Method to evaluate the dustiness of pharmaceutical powders

The trend among pharmaceutical companies to develop selective drugs of high potency has pushed the industry to consider the potential of each hazardous ingredient to become airborne. Dustiness issues are not unique to the pharmaceutical industry, but are relevant to any industry where powdered materials are mixed, transferred and handled. Interest in dustiness is also driven by concerns for worker health, the potential for plant explosions and the prevention of product loss. Unlike other industries, the pharmaceutical industry is limited by the milligram quantity of powdered material available for testing during product development. These needs have led to the development of a bench-top dustiness tester that requires only 10 mg of powder and fully contains the generated aerosol. The powder is dispersed within a 5.7 liter glass chamber that contains a respirable mass sampler and a closed-face sampler to quantify the respirable and total dust that are generated with a given energy input. The tester distinguished differences in dustiness levels of five different powders. Finer powders were dustier, and the respirable dust percentage was always less than that for total dust. Four testers have been built and evaluated using pharmaceutical grade lactose. Dustiness measurements determined using all four testers were comparable. The pharmaceutical industry uses surrogates such as lactose to represent active compounds in tests that estimate the dust concentration likely to occur in a new manufacturing operation. Differences between the dustiness of the active compound and its surrogate challenge the relevance of the surrogate tests to represent true exposures in the workplace. The tester can determine the dustiness of both the active compound and its surrogate, and the resultant ratio can help to interpret dust concentrations from surrogate tests. Further, dustiness information may allow the pharmaceutical researcher to select powder formulations that present low airborne concentrations in the workplace.     

An investigation of dust generation by free falling powders.

To identify the dust generation processes, aluminum oxide powder was dropped as a free falling slug in a test chamber. The effect of the slug's mass, diameter, and drop height upon the aerosol concentration and size distribution was measured with an aerodynamic particle sizer. To differentiate between aerosol generated during the free fall and at the end of the fall, the slug was dropped either onto a flat surface or into a container of water that suppressed dust generation associated with the impact at the end of the fall. Aerosol generation occurred during the slug's free fall as well as at the end of the fall. The falling solid induced an airflow that followed the falling solid to the end of the fall. This induced airflow contained the aerosol generated during the free fall. At the end of the free fall, the induced airflow, combined with air jets created on impact, dispersed the aerosol throughout the test chamber. Additional measurements were made by using "neutral buoyancy" helium-filled bubbles to visualize the airflow in the test chamber. The airflow and ensuing turbulence were sufficient to keep large, inspirable particles suspended throughout the test chamber for periods greater than 10 min. During experimental work, the effect of drop height, mass, and slug diameter upon aerosol generation by a single slug of powder was studied. The results indicated that the manner in which a powder is handled may be as important as material dustiness as measured by a dustiness tester. Aerosol generation can be reduced by minimizing the contact between the falling powder and the air.     

Size selective dustiness and exposure; simulated workplace comparisons

A simulated workplace study was conducted to investigate the relation between inhalation exposure and dustiness determined with a rotating drum dustiness tester. Three powders were used in the study, i.e. magnesium stearate, representing a very dusty powder, and aluminium oxide and calcium carbonate, representing low and very low dusty powders, respectively. Two scenarios of handling small volume of powders were included; sweeping/cleaning and scooping/weighing/adding. Size-selective dust exposure was assessed using MultiDust (dual-fraction) IOM and RespiCon sampling heads. For the present operation scenarios, dustiness showed itself to be the major determinant of exposure and explained approximately 70% of the exposure variances. The ratios of respirable and inhalable fractions as determined by dustiness tests were comparable with the ratios observed for exposure. The results emphasize the relevance of dustiness as a parameter to characterize substances according to potential for exposure.     

Exposure Assessment of Four Pharmaceutical Powders Based on Dustiness and Evaluation of Damaged HEPA Filters

In this study, we show the different dustiness characteristics of four molecular pharmaceutical powder candidates and evaluate the performance of HEPA filters damaged with three different pinhole sizes and exposed to dust using real industrial powders in a miniaturized EN15051 rotating drum dustiness tester. We then demonstrate the potential use of such data using first-order exposure modeling to assess the potential worker exposure and transmission of active powder ingredients into ventilation systems. The four powders had highly variable inhalable dustiness indices (1,036 – 14,501 mg/kg). Dust particle size-distributions were characterized by three peaks; the first occurred around 60–80 nm, the second around 250 nm, and the third at 2–3 μm. The second and third peaks are often observed in dustiness test studies, but peaks in the 60–80 nm range have not been previously reported. Exposure modeling in a 5 times 20 kg powder pouring scenario, suggests that excessive dust concentrations may be reached during use of powders with the highest dustiness levels. By number, filter-damage by three pinhole sizes resulted in damage-dependent penetration of 70–80 nm-size particles, but by volume and mass the penetration is still dominated by particles larger than 100 nm. Whereas the exposure potential was evident, the potential dust concentrations in air ducts following the pouring scenario above were at pg/m³ levels. Hence, filter penetration at these damage levels was assumed to be only critical, if the active ingredients were associated with high hazard or unique product purity is required.

[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: An example of a typical particle number time-series of a complete dustiness test. It provides information on the HEPA-filter used including a scanning electron microscopy image of it. It also provides APS-measurements of particles penetrating the damaged HEPA-filter.]     

Characterization of dusts collected from swine confinement buildings

As part of a project to evaluate health hazards for workers in swine confinement buildings, the air in 21 different buildings was sampled with 37 mm cassette filters with and without cyclone preselectors and with cascade impactors. Filter results yielded a mean total aerosol of 6.3 mg/m3, a mean respirable aerosol of 0.5 mg/m3; the geometric mean diameter was 2.9 microns. Cascade impactor measurements revealed a mean total aerosol of 7.6 mg/m3, a respirable aerosol of 2.5 mg/m3 and a mass median diameter of 9.6 microns. The two major constituents in these aerosols were grain particles and dried fecal matter. The grain particles were larger than fecal particles and proportionately more abundant in finishing buildings where 50 kg X 100 kg animals are housed. Therefore the respirable fraction was less in finishing buildings than in farrowing and nursery buildings. Culturing of settled dusts yielded six different mold species, with the highest counts for Verticillium sp. (5 X 10(2) cfu/mg dry dust) grown at 37 degrees C. Thermophilic Actinomycetes and both gram negative and gram positive bacteria were isolated. Azocasein proteinase activity was found in most dust samples analyzed. This dust had a protein content of about 23% and a mean adsorbed ammonia content of 0.4%.     

Sampling and analysis of aircraft engine cold start particles and demonstration of an electrostatic personal particle sampler

Aircraft engines emit an aerosol plume during startup in extremely cold weather that can drift into areas occupied by flightline ground crews. This study tested a personal sampler used to assess exposure to particles in the plume under challenging field conditions. Area and personal samples were taken at two U.S. Air Force (USAF) flightlines during the winter months. Small tube-and-wire electrostatic precipitators (ESPs) were mounted on a stationary stand positioned behind the engines to sample the exhaust. Other ESPs were worn by ground crews to sample breathing zone concentrations. In addition, an aerodynamic particle sizer 3320 (APS) was used to determine the size distribution of the particles. Samples collected with the ESP were solvent extracted and analyzed with gas chromatography-mass spectrometry. Results indicated that the plume consisted of up to 75 mg/m(3) of unburned jet fuel particles. The APS showed that nearly the entire particle mass was respirable, because the plumes had mass median diameters less than 2 micro m. These tests demonstrated that the ESP could be used at cold USAF flightlines to perform exposure assessments to the cold start particles.     

Characteristics of dusts encountered during the production of cemented tungsten carbides

Inhalation of cobalt (Co) and tungsten carbide (WC) particles, but not Co or WC alone, may cause hard metal disease, risk of which does not appear to be uniform across cemented tungsten carbide (CTC) production processes. Inhalation of Co alone or in the presence of WC may cause asthma. Hypothesizing that aerosol size, chemical content, heterogeneity, and constituent compaction may be important exposure factors, we characterized aerosols from representative CTC manufacturing processes. Six work areas were sampled to characterize aerosol size distributions (dust, Co) and 12 work areas were sampled to characterize physicochemical properties (using scanning electron microscopy with energy dispersive x-ray spectrometry [SEM-EDX]). Bulk feedstock and process-generated powders were characterized with SEM-EDX and x-ray diffraction. The dust mass median diameter was respirable and the cobalt respirable mass fraction was highest (37%) in grinding. Morphology of particles changed with processing: individual, agglomerate, or aggregates (pre-sintered materials), then mostly compacted particles (subsequent to sintering). Elemental composition of particles became increasingly heterogeneous: mostly discrete Co or W particles (prior to spray drying), then heterogeneous W/Co particles (subsequent work areas). Variability in aerosol respirability and chemical heterogeneity could translate into differences in toxicity and support detailed characterization of physicochemical properties during exposure assessments.     

Determining the dustiness of powders--a comparison of three measuring devices

The dustiness of 12 test powders was determined using three different measuring methods. One of the methods, the continuous drop method, is a reference test method according to the EN 15051 'Workplace atmospheres--Measurement of the dustiness of bulk materials--Requirements and reference test methods'. A test of equivalence between the reference test method and the other two methods, the modified Heubach Dustmeter, a rotating drum method and the Palas Dustview, a single-drop method, has been carried out as provided in Annex D of the European standard. No equivalence was found between any of the test methods. An applied best-case scenario yielded a slightly better outcome, but the results lead to the conclusion that it is impossible to generate viable values using the test of equivalence provided in the standard. This outcome was expected and is due to the different handling procedures applied-which, however, relates to the reality of the variety of material-handling procedures in the workplace.     

Factors affecting the Heubach and MRI dustiness tests

The effect of test parameters upon material dustiness measured by the Heubach dust measurement appliance and the MRI dustiness tester was studied. The users of these tests can alter test parameters such as flow rate, sampling time, mass of material tested, bulk density, and vibrator setting. The effect of these parameters upon the aerosol produced in the dustiness tester was experimentally studied. All of the parameters affected in a complicated manner, the amount of dust and the size distribution of the dust generated during these tests. Therefore, dustiness test results should not be adjusted for variations in test parameters. The users of dustiness tests need to carefully control dustiness test parameters in order to have reproducible dustiness tests.     

Dust inhalation exposures from the handling of small volumes of powders

Worker exposure to airborne particulates was stimulated in a laboratory under controlled conditions. Small volumes, 3.8 L (1 gal.), of finely divided powders were transferred at 1-min intervals to 23-L (6-gal.) containers over 30-min time intervals. A high-volume filter array in the exit vent of the specially designed exposure laboratory was used both to control the ventilation rate and to determine the emission factor of the pouring operation. The room ventilation rate, method of transfer, and drop height were varied, and the resulting particulate concentrations were monitored by personal and area samplers. The four powders studied were talc, sodium chloride, Portland cement, and Direct Yellow 4 dye. Based on this study, a model was developed to predict potential worker exposure from the pouring of small volumes of powders. The model is based on the following major conclusions. First, the space- and time-averaged concentration of suspended particulate matter at breathing height agrees well with the mean concentration of suspended particulate matter in the room air effluent. Second, material-specific suspended particulate emission factors vary approximately in direct proportion to the drop height. Third, emission factors for scooping/dumping operations agree well with factors for pouring operations for a given drop height. Fourth, emission factors compare well with dustiness indexes that were determined using a bench-scale dustiness test chamber described in a companion paper. Parameters of the exposure model include dustiness index, drop height of the pouring operation, total quantity of material poured, averaging time, and the fraction of respirable material. For the validation of the model, additional data would be necessary.     

Silica exposure assessment in a mortality study of Vermont granite workers

A study of past silica and respirable dust exposures in the Vermont granite industry was conducted to develop a job exposure matrix (JEM) that used 5204 industrial hygiene measurements made from 1924-2004. The construction of the JEM involved data entry from several original sources into an Excel database that was reviewed later to ensure accuracy. Exposure measurements by job or location were grouped in two broad categories of quarry or shed and then into 22 job classes. Missing exposure data by time period were computed, taking into account improvements in dust control and periods of significant reduction in dustiness. Percent free silica (α-quartz) in respirable dust was estimated to be 11.0% based on previous published studies in Vermont and on data in the current database. About 60% of all measurement data (primarily from years prior to 1972) were obtained using the impinger and expressed in millions of particles per cubic foot (mppcf), which were converted to equivalent respirable free silica concentrations using the conversion of 10 mppcf = 0.1 mg/m(3) of respirable silica. For impinger data, respirable dust was calculated by multiplying respirable silica by a factor of 9.091 to reflect that the respirable silica was 11.0% respirable dust. This JEM has been used in a recent epidemiologic study to assess mortality in Vermont granite workers and to examine the relationships among mortality from silicosis, lung cancer, and other nonmalignant respiratory diseases.     

Parametric study of selective removal of atmospheric aerosol by coagulation, condensation and gravitational settling

This work studies the scavenging efficiencies of aerosol particles after a given mechanism of removal (coagulation, heterogeneous nucleation and gravitational settling) as a function of time. It also analyses the health impact of the aerosol before and after the above dynamic mechanisms by comparing the respirable dust fractions. The well-known equations of scavenging are applied to three atmospheric environments (clear, hazy and urban) that represent the aerosol PSDs in the countryside, industry and the city, respectively. From this study it is inferred that respirable dust is hardly scavenged and when compared with the initial volume of respirable aerosol, roughly 10% remains after 18 h of gravitational settling. Therefore, gravitational settling is the main removal mechanism of respirable aerosol compared to condensation and coagulation and is almost six times better than rainout.     

Quantity and size distribution of cough-generated aerosol particles produced by influenza patients during and after illness

The question of whether influenza is transmitted to a significant degree by aerosols remains controversial, in part, because little is known about the quantity and size of potentially infectious airborne particles produced by people with influenza. In this study, the size and amount of aerosol particles produced by nine subjects during coughing were measured while they had influenza and after they had recovered, using a laser aerosol particle spectrometer with a size range of 0.35 to 10 μm. Individuals with influenza produce a significantly greater volume of aerosol when ill compared with afterward (p = 0.0143). When the patients had influenza, their average cough aerosol volume was 38.3 picoliters (pL) of particles per cough (SD 43.7); after patients recovered, the average volume was 26.4 pL per cough (SD 45.6). The number of particles produced per cough was also higher when subjects had influenza (average 75,400 particles/cough, SD 97,300) compared with afterward (average 52,200, SD 98,600), although the difference did not reach statistical significance (p = 0.1042). The average number of particles expelled per cough varied widely from patient to patient, ranging from 900 to 302,200 particles/cough while subjects had influenza and 1100 to 308,600 particles/cough after recovery. When the subjects had influenza, an average of 63% of each subject's cough aerosol particle volume in the detection range was in the respirable size fraction (SD 22%), indicating that these particles could reach the alveolar region of the lungs if inhaled by another person. This enhancement in aerosol generation during illness may play an important role in influenza transmission and suggests that a better understanding of this phenomenon is needed to predict the production and dissemination of influenza-laden aerosols by people infected with this virus. [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 resources: a PDF file of demographic information, influenza test results, and volume and peak flow rate during each cough and a PDF file containing number and size of aerosol particles produced.].     

Determination of exposure to respirable quartz in the stone crushing units at Azendarian-West of Iran

The purpose of this study is to describe the personal exposure to respirable dust and quartz and in stone crushing units located at west of Iran. A size of 40 personal samples and 40 stationary samples were obtained and analysis was done by X-ray diffraction (XRD). The results of personal sampling were shown the concentrations of respirable dust exposure level in workers of process, hopper and drivers were 1.90, 2.22, 1.41 times greater than Occupational Safety and Health Administration permissible exposure limit (OSHA PEL). The average value of total dust and respirable dust emission from stationary sources was 9.46 mg/m(3), 1.24 mg/m(3) respectively, showing that 13.8 % of total dust is respirable. The efficiency of local exhaust ventilation (LEV) to control of particles inside of industrial units was greater than 99%. It is concluded from this research the particulate generated from stone crushing activities contain a significant amount of respirable particle. The amount of free silica in stone quartz is 85 to 97 percent that emission of particles effect to health workers. LEV has important effect in the removal of silica particles in stone crushing units. The worker of hoppers still exposed to silica more than standard limits.     

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.     

Use of a jet mill for dispersing dry powder for inhalation studies

Compressed air-powered jet mills are used in the chemical and food industries for grinding and classifying powders. We adapted one type of these fluid energy mills as a powder generator for inhalation experiments. The generating system included a jet mill and a screw feeder, the jet mill consisting of an elongated channel, a feeding jet to deliver the material into the channel, and two high-speed air jets. High speed air circulating in the channel created turbulence and centrifugal forces to disperse powder. The jet mill used can be operated from 25 to 100 psig at flow rates of 300 to 900 L/min. Two test materials--a solvent yellow dye and a dye mixture of solvent green and solvent yellow--were used. Both dyes were soft and sticky and could not be dispersed with several other powder generators tested at the concentrations required for toxicity studies. Aerosol concentrations ranging from 10 to 1500 mg/m3 at a flow rate of 400 L/min were obtained by adjusting the feed rate to the jet mill. Stability of aerosol concentration during six-hour continuous generation was 15 to 20%. Comparisons of several generators for producing sticky organic powders are also discussed.     

Hexavalent chromium responsible for lung lesions induced by intratracheal instillation of chromium fumes in rats

Lung toxicity of chromium fumes (Cr fumes) was examined by a single intratracheal instillation into rats of 10.6 mg and 21.3 mg Cr fumes/kg body weight and by repeated (3 times) instillations of 10.8 mg and 21.7 mg Cr fumes/kg. The pathological changes were compared with those induced by single administrations of 3.2 mg and 19.2 mg Na2CO3 solution-insoluble fraction of Cr fumes (Cr-Fr)/kg and 20.8 mg commercially available chromium (III) oxide powder (Cr (III) oxide)/kg. Single and repeated administrations of Cr fumes suppressed growth rate in a dose-dependent manner, but administrations of Cr-Fr and Cr (III) oxide did not. A single administration of Cr fumes produced granulomas in the entire airways and alveoli with progressive fibrotic changes, as well as severe mobilization and destruction of macrophages and foamy cells. Those histopathological changes were aggravated by the repeated administration of Cr fumes. On the other hand, single administrations of Cr-Fr and Cr (III) oxide produced no remarkable histopathological changes. Cr fumes were found to be composed of 73.5% chromium (III) oxide and 26.5% chromium (VI) oxide. The primary particles of Cr fumes and Cr-Fr were similar, 0.02 micron in size (sigma g: 1.25), and Cr (III) oxide particles were 0.30 micron in size (sigma g: 1.53), measured by analytical electron microscopy (ATEM). Diffuse clusters of the primary particles in Cr fumes were identified as Cr (VI) oxide. The present results suggested that the lung toxicity of Cr fumes was mainly caused by these Cr (VI) oxide (CrO3) particles in Cr fumes.     

Critique of 1985 ACGIH report on particle size-selective sampling in the workplace

The criteria recently proposed by ACGIH for judging the acceptability of respirable and other dust fraction samplers are analyzed. Implications on the sampling of workplace aerosol are determined. With the consideration of both bias and imprecision, the overall accuracy limited by the criteria is estimated for the sampling of coal mine dust as characterized by various researchers. The accuracy limits thus found appear to be excessively broad. As an example with actual workplace dust distributions in the sampling of a single aerosol (mass median diameter = 18.6 micrometers and geometric standard deviation = 2.3) with respirable dust concentration near 2 mg/m3, two samplers acceptable according to the proposed criteria could be found giving respirable dust measurements equal to 0.71 mg/m3 and 4.3 mg/m3 (even after excluding 5% of the low and high measurements from each sampler, respectively). Large variation in samplers acceptable according to the criteria is found for many other distributions as well; this indicates that tighter requirements are necessary. Seldom attained are both the single-sample +/- 25% accuracy at the 95% confidence level required of sampling/analytical methods endorsed by the National Institute for Occupational Safety and Health (NIOSH) and the tighter ISO dust fraction measurement requirement that 67% of the measurements of a sampled dust fall within 10% of a true value. Suggestions are given for sharpening the criteria without eliminating all samplers from acceptability.     

劳动卫生气溶胶颗粒组分和采样方法的新进展

为评价工人接触有害的气溶胶,应测定直接参与生物效应的气溶胶组分。劳动卫生学最早提出与健康有关的气溶胶组分（health-related aerosol fraction）这一概念,并用于工作场所粉尘按颗粒大小的选择性采样测定。英国医学研究委员会（BMRC）对呼吸性粉尘组分的定义在1960年即得到国际公认,尔后也制订了其他一些规则。值得注意的是,欧盟标准委员会（CEN）、国际标准化组织（ISO）和美国政府工业卫生工作者协会（ACGIH）在上世纪90年代就可吸入性、胸腔的和呼吸性气溶胶3个组分的定义达成一致意见,在世界范围采用了同一个规则。我国职业卫生标准在2002年要求测定呼吸性粉尘。近年,人们又提出超细颗粒（ultrafine particulates）这个新名词。由于它粒径小（直径≤100nm）,可自由地进出细胞,其健康效应令人担心。ISO/CEN 2004年制订了一个草案,讨论其职业接触和评价问题。近期《The Annals ofOccupational Hygiene》发表的文章中,BARTLEY博士阐述了7个组分的气溶胶采样规则,包括呼吸道5个特定的区域（而不是传统的3个区域）;在粒径上包括了超细气溶胶颗粒;需要多个热动力学和空气动力学不同工作原理的采样器矩阵进行测定。其目的并不是取代现有的国际标准,而是要促进采样器的创新设计。本文主要根据BARTLEY博士的述评和有关资料,简要介绍气溶胶组分和采样的一些进展,以期引起同行的关注。     

Subacute inhalation toxicity of mineral oils, C15-C20 alkylbenzenes, and polybutene in male rats

Male Wistar rats were exposed to mist and vapor of two mineral oils, two C15-C20 alkylbenzenes, and one polybutene at aerosol concentrations of 70 mg.m-3 and 700 mg.m-3 for 2 weeks. Of oil mist particles, 82-97 wt% were respirable (less than 4.7 microns). High-level exposure to polybutene was lethal to three of four animals, due to pulmonary edema. Elevated numbers of pulmonary macrophages and increased macrophage vacuolization were observed after exposure to the polybutene, both mineral oils, and one alkylbenzene. The same alkylbenzene produced body weight loss. Deposition analysis was performed for one mineral oil. No oil was detected in brain tissue, while retroperitoneal fat tissue contained 541 (401-702) micrograms oil/g tissue, half of this still present after an exposure-free period of 2 weeks. It is concluded that inhalation of the polybutene and one of the mineral cable oils tested here produces toxic effects in lung.