Association between occupational exposure to trichloroethylene and serum levels of microRNAs: a cross-sectional molecular epidemiology study in China.

OBJECTIVES: The objective of our study was to evaluate the association between occupational exposure to trichloroethylene (TCE), a suspected lymphomagen, and serum levels of miRNAs in a cross-sectional molecular epidemiology study of TCE-exposed workers and comparable unexposed controls in China. METHODS: Serum levels of 40 miRNAs were compared in 74 workers exposed to TCE (median: 12 ppm) and 90 unexposed control workers. Linear regression models were used to test for differences in serum miRNA levels between exposed and unexposed workers and to evaluate exposure-response relationships across TCE exposure categories using a three-level ordinal variable [i.e., unexposed, < 12 ppm, the median value among workers exposed to TCE) and ≥ 12 ppm)]. Models were adjusted for sex, age, current smoking, current alcohol use, and recent infection. RESULTS: Seven miRNAs showed significant differences between exposed and unexposed workers at FDR (false discovery rate) < 0.20. miR-150-5p and let-7b-5p also showed significant inverse exposure-response associations with TCE exposure (Ptrend= 0.002 and 0.03, respectively). The % differences in serum levels of miR-150-5p relative to unexposed controls were - 13% and - 20% among workers exposed to < 12 ppm and ≥ 12 ppm TCE, respectively. CONCLUSIONS: miR-150-5p is involved in B cell receptor pathways and let-7b-5p plays a role in the innate immune response processes that are potentially important in the etiology of non-Hodgkin lymphoma (NHL). Further studies are needed to replicate these findings and to directly test the association between serum levels of these miRNAs and risk of NHL in prospective studies.

Alterations in immune and renal biomarkers among workers occupationally exposed to low levels of trichloroethylene below current regulatory standards.

OBJECTIVES: The occupational exposure limit for trichloroethylene (TCE) in different countries varies from 1 to 100 ppm as an 8-hour time-weighted average (TWA). Many countries currently use 10 ppm as the regulatory standard for occupational exposures, but the biological effects in humans at this level of exposure remain unclear. The objective of our study was to evaluate alterations in immune and renal biomarkers among workers occupationally exposed to low levels of TCE below current regulatory standards. METHODS: We conducted a cross-sectional molecular epidemiology study of 80 healthy workers exposed to a wide range of TCE (ie, 0.4-229 ppm) and 96 comparable unexposed controls in China, and previously reported that TCE exposure was associated with multiple candidate biological markers related to immune function and kidney toxicity. Here, we conducted further analyses of all of the 31 biomarkers that we have measured to determine the magnitude and statistical significance of changes in the subgroup of workers (n=35) exposed to <10 ppm TCE compared with controls. RESULTS: Six immune biomarkers (ie, CD4+ effector memory T cells, sCD27, sCD30, interleukin-10, IgG and IgM) were significantly decreased (% difference ranged from -16.0% to -72.1%) and one kidney toxicity marker (kidney injury molecule-1, KIM-1) was significantly increased (% difference: +52.5%) among workers exposed to <10 ppm compared with the control group. These associations remained noteworthy after taking into account multiple comparisons using the false discovery rate (ie, <0.20). CONCLUSION: Our results suggest that occupational exposure to TCE below 10 ppm as an 8-hour TWA may alter levels of key markers of immune function and kidney toxicity.

Comparison of hematological alterations and markers of B-cell activation in workers exposed to benzene, formaldehyde and trichloroethylene.

Benzene, formaldehyde (FA) and trichloroethylene (TCE) are ubiquitous chemicals in workplaces and the general environment. Benzene is an established myeloid leukemogen and probable lymphomagen. FA is classified as a myeloid leukemogen but has not been associated with non-Hodgkin lymphoma (NHL), whereas TCE has been associated with NHL but not myeloid leukemia. Epidemiologic associations between FA and myeloid leukemia, and between benzene, TCE and NHL are, however, still debated. Previously, we showed that these chemicals are associated with hematotoxicity in cross-sectional studies of factory workers in China, which included extensive personal monitoring and biological sample collection. Here, we compare and contrast patterns of hematotoxicity, monosomy 7 in myeloid progenitor cells (MPCs), and B-cell activation biomarkers across these studies to further evaluate possible mechanisms of action and consistency of effects with observed hematologic cancer risks. Workers exposed to benzene or FA, but not TCE, showed declines in cell types derived from MPCs, including granulocytes and platelets. Alterations in lymphoid cell types, including B cells and CD4+ T cells, and B-cell activation markers were apparent in workers exposed to benzene or TCE. Given that alterations in myeloid and lymphoid cell types are associated with hematological malignancies, our data provide biologic insight into the epidemiological evidence linking benzene and FA exposure with myeloid leukemia risk, and TCE and benzene exposure with NHL risk.

Circulating immune/inflammation markers in Chinese workers occupationally exposed to formaldehyde.

BACKGROUND: Formaldehyde has been classified as a human myeloid leukemogen. However, the mechanistic basis for this association is still debated. OBJECTIVES: We aimed to evaluate whether circulating immune/inflammation markers were altered in workers occupationally exposed to formaldehyde. METHODS: Using a multiplexed bead-based assay, we measured serum levels of 38 immune/inflammation markers in a cross-sectional study of 43 formaldehyde-exposed and 51 unexposed factory workers in Guangdong, China. Linear regression models adjusting for potential confounders were used to compare marker levels in exposed and unexposed workers. RESULTS: We found significantly lower circulating levels of two markers among exposed factory workers compared with unexposed controls that remained significant after adjusting for potential confounders and multiple comparisons using a false discovery rate of 10%, including chemokine (C-X-C motif) ligand 11 (36.2 pg/ml in exposed versus 48.4 pg/ml in controls, P = 0.0008) and thymus and activation regulated chemokine (52.7 pg/ml in exposed versus 75.0 pg/ml in controls, P = 0.0028), suggesting immunosuppression among formaldehyde-exposed workers. CONCLUSIONS: Our findings are consistent with recently emerging understanding that immunosuppression might be associated with myeloid diseases. These findings, if replicated in a larger study, may provide insights into the mechanisms by which formaldehyde promotes leukemogenesis.

Chromosome-wide aneuploidy study of cultured circulating myeloid progenitor cells from workers occupationally exposed to formaldehyde.

Formaldehyde (FA) is an economically important industrial chemical to which millions of people worldwide are exposed environmentally and occupationally. Recently, the International Agency for Cancer Research concluded that there is sufficient evidence that FA causes leukemia, particularly myeloid leukemia. To evaluate the biological plausibility of this association, we employed a chromosome-wide aneuploidy study approach, which allows the evaluation of aneuploidy and structural chromosome aberrations (SCAs) of all 24 chromosomes simultaneously, to analyze cultured myeloid progenitor cells from 29 workers exposed to relatively high levels of FA and 23 unexposed controls. We found statistically significant increases in the frequencies of monosomy, trisomy, tetrasomy and SCAs of multiple chromosomes in exposed workers compared with controls, with particularly notable effects for monosomy 1 [P = 6.02E-06, incidence rate ratio (IRR) = 2.31], monosomy 5 (P = 9.01E-06; IRR = 2.24), monosomy 7 (P = 1.57E-05; IRR = 2.17), trisomy 5 (P = 1.98E-05; IRR = 3.40) and SCAs of chromosome 5 (P = 0.024; IRR = 4.15). The detection of increased levels of monosomy 7 and SCAs of chromosome 5 is particularly relevant as they are frequently observed in acute myeloid leukemia. Our findings provide further evidence that leukemia-related cytogenetic changes can occur in the circulating myeloid progenitor cells of healthy workers exposed to FA, which may be a potential mechanism underlying FA-induced leukemogenesis.

[Association between GPX-1 single nucleotide polymorphisms and susceptibility to noise-induced hearing loss among Chinese Han population].

OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) in glutathione peroxidase 1 (GPX-1) gene, rs3448, rs1050450, rs1800668, and rs1987628, and the susceptibility to noise-induced hearing loss (NIHL) among Chinese Han population. METHODS: A case-control study was conducted to investigate the threshold shift of the left ear at 3000 Hz among the workers of Chinese Han population who were exposed to the same level of sound pressure. Two hundred and one (10%) of the subjects with the highest level of threshold shift were recruited in susceptible group, while 202 of (10%) of the subjects with the lowest level of threshold shift were recruited in tolerant group. Targeted occupational health survey and questionnaire survey were performed among these people. For each individual, genome DNA was extracted from 5 ml of fasting peripheral venous blood. Four SNPs (GPX-1 rs3448, rs1050450, rs1800668, and rs1987628) were genotyped by the TaqMan SNP genotyping kit. The main effects of SNPs and the association between NIHL susceptibility and SNPs were analyzed by logistic regression. RESULTS: The C allele of rs1987628 was a risk factor for NIHL, with an odds ratio (OR) of 2.531 (95%CI: 1.878-3.411) as compared with the T allele. The CC genotype of rs1987628 was more associated with NIHL than the TT genotype (OR = 3.500, 95% CI: 1.984-6.174; adjusted OR = 3.544, 95% CI: 1.974 ∼ 6.364). CONCLUSION: Among Chinese Han population, GPX-1 SNP rs1987628 may be associated with the susceptibility to NIHL.

Occupational exposure to trichloroethylene and serum concentrations of IL-6, IL-10, and TNF-alpha.

To evaluate the immunotoxicity of trichloroethylene (TCE), we conducted a cross-sectional molecular epidemiology study in China of workers exposed to TCE. We measured serum levels of IL-6, IL-10, and TNF-α, which play a critical role in regulating various components of the immune system, in 71 exposed workers and 78 unexposed control workers. Repeated personal exposure measurements were taken in workers before blood collection using 3 M organic vapor monitoring badges. Compared to unexposed workers, the serum concentration of IL-10 in workers exposed to TCE was decreased by 70% (P = 0.001) after adjusting for potential confounders. Further, the magnitude of decline in IL-10 was >60% and statistically significant in workers exposed to <12 ppm as well as in workers with exposures ≥ 12 ppm of TCE, compared to unexposed workers. No significant differences in levels of IL-6 or TNF-α were observed among workers exposed to TCE compared to unexposed controls. Given that IL-10 plays an important role in immunologic processes, including mediating the Th1/Th2 balance, our findings provide additional evidence that TCE is immunotoxic in humans.

Alterations in serum immunoglobulin levels in workers occupationally exposed to trichloroethylene.

Trichloroethylene (TCE) has been associated with a variety of immunotoxic effects and may be associated with an increased risk of non-Hodgkin lymphoma (NHL). Altered serum immunoglobulin (Ig) levels have been reported in NHL patients and in animals exposed to TCE. Recently, we reported that occupational exposure to TCE is associated with immunosuppressive effects and immune dysfunction, including suppression of B-cell counts and activation, even at relatively low levels. We hypothesized that TCE exposure would also affect Ig levels in humans. We measured serum levels of IgG, IgM and IgE, by enzyme-linked immunosorbent assay, in TCE-exposed workers (n = 80) and unexposed controls (n = 45), matched by age and gender, in a cross-sectional, molecular epidemiology study of occupational exposure to TCE in Guangdong, China. Exposed workers had about a 17.5% decline in serum levels of IgG compared with unexposed controls (P = 0.0002). Similarly, serum levels of IgM were reduced by about 38% in workers exposed to TCE compared with unexposed controls (P < 0.0001). Serum levels of both IgG and IgM were significantly decreased in workers exposed to TCE levels below 12 p.p.m., the median exposure level. Adjustment for B-cell counts had minimal impact on our findings. IgE levels were not significantly different between exposed and control subjects. These results provide further evidence that TCE is immunotoxic at relatively low exposure levels and provide additional biologic plausibility for the reported association of TCE with NHL.

Occupational exposure to formaldehyde and alterations in lymphocyte subsets.

BACKGROUND: Formaldehyde is used in many occupational settings, most notably in manufacturing, health care, and embalming. Formaldehyde has been classified as a human carcinogen, but its mechanism of action remains uncertain. METHODS: We carried out a cross-sectional study of 43 formaldehyde-exposed workers and 51 unexposed age and sex-matched controls in Guangdong, China to study formaldehyde's early biologic effects. To follow up our previous report that the total lymphocyte count was decreased in formaldehyde-exposed workers compared with controls, we evaluated each major lymphocyte subset (i.e., CD4(+) T cells, CD8(+) T cells, natural killer [NK] cells, and B cells) and T cell lymphocyte subset (CD4(+) naïve and memory T cells, CD8(+) naïve and memory T cells, and regulatory T cells). Linear regression of each subset was used to test for differences between exposed workers and controls, adjusting for potential confounders. RESULTS: Total NK cell and T cell counts were about 24% (P = 0.037) and 16% (P = 0.0042) lower, respectively, among exposed workers. Among certain T cell subsets, decreased counts among exposed workers were observed for CD8(+) T cells (P = 0.026), CD8(+) effector memory T cells (P = 0.018), and regulatory T cells (CD4(+) FoxP3(+) : P = 0.04; CD25(+) FoxP3(+) : P = 0.008). CONCLUSIONS: Formaldehyde-exposed workers experienced decreased counts of NK cells, regulatory T cells, and CD8(+) effector memory T cells; however, due to the small sample size; these findings need to be confirmed in larger studies.

Elevated urinary levels of kidney injury molecule-1 among Chinese factory workers exposed to trichloroethylene.

Epidemiological studies suggest that trichloroethylene (TCE) exposure may be associated with renal cancer. The biological mechanisms involved are not exactly known although nephrotoxicity is believed to play a role. Studies on TCE nephrotoxicity among humans, however, have been largely inconsistent. We studied kidney toxicity in Chinese factory workers exposed to TCE using novel sensitive nephrotoxicity markers. Eighty healthy workers exposed to TCE and 45 comparable unexposed controls were included in the present analyses. Personal TCE exposure measurements were taken over a 2-week period before urine collection. Ninety-six percent of workers were exposed to TCE below the current US Occupational Safety and Health Administration permissible exposure limit (100 ppm 8h TWA), with a mean (SD) of 22.2 (35.9) ppm. Kidney injury molecule-1 (KIM-1) and Pi-glutathione S transferase (GST) alpha were elevated among the exposed subjects as compared with the unexposed controls with a strong exposure-response association between individual estimates of TCE exposure and KIM-1 (P < 0.0001). This is the first report to use a set of sensitive nephrotoxicity markers to study the possible effects of TCE on the kidneys. The findings suggest that at relatively low occupational exposure levels a toxic effect on the kidneys can be observed. This finding supports the biological plausibility of linking TCE exposure and renal cancer.

Decreased Numbers of CD4(+) Naive and Effector Memory T Cells, and CD8(+) Naïve T Cells, are Associated with Trichloroethylene Exposure.

Trichloroethylene (TCE) is a volatile chlorinated organic compound that is commonly used as a solvent for lipophilic compounds. Although recognized as an animal carcinogen, TCE's carcinogenic potential in humans is still uncertain. We have carried out a cross-sectional study of 80 workers exposed to TCE and 96 unexposed controls matched on age and sex in Guangdong, China to study TCE's early biologic effects. We previously reported that the total lymphocyte count and each of the major lymphocyte subsets (i.e., CD4(+) T cells, CD8(+) T cells, natural killer cells, and B cells) were decreased in TCE-exposed workers compared to controls, suggesting a selective effect on lymphoid progenitors, and/or lymphocyte survival. To explore which T lymphocyte subsets are affected in the same study population, we investigated the effect of TCE exposure on the numbers of CD4(+) naïve and memory T cells, CD8(+) naïve and memory T cells, and regulatory T cells by FACS analysis. Linear regression of each subset was used to test for differences between exposed workers and controls adjusting for potential confounders. We observed that CD4(+) and CD8(+) naïve T cell counts were about 8% (p = 0.056) and 17% (p = 0.0002) lower, respectively, among exposed workers. CD4(+) effector memory T cell counts were decreased by about 20% among TCE-exposed workers compared to controls (p = 0.001). The selective targeting of TCE on CD8(+) naive and possibly CD4(+) naive T cells, and CD4(+) effector memory T cells, provide further insights into the immunosuppression-related response of human immune cells upon TCE exposure.

Occupational exposure to trichloroethylene is associated with a decline in lymphocyte subsets and soluble CD27 and CD30 markers.

Occupational cohort and case-control studies suggest that trichloroethylene (TCE) exposure may be associated with non-Hodgkin lymphoma (NHL) but findings are not consistent. There is a need for mechanistic studies to evaluate the biologic plausibility of this association. We carried out a cross-sectional molecular epidemiology study of 80 healthy workers that used TCE and 96 comparable unexposed controls in Guangdong, China. Personal exposure measurements were taken over a three-week period before blood collection. Ninety-six percent of workers were exposed to TCE below the current US Occupational Safety and Health Administration Permissible Exposure Limit (100 p.p.m. 8 h time-weighted average), with a mean (SD) of 22.2 (36.0) p.p.m. The total lymphocyte count and each of the major lymphocyte subsets including CD4+ T cells, CD8+ T cells, natural killer (NK) cells and B cells were significantly decreased among the TCE-exposed workers compared with controls (P < 0.05), with evidence of a dose-dependent decline. Further, there was a striking 61% decline in sCD27 plasma level and a 34% decline in sCD30 plasma level among TCE-exposed workers compared with controls. This is the first report that TCE exposure under the current Occupational Safety and Health Administration workplace standard is associated with a decline in all major lymphocyte subsets and sCD27 and sCD30, which play an important role in regulating cellular activity in subsets of T, B and NK cells and are associated with lymphocyte activation. Given that altered immunity is an established risk factor for NHL, these results add to the biologic plausibility that TCE is a possible lymphomagen.

Occupational exposure to formaldehyde, hematotoxicity, and leukemia-specific chromosome changes in cultured myeloid progenitor cells.

There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing, and other industries. Epidemiologic studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on the ability of formaldehyde to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures.

[Epidemiological investigation of welder's pneumoconiosis in two container manufacturing industries in Guangdong province].

OBJECTIVE: To investigate the incidence of welder's pneumoconiosis in container manufacturing industries in Guangdong province and present some preventive and curative strategy. METHODS: Occupational epidemiology study methods were used to study the incidence of welder's pneumoconiosis in two container manufacturing enterprises (enterprise A and enterprise B). RESULTS: Before 2004, the rate of up-to-standard of weld fume concentration in the workplaces was relatively low (< or = 40%), and the maximum value of time weighted average (TWA) was 26.7 mg/m(3). After 2004, with the system of dust control, the rate of up-to-standard was 85% in the enterprise A. Of the 813 weld workers examined, 19 were diagnosed as welder's pneumoconiosis (stage I was 15, while I (+) was 4 ) and the incidence was 2.34% (19/813). The age of electric welders suffering from welder's pneumoconiosis and the duration of dust exposure were (33.45 + 4.64) and (8.04 + 1.97) years respectively. Chest radiographic examination showed mainly small round opacities "p". The value of MVV, FEF25%, FEF50% and FEF75% in lung function tests were significantly lower than those of the control group (P < 0.05 or P < 0.01). CONCLUSION: The main features of welder's pneumoconiosis in container manufacturing industries are the short duration of dust exposure, and small round opacities "p" in the chest radiographs. Therefore, it should be the key point of the prevention and treatment of occupational diseases in this industry to control the harmful weld fume.

[Epidemiological study of gem worker's silicosis].

OBJECTIVE: To study the hazards of gem dusts and the epidemiological features of the occurrence of gem worker's silicosis (GWS). METHODS: Epidemiological investigation in a gem factory in Guangdong province was carried out. RESULTS: The average dusts concentration in workshop was 2.3 mg/m(3), average free silica content was 94.64%. There were 47 patients diagnosed as silicosis. The prevalence of GWS was 4.58% (47/ 1,027). The age of patients suffering from silicosis and the duration of dust exposure were (27.04 +/- 3.25) years and (4.67 +/- 1.17) years respectively. Chest radiographic examination showed mainly small round opacities "q". The incidences of GWS complicated by pulmonary tuberculosis, spontaneous pneumothorax and pulmonary emphysema were 10.64%, 10.64%, 44.68% respectively. CONCLUSION: The hazards of gem dust to workers might be serious. Higher incidence, younger age suffered from silicosis, shorter duration of dust exposure, more complications, and poorer prognosis in gem workers appeared to be the main epidemiological features of GWS in Guangdong.