Lung Cancer Risks Associated with Occupational Exposure to Pairs of Five Lung Carcinogens: Results from a Pooled Analysis of Case-Control Studies (SYNERGY).

BACKGROUND: While much research has been done to identify individual workplace lung carcinogens, little is known about joint effects on risk when workers are exposed to multiple agents. OBJECTIVES: We investigated the pairwise joint effects of occupational exposures to asbestos, respirable crystalline silica, metals (i.e., nickel, chromium-VI), and polycyclic aromatic hydrocarbons (PAH) on lung cancer risk, overall and by major histologic subtype, while accounting for cigarette smoking. METHODS: In the international 14-center SYNERGY project, occupational exposures were assigned to 16,901 lung cancer cases and 20,965 control subjects using a quantitative job-exposure matrix (SYN-JEM). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for ever vs. never exposure using logistic regression models stratified by sex and adjusted for study center, age, and smoking habits. Joint effects among pairs of agents were assessed on multiplicative and additive scales, the latter by calculating the relative excess risk due to interaction (RERI). RESULTS: All pairwise joint effects of lung carcinogens in men were associated with an increased risk of lung cancer. However, asbestos/metals and metals/PAH resulted in less than additive effects; while the chromium-VI/silica pair showed marginally synergistic effect in relation to adenocarcinoma (RERI: 0.24; CI: 0.02, 0.46; p = 0.05). In women, several pairwise joint effects were observed for small cell lung cancer including exposure to PAH/silica (OR = 5.12; CI: 1.77, 8.48), and to asbestos/silica (OR = 4.32; CI: 1.35, 7.29), where exposure to PAH/silica resulted in a synergistic effect (RERI: 3.45; CI: 0.10, 6.8). DISCUSSION: Small or no deviation from additive or multiplicative effects was observed, but co-exposure to the selected lung carcinogens resulted generally in higher risk than exposure to individual agents, highlighting the importance to reduce and control exposure to carcinogens in workplaces and the general environment. https://doi.org/10.1289/EHP13380.

Respirable crystalline silica and lung cancer in community-based studies: impact of job-exposure matrix specifications on exposure-response relationships.

OBJECTIVES: The quantitative job-exposure matrix SYN-JEM consists of various dimensions: job-specific estimates, region-specific estimates, and prior expert ratings of jobs by the semi-quantitative DOM-JEM. We analyzed the effect of different JEM dimensions on the exposure-response relationships between occupational silica exposure and lung cancer risk to investigate how these variations influence estimates of exposure by a quantitative JEM and associated health endpoints. METHODS: Using SYN-JEM, and alternative SYN-JEM specifications with varying dimensions included, cumulative silica exposure estimates were assigned to 16 901 lung cancer cases and 20 965 controls pooled from 14 international community-based case-control studies. Exposure-response relationships based on SYN-JEM and alternative SYN-JEM specifications were analyzed using regression analyses (by quartiles and log-transformed continuous silica exposure) and generalized additive models (GAM), adjusted for age, sex, study, cigarette pack-years, time since quitting smoking, and ever employment in occupations with established lung cancer risk. RESULTS: SYN-JEM and alternative specifications generated overall elevated and similar lung cancer odds ratios ranging from 1.13 (1st quartile) to 1.50 (4th quartile). In the categorical and log-linear analyses SYN-JEM with all dimensions included yielded the best model fit, and exclusion of job-specific estimates from SYN-JEM yielded the poorest model fit. Additionally, GAM showed the poorest model fit when excluding job-specific estimates. CONCLUSION: The established exposure-response relationship between occupational silica exposure and lung cancer was marginally influenced by varying the dimensions of SYN-JEM. Optimized modelling of exposure-response relationships will be obtained when incorporating all relevant dimensions, namely prior rating, job, time, and region. Quantitative job-specific estimates appeared to be the most prominent dimension for this general population JEM.

Occupational Benzene Exposure and Lung Cancer Risk: A Pooled Analysis of 14 Case-Control Studies.

Rationale: Benzene has been classified as carcinogenic to humans, but there is limited evidence linking benzene exposure to lung cancer. Objectives: We aimed to examine the relationship between occupational benzene exposure and lung cancer. Methods: Subjects from 14 case-control studies across Europe and Canada were pooled. We used a quantitative job-exposure matrix to estimate benzene exposure. Logistic regression models assessed lung cancer risk across different exposure indices. We adjusted for smoking and five main occupational lung carcinogens and stratified analyses by smoking status and lung cancer subtypes. Measurements and Main Results: Analyses included 28,048 subjects (12,329 cases, 15,719 control subjects). Lung cancer odds ratios ranged from 1.12 (95% confidence interval, 1.03-1.22) to 1.32 (95% confidence interval, 1.18-1.48) (Ptrend = 0.002) for groups with the lowest and highest cumulative occupational exposures, respectively, compared with unexposed subjects. We observed an increasing trend of lung cancer with longer duration of exposure (Ptrend < 0.001) and a decreasing trend with longer time since last exposure (Ptrend = 0.02). These effects were seen for all lung cancer subtypes, regardless of smoking status, and were not influenced by specific occupational groups, exposures, or studies. Conclusions: We found consistent and robust associations between different dimensions of occupational benzene exposure and lung cancer after adjusting for smoking and main occupational lung carcinogens. These associations were observed across different subgroups, including nonsmokers. Our findings support the hypothesis that occupational benzene exposure increases the risk of developing lung cancer. Consequently, there is a need to revisit published epidemiological and molecular data on the pulmonary carcinogenicity of benzene.

Influence of face masks on the subjective impairment at different physical workloads.

To quantify the subjective and cognitive impairment caused by wearing face masks at work, 20 men and 20 women (median age 47 years, range 19-65) were tested under different ergometer workloads while wearing surgical mask, community mask, FFP2 respirator or no mask in a randomized and partially double-blinded design. Masks were worn also at the workplace for four hours. Subjective impairment was recorded by questionnaires. Cognitive performance was tested before and after the workplace examination. Subjective feeling of heat, humidity, and difficult breathing increased with rising physical exertion and wearing time for all three mask types, most notably for FFP2. Even when blinded, participants with FFP2 reported difficult breathing already at rest. During physical exertion, individuals with low tolerance to discomfort reported significantly stronger impairment (OR 1.14, 95% CI 1.02-1.27). Regarding light work, older subjects (OR 0.95, 95% CI 0.92-0.98) and women (OR 0.84, 95% CI 0.72-0.99) showed significantly lower and atopic subjects stronger impairment (OR 1.16, 95% CI 1.06-1.27). No significant influence of mask wearing was detected on cognitive performance. Wearing a mask had no effect on cognitive performance, but led to discomfort which increased with physical exertion and wearing time. Individuals who tolerate discomfort poorly felt more impaired by wearing a mask during physical exertion.

Effects of wearing different face masks on cardiopulmonary performance at rest and exercise in a partially double-blinded randomized cross-over study.

The use of face masks became mandatory during SARS-CoV-2 pandemic. Wearing masks may lead to complaints about laboured breathing and stress. The influence of different masks on cardiopulmonary performance was investigated in a partially double-blinded randomized cross-over design. Forty subjects (19-65 years) underwent body plethysmography, ergometry, cardiopulmonary exercise test and a 4-h wearing period without a mask, with a surgical mask (SM), a community mask (CM), and an FFP2 respirator (FFP2). Cardiopulmonary, physical, capnometric, and blood gas related parameters were recorded. Breathing resistance and work of breathing were significantly increased while wearing a mask. During exercise the increase in minute ventilation tended to be lower and breathing time was significantly longer with mask than without mask. Wearing a mask caused significant minimal decreases in blood oxygen pressure, oxygen saturation, an initial increase in blood and inspiratory carbon dioxide pressure, and a higher perceived physical exertion and temperature and humidity behind the mask under very heavy exercise. All effects were stronger when wearing an FFP2. Wearing face masks at rest and under exercise, changed breathing patterns in the sense of physiological compensation without representing a health risk. Wearing a mask for 4-h during light work had no effect on blood gases.

Occupational exposure to nickel and hexavalent chromium and the risk of lung cancer in a pooled analysis of case-control studies (SYNERGY).

There is limited evidence regarding the exposure-effect relationship between lung-cancer risk and hexavalent chromium (Cr(VI)) or nickel. We estimated lung-cancer risks in relation to quantitative indices of occupational exposure to Cr(VI) and nickel and their interaction with smoking habits. We pooled 14 case-control studies from Europe and Canada, including 16 901 lung-cancer cases and 20 965 control subjects. A measurement-based job-exposure-matrix estimated job-year-region specific exposure levels to Cr(VI) and nickel, which were linked to the subjects' occupational histories. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated by unconditional logistic regression, adjusting for study, age group, smoking habits and exposure to other occupational lung carcinogens. Due to their high correlation, we refrained from mutually adjusting for Cr(VI) and nickel independently. In men, ORs for the highest quartile of cumulative exposure to CR(VI) were 1.32 (95% CI 1.19-1.47) and 1.29 (95% CI 1.15-1.45) in relation to nickel. Analogous results among women were: 1.04 (95% CI 0.48-2.24) and 1.29 (95% CI 0.60-2.86), respectively. In men, excess lung-cancer risks due to occupational Cr(VI) and nickel exposure were also observed in each stratum of never, former and current smokers. Joint effects of Cr(VI) and nickel with smoking were in general greater than additive, but not different from multiplicative. In summary, relatively low cumulative levels of occupational exposure to Cr(VI) and nickel were associated with increased ORs for lung cancer, particularly in men. However, we cannot rule out a combined classical measurement and Berkson-type of error structure, which may cause differential bias of risk estimates.

Lifetime Exposure to Welding Fumes and Risk of Some Rare Cancers.

We investigated the association between exposure to welding fumes and the risk of biliary tract, male breast, bone, and thymus cancer, as well as cancer of the small intestine, eye melanoma, and mycosis fungoides, among men in a European, multicenter case-control study. From 1995-1997, 644 cases and 1,959 control subjects from 7 countries were studied with respect to information on welding and potential confounders. We linked the welding histories of the participants with a measurement-based exposure matrix to calculate lifetime exposure to welding fumes. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, conditional on country and 5-year age groups, and adjusted for education and relevant confounders. Regular welding was associated with an increased risk of cancer of the small intestine (OR = 2.30, 95% CI: 1.17, 4.50). Lifetime exposure to welding fumes above the median of exposed controls was associated with an increased risk of cancer of the small intestine (OR = 2.00, 95% CI: 1.07, 3.72) and male breast (OR = 2.07, 95% CI: 1.14, 3.77), and some elevation in risk was apparent for bone cancer (OR = 1.92, 95% CI: 0.85, 4.34) with increasing lifetime exposure to welding fumes. Welding fumes could contribute to an increased risk of some rare cancers.

No inflammatory effects after acute inhalation of barium sulfate particles in human volunteers.

BACKGROUND: Most threshold limit values are based on animal experiments. Often, the question remains whether these data reflect the situation in humans. As part of a series of investigations in our exposure lab, this study investigates whether the results on the inflammatory effects of particles that have been demonstrated in animal models can be confirmed in acute inhalation studies in humans. Such studies have not been conducted so far for barium sulfate particles (BaSO4), a substance with very low solubility and without known substance-specific toxicity. Previous inhalation studies with zinc oxide (ZnO), which has a substance-specific toxicity, have shown local and systemic inflammatory respones. The design of these human ZnO inhalation studies was adopted for BaSO4 to compare the effects of particles with known inflammatory activity and supposedly inert particles. For further comparison, in vitro investigations on inflammatory processes were carried out. METHODS: Sixteen healthy volunteers were exposed to filtered air and BaSO4 particles (4.0 mg/m3) for two hours including one hour of ergometric cycling at moderate workload. Effect parameters were clinical signs, body temperature, and inflammatory markers in blood and induced sputum. In addition, particle-induced in vitro-chemotaxis of BaSO4 was investigated with regard to mode of action and differences between in vivo and in vitro effects. RESULTS: No local or systemic clinical signs were observed after acute BaSO4 inhalation and, in contrast to our previous human exposure studies with ZnO, no elevated values of biomarkers of inflammation were measured after the challenge. The in vitro chemotaxis induced by BaSO4 particles was minimal and 15-fold lower compared to ZnO. CONCLUSION: The results of this study indicate that BaSO4 as a representative of granular biopersistent particles without specific toxicity does not induce inflammatory effects in humans after acute inhalation. Moreover, the in vitro data fit in with these in vivo results. Despite the careful and complex investigations, limitations must be admitted because the number of local effect parameters were limited and chronic toxicity could not be studied.

Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Lung Cancer Risk: Results from a Pooled Analysis of Case-Control Studies (SYNERGY).

BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAH) occurs widely in occupational settings. We investigated the association between occupational exposure to PAH and lung cancer risk and joint effects with smoking within the SYNERGY project. METHODS: We pooled 14 case-control studies with information on lifetime occupational and smoking histories conducted between 1985 and 2010 in Europe and Canada. Exposure to benzo[a]pyrene (BaP) was used as a proxy of PAH and estimated from a quantitative general population job-exposure matrix. Multivariable unconditional logistic regression models, adjusted for smoking and exposure to other occupational lung carcinogens, estimated ORs, and 95% confidence intervals (CI). RESULTS: We included 16,901 lung cancer cases and 20,965 frequency-matched controls. Adjusted OR for PAH exposure (ever) was 1.08 (CI, 1.02-1.15) in men and 1.20 (CI, 1.04-1.38) in women. When stratified by smoking status and histologic subtype, the OR for cumulative exposure ≥0.24 BaP µg/m3-years in men was higher in never smokers overall [1.31 (CI, 0.98-1.75)], for small cell [2.53 (CI, 1.28-4.99)] and squamous cell cancers [1.33 (CI, 0.80-2.21)]. Joint effects between PAH and smoking were observed. Restricting analysis to the most recent studies showed no increased risk. CONCLUSIONS: Elevated lung cancer risk associated with PAH exposure was observed in both sexes, particularly for small cell and squamous cell cancers, after accounting for cigarette smoking and exposure to other occupational lung carcinogens. IMPACT: The lack of association between PAH and lung cancer in more recent studies merits further research under today's exposure conditions and worker protection measures.

Smoking intensity and urinary nicotine metabolites by socioeconomic status in the Heinz Nixdorf Recall study.

BACKGROUND: Smoking intensity, which is generally based on self-reported average cigarettes per day (CPD), is a major behavioural risk factor and strongly related to socioeconomic status (SES). To assess the validity of the CPD measure, correlations with objective markers of tobacco smoke exposure - such as urinary nicotine metabolites - were examined. Yet, it remains unclear, whether this correlation is affected by SES, which may indicate imprecise or biased self-reports of smoking intensity. METHODS: We investigated the role of SES in the association between CPD and nicotine metabolites in current smokers among the participants of the population-based, prospective Heinz Nixdorf Recall Study. We determined urinary cotinine and additionally trans-3'-hydroxy-cotinine. SES was assessed by the International Socio-Economic Index of occupational status, and education. We calculated correlations (Pearson's r) between logarithmised CPD and cotinine in subgroups of SES and analysed SES and further predictors of cotinine in multiple linear regression models separately by gender. RESULTS: Median reported smoking intensity was 20 CPD in male and 19 CPD in female smokers. Men showed higher cotinine concentrations (median 3652 µg/L, interquartile range (IQR) 2279-5422 µg/L) than women (3127 µg/L, IQR 1692-4920 µg/L). Logarithmised CPD correlated moderately with cotinine in both, men and women (Pearson's r 0.4), but correlations were weaker in smokers with lower SES: Pearson's r for low, intermediate, and high occupational SES was 0.35, 0.39, and 0.48 in men, and 0.28, 0.43, and 0.47 in women, respectively. Logarithmised CPD and urinary creatinine were main predictors of cotinine in multiple regression models, whereas SES showed a weak negative association in women. Results were similar for trans-3'-hydroxy-cotinine. CONCLUSIONS: Decreasing precision of self-reported CPD was indicated for low SES in men and women. We found no strong evidence for biased self-reports of smoking intensity by SES.

How to Reduce the Exposure of Welders to an Acceptable Level: Results of the InterWeld Study.

OBJECTIVES: Workplace measurements in the past have shown that the applicable occupational exposure limits (OELs) are regularly exceeded in practice when high-emission welding processes are applied. The InterWeld pilot study was planned as part of an intervention study to show under which conditions compliance with the OEL is achievable in gas metal arc welding (GMAW) with solid wire. The investigation focussed on local exhaust ventilation, i.e. captor hoods and welding torches with integrated fume extraction. METHODS: Forty tests with hand-guided GMAW were configured by experts with regard to all technical parameters and carried out by a professional welder. Effects of protective measures and process parameters on the exposure to respirable welding fumes and airborne manganese (Mn), chromium, nickel, and hexavalent chromium were investigated. Personal sampling was carried out in the welder's breathing zone outside the face shield at high flow rates (10 l min-1) in order to achieve sufficient filter loading. Particle masses and welding fume concentrations were determined by weighing the sampling filters. Metal concentrations were analysed by inductive coupled plasma mass spectrometry. In order to evaluate the effects on exposure, the measurements were performed under similar conditions. The data were analysed descriptively and with mixed linear models. For measurements below the limit of detection, the exposure level was estimated using multiple imputation. RESULTS: Two to five times higher exposures to respirable welding fumes and airborne metals were observed during welding of 10 mm sheets than during welding of 2- or 3-mm sheets. Welding fume and Mn exposure were reduced by 70 and 90% when on-torch extraction or a captor hood was applied. Other airborne metals were reduced to a similar extent. Modifications on welding parameters led to a reduction of exposure against respirable particles by 51 up to 54%. CONCLUSIONS: Although proper extraction at the point of origin and lower-emitting process variants ensure a drastic reduction in exposure, compliance with current OELs is not guaranteed. In order to ensure adequate health protection, especially at workplaces where thick sheets with long relative arc times are processed, there is a need for technical development.

Lung cancer risk in painters: results from the SYNERGY pooled case-control study consortium.

OBJECTIVES: We evaluated the risk of lung cancer associated with ever working as a painter, duration of employment and type of painter by histological subtype as well as joint effects with smoking, within the SYNERGY project. METHODS: Data were pooled from 16 participating case-control studies conducted internationally. Detailed individual occupational and smoking histories were available for 19 369 lung cancer cases (684 ever employed as painters) and 23 674 age-matched and sex-matched controls (532 painters). Multivariable unconditional logistic regression models were adjusted for age, sex, centre, cigarette pack-years, time-since-smoking cessation and lifetime work in other jobs that entailed exposure to lung carcinogens. RESULTS: Ever having worked as a painter was associated with an increased risk of lung cancer in men (OR 1.30; 95% CI 1.13 to 1.50). The association was strongest for construction and repair painters and the risk was elevated for all histological subtypes, although more evident for small cell and squamous cell lung cancer than for adenocarcinoma and large cell carcinoma. There was evidence of interaction on the additive scale between smoking and employment as a painter (relative excess risk due to interaction >0). CONCLUSIONS: Our results by type/industry of painter may aid future identification of causative agents or exposure scenarios to develop evidence-based practices for reducing harmful exposures in painters.

Health effects after inhalation of micro- and nano-sized zinc oxide particles in human volunteers.

Inhalation of ZnO particles can cause inflammation of the airways and metal fume fever. It is unclear if different sizes of the particles alter these effects. However, various studies report higher biological activity of other nano-sized particles compared to microparticles. No effects at all were observed after inhalation of micro- and nano-sized zinc oxide (ZnO) particle concentrations of 0.5 mg/m3. Studies with different particle sizes of ZnO at higher exposures are not available. Accordingly, we hypothesized that inhalation of nano-sized ZnO particles induces stronger health effects than the inhalation of the same airborne mass concentration of micro-sized ZnO particles. 16 healthy volunteers (eight men, eight women) were exposed to filtered air and ZnO particles (2.0 mg/m3) for 2 h (one session with nano- and one with micro-sized ZnO) including 1 h of cycling at moderate workload. Effect parameters were symptoms, body temperature, inflammatory markers in blood and in induced sputum. Induced sputum was obtained at baseline examination, 22 h after exposure and at the end of the final test. The effects were assessed before, immediately after, about 22 h after, as well as two and three days after each exposure. Neutrophils, monocytes and acute-phase proteins in blood increased 22 h after micro- and nano-sized ZnO exposure. Effects were generally stronger with micro-sized ZnO particles. Parameters in induced sputum showed partial increases on the next day, but the effect strengths were not clearly attributable to particle sizes. The hypothesis that nano-sized ZnO particles induce stronger health effects than micro-sized ZnO particles was not supported by our data. The stronger systemic inflammatory responses after inhalation of micro-sized ZnO particles can be explained by the higher deposition efficiency of micro-sized ZnO particles in the respiratory tract and a substance-specific mode of action, most likely caused by the formation of zinc ions.

Respirable Crystalline Silica Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Analysis of Case-Control Studies.

Rationale: Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype.Objectives: We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks.Methods: Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed.Measurements and Main Results: Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated (P trend < 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated (P trend ≤ 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes.Conclusions: Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype.

Heart rate variability and cardiac repolarization after exposure to zinc oxide nanoparticles in healthy adults.

BACKGROUND: Exposure to airborne zinc oxide (ZnO) particles occurs in many industrial processes, especially in galvanizing and welding. Systemic inflammation after experimental inhalation of ZnO particles has been demonstrated previously, but little is known about the impact on the cardiovascular system, particularly on the autonomic cardiac system and the risk of arrhythmias. In this study we investigated the short-term effects of ZnO nanoparticles on heart rate variability (HRV) and repolarization in healthy adults in a concentration-dependent manner at rest and during exercise in a controlled experimental set-up. METHODS: Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0 and 2.0 mg/m3) for 4 h, including 2 h of cycling at low workloads. Parameters were assessed before, during, immediately after, and about 24 h after each exposure. For each subject, a total number of 46 10-min-sections from electrocardiographic records were analyzed. Various parameters of HRV and QT interval were measured. RESULTS: Overall, no statistically significant effects of controlled ZnO inhalation on HRV parameters and QT interval were observed. Additionally, a concentration-response was absent. CONCLUSION: Inhalation of ZnO nanoparticles up to 2.0 mg/m3 for 4 h does not affect HRV and cardiac repolarization in healthy adults at the chosen time points. This study supports the view that cardiac endpoints are insensitive for the assessment of adverse effects after short-term inhalation of ZnO nanoparticles.

Whole Blood Assay as a Tool to Describe the Effects of Zinc Oxide Exposure on Innate Immunity.

Inhalation of high concentrations of zinc oxide (ZnO) particles may cause metal fume fever. A useful tool to characterize the reactivity of innate immune cells of an individual, e.g., after in vivo exposure, is the whole blood assay (WBA). The measurable outcome of WBA is the release of cytokines, especially pro-inflammatory and pyrogenic cytokines induced by stimulation in vitro. The aim of the study was to evaluate whether inhalation of nano-sized zinc oxide particles modifies the results of WBA from healthy blood donors. Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0, and 2.0 mg/m3) for 4 h on four different days. Blood was collected before and 24 h after exposure, and ex vivo stimulation of the whole blood was performed using different endotoxin concentrations. The release of interleukin (IL)-1ß and IL-8 after 22-h incubation was quantified with specific immunoassays. The dose-response relationship of ex vivo stimulation with different endotoxin concentrations was not affected by previous ZnO exposure. However, based on the previously established calculation models, changes due to ZnO exposure could be described. The range of cytokine release in WBA was calculated for the whole group of blood donors, for the subgroups of low and high responders (each n = 8), and on the individual level. Most changes were observed after 0.5 mg/m3 ZnO exposure. Higher ZnO exposure did not yield higher effects. We conclude that the effects of inhalation of nano-sized ZnO particles in blood of healthy donors using the WBA could be determined. However, it should be noted that cytokine release as outcome of WBA is not a marker of disease.

Exposure to Welding Fumes, Hexavalent Chromium, or Nickel and Risk of Lung Cancer.

To investigate the risk of lung cancer after exposure to welding fumes, hexavalent chromium (Cr(VI)), and nickel, we analyzed 3,418 lung cancer cases and 3,488 controls among men from 2 German case-control studies (1988-1996). We developed a welding-process exposure matrix from measurements of these agents, and this was linked with welding histories from a job-specific questionnaire to calculate cumulative exposure variables. Logistic regression models were fitted to estimate odds ratios with confidence intervals conditional on study, and they adjusted for age, smoking, and working in other at-risk occupations. Additionally, we mutually adjusted for the other exposure variables under study. Overall, 800 cases and 645 controls ever worked as regular or occasional welders. Odds ratios for lung cancer with high exposure were 1.55 (95% confidence interval (CI): 1.17, 2.05; median, 1.8 mg/m3 × years) for welding fumes, 1.85 (95% CI: 1.35, 2.54; median, 1.4 µg/m3 × years) for Cr(VI), and 1.60 (95% CI: 1.21, 2.12; median, 9 µg/m3 × years) for nickel. Risk estimates increased with increasing cumulative exposure to welding fumes and with increasing exposure duration for Cr(VI) and nickel. Our results showed that welding fumes, Cr(VI), and nickel might contribute independently to the excess lung cancer risk associated with welding. However, quantitative exposure assessment remains challenging.

Smoking and urinary cotinine by socioeconomic status in the Heinz Nixdorf Recall Study.

BACKGROUND: Associations of socioeconomic status (SES) and smoking-related diseases depend on uniform validity of self-reported smoking habits in different SES groups. We investigated the influence of SES on validity of self-reported smoking status by means of urinary cotinine. METHODS: We determined total urinary cotinine in the baseline population of the Heinz Nixdorf Recall Study. Participants with cotinine>200 µg/L were potential current smokers. We defined upper and lower 20% of the gender-specific distribution of the International Socio-Economic Index (ISEI) as high and low SES, respectively, else as intermediate. We analysed the association of self-reported smoking status and cotinine by ISEI and additional SES measures, stratified by gender. In self-reported non-smokers, we estimated age-adjusted ORs with 95% CI to detect differences by SES in the validity of self-reported smoking status. RESULTS: In 2004 men and 1887 women, 78% and 80%, respectively, reported to be non-smokers. Median cotinine concentrations were 2 µg/L in non-smokers, and 3651 µg/L in male and 3127 µg/L in female smokers. Based on cotinine in non-smokers, 2.0 % of men (n = 32) and 1.8 % of women (n = 27) were potential smokers, with lower proportions in the subgroup of never-smokers (men: 0.7%, women: 0.5%). The validity of self-reported smoking status did not substantially differ by SES. Tendencies for increased underreporting were indicated for women with low ISEI (OR 1.35; 95% CI 0.54 to 3.39) and men in blue-collar jobs (OR 1.39; 95% CI 0.67 to 2.87). CONCLUSION: Validity of self-reported smoking status in this elderly German cohort was high and did not depend on SES.

Modelling of exposure to respirable and inhalable welding fumes at German workplaces.

The International Agency for Research on Cancer classified welding fumes as carcinogenic to humans, and occupational exposure limits should be established to protect welders. The aim of this study is to estimate exposure levels to inhalable and respirable welding fumes by welding process to use them for exposure assessment in epidemiological studies and to derive occupational exposure limits. In total, 15,473 mass concentrations of inhalable and 9,161 concentrations of respirable welding fumes could be analyzed along with welding-related and sampling information, which were compiled in the German database MEGA between 1983 and 2016. In both particle-size fractions, model-based geometric means of the concentrations were estimated by welding process and material for frequently used welding processes adjusted for sampling time and median-centered for calendar years. The inhalable concentrations were approximately twice the respirable concentrations, with medians of 3 mg/m3 (inter-quartile range: 1.2-7.0 mg/m3) and 1.5 mg/m3 (inter-quartile range: < limit of detection -3.8 mg/m3), respectively. The adjusted geometric means of flux-cored arc welding, metal inert and active gas welding, shielded metal arc welding and torch cutting ranged from 0.9 to 2.2 mg/m3 for respirable welding fumes and from 2.3 to 4.7 mg/m3 for inhalable fumes. In both particle-size fractions, geometric means were between 0.1 and 0.9 mg/m3 when performing tungsten inert gas, autogeneous, resistance, laser, and plasma welding or spraying. Results derived from this large dataset are useful for a quantitative exposure assessment to estimate health risks of welders.

Airway inflammation after inhalation of nano-sized zinc oxide particles in human volunteers.

BACKGROUND: Workers in the zinc production and processing of galvanized sheet steel are exposed to a complex mixture of particles and gases, including zinc oxide (ZnO) that can affect human health. We aimed to study the effects of short-term controlled exposure to nano-sized ZnO on airway inflammatory markers in healthy volunteers. METHODS: Sixteen subjects (8 females, 8 men; age 19-42, non-smokers) were exposed to filtered air and ZnO nanoparticles (0.5, 1.0 and 2.0 mg/m3) for 4 h, including 2 h of cycling with a low workload. Induced sputum samples were collected during a medical baseline and a final examination and also about 24 h after each exposure. A number of inflammatory cellular and soluble markers were analyzed. RESULTS: Frequency and intensity of symptoms of airway irritation (throat irritation and cough) were increased in some subjects 24 h after ZnO exposures when compared to filtered air. The group comparison between filtered air and ZnO exposures showed statistically significant increases of neutrophils and interleukin-8 (IL-8), interleukin-6 (IL-6), matrix metalloproteinase (MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1) in sputum starting at the lowest ZnO concentration of 0.5 mg/m3. However, a concentration-response relationship was absent. Effects were reversible. Strong correlations were found between neutrophil numbers and concentrations of total protein, IL-8, MMP-9, and TIMP-1. CONCLUSIONS: Controlled exposures of healthy subjects to ZnO nanoparticles induce reversible airway inflammation which was observed at a concentration of 0.5 mg/m3 and higher. The lack of a concentration-response relationship warrants further studies.