCC16 showed significantly lower nuclear levels and higher cytosol levels of NF-κB p65, as well as lower co-localization coefficients through immunofluorescence. Additionally, the administration of rCC16 significantly attenuated the increase of pro-IL-1ß, NLRP3 and caspase-1 levels induced by silica particle exposure. Our results suggested that exogenous CC16 could inhibit silica particles-induced inflammation in THP-1 macrophages, mainly through suppressing NF-κB pathway and caspase-1 activation.

Association of Silica Dust Exposure and Cigarette Smoking With Mortality Among Mine and Pottery Workers in China.

Importance: The joint association of long-term silica dust exposure and cigarette smoking with mortality has not been well established. Objective: To evaluate the joint association of silica dust exposure and cigarette smoking with mortality in a large cohort of workers at mines and factories in China. Design, Setting, and Participants: This cohort study included 44 708 adults who were employed in 20 metal mines and 9 pottery factories in central and southern China for at least 1 year between January 1, 1960, and December 31, 1974. Participants were retrospectively followed up to January 1, 1960, and prospectively followed up to December 31, 2003. Data analysis was conducted from April 5, 2019, to October 26, 2019. Exposures: Cumulative respirable silica dust exposure was estimated by linking a job-exposure matrix to participants' personal work histories. Cigarette smoking data were collected through participant questionnaires. Main Outcomes and Measures: The main outcome was mortality, with codes from the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) used to categorize diseases associated with mortality. Results: Among 44 708 participants, 38 221 (85.49%) were men, with a mean (SD) age at cohort entrance of 26.9 (8.1) years. A total of 13 700 deaths were observed during 1 534 005 person-years of follow-up, with a median follow-up period of 34.9 years (range, 4.8-43.9 years). Silica exposure was associated with a higher risk of mortality among individuals with all diseases, lung cancer, respiratory tuberculosis, cardiovascular diseases, and diseases of the respiratory system; cigarette smoking was associated with an increased risk of mortality among individuals with all diseases, lung cancer, respiratory tuberculosis, cerebrovascular diseases, and diseases of the respiratory tract. The hazard ratios for the joint association of silica dust exposure and cigarette smoking with mortality were 4.51 (95% CI, 3.23-6.29) for lung cancer, 3.21 (95% CI, 2.53-4.08) for certain infectious and parasitic diseases, 3.93 (95% CI, 2.99-5.15) for respiratory tuberculosis, 6.27 (95% CI, 4.83-8.15) for diseases of the respiratory system, and 12.52 (95% CI, 7.92-19.80) for pneumoconiosis, with a significant additive interaction (P < .001). The proportions of the joint association for the additive interaction of silica dust exposure and cigarette smoking were 21.63% for lung cancer, 42.12% for certain infectious and parasitic diseases, 42.25% for respiratory tuberculosis, 29.55% for diseases of the respiratory system, and 36.46% for pneumoconiosis. Conclusions and Relevance: These findings suggest that cigarette smoking is associated with an increased risk of mortality in individuals exposed to silica dust. Smoking cessation and the control of silica dust concentrations may be important for reducing the risk of mortality among individuals exposed to silica.

Comparison of Risk of Silicosis in Metal Mines and Pottery Factories: A 44-Year Cohort Study.

BACKGROUND: Little is known about the different risk of silicosis in metal mines and pottery factories. We aimed to compare the silicosis risks among silica-exposed workers in different industrial circumstances. RESEARCH QUESTION: Are the silicosis risks among silica-exposed workers in industrial circumstances different? STUDY DESIGN AND METHODS: We studied 39,808 workers followed up from January 1, 1960 to December 31, 2003 in China. Cumulative respirable silica dust exposure (CDE) was estimated by linking a job-exposure matrix to personal work history. Silicosis of stage I or higher was diagnosed by Chinese pneumoconiosis Roentgen diagnostic criteria. RESULTS: A total of 9,377 silicosis patients were diagnosed during 1,153,580.9 person-years' follow-up in the cohort. Hazard ratios of silicosis for each 1 mg/m3-year increase in CDE were 1.08 (1.07-1.08) for tungsten mines, 1.41 (1.33-1.48) for iron and copper mines, 1.14 (1.11-1.17) for tin mines, and 1.03 (1.02-1.04) for pottery factories, respectively. When exposed to 0.05 mg/m3 of respirable silica dust for 45 years, the cumulative risks in metal mines (2.3%, 9.9%, 1.5% for tungsten mines, iron and copper mines, and tin mines, respectively) were still higher than those in pottery factories (0.6%). The joint effect of silica and smoking on silicosis was more than multiplicative. INTERPRETATION: The risk of silicosis in metal miners is higher than that in pottery workers when exposed to the same level of silica dust. The silica dust exposed years should be under 10 years for metal miners and 40 years for pottery workers at 0.05 mg/m3 to keep lifetime risk within 0.1%. Current exposure limits should take into account differences in various industrial circumstances. Smoking cessation could help reduce silicosis risk for silica-exposed workers.

Association of urinary dimethylformamide metabolite with lung function decline: The potential mediating role of systematic inflammation estimated by C-reactive protein.

Dimethylformamide (DMF) is a volatile organic compound listed as one of the four toxicants with the highest priority for human field study. However, the effect of DMF exposure on lung function and the underlying mechanisms remain unknown. We aimed to investigate the exposure-response relationship and possible mechanism between internal DMF exposure and lung function alteration. We studied 3701 Chinese adults from the Wuhan-Zhuhai cohort with a 3-year follow-up. The cross-sectional relationship between urinary biomarker of DMF exposure (N-Acetyl-S-(N-methylcarbamoyl)-L-cysteine, AMCC) and lung function, and the mediating role of plasma C-reactive protein (CRP) were assessed. We also convened a sub-cohort (N = 138) to assess the stability of AMCC in repeated urine samples collected for continuous 3 days and intervals of 1, 2 and 3 years. The longitudinal association between AMCC and lung function change in 3 years was further assessed. We found a dose-response relationship between AMCC and lung function reduction. Each 2-fold increase in AMCC was cross-sectionally associated with a 23.12-mL (95% CI: -36.68, -9.55) decrease in FVC and a 19.01-mL (95% CI: -31.08, -6.93) decrease in FEV1. Increased CRP significantly mediated 5.39% and 5.87% of the AMCC-associated FVC and FEV1 reductions, respectively. With 3-year follow-up, AMCC showed a fair to excellent stability (intra-class correlation coefficients were 0.88, 0.55, 0.60 and 0.50 for continuous 3 days, intervals of 1, 2 and 3 years, respectively) and was dose-dependently associated with longitudinal lung function decline. Compared with those with persistent low AMCC levels, participants with persistent high AMCC levels had a 101.09-mL/year (95% CI: -167.40, -34.77) decline in FVC and a 66.27-mL/year (95% CI: -114.14, -18.41) decline in FEV1 in the sub-cohort. Similar results were found in the full-cohort. Our findings suggest that exposure of general population to environmental DMF may impair lung function, and systematic inflammation may be an underlying mechanism.

Residential Radon and Histological Types of Lung Cancer: A Meta-Analysis of Case‒Control Studies.

Epidemiological studies on residential radon exposure and the risk of histological types of lung cancer have yielded inconsistent results. We conducted a meta-analysis on this topic and updated previous related meta-analyses. We searched the databases of Cochrane Library, Embase, PubMed, Web of Science and Chinese National Knowledge Infrastructure for papers published up to 13 November 2018. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed and random effects models. Subgroup and dose‒response analyses were also conducted. This study was registered with PROSPERO (No. CRD42019127761). A total of 28 studies, which included 13,748 lung cancer cases and 23,112 controls, were used for this meta-analysis. The pooled OR indicated that the highest residential radon exposure was significantly associated with an increased risk of lung cancer (OR = 1.48, 95% CI = 1.26-1.73). All histological types of lung cancer were associated with residential radon. Strongest association with small-cell lung carcinoma (OR = 2.03, 95% CI = 1.52-2.71) was found, followed by adenocarcinoma (OR = 1.58, 95% CI = 1.31-1.91), other histological types (OR = 1.54, 95% CI = 1.11-2.15) and squamous cell carcinoma (OR = 1.43, 95% CI = 1.18-1.74). With increasing residential radon levels per 100 Bq/m3, the risk of lung cancer, small-cell lung carcinoma and adenocarcinoma increased by 11%, 19% and 13%, respectively. This meta-analysis provides new evidence for a potential relationship between residential radon and all histological types of lung cancer.

Effects of environmental and lifestyle exposures on urinary levels of polycyclic aromatic hydrocarbon metabolites: A cross-sectional study of urban adults in China.

Urinary polycyclic aromatic hydrocarbon (PAH) metabolites, biomarkers of internal PAH exposure, are commonly used to explore the effects of PAH on human health. However, the correlation between environmental PAH exposure and the species or levels of urinary PAH metabolites remains unclear. We collected detailed information on PAH exposure sources, including cigarette smoking, cooking, traffic and diet habits via structured questionnaires, and determined 12 urinary monohydroxylated PAH metabolites (OH-PAHs) among 4092 participants from the Wuhan-Zhuhai cohort. Linear mixed models and generalized linear models were conducted to explore the associations of urinary metabolite levels with single or multiple PAH exposure sources. We also calculated the standardized regression coefficients to further compare the contributions of different sources to urinary OH-PAH levels. Our results showed that increasing levels of urinary 1-, 2-hydroxynaphthalene (1-, 2- OHNa) and 2-hydroxyfluorene (2-OHFlu) were significantly correlated with tobacco smoking (all P < 0.01). The concentrations of 1-, 2- OHNa and 9-hydroxyfluorene (9-OHFlu) were positively correlated with dietary intake (all P < 0.05). Individuals who spent a long time in traffic showed elevated levels of 9-OHFlu and 1-hydroxyphenanthrene (1-OHPh) compared with individuals who spent a short time in traffic (all P < 0.05). Self-cooking was associated only with elevated 1-hydroxypyrene (1-OHP) levels. Moreover, good kitchen ventilation resulted in significantly decreased urinary low-molecular-weight OH-PAH levels. These findings suggested that cigarette smoking, self-cooking, high dietary PAH intake and a long time spent in traffic were associated with increased levels of specific urinary PAH metabolites, and good kitchen ventilation effectively reduced the exposure to low-molecular-weight PAHs in self-cooking participants.

Genetic loss of Gas6/Mer pathway attenuates silica-induced lung inflammation and fibrosis in mice.

Long-term inhalation of crystalline silica particles leads to silicosis characterized by pulmonary inflammation and interstitial fibrosis. The growth arrest-specific protein 6 (Gas6) and its tyrosine receptor Mer have been implicated to involve in the regulation of inflammation, innate immunity and tissue repair. However, the role of Gas6 or Mer in silica-induced lung inflammation and fibrosis has not been investigated previously. In this study, we observed a remarkable increase of Gas6 in bronchoalveolar lavage fluid (BALF) from wild-type C57BL/6 mice after silica intratracheal administration. Then, we investigated whether genetic loss of Gas6 or Mer could attenuate silica-induced lung inflammation and fibrosis. Our results showed that Gas6-/- and Mer-/- mice exhibited reduced lung inflammation response from days 7 to 84 after silica exposure. We also uncovered an overexpression of the suppressor of cytokine signaling protein 1 in silica-treated deficient mice. Moreover, Gas6 or Mer deficiency attenuated silica-induced collagen deposition by inhibiting the expression of transforming growth factor-ß. We conclude that gene absence of Gas6 or Mer is protective against silica-induced lung inflammation and fibrosis in mice. Targeting Gas6/Mer pathway may be a potential therapeutic approach to treat pulmonary fibrosis in patients with silicosis.

Associations between polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans exposure and oxidatively generated damage to DNA and lipid.

Polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans (PCDD/Fs) have been reported to induce reactive oxygen species and oxidative stress, but the dose-response relationships have not been explored in molecular epidemiological studies. In this study, a total of 602 participants were recruited, comprising of 215 foundry workers, 171 incineration workers and 216 residents living more than 5 km away from the plants as the reference group. Individual PCDD/Fs exposures were estimated according to PCDD/Fs levels of working and living ambient air and daily foods. Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-iso-prostaglandin-F2α (8-isoPGF2α) were determined to reflect oxidatively generated damage to DNA and lipid. Generalized linear models were used to access the associations between PCDD/Fs exposure and oxidative stress biomarkers. We found that PCDD/Fs exposure and urinary oxidative stress biomarkers of workers were all higher than those of the reference group. Significantly positive exposure-response relationships between individual PCDD/Fs exposures and urinary 8-oxodG and 8-iso-PGF2α were found. Each 1-unit increase in ln-transformed levels of PCDD/Fs exposure generated a 0.78 nmol/mmol creatinine increase in ln-transformed 8-oxodG and a 0.50 ng/mmol creatinine increase in ln-transformed 8-isoPGF2α in foundry workers, a 0.49 nmol/mmol creatinine increase in ln-transformed 8-oxodG and a 0.26 ng/mmol creatinine increase in ln-transformed 8-isoPGF2α in incineration workers, compared with the reference group. And such associations were not modified by tobacco use. Our findings could help to understand the dose-response relationships between PCDD/Fs and oxidatively generated damage to DNA and lipid, and provide an epidemiologic basis for conducting research on the carcinogenesis and other toxicity mechanisms of PCDD/Fs.

Combined effect of silica dust exposure and cigarette smoking on total and cause-specific mortality in iron miners: a cohort study.

BACKGROUND: Both cigarette smoking and long-term exposure to crystalline silica dust were reported to be associated with increased mortality. However, the combined effect of both factors has not been well evaluated. METHODS: We investigated a retro-prospective cohort of 7,665 workers from one Chinese iron mine with a median follow-up of 42.8 years. Cumulative silica exposure was estimated for each worker by linking work histories with a job-exposure matrix. Cigarette smoking information was collected through face-to-face questionnaires. Hazard ratios (HRs) for total and cause-specific mortality due to silica exposure and smoking were estimated using Cox proportional hazards models. RESULTS: A total of 2,814 deaths occurred during 315,772.9 person-years of follow-up. Significantly elevated mortality from all causes, cardiovascular disease, non-malignant respiratory disease and lung cancer was observed among silica-exposed workers, while elevated mortality from non-malignant respiratory disease and lung cancer was observed among smokers. Combined exposure to silica dust and cigarette smoking elevated the proportion of mortality and accounted for 21.2, 76.0, 35.7 and 81.4% of all causes, non-malignant respiratory disease, cardiovascular disease, and lung cancer, respectively. Significant additive joint effects of silica exposure and cigarette smoking on mortality from lung cancer (HR 1.893, 95% CI 0.628 to 3.441) and pneumoconiosis (6.457, 0.725 to 39.114), together with a significant multiplicative joint effect from all causes (1.002, 1.000 to 1.004) were observed. CONCLUSIONS: The present findings indicated that silica exposure in combination with cigarette smoking accounted for a fraction of extra deaths in our cohort. Our research showed the urgent need for smoking cessation and silica control among iron miners.

Total and Cause-Specific Mortality Risk Associated With Low-Level Exposure to Crystalline Silica: A 44-Year Cohort Study From China.

The association between low-level crystalline silica (silica) exposure and mortality risk is not well understood. We investigated a cohort of 44,807 Chinese workers who had worked in metal mines or pottery factories for at least 1 year from January 1, 1960, to December 31, 1974, and were followed through 2003. Low-level silica exposure was defined as having a lifetime highest annual mean silica exposure at or under a permissible exposure limit (PEL). We considered 3 widely used PELs, including 0.05 mg/m3, 0.10 mg/m3, and 0.35 mg/m3. Cumulative silica exposure was estimated by linking a job exposure matrix with each participant's work history. For the 0.10-mg/m3 exposure level, Cox proportional hazards models showed significantly increased risk of mortality from all diseases (for each 1-ln mg/m3-years increase in logged cumulative silica exposure, hazard ratio (HR) = 1.05, 95% confidence interval (CI): 1.03, 1.07), malignant neoplasms (HR = 1.06, 95% CI: 1.03, 1.09), lung cancer (HR = 1.08, 95% CI: 1.02, 1.14), ischemic heart disease (HR = 1.09, 95% CI: 1.02, 1.16), pulmonary heart disease (HR = 1.08, 95% CI: 1.00, 1.16), and respiratory disease (HR = 1.20, 95% CI: 1.14, 1.26). The 0.05-mg/m3 and 0.35-mg/m3 exposure levels yielded similar associations. Long-term exposure to low levels (PELs ≤0.05 mg/m3, ≤0.10 mg/m3, or ≤0.35 mg/m3) of silica is associated with increased total and certain cause-specific mortality risk. Control of ambient silica levels and use of personal protective equipment should be emphasized in practice.

Short-term Effects of Outdoor Air Pollution on Lung Function among Female Non-smokers in China.

Short-term exposures to outdoor air pollutants have been associated with lower lung function, but the results are inconsistence. The effects of different pollutant levels on lung function changes are still unclear. We quantified the effects of outdoor air pollution exposure (NO2, PM10, O3, and PM2.5) on lung function among 1,694 female non-smokers from the Wuhan-Zhuhai Cohort in China by using linear mixed model. We further investigated the associations in the two cities with different air quality levels separately to quantify the effects of different pollutant level exposure on lung function. We found the moving averages of NO2, PM10, and PM2.5 concentrations were significantly associated with reduced FVC. In city at high pollutant level, the moving average of NO2, PM10, O3, and PM2.5 exposures were significantly associated with both FVC and FEV1 reductions. In the low-level air pollution city, PM10 (Lag03-Lag05) and O3 concentrations (Lag01-Lag03) were significantly associated with reduced FVC, while PM10 (Lag03-Lag05), O3 (Lag0-Lag03), and PM2.5 (Lag04-Lag06) exposure were significantly associated with reduced FEV1. Our results suggest that outdoor air pollution is associated with short-term adverse effects on lung function among female non-smokers. The adverse effects may persist for longer durations within 7 days at higher air pollutant levels.

Size-dependent biological effects on vascular endothelial cells induced by different particulate matters.

The contribution of particles to cardiovascular mortality and morbidity has been enlightened by epidemiologic and experimental studies. However, adverse biological effects of the particles with different sizes on cardiovascular cells have not been well recognized. In this study, sub-cultured human umbilical vein endothelial cells (HUVECs) were exposed to increasing concentrations of pure quartz particles (DQ) of three sizes (DQPM1, <1 µm; DQPM3-5, 3-5 µm; DQPM5, 5 µm) and carbon black particles of two sizes (CB0.1, <0.1 µm; CB1, <1 µm) for 24 h. Cytotoxicity was estimated by measuring the activity of lactate dehydrogenase (LDH) and cell viability. Nitric oxide (NO) generation and cytokines (TNF-α and IL-1ß) releases were analyzed by using NO assay and enzyme-linked immunoabsorbent assay (ELISA), respectively. It was found that both particles induced adverse biological effects on HUVECs in a dose-dependent manner. The size of particle directly influenced the biological activity. For quartz, the smaller particles induced stronger cytotoxicity and higher levels of cytokine responses than those particles of big size. For carbon black particles, CB0.1 was more capable of inducing adverse responses on HUVECs than CB1 only at lower particle concentrations, in contrast to those at higher concentrations. Meanwhile, our data also revealed that quartz particles performed stronger cell damage and produced higher levels of TNF-α than carbon black particles, even if particles size was similar. In conclusion, particle size as well as particle composition should be both considered in assessing vascular endothelial cells injury and inflammation responses induced by particles.

Exposure-response analysis and risk assessment for lung cancer in relationship to silica exposure: a 44-year cohort study of 34,018 workers.

Crystalline silica has been classified as a human carcinogen by the International Agency for Research on Cancer (Lyon, France); however, few previous studies have provided quantitative data on silica exposure, silicosis, and/or smoking. We investigated a cohort in China (in 1960-2003) of 34,018 workers without exposure to carcinogenic confounders. Cumulative silica exposure was estimated by linking a job-exposure matrix to work history. Cox proportional hazards model was used to conduct exposure-response analysis and risk assessment. During a mean 34.5-year follow-up, 546 lung cancer deaths were identified. Categorical analyses by quartiles of cumulative silica exposure (using a 25-year lag) yielded hazard ratios of 1.26, 1.54, 1.68, and 1.70, respectively, compared with the unexposed group. Monotonic exposure-response trends were observed among nonsilicotics (P for trend < 0.001). Analyses using splines showed similar trends. The joint effect of silica and smoking was more than additive and close to multiplicative. For workers exposed from ages 20 to 65 years at 0.1 mg/m(3) of silica exposure, the estimated excess lifetime risk (through age 75 years) was 0.51%. These findings confirm silica as a human carcinogen and suggest that current exposure limits in many countries might be insufficient to protect workers from lung cancer. They also indicate that smoking cessation could help reduce lung cancer risk for silica-exposed individuals.

Neutralization of interleukin-1 beta attenuates silica-induced lung inflammation and fibrosis in C57BL/6 mice.

The inflammation and fibrosis induced by silica dust are considered to be substantial responses in silicosis progression. Interleukin-1 beta (IL-1ß) plays an important role in silica-induced lung inflammation, but the mechanisms that underlie the influence of IL-1ß on the progression of silicosis remain unclear. In this study, the role of IL-1ß in silica-induced inflammation and fibrosis was evaluated by administering a suspension of 2.5-mg silica dust, either with or without 40 µg anti-mouse IL-1ß monoclonal antibody (mAb), to the lungs of male C57BL/6 mice. Silica + anti-IL-1ß mAb-treated mice showed the depletion of IL-1ß as well as the attenuation of inflammation, as evaluated in the bronchoalveolar lavage fluid (BALF) and histological sections from 1 to 84 days after silica exposure. Further study of the BALF indicated that inhibition of IL-1ß could reduce the contents of tumor necrosis factor-alpha and monocyte chemoattractant protein-1. The real-time PCR and pathology results showed that the neutralization of IL-1ß attenuated silica-induced fibrosis by inhibiting the gene expression of transforming growth factor-beta 1, collagen I and fibronectin. The examination of Th1-cytokine and Th2-cytokine suggested that depletion of IL-1ß decelerated the Th1/Th2 balance toward a Th2-dominant response. In conclusion, the present study suggests that the neutralization of IL-1ß attenuates silica-induced inflammation and fibrosis by inhibiting other inflammatory and fibrogenic mediators and modulating the Th1/Th2 balance.

Polychlorinated dibenzo-p-dioxins and dibenzofurans and their association with cancer mortality among workers in one automobile foundry factory.

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) have been reported as possible carcinogenic hazards to humans. However, epidemiological studies on their carcinogenic roles are limited. The current study was designed to determine the concentrations and characteristics of PCDD/Fs and evaluate their association with cancer mortality in exposed workers in one automobile foundry factory. PCDD/F levels in factory and surrounding environment were analyzed through air and settling dust sampling. The cancer mortalities among workers in this foundry factory were calculated using data from a cohort study. The results showed that the PCDD/F concentrations of air in workplace ranged 0.36-2.25 pg World Health Organization-Toxic Equivalent (WHO-TEQ) Nm(-3) (average 1.01 pg WHO-TEQ Nm(-3)), which were 1.16-7.26 times higher than those outside the factory. The PCDD/F concentrations of settling dust in the workplace ranged 3.34-18.64 pg WHO-TEQ g(-1) (average 8.25 pg WHO-TEQ g(-1)), which were lower than those just outside the factory (average 16.13 pg WHO-TEQ g(-1)). Furthermore, a cohort study of workers in this factory with average follow-up of 24.52 years showed that cancer was the leading cause of death, with significant elevated mortality (standardized mortality ratio (SMR)=1.70, 95% confidence interval (CI): 1.35-2.13) among workers, when compared with Chinese national mortality. The cancer mortality among front-line workers was increased significantly (adjusted relative risk (RR)=1.73, 95% CI: 1.14-2.60), particularly among melting and casting workers, when compared with that among assistant workers. Our results indicated that there was a dose-response relationship between PCDD/F exposure and cancer mortality among foundry workers.

[Smoking status or age impact on urinary 8-hydroxy-2'-deoxyguanosine in electrical and electronic equipment waste dismantling workers].

OBJECTIVE: To investigate the smoking or age impact on occupational workers in electrical and electronic equipment waste (e-waste) dismantling procedure, using 8-Hydroxy-2'-deoxyguanosine (8-OHdG) in the urine as a biomarker for oxidative damage to DNA. METHODS: The pre-workshift and post-workshift urinary samples of 64 male workers in e-waste dismantling procedure were detected by solid-phase extraction-high performance liquid chromatography-electrochemical detector (SPE-HPLC-ECD). The data were statistically analyzed by two factors, age or smoking status. RESULTS: The 8-OHdG levels in non-smokers' urines (n = 42) were higher than those in smokers' urines (n = 22). The levels in pre-workshift urines were detected at (8.25 +/- 4.23) micromol/mol creatinine in non-smokers, while the values were (5.44 +/- 1.18) micromol/mol in smokers. And, the levels in post-workshift were detected at (43.12 +/- 16.19) micromol/mol creatinine in non-smokers, while the values were (14.82 +/- 2.51) micromol/mol in smokers. The 8-OHdG levels in pre-workshift urines were not different between non-smokers and smokers (t = -0.81, P = 0.42), however after 1 day exposure, urinary 8-OHdG levels were significantly increased in non-smokers than those in smokers (t = - 2.33, P < 0.05). On the other hand, the subjects were divided into five groups according to their age. The 8-OHdG levels in pre-workshift urines were (1.86 +/- 0.66), (3.57 +/- 0.54), (8.12 +/- 4.10), (11.39 +/- 3.70) micromol/mol creatinine in < 20 years group (n = 6), 20 -years group (n = 22), 30 - years group ( n = 23), 40 - 49 years group (n = 11) respectively. No effect of age was found on the pre-workshift urinary 8-OHdG levels (F = 0.98, t = 0.41). However, it was found that the post-workshift urinary 8-OHdG levels increased along with the e-waste workers' age (F = 4.81, P = 0.03), and they were (4.19 +/- 2.85), (19.89 +/- 5.26), (28.89 +/- 14.61), (34.94 +/- 12.50) micromol/mol creatinine in < 20 years group, 20 - years group, 30 - years group, 40 - 49 years group respectively. CONCLUSION: The urinary 8-OHdG levels in the e-waste dismantling workers might be inhibited by smoking status. The post-workshift urinary 8-OHdG levels increased along with the e-waste workers' age.

Curcumin protects against cytotoxic and inflammatory effects of quartz particles but causes oxidative DNA damage in a rat lung epithelial cell line.

Chronic inhalation of high concentrations of respirable quartz particles has been implicated in various lung diseases including lung fibrosis and cancer. Generation of reactive oxygen species (ROS) and oxidative stress is considered a major mechanism of quartz toxicity. Curcumin, a yellow pigment from Curcuma longa, has been considered as nutraceutical because of its strong anti-inflammatory, antitumour and antioxidant properties. The aim of our present study was to investigate whether curcumin can protect lung epithelial cells from the cytotoxic, genotoxic and inflammatory effects associated with quartz (DQ12) exposure. Electron paramagnetic resonance (EPR) measurements using the spin-trap DMPO demonstrated that curcumin reduces hydrogen peroxide-dependent hydroxyl-radical formation by quartz. Curcumin was also found to reduce quartz-induced cytotoxicity and cyclooxygenase 2 (COX-2) mRNA expression in RLE-6TN rat lung epithelial cells (RLE). Curcumin also inhibited the release of macrophage inflammatory protein-2 (MIP-2) from RLE cells as observed upon treatment with interleukin-1 beta (IL-1beta) and tumour necrosis factor-alpha (TNFalpha). However, curcumin failed to protect the RLE cells from oxidative DNA damage induced by quartz, as shown by formamidopyrimidine glycosylase (FPG)-modified comet assay and by immunocytochemistry for 8-hydroxydeoxyguanosine. In contrast, curcumin was found to be a strong inducer of oxidative DNA damage itself at non-cytotoxic and anti-inflammatory concentrations. In line with this, curcumin also enhanced the mRNA expression of the oxidative stress response gene heme oxygenase-1 (ho-1). Curcumin also caused oxidative DNA damage in NR8383 rat alveolar macrophages and A549 human lung epithelial cells. Taken together, these observations indicate that one should be cautious in considering the potential use of curcumin in the prevention or treatment of lung diseases associated with quartz exposure.

Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles.

Inhaled ultrafine particles show considerably stronger pulmonary inflammatory effects when tested at equal mass dose with their fine counterparts. However, the responsible mechanisms are not yet fully understood. We investigated the role of particle size and surface chemistry in initiating pro-inflammatory effects in vitro in A549 human lung epithelial cells on treatment with different model TiO(2) particles. Two samples of TiO(2), i.e. fine (40-300 nm) and ultrafine (20-80 nm) were tested in their native forms as well as upon surface methylation, as was confirmed by Fourier transformed infrared spectroscopy. Radical generation during cell treatment was determined by electron paramagnetic resonance with 5,5-dimethyl-1-pyrroline-N-oxide or 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl. Interleukin-8 mRNA expression/release was determined by RT-PCR and ELISA, whereas particle uptake was evaluated by transmission electron microscopy. TiO(2) particles were rapidly taken up by the cells, generally as membrane bound aggregates and large intracellular aggregates in vesicles, vacuoles and lamellar bodies. Aggregate size tended to be smaller for the ultrafine samples and was also smaller for methylated fine TiO(2) when compared to non-methylated fine TiO(2). No particles were observed inside nuclei or any other vital organelle. Both ultrafine TiO(2) samples but not their fine counterparts elicited significantly stronger oxidant generation and IL-8 release, despite their aggregation state and irrespective of their methylation. The present data indicate that ultrafine TiO(2), even as aggregates/agglomerates, can trigger inflammatory responses that appear to be driven by their large surface area. Furthermore, our results indicate that these effects result from oxidants generated during particle-cell interactions through a yet to be elucidated mechanism(s).