Gregory A. Day

Indium Lung Disease

BACKGROUND Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases. METHODS To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken. RESULTS Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers. CONCLUSIONS Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies.

Enhanced preventive programme at a beryllium oxide ceramics facility reduces beryllium sensitisation among new workers

Background: A 1998 survey at a beryllium oxide ceramics manufacturing facility found that 10% of workers hired in the previous 6 years had beryllium sensitisation as determined by the beryllium lymphocyte proliferation test (BeLPT). In response, the facility implemented an enhanced preventive programme to reduce sensitisation, including increased respiratory and dermal protection and particle migration control. Aim: To assess the programme’s effectiveness in preventing sensitisation. Methods: In 2000, the facility began testing newly hired workers for beryllium sensitisation with the BeLPT at time of hire and during employment. The sensitisation rate and prevalence for workers hired from 2000 to 2004 were compared with that for workers hired from 1993 to 1998, who were tested in the 1998 survey. Facility environmental conditions for both time periods were evaluated. Results: Newly hired workers in both cohorts worked for a mean of 16 months. Of the 97 workers hired from 2000 to 2004 with at least one employment BeLPT result, four had abnormal results at time of hire and one became sensitised during employment. Of the 69 workers hired from 1993 to 1998 and tested in 1998, six were found to be sensitised. The sensitisation rate for the 2000–4 workers was 0.7–2.7/1000 person-months of employment, and that for the 1993–8 workers was 5.6/1000 person-months, at least 2.1 (95% confidence interval (CI) 0.6 to 8.4) and up to 8.2 (95% CI 1.2 to 188.8) times higher than that for the 2000–4 workers. The sensitisation prevalence for the 2000–4 workers was 1% and that for the 1993–8 workers was 8.7%, 8.4 (95% CI 1.04 to 68.49) times higher than that for the 2000–4 workers. Airborne beryllium levels for production workers for the two time periods were similar. Conclusions: A comprehensive preventive programme reduced beryllium sensitisation in new workers during the first years of employment, despite airborne beryllium levels for production workers that were similar to pre-programme levels.

Identification and Measurement of Diacetyl Substitutes in Dry Bakery Mix Production

In 2008, a company using multiple buttermilk flavorings in the production of dry bakery mixes replaced one liquid flavoring containing 15–20% diacetyl with a proprietary substitute meant to lower occupational risk for diacetyl-related bronchiolitis obliterans. Subsequently, the National Institute for Occupational Safety and Health (NIOSH) evaluated buttermilk flavoring-related exposures at this companys facility, with a focus on measuring ketones by several methods. Volatile organic compounds (VOCs) were evaluated in the headspaces of six bulk flavorings samples, including the substitute buttermilk flavoring. Ketones were evaluated in workplace air via area and personal samples collected during batch preparation of the substitute buttermilk flavoring and production of a bakery mix containing the same flavoring. Air samples were evaluated using five different methods: NIOSH 2549, Modified OSHA PV2118, OSHA 1013, NIOSH Draft Procedure SMP2, and evacuated canisters. Of five buttermilk flavorings from five different flavorings manufacturers, diacetyl was present in four, including the substitute flavoring; acetoin in two; 2,3-pentanedione in four; 2,3-hexanedione in one; and 2,3-heptanedione in three. Among material safety data sheets (MSDS) for four flavorings, only one listed a hazardous ingredient, which was acetoin. The predominant flavoring ingredient identified in the headspace of the substitute flavoring was 2,3-pentanedione; all other chemicals noted above were also present. Diacetyl and 2,3-pentanedione were measured in workplace air via evacuated canisters. In one area and one personal air sample, 2,3-pentanedione was measured by OSHA Method 1013 at concentrations of 78 and 91 ppb, respectively. Without their or the employers knowledge, workers who used buttermilk flavorings were exposed to substitute ketones from many flavorings manufacturers. Because 2,3-pentanedione, 2,3-hexanedione, and 2,3-heptanedione all share the same functional α-diketone group as diacetyl, these compounds also may share diacetyls mechanism of toxicity. Until more is known about 2,3-pentanedione and other α-diketone compounds, they should not be assumed to be safe. Companies using artificial buttermilk flavorings should use a precautionary approach that assumes these flavorings pose a health risk and limit exposures through engineering and administrative controls and use of personal protective equipment.

BIOAVAILABILITY OF BERYLLIUM OXIDE PARTICLES: AN IN VITRO STUDY IN THE MURINE J774A.1 MACROPHAGE CELL LINE MODEL

Beryllium metal and its oxide and alloys are materials of industrial significance with recognized adverse effects on worker health. Currently, the degree of risk associated with exposure to these materials in the workplace is assessed through measurement of beryllium aerosol mass concentration. Compliance with the current mass-based occupational exposure limit has proven ineffective at eliminating the occurrence of chronic beryllium disease (CBD). The rationale for this research was to examine the mechanism of beryllium bioavailability, which may be pertinent to risk. The authors tested the hypothesis in vitro that dissolution of particles engulfed by macrophages is greater than dissolution in cellular medium alone. Physicochemical changes were evaluated in vitro for well-characterized high-purity beryllium oxide (BeO) particles in cell-free media alone and engulfed by and retained within murine J774A.1 monocyte-macrophage cells. The BeO particles were from a commercially available powder and consisted of diffuse clusters (aerodynamic diameter range 1.5 to 2.5 μm) of 200-nm diameter primary particles. Following incubation for 124 to 144 hours, particles were recovered and recharacterized. Recovered particles were similar in morphology, chemical composition, and size relative to the original material, confirming the relatively insoluble nature of the BeO particles. Measurable levels of dissolved beryllium, representing 0.3% to 4.8% of the estimated total beryllium mass added, were measured in the recovered intracellular fluid. Dissolved beryllium was not detected in the extracellular media. The BeO chemical dissolution rate constant in the J774A.1 cells was 2.1 ± 1.7 × 10−8 g/(cm2 ⋅ day). In contrast, the BeO chemical dissolution rate constant in cell-free media was < 8.1 × 10−9 g/(cm2 ⋅ day). In vivo, beryllium dissolved by macrophages may be released in the pulmonary alveolar environment, in the lymphatic system after transport of beryllium by macrophages, or in the alveolar interstitium after migration and dissolution of beryllium particles in tissue. These findings demonstrate a mechanism of bioavailability for beryllium, are consistent with previously observed results in canine alveolar macrophages, and provide insights into additional research needs to understand and prevent beryllium sensitization and CBD.

Sensitization and chronic beryllium disease at a primary manufacturing facility, part 3: exposure-response among short-term workers.

OBJECTIVES Exposure-response relations for beryllium sensitization (BeS) and chronic beryllium disease (CBD) using aerosol mass concentration have been inconsistent, although process-related risks found in most studies suggest that exposure-dependent risks exist. We examined exposure-response relations using personal exposure estimates in a beryllium worker cohort with limited work tenure to minimize exposure misclassification. METHODS The population comprised workers employed in 1999 with six years or less tenure. Each completed a work history questionnaire and was evaluated for immunological sensitization and CBD. A job-exposure matrix was combined with work histories to create individual estimates of average, cumulative, and highest-job-worked exposure for total, respirable, and submicron beryllium mass concentrations. We obtained odds ratios from logistic regression models for exposure-response relations, and evaluated process-related risks. RESULTS Participation was 90.7% (264/291 eligible). Sensitization prevalence was 9.8% (26/264), with 6 sensitized also diagnosed with CBD (2.3%, 6/264). A general pattern of increasing sensitization prevalence was observed as exposure quartile increased. Both total and respirable beryllium mass concentration estimates were positively associated with sensitization (average and highest job), and CBD (cumulative). Increased sensitization prevalence was identified in metal/oxide production, alloy melting and casting, and maintenance, and for CBD in melting and casting. Lower sensitization prevalence was observed in plant-area administrative work. CONCLUSIONS Sensitization was associated with average and highest job exposures, and CBD was associated with cumulative exposure. Both total and respirable mass concentrations were relevant predictors of risk. New process-related risks were identified in melting and casting and maintenance.

Characterization of exposures among cemented tungsten carbide workers. Part I: Size-fractionated exposures to airborne cobalt and tungsten particles

As many as 30,000 workers in the United States of America are exposed to cemented tungsten carbides (CTC), alloys composed primarily of tungsten carbide and cobalt, which are used in cutting tools. Inhalation of cobalt-containing particles may be sufficient for the development of occupational asthma, whereas tungsten carbide particles in association with cobalt particles are associated with the development of hard metal disease (HMD) and lung cancer. Historical epidemiology and exposure studies of CTC workers often rely only on measures of total airborne cobalt mass concentration. In this study, we characterized cobalt- and tungsten-containing aerosols generated during the production of CTC with emphasis on (1) aerosol “total” mass (n=252 closed-face 37 mm cassette samples) and particle size-selective mass concentrations (n=108 eight-stage cascade impactor samples); (2) particle size distributions; and (3) comparison of exposures obtained using personal cassette and impactor samplers. Total cobalt and tungsten exposures were highest in work areas that handled powders (e.g., powder mixing) and lowest in areas that handled finished product (e.g., grinding). Inhalable, thoracic, and respirable cobalt and tungsten exposures were observed in all work areas, indicating potential for co-exposures to particles capable of getting deposited in the upper airways and alveolar region of the lung. Understanding the risk of CTC-induced adverse health effects may require two exposure regimes: one for asthma and the other for HMD and lung cancer. All sizes of cobalt-containing particles that deposit in the lung and airways have potential to cause asthma, thus a thoracic exposure metric is likely biologically appropriate. Cobalt-tungsten mixtures that deposit in the alveolar region of the lung may potentially cause HMD and lung cancer, thus a respirable exposure metric for both metals is likely biologically appropriate. By characterizing size-selective and co-exposures as well as multiple exposure pathways, this series of papers offer an approach for developing biologically meaningful exposure metrics for use in epidemiology.

Serial evaluations at an indium-tin oxide production facility.

BACKGROUND We evaluated the effectiveness of workplace changes to prevent indium lung disease, using 2002-2010 surveillance data collected by an indium-tin oxide production facility. METHODS We assessed pulmonary function using lower limits of normal. Blood indium concentration and personal air sampling data were used to estimate exposure. RESULTS Abnormalities were uncommon at hire. After hire, prevalence of spirometric restriction was 31% (n = 14/45), about fourfold higher than expected. Excessive decline in FEV1 was elevated at 29% (n = 12/41). Half (n = 21/42) had blood indium ≥5 µg/l. More recent hires had fewer abnormalities. There was a suggestion that abnormalities were more common among workers with blood indium ≥5 µg/l, but otherwise an exposure-response relationship was not evident. Peak dust concentrations were obscured by time averaging. CONCLUSIONS Evolving lung function abnormalities consistent with subclinical indium lung disease appeared common and merit systematic investigation. Traditional measures of exposure and response were not illustrative, suggesting fresh approaches will be needed. Workplace changes seemed to have had a positive though incomplete impact; novel preventive interventions are warranted.

Physicochemical characteristics of aerosol particles generated during the milling of beryllium silicate ores: implications for risk assessment.

Inhalation of beryllium dusts generated during milling of ores and cutting of beryl-containing gemstones is associated with development of beryllium sensitization and low prevalence of chronic beryllium disease (CBD). Inhalation of beryllium aerosols generated during primary beryllium production and machining of the metal, alloys, and ceramics are associated with sensitization and high rates of CBD, despite similar airborne beryllium mass concentrations among these industries. Understanding the physicochemical properties of exposure aerosols may help to understand the differential immunopathologic mechanisms of sensitization and CBD and lead to more biologically relevant exposure standards. Properties of aerosols generated during the industrial milling of bertrandite and beryl ores were evaluated. Airborne beryllium mass concentrations among work areas ranged from 0.001 μg/m3 (beryl ore grinding) to 2.1 μg/m3 (beryl ore crushing). Respirable mass fractions of airborne beryllium-containing particles were < 20% in low-energy input operation areas (ore crushing, hydroxide product drumming) and > 80% in high-energy input areas (beryl melting, beryl grinding). Particle specific surface area decreased with processing from feedstock ores to drumming final product beryllium hydroxide. Among work areas, beryllium was identified in three crystalline forms: beryl, poorly crystalline beryllium oxide, and beryllium hydroxide. In comparison to aerosols generated by high-CBD risk primary production processes, aerosol particles encountered during milling had similar mass concentrations, generally lower number concentrations and surface area, and contained no identifiable highly crystalline beryllium oxide. One possible explanation for the apparent low prevalence of CBD among workers exposed to beryllium mineral dusts may be that characteristics of the exposure material do not contribute to the development of lung burdens sufficient for progression from sensitization to CBD. In comparison to high-CBD risk exposures where the chemical nature of aerosol particles may confer higher bioavailability, respirable ore dusts likely confer considerably less. While finished product beryllium hydroxide particles may confer bioavailability similar to that of high-CBD risk aerosols, physical exposure factors (i.e., large particle sizes) may limit development of alveolar lung burdens.

Characterization of exposures among cemented tungsten carbide workers. Part II: Assessment of surface contamination and skin exposures to cobalt, chromium and nickel.

Cobalt, chromium and nickel are among the most commonly encountered contact allergens in the workplace, all used in the production of cemented tungsten carbides (CTC). Exposures to these metal-containing dusts are frequently associated with skin sensitization and/or development of occupational asthma. The objectives of this study were to assess the levels of cobalt, chromium and nickel on work surfaces and on workers’ skin in three CTC production facilities. At least one worker in each of 26 work areas (among all facilities) provided hand and neck wipe samples. Wipe samples were also collected from work surfaces frequently contacted by the 41 participating workers. Results indicated that all surfaces in all work areas were contaminated with cobalt and nickel, with geometric means (GMs) ranging from 4.1 to 3057 μg/100 cm2 and 1.1–185 μg/100 cm2, respectively; most surfaces were contaminated with chromium (GM=0.36–67 μg/100 cm2). The highest GM levels of all metals were found on control panels, containers and hand tools, whereas lowest levels were on office and telecommunication equipment. The highest GM levels of cobalt and nickel on skin were observed among workers in the powder-handling facility (hands: 388 and 24 μg; necks: 55 and 6 μg, respectively). Levels of chromium on workers’ skin were generally low among all facilities. Geometric standard deviations associated with surface and skin wipe measurements among work areas were highly variable. Exposure assessment indicated widespread contamination of multiple sensitizing metals in these three facilities, suggesting potential transfer of contaminants from surfaces to skin. Specific action, including improved housekeeping and training workers on appropriate use and care of personal protective equipment, should be implemented to reduce pathways of skin exposure. Epidemiologic studies of associated adverse health effects will likely require more biologically relevant exposure metrics to improve the ability to detect exposure–response relationships.

Release of Beryllium from Beryllium-Containing Materials in Artificial Skin Surface Film Liquids

PURPOSE Skin exposure to soluble beryllium compounds causes systemic sensitization in humans. Penetration of poorly soluble particles through intact skin has been proposed as a mechanism for beryllium sensitization; however, this mechanism is controversial. The purpose of this study was to investigate the hypothesis that particulate beryllium compounds in contact with skin surface release ions via dissolution in sweat. METHODS Dissolution of 11 particulate beryllium materials (hydroxide, metal, oxides and copper-beryllium fume), 3 copper-beryllium alloy reference materials (chips and solid block), and 4 copper-beryllium alloy tools was measured over 7 days in artificial sweat buffered to pH 5.3 and pH 6.5. RESULTS All test materials released beryllium ions in artificial sweat. Particulate from a reduction furnace that contained both crystalline and amorphous beryllium was the most soluble compound-40% dissolved in 8 h. Rates of beryllium release from all other particulate and reference materials were faster at pH 5.3 than at pH 6.5 (P < 0.05). At pH 5.3, values of the chemical dissolution rate constant, k [g (cm² day)⁻¹] differed significantly for hydroxide, metal, and oxide -1.7 ± 0.0 × 10⁻⁷, 1.7 ± 0.6 × 10⁻⁸, and 1.0 ± 0.5 × 10⁻⁹, respectively (P < 0.05). Up to 30 μg of beryllium was released from the alloy tools within 1 h. Dissolution rates in artificial sweat were equal to or faster than values previously determined for these materials in lung models. CONCLUSIONS Poorly soluble beryllium materials undergo dissolution in artificial sweat, suggesting that skin exposure is a biologically plausible pathway for development of sensitization. Skin surface acidity, which is regulated by sweat chemistry and bacterial hydrolysis of sebum lipids varies by anatomical region and may be an exposure-modifying factor for beryllium particle dissolution.