Inhalation of beryllium is associated with the development of sensitization; however, dermal exposure may also be important. The primary aim of this study was to elucidate relationships among exposure pathways in four different manufacturing and finishing facilities. Secondary aims were to identify jobs with increased levels of beryllium in air, on skin, and on surfaces; identify potential discrepancies in exposure pathways, and determine if these are related to jobs with previously identified risk. Beryllium was measured in air, on cotton gloves, and on work surfaces. Summary statistics were calculated and correlations among all three measurement types were examined at the facility and job level. Exposure ranking strategies were used to identify jobs with higher exposures. The highest air, glove, and surface measurements were observed in beryllium metal production and beryllium oxide ceramics manufacturing jobs that involved hot processes and handling powders. Two finishing and distribution facilities that handle solid alloy products had lower exposures than the primary production facilities, and there were differences observed among jobs. For all facilities combined, strong correlations were found between air-surface (rp ≥ 0.77), glove-surface (rp ≥ 0.76), and air-glove measurements (rp ≥ 0.69). In jobs where higher risk of beryllium sensitization or disease has been reported, exposure levels for all three measurement types were higher than in jobs with lower risk, though they were not the highest. Some jobs with low air concentrations had higher levels of beryllium on glove and surface wipe samples, suggesting a need to further evaluate the causes of the discrepant levels. Although such correlations provide insight on where beryllium is located throughout the workplace, they cannot identify the direction of the pathways between air, surface, or skin. Ranking strategies helped to identify jobs with the highest combined air, glove, and/or surface exposures. All previously identified high-risk jobs had high air concentrations, dermal mass loading, or both, and none had low dermal and air. We have found that both pathways are relevant. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a file describing the forms of beryllium materials encountered during production and characteristics of the aerosols by process areas.].

Inhaled beryllium particles that deposit in the lung airway lining fluid may dissolve and interact with immune-competent cells resulting in sensitization. As such, solubilization of 17 beryllium-containing materials (ore, hydroxide, metal, oxide, alloys, and process intermediates) was investigated using artificial human airway epithelial lining fluid. The maximum beryllium release in 7 days was 11.78% (from a beryl ore melter dust), although release from most materials was < 1%. Calculated dissolution half-times ranged from 30 days (reduction furnace material) to 74,000 days (hydroxide). Despite rapid mechanical clearance, billions of beryllium ions may be released in the respiratory tract via dissolution in airway lining fluid. Beryllium-containing particles that deposit in the respiratory tract dissolve in artificial lung epithelial lining fluid, thereby providing ions for absorption in the lung and interaction with immune-competent cells in the respiratory tract.

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 microg/l. More recent hires had fewer abnormalities. There was a suggestion that abnormalities were more common among workers with blood indium ≥5 microg/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. (Am. J. Ind. Med. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

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, histopathological, radiological, 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 (ILD) 4-13 years after first exposure (n=7) or PAP 1-2 years after first exposure (n=3). Common pulmonary histopathological 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 ILD had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographical 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 co-workers. 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.

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.

OBJECTIVES: Previous epidemiologic studies of beryllium sensitization (BeS) and chronic beryllium disease (CBD) have reported inconsistent exposure-response relationships, likely due to exposure misclassification. The objective of this study was to develop historical estimates of size-selective personal exposure to beryllium for an epidemiologic study. METHODS: In 1999, a cross-sectional survey of workers hired after 1 January 1994 was conducted at a beryllium production facility. Personal exposure data from two air sampling surveys conducted in 1999 were used to obtain total, respirable, and submicron particle baseline exposure estimates (BEE) for a job-exposure matrix (JEM). General area air samples collected from 1994-1999 were used to estimate annual changes in exposures (temporal factors) for 24 different process areas. Historical exposure estimates (HEE) were calculated by applying the temporal factors to the BEE. Workers were assigned HEE based on their work history, and their historical exposure profile was summarized as cumulative, average, or highest-ever job exposure. RESULTS: Changes in exposure over a 6-year period were observed in 10 of the 24 process areas with an overall mean decline of 18% per year. The overall total exposure for study participants over their work tenure ranged from: 0.001-34.44 mcg/m (3)-year, 0.01-16.26 mcg/m (3), and 0.01-17.54 mcg /m (3)for cumulative, average, and highest-ever job, respectively. For respirable exposures, the ranges were: 0.001-15.54 mcg/m (3)-year, 0.01-3.56 mcg/m (3), 0.01-5.54 mcg /m (3)for cumulative, average, and highest-ever job, respectively. CONCLUSIONS: Using this JEM, exposure-response relationships for BeS and CBD can be explored over a range of exposure metrics such as total, respirable, and submicron beryllium mass concentrations, including summary measures such as cumulative, average, or highest exposures, with the ultimate objective of elucidating a quantitative exposure-response relationship.

OBJECTIVE: The aim of this study was to evaluate the validity of a job exposure matrix (JEM) constructed for the period 1994-1999. Historical exposure estimates (HEE) for the JEM were constructed for all job and year combinations by applying temporal factors reflecting annual change in area air measurements (1994-1998) to the personal baseline exposure estimates (BEE) collected in 1999. The JEM was generated for an epidemiologic study to examine quantitative exposure-response relationships with sensitization and chronic beryllium disease. METHODS: The validity of the BEE and HEE was evaluated by comparing them with a validation dataset of independently collected personal beryllium exposure measurements from 1999 and 1994-1998, respectively. Agreement between the JEM and validation data was assessed using relative bias and concordance correlation coefficients (CCC). RESULTS: The BEE and HEE overestimated the measured exposures in their respective validation datasets by 8% and 6%, respectively. The CCC reflecting the deviation of the fitted line from the concordance line, showed good agreement for both BEE (CCC=0.80) and HEE (CCC=0.72). Proportional difference did not change with exposure levels or by process area and year. Overall, the agreement between the JEM and validation estimates (from combined HEE and BEE) was high (CCC=0.77). CONCLUSIONS: This study demonstrated that the reconstructed beryllium exposures at a manufacturing facility were reliable and can be used in epidemiologic studies.

Dissolution of a lung burden of poorly soluble beryllium particles is hypothesized to be necessary for development of chronic beryllium lung disease (CBD) in humans. As such, particle dissolution rate must be sufficient to activate the lung immune response and dissolution lifetime sufficient to maintain chronic inflammation for months to years to support development of disease. The purpose of this research was to investigate the hypothesis that poorly soluble beryllium compounds release ions via dissolution in lung fluid. Dissolution kinetics of 17 poorly soluble particulate beryllium materials that span extraction through ceramics machining (ores, hydroxide, metal, copper-beryllium [CuBe] fume, oxides) and three CuBe alloy reference materials (chips, solid block) were measured over 31d using artificial lung alveolar macrophage phagolysosomal fluid (pH 4.5). Differences in beryllium-containing particle physicochemical properties translated into differences in dissolution rates and lifetimes in artificial phagolysosomal fluid. Among all materials, dissolution rate constant values ranged from 10(-5) to 10(-10)gcm(-2)d(-1) and half-times ranged from tens to thousands of days. The presence of magnesium trisilicate in some beryllium oxide materials may have slowed dissolution rates. Materials associated with elevated prevalence of CBD had faster beryllium dissolution rates [10(-7)-10(-8)gcm(-2)d(-1)] than materials not associated with elevated prevalence (p<0.05).

Epidemiological studies have reported process-specific elevated prevalence of beryllium sensitization (BeS) and chronic beryllium disease (CBD) among workers. However, exposure-response relationships have been inconsistent, possibly due to incomplete characterization of many biologically relevant aspects of exposure, including particle size. In 1999, two surveys were conducted 3-5 months apart at a beryllium metal, oxide, and alloy production facility during which personal impactor samples (n = 198) and personal 37-mm closed-face cassette (CFC) 'total' samples (n = 4026) were collected. Among process areas, median particle mass median aerodynamic diameter ranged from 5 to 14 mum. A large fraction of the beryllium aerosol was in the nonrespirable size range. Respirable beryllium concentrations were among the highest for oxide production [geometric mean (GM) = 2.02 mug m(-3), geometric standard deviation (GSD) = 1.3] and pebbles plant (GM = 1.05 mug m(-3), GSD = 2.9), areas historically associated with high risk of BeS and CBD. The relationship between GM 'CFC total' and GM respirable beryllium for jobs varied by process areas; the rank order of the jobs showed high overall consistency (Spearman r = 0.84), but the overall correlation was moderate (Pearson r = 0.43). Total beryllium concentrations varied greatly within and between workers among process areas; within-worker variance was larger than between-worker variance for most processes. A review of exposure characteristics among process areas revealed variation in chemical forms and solubility. Process areas with high risk of BeS and CBD had exposure to both soluble and insoluble forms of beryllium. Consideration of biologically relevant aspects of exposure such as beryllium particle size distribution, chemical form, and solubility will likely improve exposure assessment.

Skin exposure to cobalt-containing materials can cause systemic immune sensitization and upon repeat contact, elicitation of allergic contact dermatitis (ACD). Data on cobalt dissolution rates are needed to calculate uptake through skin and for development of models to understand risk of sensitization or dermatitis. The purpose of this research was to measure the dissolution kinetics of feedstock and process-sampled powders encountered in the production of hard metal alloys using artificial sweat. The physicochemical properties of each material were characterized prior to evaluation of dissolution behavior. Variations in artificial sweat solvent pH and chemistry were used to understand critical factors in dissolution. Dissolution of cobalt, tungsten, and tungsten carbide was often biphasic with the initial rapid phase being up to three orders of magnitude faster than the latter long-term phase. Artificial sweat pH did not influence dissolution of cobalt or tungsten carbide. Solvent composition had little influence on observed dissolution rates; however, vitamin E suppressed the dissolution of cobalt and tungsten carbide from sintered particles obtained from a chamfer grinder. There was no effect of particle size on dissolution of feedstock cobalt, tungsten, tungsten carbide, and admixture powders. Particle physicochemical properties influenced observed dissolution rates with more cobalt and tungsten carbide dissolving from chamfer grinder particles compared to the feedstock powders or admixture powder. Calculations using the observed dissolution rates revealed that skin exposure concentrations were similar to concentrations known to induce cobalt sensitization and elicit ACD. Observed dissolution rates for cobalt in artificial sweat indicate that dermal uptake may be sufficient to induce cobalt sensitization and allergic dermatitis.

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 (cm(2) day)(-1)] differed significantly for hydroxide, metal, and oxide -1.7 +/- 0.0 x 10(-7), 1.7 +/- 0.6 x 10(-8), and 1.0 +/- 0.5 x 10(-9), respectively (P < 0.05). Up to 30 mug 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.

The dissolution of metal-containing particles in the gastric compartment is poorly understood. The purpose of this study was to elucidate the influence of artificial gastric juice chemical composition on bioaccessibility of metals associated with ingestion-based health concerns. Dissolution rates were evaluated for well-characterized feedstock cobalt, tungsten metal, and tungsten carbide powders, chemically bonded pre-sintered (spray dryer material) and post-sintered (chamfer grinder) cemented tungsten carbide materials, and an admixture of pure cobalt and pure tungsten carbide, prepared by mechanically blending the two feedstock powders. Dissolution of each study material was evaluated in three different formulations of artificial gastric juice (from simplest to most chemically complex): American Society of Testing Materials (ASTM), U.S. Pharmacopoeia (USP), and National Institute for Occupational Safety and Health (NIOSH). Approximately 20% of cobalt dissolved in the first dissolution phase (t(1/2) = 0.02 days) and the remaining 80% was released in the second long-term dissolution phase (t(1/2) = 0.5 to 1 days). Artificial gastric juice chemical composition did not influence dissolution rate constant values (k, g/cm(2)day) of cobalt powder, either alone or as an admixture. Approximately 100% of the tungsten and tungsten carbide that dissolved was released in a single dissolution phase; k-values of each material differed significantly in the solvents: NIOSH > ASTM > USP (p<0.05). The k-values of cobalt and tungsten carbide in pre- and post-sintered cemented tungsten carbide powders were significantly different from values for the pure feedstock powders. Solvent composition had little influence on oral bioaccessibility of highly soluble cobalt and our data support consideration of the oral exposure route as a contributing pathway to total-body exposure. Solvent composition appeared to influence bioaccessibility of the low soluble tungsten compounds, though differences may be due to variability in the data associated with the small masses of materials that dissolved. Nonetheless, ingestion exposure may not contribute appreciably to total body burden given the short residence time of material in the stomach and relatively long dissolution half-times of these materials (t(1/2) = 60 to 380 days).

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.