Non-malignant Respiratory Disease Research Articles

Long-term exposure to PM2.5 and mortality among Japanese community-dwelling adults

Abstract Background Long-term exposure to PM2.5 (particulate matter with a diameter of 2.5 μm or smaller) is a risk factor for mortality and cardiovascular disease including stroke. However, there was limited evidence for the association between PM2.5 exposure and stroke in Asia where the major cardiovascular disease is stroke. Additionally, the causal association between PM2.5 and respiratory disease is still unresolved. The aim of this study was to investigate the association between long-term exposure to PM2.5 and all-cause, cardiovascular, and respiratory disease mortality in a Japanese community-based prospective cohort. Methods This study included 46,974 participants (19,707 men; 27,267 women) from the second cohort of the Ibaraki Prefectural Health Study. The participants were followed up from baseline survey (in 2009) to 31 December 2019. We confirmed underlying causes by death certificates. Using the PM2.5 concentrations estimated by the inverse distance weighting methods based on ambient air monitoring data, administrative area level concentrations were assigned to each participant. The hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality using a Cox proportional hazard model were presented. Results We identified 2,789 all-cause deaths during the 470,178 person-years of follow-up. PM2.5 exposure had no significant association with all-cause and cause-specific mortality. The multivariable-adjusted HRs per 1 μg/m3 increase in the PM2.5 concentration were 0.94 (95% CI = 0.80-1.12) for coronary heart disease, 0.92 (95% CI = 0.81-1.04) for stroke and 1.09 (95% CI = 0.97-1.23) for non-malignant respiratory disease. Conclusions We observed little evidence of increased risk of all-cause and cause-specific mortality by long-term exposure to PM2.5 whose concentrations ranged from 8.3 to 13.1 μg/m3. A somewhat increased trend for non-malignant respiratory disease mortality may not be negligible. Key messages • We found little evidence of increased risk of all-cause and cause-specific mortality by long-term exposure to PM2.5. • Somewhat increased tendency for non-malignant respiratory disease mortality associated with PM2.5 exposure was observed.

Association between Long-Term Exposure to PM2.5 Inorganic Chemical Compositions and Cardiopulmonary Mortality: A 22-Year Cohort Study in Northern China.

Particulate matter with diameters ≤2.5 μm (PM2.5) has been identified as a significant air pollutant contributing to premature mortality. Nevertheless, the specific compositions within PM2.5 that play the most crucial role remain unclear, especially in areas with high pollution concentrations. This study aims to investigate the individual and joint mortality risks associated with PM2.5 inorganic chemical compositions and identify primary contributors. In 1998, we conducted a prospective cohort study in four northern Chinese cities (Tianjin, Shenyang, Taiyuan, and Rizhao). Satellite-based machine learning models calculated PM2.5 inorganic chemical compositions, including sulfate (SO4 2-), nitrate (NO3 -), ammonium (NH4 +), and chloride (Cl-). A time-varying Cox proportional hazards model was applied to analyze associations between these compositions and cardiorespiratory mortality, encompassing nonaccidental causes, cardiovascular diseases (CVDs), nonmalignant respiratory diseases (RDs), and lung cancer. The quantile-based g-computation model evaluated joint exposure effects and relative contributions of the compositions. Stratified analysis was used to identify vulnerable subpopulations. During 785,807 person-years of follow-up, 5812 (15.5%) deaths occurred from nonaccidental causes, including 2932 (7.8%) from all CVDs, 479 (1.3%) from nonmalignant RDs, and 552 (1.4%) from lung cancer. Every interquartile range (IQR) increase in SO4 2- was associated with mortality from nonaccidental causes (hazard ratio: 1.860; 95% confidence interval: 1.809, 1.911), CVDs (1.909; 1.836, 1.985), nonmalignant RDs (2.178; 1.975, 2.403), and lung cancer (1.773; 1.624, 1.937). In the joint exposure model, a simultaneous rise of one IQR in all four compositions increased the risk of cardiorespiratory mortality by at least 36.3%, with long-term exposure to SO4 2- contributing the most to nonaccidental and cardiopulmonary deaths. Individuals with higher incomes and lower education levels were found to be more vulnerable. Long-term exposure to higher levels of PM2.5 inorganic compositions was associated with significantly increased cardiopulmonary mortality, with SO4 2- potentially being the primary contributor. These findings offer insights into how PM2.5 sources impact health, aiding the development of more effective governance measures.

Narrative review of occupational exposures and noncommunicable diseases.

Within the scope of the Exposome Project for Health and Occupational Research on applying the exposome concept to working life health, we aimed to provide a broad overview of the status of knowledge on occupational exposures and associated health effects across multiple noncommunicable diseases (NCDs) to help inform research priorities. We conducted a narrative review of occupational risk factors that can be considered to have "consistent evidence for an association," or where there is "limited/inadequate evidence for an association" for 6 NCD groups: nonmalignant respiratory diseases; neurodegenerative diseases; cardiovascular/metabolic diseases; mental disorders; musculoskeletal diseases; and cancer. The assessment was done in expert sessions, primarily based on systematic reviews, supplemented with narrative reviews, reports, and original studies. Subsequently, knowledge gaps were identified, e.g. based on missing information on exposure-response relationships, gender differences, critical time-windows, interactions, and inadequate study quality. We identified over 200 occupational exposures with consistent or limited/inadequate evidence for associations with one or more of 60+ NCDs. Various exposures were identified as possible risk factors for multiple outcomes. Examples are diesel engine exhaust and cadmium, with consistent evidence for lung cancer, but limited/inadequate evidence for other cancer sites, respiratory, neurodegenerative, and cardiovascular diseases. Other examples are physically heavy work, shift work, and decision latitude/job control. For associations with limited/inadequate evidence, new studies are needed to confirm the association. For risk factors with consistent evidence, improvements in study design, exposure assessment, and case definition could lead to a better understanding of the association and help inform health-based threshold levels. By providing an overview of knowledge gaps in the associations between occupational exposures and their health effects, our narrative review will help setting priorities in occupational health research. Future epidemiological studies should prioritize to include large sample sizes, assess exposures prior to disease onset, and quantify exposures. Potential sources of biases and confounding need to be identified and accounted for in both original studies and systematic reviews.

Diesel exhaust and respiratory dust exposure in miners and chronic obstructive pulmonary disease (COPD) mortality in DEMS II

BackgroundDiesel exhaust and respirable dust exposures in the mining industry have not been studied in depth with respect to non-malignant respiratory disease including chronic obstructive pulmonary disease (COPD), with most available evidence coming from other settings. ObjectivesTo assess the relationship between occupational diesel exhaust and respirable dust exposures and COPD mortality, while addressing issues of survivor bias in exposed miners. MethodsThe study population consisted of 11,817 male workers from the Diesel Exhaust in Miners Study II, followed from 1947 to 2015, with 279 observed COPD deaths. We fit Cox proportional hazards models for the relationship between respirable elemental carbon (REC) and respirable dust (RD) exposure and COPD mortality. To address healthy worker survivor bias, we leveraged the parametric g-formula to assess effects of hypothetical interventions on both exposures. ResultsCox models yielded elevated estimates for the associations between average intensity of REC and RD and COPD mortality, with hazard ratios (HR) corresponding to an interquartile range width increase in exposure of 1.46 (95 % confidence interval (CI): 1.12, 1.91) and 1.20 (95 % CI: 0.96, 1.49), respectively for each exposure. HRs for cumulative exposures were negative for both REC and RD. Based on results from the parametric g-formula, the risk ratio (RR) for COPD mortality comparing risk under an intervention eliminating REC to the observed risk was 0.85 (95 % CI: 0.55, 1.06), equivalent to an attributable risk of 15 %. The corresponding RR comparing risk under an intervention eliminating RD to the observed risk was 0.93 (95 % CI: 0.56, 1.31). ConclusionsOur findings, based on data from a cohort of nonmetal miners, are suggestive of an increased risk of COPD mortality associated with REC and RD, as well as evidence of survivor bias in this population leading to negative associations between cumulative exposures and COPD mortality in traditional regression analysis.

Non-malignant occupational respiratory diseases and climate change.

BACKGROUND: Respiratory diseases of infectious, allergic, neoplastic or degenerative origin are due to the interaction of environmental and occupational risk factors, individual susceptibility and other co-factors and comorbidities. Asthma and other respiratory pathologies can be worsened by climate change and exposure to other agents in occupational environments.METHODS: PubMed and Scopus, and several websites on public and occupational health were queried to find publications and documents on work-related respiratory diseases, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pneumoconiosis and allergic alveolitis in association with climate change.RESULTS: Most of the retrieved articles concerned asthma (75 in Scopus), while the other topics were less frequently covered in the scientific literature, with a maximum of 29 papers for rhinitis and 23 for COPD. The most important terms highlighted by the word clouds were 'health', 'air', 'pollution', and, only for asthma and rhinitis, 'pollen' and 'allergic/allergy'. Website data on public and occupational health, and climate change were reported.CONCLUSIONS: Assessment and management of respiratory diseases that recognise occupational exposures should be improved, and more research into integrated approaches should be favoured. Health surveillance practices for workers exposed to agents that cause respiratory diseases should be implemented. The development of biomarkers of exposure, effect and susceptibility needs further study.

Beneficial role of kaempferol and its derivatives from different plant sources on respiratory diseases in experimental models.

Respiratory illnesses impose a significant health burden and cause deaths worldwide. Despite many advanced strategies to improve patient outcomes, they are often less effective. There is still considerable room for improvement in the treatment of various respiratory diseases. In recent years, alternative medicinal agents derived from food plants have shown better beneficial effects against a wide variety of disease models, including cancer. In this regard, kaempferol (KMF) and its derivatives are the most commonly found dietary flavonols. They have been found to exhibit protective effects on multiple chronic diseases like diabetes, fibrosis, and so on. A few recent articles have reviewed the pharmacological actions of KMF in cancer, central nervous system diseases, and chronic inflammatory diseases. However, there is no comprehensive review that exists regarding the beneficial effects of KMF and its derivatives on both malignant- and non-malignant respiratory diseases. Many experimental studies reveal that KMF and its derivatives are helpful in managing a wide range of respiratory diseases, including acute lung injury, fibrosis, asthma, cancer, and chronic obstructive pulmonary disease, and their underlying molecular mechanisms. In addition, we also discussed the chemistry and sources, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, methods to enhance bioavailability, as well as our perspective on future research with KMF and its derivatives.

Natural mineral fibers: conducting inhalation toxicology studies—part B: development of a nose-only exposure system for repeat-exposure in vivo study of Libby amphibole aerosol

Background Exposure to asbestos is associated with malignant and nonmalignant respiratory disease. To strengthen the scientific basis for risk assessment on fibers, the National Institute of Environmental Health Sciences (NIEHS) has initiated a series of studies to address fundamental questions on the toxicology of naturally occurring asbestos and related mineral fibers after inhalation exposure. A prototype nose-only exposure system was previously developed and validated. The prototype system was expanded to a large-scale exposure system in this study for conducting subsequent in vivo rodent inhalation studies of Libby amphibole (LA) 2007, selected as a model fiber. Results The exposure system consisting of six exposure carousels was able to independently deliver stable LA 2007 aerosol to individual carousels at target concentrations of 0 (control group), 0.1, 0.3, 1, 3, or 10 mg/m3. A single aerosol generator was used to provide aerosol to all carousels to ensure that exposure atmospheres were chemically and physically similar, with aerosol concentration as the only major variable among the carousels. Transmission electron microscopy (TEM) coupled with energy dispersive spectrometry (EDS) and selected area electron diffraction (SAED) analysis of aerosol samples collected at the exposure ports indicated the fiber dimensions, chemical composition, and mineralogy were equivalent across exposure carousels and were comparable to the bulk LA 2007 material. Conclusion The exposure system developed is ready for use in conducting nose-only inhalation toxicity studies of LA 2007 in rats. The exposure system is anticipated to have applicability for the inhalation toxicity evaluation of other natural mineral fibers of concern.

Individual and joint associations of long-term exposure to air pollutants and cardiopulmonary mortality: a 22-year cohort study in Northern China

Evidence on the associations between long-term exposure to multiple air pollutants and cardiopulmonary mortality is limited, especially for developing regions with higher pollutant levels. We aimed to characterise the individual and joint (multi-pollutant) associations of long-term exposure to air pollutants with cardiopulmonary mortality, and to identify air pollutant that primarily contributes to the mortality risk. We followed 37,442 participants with a mean age of 43.5 years in four cities in northern China (Tianjin, Shenyang, Taiyuan, and Rizhao) from January 1998 to December 2019. Annual particulate matter (PM) with diameters ≤2.5μm (PM2.5), ≤10μm (PM10), sulfur dioxide (SO2) and nitrogen dioxide (NO2) were estimated using daily average values from satellite-derived machine learning models and monitoring stations. Time-varying Cox proportional hazards model was used to evaluate the individual association between air pollutants and mortality from non-accidental causes, cardiovascular diseases (CVDs), non-malignant respiratory diseases (RDs) and lung cancer, accounting for demographic and socioeconomic factors. Effect modifications by age, sex, income and education level were also examined. Quantile-based g-Computation integrated with time-to-event data was additionally applied to evaluate the co-effects and the relative weight of contributions for air pollutants. During 785,807 person-years of follow-up, 5812 (15.5%) died from non-accidental causes, among which 2932 (7.8%) were from all CVDs, 479 (1.3%) from non-malignant RDs, and 552 (1.4%) from lung cancer. Long-term exposure to PM10 (mean [baseline]: 136.5μg/m3), PM2.5 (mean [baseline]: 70.2μg/m3), SO2 (mean [baseline]: 113.0μg/m3) and NO2 (mean [baseline]: 39.2μg/m3) were adversely and consistently associated with all mortality outcomes. A 10μg/m3 increase in PM2.5 was associated with higher mortality from non-accidental causes (hazard ratio 1.20; 95% confidence interval 1.17-1.23), CVDs (1.23; 1.19-1.28), non-malignant RDs (1.37; 1.25-1.49) and lung cancer (1.14; 1.05-1.23). A monotonically increasing curve with linear or supra-linear shape with no evidence of a threshold was observed for the exposure-response relationship of mortality with individual or joint exposure to air pollutants. PM2.5 consistently contributed most to the elevated mortality risks related to air pollutant mixture, followed by SO2 or PM10. There was a strong and positive association of long-term individual and joint exposure to PM10, PM2.5, SO2, and NO2 with mortalities from non-accidental causes, CVDs, non-malignant RDs and lung cancer in high-exposure settings, with PM2.5 potentially being the main contributor. The shapes of associations were consistent with a linear or supra-linear exposure-response relationship, with no lower threshold observed within the range of concentrations in this study. National Key Research and Development Program of China, the China Scholarship Council, the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province.

Association between exposure to multiple air pollutants, transportation noise and cause-specific mortality in adults in Switzerland

BackgroundLong-term exposure to air pollution and noise is detrimental to health; but studies that evaluated both remain limited. This study explores associations with natural and cause-specific mortality for a range of air pollutants and transportation noise.MethodsOver 4 million adults in Switzerland were followed from 2000 to 2014. Exposure to PM2.5, PM2.5 components (Cu, Fe, S and Zn), NO2, black carbon (BC) and ozone (O3) from European models, and transportation noise from source-specific Swiss models, were assigned at baseline home addresses. Cox proportional hazards models, adjusted for individual and area-level covariates, were used to evaluate associations with each exposure and death from natural, cardiovascular (CVD) or non-malignant respiratory disease. Analyses included single and two exposure models, and subset analysis to study lower exposure ranges.ResultsDuring follow-up, 661,534 individuals died of natural causes (36.6% CVD, 6.6% respiratory). All exposures including the PM2.5 components were associated with natural mortality, with hazard ratios (95% confidence intervals) of 1.026 (1.015, 1.038) per 5 µg/m3 PM2.5, 1.050 (1.041, 1.059) per 10 µg/m3 NO2, 1.057 (1.048, 1.067) per 0.5 × 10–5/m BC and 1.045 (1.040, 1.049) per 10 dB Lden total transportation noise. NO2, BC, Cu, Fe and noise were consistently associated with CVD and respiratory mortality, whereas PM2.5 was only associated with CVD mortality. Natural mortality associations persisted < 20 µg/m3 for PM2.5 and NO2, < 1.5 10–5/m BC and < 53 dB Lden total transportation noise. The O3 association was inverse for all outcomes. Including noise attenuated all outcome associations, though many remained significant. Across outcomes, noise was robust to adjustment to air pollutants (e.g. natural mortality 1.037 (1.033, 1.042) per 10 dB Lden total transportation noise, after including BC).ConclusionLong-term exposure to air pollution and transportation noise in Switzerland contribute to premature mortality. Considering co-exposures revealed the importance of local traffic-related pollutants such as NO2, BC and transportation noise.

Workers in Australian prebake aluminium smelters: update on risk of mortality and cancer incidence in the Healthwise cohort

ObjectivesTo investigate mortality and the rates of incident cancer among a cohort of aluminium industry workers.MethodsAmong 4507 male employees who worked in either of two Australian prebake smelters for at...

Increased odds of mortality from non-malignant respiratory disease and lung cancer are highest among US coal miners born after 1939

ObjectivesCoal miners suffer increased mortality from non-malignant respiratory diseases (NMRD), including pneumoconioses and chronic obstructive pulmonary disease, compared with the US population. We characterised mortality trends from NMRD, lung cancer...

Mortality among mine and mill workers exposed to respirable crystalline silica.

BackgroundMillions of workers are potentially exposed to respirable crystalline silica (RCS) which has been associated with several diseases. We updated the mortality experience of a cohort of 2,650 mine and mill workers at four manufacturing facilities to assess cause-specific mortality risks associated with estimated cumulative RCS exposure.MethodsStudy eligibility was defined as any employee who had ≥1 year of service by 2000, with work history experience available from 1945 through 2004. Vital status and cause of death were ascertained from 1945 through 2015. RCS exposure was estimated across plant-, department-, job-, and time-dependent categories using historic industrial hygiene sampling data and professional judgment. Associations between cumulative RCS (mg/m3-years) and cause-specific mortality were examined using Cox proportional hazard regression models.ResultsIn the exposure-response analysis defined on quartiles of cumulative RCS exposure, no increasing trend (ptrend = 0.37) in lung cancer mortality (n = 116 deaths) was observed (Hazard ratio (HR) = 1.00 (referent), 1.20, 1.85, 0.92). Mortality risk for non-malignant respiratory disease was increased across quartiles (HR = 1.00, 1.35, 1.89, 1.70; ptrend = 0.15), based on 83 deaths. Non-malignant renal disease mortality was increased across quartiles (HR = 1.00, 6.64, 3.79, 3.29; ptrend = 0.11), based on 26 deaths.ConclusionsAfter nearly seven decades of follow-up, the exposure-response analyses showed no evidence of a positive trend for lung cancer, and limited evidence of a trend for non-malignant respiratory disease, and non-malignant renal disease mortality as a result of cumulative RCS exposure in this occupational cohort.

Risk of Mortality from Respiratory Malignant and Non-Malignant Diseases among Talc Miners and Millers: A Systematic Review and Meta-Analysis.

There is contrasting data on the association between talc exposure and lung and pleural cancer. Given the potential importance of this aspect, we performed a systematic review and meta-analysis to investigate the association between working in the talc extractive industry and mortality from malignant and non-malignant respiratory diseases. We followed PRISMA guidelines to systematically search for pertinent articles in three relevant electronic databases: Pubmed, Scopus, and WebOfScience, from their inception to 30 November 2021. The methodological quality of included articles was evaluated using the US National Institutes of Health tool. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) for malignant and non-malignant respiratory diseases as well as respective 95% confidence intervals (CIs) were extracted or calculated for each included cohort. Six articles comprising 7 cohorts were included in the metanalysis. There was increased mortality for pneumoconiosis, especially in the miner’s group (SMR = 7.90, CI 95% 2.77–22.58) and especially in those exposed to higher quartz concentration and for non-malignant respiratory diseases in the overall analysis (SMR = 1.81, CI 95% 1.15–2.82). The risk for lung cancer mortality was slightly increased in the overall analysis (SMR = 1.42, CI 95% 1.07–1.89). The risk for malignant mesothelioma could not be calculated due to an insufficient number of studies assessing this outcome. This systematic review and meta-analysis provides evidence that men working in the talc mining industry have increased mortality for non-malignant respiratory diseases including pneumoconiosis. The small excess in lung cancer mortality may be, in part, explained by the high prevalence of the smokers in some of the analyzed cohorts or by the exposure to other carcinogens like radon decay products and diesel engine exhaust.

Deep Breaths: A Systematic Review of the Potential Effects of Employment in the Nuclear Industry on Mortality from Non-Malignant Respiratory Disease.

Ionizing radiation is an established carcinogen, but its effects on non-malignant respiratory disease (NMRD) are less clear. Cohorts exposed to multiple risk factors including radiation and toxic dusts conflate these relationships, and there is a need for clarity in previous findings. This systematic review was conducted to survey the body of existing evidence for radiation effects on NMRD in global nuclear worker cohorts. A PubMed search was conducted for studies with terms relating to radiation or uranium and noncancer respiratory outcomes. Papers were limited to the most recent report within a single cohort published between January 2000 and December 2020. Publication quality was assessed based upon UNSCEAR 2017 criteria. In total, 31 papers were reviewed. Studies included 29 retrospective cohorts, one prospective cohort, and one longitudinal cohort primarily comprising White men from the U.S., Canada and Western Europe. Ten studies contained subpopulations of uranium miners or millers. Papers reported standardized mortality ratio (SMR) analyses, regression analyses, or both. Neither SMR nor regression analyses consistently showed a relationship between radiation exposure and NMRD. A meta-analysis of excess relative risks (ERRs) for NMRD did not present evidence for a dose-response (overall ERR/Sv: 0.07; 95% CI: -0.07, 0.21), and results for more specific outcomes were inconsistent. Significantly elevated SMRs for NMRD overall were observed in two studies among the subpopulation of uranium miners and millers (combined n = 4229; SMR 1.42-1.43), indicating this association may be limited to mining and milling populations and may not extend to other nuclear workers. A quality review showed limited capacity of 17 out of 31 studies conducted to provide evidence for a causal relationship between radiation and NMRD; the higher-quality studies showed no consistent relationship. All elevated NMRD SMRs were among mining and milling cohorts, indicating different exposure profiles between mining and non-mining cohorts; future pooled cohorts should adjust for mining exposures or address mining cohorts separately.

Nonmalignant respiratory disease mortality in male Colorado Plateau uranium miners, 1960-2016.

To evaluate trends of nonmalignant respiratory disease (NMRD) mortality among US underground uranium miners on the Colorado Plateau, and to estimate the exposure-response association between cumulative radon progeny exposure and NMRD subtype mortality. Standardized mortality ratios (SMRs) and excess relative rates per 100 working level months (excess relative rate[ERR]/100 WLM) were estimated in a cohort of 4021 male underground uranium miners who were followed from 1960 through 2016. We observed elevated SMRs for all NMRD subtypes. Silicosis had the largest SMR (n = 52, SMR = 41.4; 95% confidence interval [CI]: 30.9, 54.3), followed by other pneumoconiosis (n = 49, SMR = 39.6; 95%CI: 29.6, 52.3) and idiopathic pulmonary fibrosis (IPF) (n = 64, SMR = 4.77; 95%CI 3.67, 6.09). SMRs for silicosis increased with duration of employment; SMRs for IPF increased with duration of employment and calendar period. There was a positive association between cumulative radon exposure and silicosis with evidence of modification by smoking (ERR/100 WLM≥10 pack-years = 0.78; 95%CI: 0.05, 24.6 and ERR/100 WLM<10 pack-years = 0.01; 95%CI: -0.03, 0.52), as well as a small positive association between radon and IPF (ERR/100 WLM = 0.06, 95%CI: 0.00, 0.24); these associations were driven by workers with prior employment in hard rock mining. Uranium mining workers had excess NMRD mortality compared with the general population; this excess persisted throughout follow-up. Exposure-response analyses indicated a positive association between radon exposure and IPF and silicosis, but these analyses have limitations due to outcome misclassification and missing information on occupational co-exposures such as silica dust.

Carcinogenicity of Poorly Soluble Low Toxicity Particles: Commentary on Epidemiology as a Risk Assessment "Reality Check".

Inhaled particles that are poorly soluble or insoluble and of low toxicity (“poorly soluble low toxicity” or “PSLT” particles), can accumulate in the lung and at lung overload levels induce lung cancers in rats. The question of whether PSLT particles increase lung cancer risk in humans is complicated by large differences between rats and humans and the relatively large particle doses administered in animal studies even when compared with heavy human occupational exposures. We review the findings of epidemiological studies on occupational exposure to each of three different PSLT particles (carbon black, talc and taconite). The epidemiological evidence indicates that at even very high occupational exposure levels at which non-malignant respiratory diseases including pneumoconiosis and even talcosis are observed, lung cancer risks appear not to be elevated. Although positive human cancer risks might be predicted based on extrapolation from overload doses in rats to relevant exposures in humans, the epidemiological “reality check” based on the three examples indicates that these PSLT particles are unlikely to increase lung cancer risk in humans even at high occupational levels of exposure. Therefore, we propose that careful evaluation of the epidemiological evidence can serve as a “reality check” for human risk assessment and help balance the risk evaluation process.

Mortality among Tennessee Eastman Corporation (TEC) uranium processing workers, 1943–2019

Background There are few occupational studies of women exposed to ionizing radiation. During World War II, the Tennessee Eastman Corporation (TEC) operated an electromagnetic field separation facility of 1152 calutrons to obtain enriched uranium (235U) used for the Hiroshima atomic bomb. Thousands of women were involved in these operations. Materials and methods A new study was conducted of 13,951 women and 12,699 men employed at TEC between 1943 and 1947 for at least 90 days. Comprehensive dose reconstruction techniques were used to estimate lung doses from the inhalation of uranium dust based on airborne measurements. Vital status through 2018/2019 was obtained from the National Death Index, Social Security Death Index, Tennessee death records and online public record databases. Analyses included standardized mortality ratios (SMRs) and Cox proportional hazards models. Results Most workers were hourly (77.7%), white (95.6%), born before 1920 (58.3%), worked in dusty environments (57.0%), and had died (94.9%). Vital status was confirmed for 97.4% of the workers. Women were younger than men when first employed: mean ages 25.0 years and 33.0 years, respectively. The estimated mean absorbed dose to the lung was 32.7 mGy (max 1048 mGy) for women and 18.9 mGy (max 501 mGy) for men. The mean dose to thoracic lymph nodes (TLNs) was 127 mGy. Statistically significant SMRs were observed for lung cancer (SMR 1.25; 95% CI 1.19, 1.31; n = 1654), nonmalignant respiratory diseases (NMRDs) (1.23; 95% CI 1.19, 1.28; n = 2585), and cerebrovascular disease (CeVD) (1.13; 95% CI 1.08, 1.18; n = 1945). For lung cancer, the excess relative rate (ERR) at 100 mGy (95% CI) was 0.01 (–0.10, 0.12; n = 652) among women, and −0.15 (–0.38, 0.07; n = 1002) among men based on a preferred model for men with lung doses <300 mGy. NMRD and non-Hodgkin lymphoma were not associated with estimated absorbed dose to the lung or TLN. Conclusions There was little evidence that radiation increased the risk of lung cancer, suggesting that inhalation of uranium dust and the associated high-LET alpha particle exposure to lung tissue experienced over a few years is less effective in causing lung cancer than other types of exposures. There was no statistically significant difference in the lung cancer risk estimates between men and women. The elevation of certain causes of death such as CeVD is unexplained and will require additional scrutiny of workplace or lifestyle factors given that radiation is an unlikely contributor since only the lung and lymph nodes received appreciable dose.

Real-world opioid prescription to patients with serious, non-malignant, respiratory illnesses and chronic breathlessness.

Chronic breathlessness is a disabling symptom that is often under-recognised and challenging to treat despite optimal disease-directed therapy. Low-dose, oral opioids are recommended to relieve breathlessness, but little is known regarding long-term opioid prescription in this setting. To investigate the long-term efficacy of, and side-effects from, opioids prescribed for chronic breathlessness to patients with advanced, non-malignant, respiratory diseases. A prospective cohort study of all patients managed by the advanced lung disease service, an integrated respiratory and palliative care service, at the Royal Melbourne Hospital from 1 April 2013 to 3 March 2020. One hundred and nine patients were prescribed opioids for chronic breathlessness. The median length of opioid use was 9.8 (interquartile range (IQR)=2.8-19.8) months. The most commonly prescribed initial regimen was an immediate-release preparation (i.e. Ordine) used as required (37; 33.9%). For long-term treatment, the most frequently prescribed regimen included an extended-release preparation with an as needed immediate-release (37; 33.9%). The median dose prescribed was 12 (IQR=8-28) mg oral morphine equivalents/day. Seventy-one (65.1%) patients reported a subjective improvement in breathlessness. There was no significant change in the mean modified Medical Research Council dyspnoea score (P = 0.807) or lung function measurements (P = 0.086-0.727). There was no association between mortality and the median duration of opioid use (P = 0.201) or dose consumed (P = 0.130). No major adverse events were reported. Within this integrated respiratory and palliative care service, patients with severe, non-malignant respiratory diseases safely used long-term, low-dose opioids for breathlessness with subjective benefits reported and no serious adverse events.

Expectations of respiratory physicians from psychologists in palliative care for patients with non-cancer respiratory diseases.

Psychological symptoms are common in patients with non-malignant respiratory disease (NMRD). Psychologists can likely play a role in NMRD palliative care. We aimed to explore the expectations of respiratory physicians from psychologists in NMRD palliative care. An ad hoc questionnaire was developed based on a free-descriptive questionnaire survey among respiratory physicians from four hospitals in Japan. Using this questionnaire, we surveyed respiratory physicians from eight hospitals in Japan and assessed their expectations of psychologists' support and outcomes. Expectations were compared between physicians with and without experience of working with psychologists. The quantitative questionnaire was completed by 129 physicians. Data analysis from 108 participants revealed that the highly expected support included "getting early information on patients' psychological distress" (97.2%) and "counseling family members regarding anxiety caused by changes in patient's condition" (96.3%). Physicians also expected "relief in patient's psychological distress" (96.3%) and "providing the psychological support that families need" (95.4%) from psychologists. Compared to physicians with experience of working with psychologists, those without expected more in terms of "giving specific advice on the way of communication and psychological support" (p=0.035) and "providing psychological support for difficult-to-handle patients and families on behalf of other medical staff" (p=0.036). Respiratory physicians may expect relief of psychological distress experienced by patients and their families from psychologists by getting information about their distress and providing psychological support. These results may be useful for psychologists to provide palliative care for patients with NMRD in collaboration with respiratory physicians.

Genomic DNA hydroxymethylation reveals potential role in identification of lung injury in coal-burning arsenicosis populations.

Arsenic (As) is a toxic metalloid element that causes lung cancer and multiple non-malignant respiratory diseases. The toxicity of arsenic is mediated in part by epigenetic mechanisms, such as alterations in DNA methylation. While increasing studies have highlighted the potential importance of arsenic exposure to DNA methylation patterns and the subsequent risks for arsenic toxicity, there has been little focus on DNA hydroxymethylation-a negative regulation mechanism of DNA methylation. Therefore, this study aimed to investigate the relationship between genomic DNA methylation/hydroxymethylation and lung injury in arsenicosis populations. First, an increased risk of lung injury and exacerbation of lung function impairment in the arsenicosis population was confirmed. Levels of 5-methylcytosine/deoxycytidine (5mC/dC), 5-hydroxymethylcytosine/deoxycytidine (5hmC/dC) and 5hmC/5mC in genomic DNA of peripheral blood were decreased in the arsenicosis population compared to in the control. Additionally, multivariate logistic regression models showed an increased risk of chest digital radiography (DR) abnormalities when 5hmC/dC and 5hmC/5mC levels were lower (OR=3.12 and 3.96, all P< 0.001). For 3 years follow-up, regression analysis showed that a decline in 5hmC/dC was significantly associated with the decline of lung function parameters [forced vital capacity (FVC), forced expiratory volume in 1s (FEV1) and maximal mid-expiratory flow (MMEF); β=0.167, 0.122 and 0.073, respectively; all P< 0.05]. Using the receiver operating characteristic (ROC) curve, a combination of 5hmC/5dC and 5hmC/5mC obtained the highest value for distinguishing lung injury in all subjects (AUC=0.82, P< 0.01). In contrast, in arsenicosis subjects, 5hmC/dC was better at distinguishing lung injury (AUC=0.84, P< 0.01). Together, the results revealed that a decrease in genomic DNA hydroxymethylation markers was associated with lung injury in coal-burning arsenicosis populations. Genomic DNA hydroxymethylation could be a novel biomarker for identifying the risk of lung injury caused by coal-burning arsenicosis.