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Health Effects of Beryllium Exposure: A Literature Review 2 Exposure Assessment The literature describing exposure to beryllium has been reviewed to provide the basis for examining questions relevant to identifying exposure-response relationships and the development of health-protection standards. Although worker-protection standards are the focus of this effort, an understanding of natural background exposures and anthropogenic exposures in other settings provides a useful context for understanding occupational exposures that lead to disease. Consequently, these exposures are briefly discussed here. This literature review has been conducted with the recognition that appropriate standards may vary with health end point. Exposures that lead to the principal end points of concern in connection with beryllium now—cancer and chronic beryllium disease (CBD)—are likely to have distinct physiochemical and dose-response characteristics. The following specific questions were formulated to guide the literature review: What are the current and potential future uses and sources of beryllium? What are the nature and magnitude of and variation in natural and anthropogenic background exposure via diet, drinking water, soil contact, and inhalation? What are the nature and magnitude of and variation in occupational exposures to beryllium, and how have changes in workplace practices changed beryllium exposures? How have changes in workplace practices and exposures affected the ability to identify exposure-response relationships? What sampling and analytic methods have been used, and how have changes in them affected exposure estimates? What exposure metrics should be used to evaluate air and surface contamination or skin exposures? Will the metrics for sensitization and CBD differ from those for cancer risk? We first describe beryllium sources and uses and then briefly review beryllium toxicokinetics. Exposure data on naturally occurring, background, and occupational exposures to beryllium are described next, and later sections examine sampling and analytic methods and exposure metrics for air and surface contamination and skin exposures. SOURCES AND USES This section reviews forms and characteristics of beryllium that are present in natural and anthropogenic settings. Beryllium metal, with atomic number 4, belongs to group IIA of the periodic
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Health Effects of Beryllium Exposure: A Literature Review table (alkaline-earth elements) and is chemically similar to aluminum with a high charge-to-nucleus ratio that leads to amphoteric behavior and a strong tendency to hydrolyze (EPA 1998b; ATSDR 2002). It has many unique chemical properties, being less dense than aluminum and stronger than steel (EPA 1998b). Because of its small atomic size, its most stable compounds are formed with small anions, such as fluoride and oxide. Beryllium is also capable of forming strong covalent bonds and may form organometallics, such as (CH3)2Be (EPA 1998b). Beryllium has been estimated to be present in the earth’s crust at 2-5 mg/kg, and soil concentrations in the United States were reported to average 0.63 mg/kg and range from less than 1 to 15 mg/kg (ATSDR 2002). In its review of beryllium, ATSDR (2002) reported that surveys have detected beryllium in less than 10% of samples of U.S. surface water and springs, but detection limits are not reported in the review. The low water concentrations probably reflect beryllium’s typically entering water as beryllium oxide, which slowly hydrolyzes to the insoluble compound beryllium hydroxide (EPA 1998b). Beryllium concentrations in U.S. air have typically been less than the detection limit of 0.03 ng/m3 (ATSDR 2002). Natural sources of airborne beryllium are windblown dust and volcanic particles, estimated to contribute 5 and 0.2 metric tons per year, respectively, to the atmosphere (Table 2-1). The principal anthropogenic contribution from airborne emissions is coal combustion. World coals have been reported to have a wide range of beryllium concentrations, from 0.1 to 1,000 mg/kg (Fishbein 1981), and the range in U.S. coal is 1.8-2.2 mg/kg (ATSDR 2002). On the basis of coal combustion of 640 million metric tons per year and a beryllium emission factor of 0.28 g/ton, EPA (1998b) has estimated that as much as 180 metric tons of beryllium may be emitted each year from U.S. coal combustion; fuel oil is burned at the rate of 148 million metric tons per year and has a beryllium emission factor of 0.048 g/ton, which would mean another 7.1 metric tons of beryllium released each year. Those estimates appear to conflict with emission estimates from the Toxic Release Inventory (TRI), which suggest a total of 3.5 tons per year released by electric utilities (Table 2-1); however, the TRI data are noted to be limited to particular types of facilities and to constitute an incomplete list (ATSDR 2002). The U.S. Department of Energy (DOE 1996) reported that beryllium in stack emissions of coal-fired power plants were 2-3 orders of magnitude greater than ambient air concentrations. As of 1991, Rossman et al. (1991) reported that 45 beryllium-containing minerals had been identified, including silicates, aluminum silicates, and aluminum oxides. Four of them were commercially important: beryl, phenakite, bertrandite, and chrysoberyl. Unlike such metals as lead and TABLE 2-1 Anthropogenic and Natural Emissions of Beryllium and Beryllium Compounds to the Atmospherea Emission Source Emission (tons/year)b Natural Windblown dust 5 Volcanic particles 0.2 Anthropogenicc,d Industry 0.6 Metal mining 0.2 Electric utilities 3.5 Waste and solvent recovery (RCRA) 0.007 Total 9.507 aAdapted from Drury et al. 1978; EPA 1987; TRI99 2002. bUnits are metric tons. cData in Toxic Release Inventory (TRI) are maximum amounts released by each industry. dThe sum of fugitive and stack releases is included in releases to air by a given industry. ABBREVIATION: RCRA = Resource Conservation and Recovery Act. SOURCE: ATSDR 2002.
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Health Effects of Beryllium Exposure: A Literature Review copper, which have a long history of use, beryllium had no known commercial use until a patent was issued for a beryllium-aluminum alloy in 1918 (Rossman et al. 1991). Production of beryllium-copper alloys began during the 1920s and was substantially increased during World War II. Until 1969, beryl ore from pegmatite dikes found widely distributed around the world was the only commercial source of beryllium (Rossman et al. 1991). Since that time, a bertrandite deposit in Utah has also been mined. In 1991, world beryllium production was estimated at 3,600 metric tons (Rossman et al. 1991). Releases to the environment from U.S. facilities that produce, process, or use beryllium compounds are tracked in the TRI database. Releases to air, water, underground injection, and land are summarized in Table 2-2 for beryllium and Table 2-3 for beryllium compounds. Releases of beryllium are exceptionally high in Ohio because the sole U.S. producer and processor of beryllium (Brush Wellman) is located there. Releases of beryllium compounds are more dispersed around the country because there are many more companies and industries that process and use beryllium compounds. Through the middle of the 20th century, beryllium was used predominantly in fluorescent lamps, nuclear-weapon components, and other defense applications. It is now used in a wide variety of products in about a dozen industries (see Table 2-4). As described by Kreiss et al. (2007), its diverse uses may put a growing number of workers at risk of beryllium exposure. Henneberger et al. (2004) relied on sampling compliance data from the Occupational Safety and Health Administration (OSHA) to estimate that 134,000 U.S. workers are potentially exposed to beryllium; however, Kreiss et al. (2007) believe that the number is far higher because OSHA has not sampled for beryllium in military and nuclear-weapons cycle workplaces. Other workplaces, such as those recycling electronic equipment, may also be a source of previously unsuspected exposure. TABLE 2-2 Releases of Beryllium Metal to the Environment from Facilities that Produce, Process, or Use It (TRI99 2002) Reported Amounts Released (lb/year)a Stateb Number of Facilities Airc Water Underground Injection Land Total On-Site Released Total Off-Site Releasee Total On-and Off-Site Release CA 3 0 No data No data No data 0 No data 0 IN 3 0 No data No data 2,650 2,650 2,415 5,065 LA 1 2 No data No data No data 2 No data 2 MO 1 0 No data No data 10 10 0 10 NC 1 38 No data No data No data 38 No data 38 OH 6 721 27 No data 50,352 51,280 9,870 61,150 OK 2 No data 23 No data 5 28 6,830 6,858 PA 1 1 7 No data No data 8 966 974 SC 1 7 No data No data 74 81 No data 81 TN 1 No data No data No data No data No data No data No data UT 1 0 No data No data 0 0 No data 0 WI 1 No data No data No data No data No data No data No data Total 22 769 57 0 53,271 54,097 20,081 74,178 aData in Toxic Release Inventory (TRI) are maximum amounts released by each facility. bPostal Service state abbreviations are used. cThe sum of fugitive and stack releases is included in releases to air from a given facility. dThe sum of all releases of the chemical to air, land, water, and underground injection wells. eTotal amount of chemical transferred off site, including to publicly owned treatment works (POTWs). SOURCE: ATSDR 2002.
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Health Effects of Beryllium Exposure: A Literature Review TABLE 2-3 Releases of Beryllium Compounds to the Environment from Facilities that Produce, Process, or Use Them (TRI99 2002) Reported Amounts Released (lb/year)a Stateb Number of Facilities Airc Water Underground Injection Land Total On-Site Released Total Off-Site Releasee Total On-and Off-Site Release AL 6 419 250 No data 62,691 63,360 326 63,686 AR 2 197 48 No data 9,130 9,375 1 9,376 AZ 4 50 No data No data 16,421 16,471 1,630 18,101 FL 3 390 250 No data 5,745 6,385 5 6,390 GA 5 764 0 No data 76,925 77,689 No data 77,689 IL 1 79 850 No data 8,500 9,429 No data 9,429 IN 4 340 63 No data 40,019 40,422 3,808 44,230 KY 5 351 1,221 No data 21,730 29,302 No data 29,302 MD 1 No data No data No data No data No data No data No data MI 2 313 17 No data 15,000 15,330 250 15,580 MO 3 10 No data No data No data 10 555 565 MS 1 2 20 4,100 19 4,141 0 4,141 MT 1 250 No data No data 6,900 7,150 750 7,900 NC 4 817 403 No data 51,010 52,230 260 52,490 NM 4 112 77 No data 47,724 47,913 39,000 86,913 NY 1 20 0 No data 400 420 No data 420 OH 4 450 30 No data 25,846 26,326 11,422 37,748 PA 4 1,580 16 No data 8,700 10,296 6,411 16,707 TN 2 256 250 No data 14,100 14,606 640 15,246 TX 1 19 0 No data 31,400 31,419 No data 31,419 UT 4 366 No data No data 299,952 300,318 5 300,323 WI 1 10 5 No data No data 15 255 270 WV 9 861 10 No data 70,765 71,636 6,800 78,436 WY 1 160 No data No data 3,970 4,130 No data 4,130 Total 73 7,816 3,510 4,100 822,947 838,373 72,118 910,491 aData in Toxic Release Inventory (TRI) are maximum amounts released by each facility. bPostal Service state abbreviations are used. cThe sum of fugitive and stack releases is included in releases to air from a given facility. dThe sum of all releases of the chemical to air, land, water, and underground injection wells. eTotal amount of chemical transferred off site, including to publicly owned treatment works (POTWs). SOURCE: ATSDR 2002. TOXICOKINETICS The toxicokinetic profile of beryllium compounds varies with solubility; more soluble forms undergo greater systemic absorption, distribution, and urinary elimination. EPA (1998b) did not identify any human studies of the deposition or absorption of inhaled beryllium but provides a review of the available animal studies. A more detailed review is provided by the Agency for Toxic Substances and Disease Registry (ATSDR 2002). The more soluble compounds were generally cleared more rapidly by dissolution in respiratory tract fluid. Insoluble particles deposited in the upper respiratory tract and tracheobronchial tree are cleared by mucociliary transport; those deposited in the pulmonary regions are cleared by a number of mechanisms and pathways, primarily via alveolar macrophages. The clearance of insoluble compounds from the lung was generally shown to be biphasic, with clearance half-times of days (via mucus transport and alveolar macrophages) to years (by dissolution and other translocation mechanisms) (Schlesinger 1995; NCRP 1997). In humans, residence times in the lung were assumed to
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Health Effects of Beryllium Exposure: A Literature Review TABLE 2-4 Industries That Use Beryllium Industry Products Aerospace Altimeters, braking systems, bushings and bearings for landing gear, electronic and electric connectors, engines, gyroscopes, mirrors (for example, in space telescopes), precision tools, rockets, satellites, structural components Automotive Air-bag triggers, antilock brake system terminals, electronic and electric connectors, steering-wheel connecting springs, valve seats for drag- racing engines Biomedical Dental crowns, bridges, partials, and other prostheses; medical laser and scanning electron microscope components; x-ray tube windows Defense Heat shields, mast-mounted sights, missile guidance systems, nuclear- reactor components and nuclear triggers, submarine hatch springs, tank mirrors Energy and electricity Heat-exchanger tubes, microelectronics, microwave devices, nuclear- reactor components, oil-field drilling and exploring devices, relays and switches Fire prevention Nonsparking tools, sprinkler-system springs Instruments, equipment, and objects Bellows, camera shutters, clock and watch gears and springs, commercial speaker domes, computer disk drives, musical-instrument valve springs, pen clips, commercial phonograph styluses Manufacturing Injection molds for plastics Sporting goods and jewelry items Golf clubs; fishing rods; naturally occurring beryl and chrysoberyl gemstones, such as aquamarine, emerald, and alexandrite; man-made gemstones, such as emeralds with distinctive colors Scrap recovery and recycling Various beryllium-containing products Telecommunications Cellular-telephone components, electromagnetic shields, electronic and electric connectors, personal-computer components, rotary-telephone springs and connectors, undersea repeater housings SOURCE: Kreiss et al. 2007. Reprinted with permission; copyright 2007, Annual Review of Public Health. be years because of the presence of insoluble beryllium many years after cessation of occupational exposure (ATSDR 2002). Substantial fractions of inhaled beryllium doses are removed by mucociliary clearance and enter the gastrointestinal tract. Gastrointestinal absorption is less than 1%, so most beryllium taken in orally and much taken in by inhalation (that is cleared and subsequently ingested) is excreted in feces (EPA 1998b). Beryllium that is cleared from the lung and absorbed into the systemic circulation is distributed primarily to the skeleton, liver, and tracheobronchial lymph nodes. ATSDR (2002) and EPA (1998b) suggest that skin absorption of beryllium compounds in the systemic circulation is minimal, although absorption through bruises and cut wounds has been demonstrated (Rossman et al. 1991). Nevertheless, after skin contact beryllium may become bound to epidermal constituents, such as alkaline phosphatase and nucleic acids, as has been demonstrated in guinea pig epidermis (Belman 1969). REVIEW OF EXPOSURE DATA Naturally Occurring and Background Exposure This section reviews available information on the nature and magnitude of and variation in exposure via diet, drinking water, soil contact, and inhalation. As described above, naturally occurring concentrations of beryllium in air are very low, although localized areas with greater concentrations would be expected around coal-fired power plants and other facilities that emit beryllium. Cigarette smoke contains various low amounts of beryllium but is not known to be a significant source of inhaled
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Health Effects of Beryllium Exposure: A Literature Review beryllium (ATSDR 2002). During the early 1970s, increased aerosolized beryllium from newly ignited camp-lantern mantles was reported. The mantles were reported to contain up to 600 μg of beryllium, most of which was volatilized soon after ignition (Griggs 1973). Average concentrations of beryllium in U.S. tapwater and bottled water are reported to be 0.013 μg/L and less than 0.1 μg/L, respectively (ATSDR 2002). Beryllium is also present in grains and produce at generally low (nanograms per gram) fresh-weight concentrations (ATSDR 2002); however, reliable estimates of daily dietary intake have not been reported. Occupational Exposure Inhalation-Exposure Studies Table 2-5 summarizes historical airborne-beryllium exposure studies. Studies have been conducted in beryllium mines, metal-processing and production facilities, alloying facilities, and nuclear-weapons facilities. Exposure data are available dating back to the 1930s and 1940s. The following observations can be garnered from the literature summarized in Table 2-5: Exposure in the early years of beryllium production and use was often in excess of the 2-μg/m3 exposure limit, and exposure at 100-1,000 times the current concentrations was not unusual. For example, Sanderson et al. (2001a) reported on daily weighted average exposure in a beryllium-copper alloy plant dating back to 1935 that was generally 10-100 μg/m3. Stefaniak et al. (2003a) reported on exposure at Los Alamos National Laboratory (LANL) dating back to the 1940s that averaged 32 μg/m3. Exposures to beryllium have generally decreased over time. In 1930-1950, exposures typically ranged from micrograms per cubic meter to hundreds of micrograms per cubic meter; in 1950-1970, micrograms to tens of micrograms per cubic meter; in 1970-1980, tenths of a microgram to tens of micrograms per cubic meter; and in 1980-1990, from hundredths to tenths of a microgram per cubic meter. While this indicates a general trend, it should be noted that beryllium exposures can vary considerably and there was potential for exposures outside those general ranges. Beryllium exposure within a given facility is highly variable. Stefaniak et al. (2003a) indicate annual geometric standard deviations (GSDs) ranging from 2 to 14 for exposures within LANL. Barnard et al. (1996) reported a coefficient of variation of 120% in personal exposure at Rocky Flats. Day et al. (2007) report a GSD of 3.4 for area air samples collected within a copper-beryllium alloy facility. Within beryllium production facilities, hot process environments (such as foundry and furnace operations) generally have the highest exposure (Kriebel et al. 1988; Johnson et al. 2001; Sanderson et al. 2001a). In contrast, Cullen et al. (1987) report the highest exposure at a precious-metal refinery for ball-mill and crusher job titles. Hydrolysis and wet grinding operations produced the highest exposure within mining and milling operations (Deubner et al. 2001a). Grinders, lappers, deburrers, and lathe operators have high exposure in beryllium machining operations (Kelleher et al. 2001). Kreiss et al. (1996) report machining and lapping as high-exposure jobs at a beryllium ceramics plant. Maintenance workers are at risk for high uncontrolled exposure (Donaldson and Stringer 1980; Stange et al. 1996b). Area samples underestimate exposure and are not statistically correlated with personal exposure (Donaldson and Stringer 1980; Barnard et al. 1996; Stange et al. 1996a; Johnson et al. 2001).
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Health Effects of Beryllium Exposure: A Literature Review TABLE 2-5 Summary of Beryllium Airborne-Exposure Studies Reference Setting Sample Type Summary of Key Findings Comments Cummings et al. 2007 Beryllium oxide ceramics facility Personal Production 1994-1999 Range: <0.02-62.4 µg/m3 Median: 0.20 µg/m3 Geometric mean: 0.21 µg/m3 2% of samples were >2 µg/m3 55% of samples were >0.2 µg/m3 2000-2003 Range: <0.02-53.3 µg/m3 Median: 0.18 µg/m3 Geometric mean: 0.18 µg/m3 4% of samples were >2 µg/m3 50% of samples were >0.2 µg/m3 Production support 1994-1999 Range: <0.02-0.80 µg/m3 Median: 0.10 µg/m3 Geometric mean: 0.11 µg/m3 <1% of samples were >2 µg/m3 29% of samples were >0.2 µg/m3 2000-2003 Range: <0.02-7.70 µg/m3 Median: 0.04 µg/m3 Geometric mean: 0.04 µg/m3 <1% of samples were >2 µg/m3 12% of samples were >0.2 µg/m3 Administration 1994-1999 Range: <0.20 µg/m3 2000-2003 Range: <0.02-0.35 µg/m3 Median: 0.02 µg/m3 Geometric mean: 0.02 µg/m3 <1% of samples were >2 µg/m3 <1% of samples were >0.2 µg/m3 Day et al. 2007 Alloy strip and wire finishing Area 0.003 µg/m3 (GM), 3.4 (GSD) Range: 0.007-0.02 µg/m3 72-h TWA
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Health Effects of Beryllium Exposure: A Literature Review Stanton et al. 2006 Copper-beryllium distribution centers Personal Production of bulk products Range: <0.02-1.62 µg/m3 Median: 0.04 µg/m3 Geometric mean: 0.04 µg/m3 <1% of samples were >2 µg/m3 9% of samples were >0.2 µg/m3 Production of strip metal Range: <0.01-1.40 µg/m3 Median: 0.03 µg/m3 Geometric mean: 0.03 µg/m3 <1% of samples were >2 µg/m3 2% of samples were >0.2 µg/m3 Production support Range: <0.02-0.13 µg/m3 Median: 0.01 µg/m3 Geometric mean: 0.02 µg/m3 <1% of samples were >2 µg/m3 <1% of samples were >0.2 µg/m3 Administration Range: <0.02-0.32 µg/m3 Median: 0.01 µg/m3 Geometric mean: 0.02 µg/m3 <1% of samples were >2 µg/m3 2% of samples were >0.2 µg/m3 Rosenman et al. 2005 Processing facility in PA Daily weighted average Mean average range: 7.1-8.7 µg/m3 Mean peak range: 53-87 µg/m3 Mean cumulative range: 100-209 µg/m3 Exposure data were presented in relation to subjects classified with BeS or CBD or as normal
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Health Effects of Beryllium Exposure: A Literature Review Reference Setting Sample Type Summary of Key Findings Comments Schuler et al. 2005 Copper-beryllium alloy processing Personal Production of rod and wire Range: <0.01-7.80 µg/m3 Median: 0.06 µg/m3 <1% of samples were >2 µg/m3 24% of samples were >0.2 µg/m3 Production of strip metal Range: <0.01-0.72 µg/m3 Median: 0.02 µg/m3 <1% of samples were >2 µg/m3 <1% of samples were >0.2 µg/m3 Production support Range: <0.01-0.33 µg/m3 Median: 0.02 µg/m3 <1% of samples were >2 µg/m3 2% of samples were >0.2 µg/m3 Administration Range: <0.01-0.11 µg/m3 Median: 0.02 µg/m3 <1% of samples were >2 µg/m3 <1% of samples were >0.2 µg/m3 Sampling from 1977 to 200 Stefaniak et al. 2003a Department of Energy Los Alamos National Laboratory Area and personal 1940s: 31.94 µg/m3 (mean) 1950s: 2.3 µg/m3 (mean) 1960s: 0.25 µg/m3 (mean) 1970s: 1.34 µg/m3 (mean) 1980s: 2.36 µg/m3 (mean) Historical data Deubner et al. 2001a Mining and mill facility Products facility Ceramics facility Area Mining and milling: 0.3-1.9 µg/m3 (annual medians) Mining and milling annual maximums: 6.2-234.5 µg/m3 Mixed product production: 0.1-1.0 µg/m3 (annual medians) Ceramic production: 0.1-0.4 µg/m3 (annual medians) 1970-1999 historical data Breathing zone Mining and milling: 0.3-15.9 μg/m3 (annual medians) Mixed product production: 0.7-2.1 μg/m3 (annual medians) Ceramic production: 0.1-0.9 μg/m3 (annual medians)
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Health Effects of Beryllium Exposure: A Literature Review Daily weighted averages Mining and milling: 0.08-0.2 µg/m3 (annual medians) Mixed product production: 0.1-2.5 µg/m3 (annual medians) Ceramic production: 0.1-0.5 µg/m3 (annual medians) Based on general area and breathing-zone samples Personal Mining and milling: 0.05-0.8 µg/m3 Mining and milling annual maximums: 0.04-165.7 µg/m3 Johnson et al. 2001 Cardiff Atomic Weapons Plant Area Annual mean range: 0.02 (in 1997) to 0.32 µg/m3 (in 1985) Annual maximum range: 7.02 (in 1997) to 1,128 µg/m3 (in 1985) Foundry mean range for entire period: 0.05-0.39 µg/m3 Old machine-shop mean range for entire period: 0.01-0.05 µg/m3 New machine-shop mean range for entire period: 0.02-0.01 µg/m3 1981-1997 historical data Personal Annual mean range: 0.12 (in 1997) to 0.28 µg/m3 (in 1984) Annual 95th percentile range: 0.22 (in 1997) to 1.1 µg/m3 (in 1983) Overall mean foundry workers: 0.87 µg/m3 Overall mean inspection workers: 0.22 µg/m3 Overall mean laboratory workers: 0.22 µg/m3 Overall mean machine-shop workers: 0.32 µg/m3 Overall mean safety workers: 0.19 µg/m3 Overall mean service workers: 0.29 µg/m3 Kelleher et al. 2001 Machining facility Personal Individual lifetime weighted exposure: 0.08-0.6 µg/m3 20 workers with BeS or CBD Apostoli and Schaller 2001 Metallurgy workers Area Steel-plant furnace area: 0.11µg/m3 (median) Steel-plant casting area: 0.03 µg/m3 (median) Copper-alloy plant furnace area: 0.4µg/m3 (median) Copper-alloy plant casting area: 0.2µg/m3 (median) 30 control workers, exposure was not detected Kent et al. 2001 Manufacturing plant, Elmore, OH Personal Total mass mean range: 0.13-1.04 µg/m3 Alveolar deposition: 0.05-0.63 µg/m3 Andersen impactor Ammonium beryllium fluoride and beryllium fluoride reduction furnace had highest concentrations
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Health Effects of Beryllium Exposure: A Literature Review Reference Setting Sample Type Summary of Key Findings Comments Area Total mass mean range: 0.85-2.74 µg/m3 MOUDI Alveolar deposition: 0.02-0.29 µg/m3 Ammonium beryllium fluoride and beryllium fluoride reduction furnace had highest concentrations Sanderson et al. 2001a Beryllium plant in PA (lung cancer case-control study) Daily weighted average 1935-1960: 1.7-767 µg/m3 (mean) 1961-1970: 1.0-69 µg/m3 (mean) 1971-1980: 0.1-3.1 µg/m3 (mean) 1981-1992: 0.03-1.4 µg/m3 (mean) 1935-1992 historical data Hennenberger et al. 2001 Ceramics plant Area 1.7% of samples were >2 µg/m3 0.6% of samples were >5 µg/m3 0.2% of samples were >25 µg/m3 Sampling from 1981 to 1998 Breathing zone 6.4% of sample were >2 µg/m3 2.4% of samples were >5 µg/m3 0.3% of samples were >25 µg/m3 Martyny et al. 2000 Precision machining plant Point of operation Mean: 7.19 µg/m3 (TWA) Range: 0.02-122.32 µg/m3 (TWA) Nearest worker location Mean: 0.91 µg/m (TWA) Range: 0.01-18.13 µg/m3 (TWA) Personal impactor Mean: 1.51 µg/m3 (TWA) Range: 0.03-22.68 µg/m3 (TWA) Total beryllium Mean: 1.48 µg/m3 (TWA) Range: 0.03-41.48 µg/m3 Viet et al. 2000 Department of Energy Rocky Flats beryllium shop Area Annual mean ranges 1960s: 0.116-0.662 µg/m3 1970s: 0.104-0.416 µg/m3 1980s: 0.083-0.271 µg/m3 Maximum daily ranges 1960s: 3.49-36.80 µg/m3 1970s: 1.57-11.34 µg/m3 1980s: 0.54-20.00 µg/m3 Machine shop sampling from 1960 to 1988 Yoshida et al. 1997 Beryllium-copper alloy plants Area Plant 1 alloy process: 0.16-0.26 µg/m3 (GM range for 1992-1995); maximum: 1.85 µg/m3 Plant 1 process without beryllium: 0.01-0.02 µg/m3 (GM range for 1992-1995)
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Health Effects of Beryllium Exposure: A Literature Review Plant 2 alloy cold rolling, drawing, and heat treatment: 0.03-0.19 µg/m3 (GM range for 1993-1995); maximum: 0.28 µg/m3 Plant 2 processes without beryllium: <0.01 µg/m3 Kreiss et al. 1997 Beryllium and beryllium-alloy plant Area Median: 0.4 µg/m3 Range: 0.1-0.7 µg/m3 Pebble plant median: 0.4 µg/m3 Pebble plant range: 0.1-79.2 µg/m3 1984-1993 historical data Breathing zone Median: 1.4 µg/m3 Range: 0.1-2.0 µg/m3 Pebble plant median: 1.1 µg/m3 Pebble plant range: 0.1-293.3 µg/m3 Personal Median: 1.0 µg/m3 Range: 0.1-52.6 µg/m3 Beryllium oxide production median: 3.8 µg/m3 Alloy melting and casting median: 1.75 µg/m3 Arc-furnace workers median: 1.75 µg/m3 Pebble plant median: 0.9 µg/m3 Pebble plant range: 0.1-19.0 µg/m3 Daily weighted average Range: 0.5-63.11 µg/m3 Arc-furnace workers median: 1.65 µg/m3 Furnace rebuild workers median: 1.63 µg/m3 Pebble plant median: 0.7 µg/m3 Pebble plant range: 0.1-7.9 µg/m3 1984-1993 historical data Quarterly estimates based on area, breathing zone, and personal samples Barnard et al. 1996 Department of Energy Rocky Flats beryllium shop Area 1970-1974: 0.34 µg/m3 (weighted mean) 1975-1982: 0.14 µg/m3 (weighted mean) 1983-1986: 0.2 µg/m3 (weighted mean) 1987-1988: 0.04 µg/m3 (weighted mean) Retrospective reconstruction, 62% of samples below detection limit Personal 1984-1987: 0.79 µg/m3 6-8 h TWA Kreiss et al. 1996 Beryllia ceramics plant Area Machining median: 0.3 µg/m3 (n = 58) Other areas median: <0.1 µg/m3 (n = 865) 1981-1992 historical data Breathing zone Machining median: 0.6 µg/m3 (n = 130) Other areas median: <0.3 µg/m3 (n = 636) Daily weighted average Machining median range: 0.1-0.9 µg/m3 Kiln operator median: 0.3 µg/m3 Lapping median: 0.6 µg/m3 Highest exposure for machining job of sawing and grinding Seiler et al. 1996 Various facilities (five plants in PA and OH) Area Mean range: 0.3-2.0 µg/m3 (n = 50) 1950-1978 historical data Breathing zone Mean range: 0.4-25.6 µg/m3 (n = 36)
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Health Effects of Beryllium Exposure: A Literature Review Reference Setting Sample Type Summary of Key Findings Comments Daily weighted average Mean range: 0.3-4.8 µg/m3 Stange et al. 1996a Department of Energy Rocky Flats, main production building Area Annual average range (1970-1988): 0.03 µg/m3 (in 1987) to 0.42 (in 1973) Based on random sample of results Personal Annual average range (1984-1987): 0.19 (in 1987) to 1.2 µg/m3 (in 1985) Stange et al. 1996b Department of Energy Rocky Flats, main production building Fixed airhead Annual mean ranges: 1970-1979: 0.10-0.42 µg/m3 1980-1988: 0.03-0.27 µg/m3 Personal Annual mean: 1985: 1.09 µg/m3 1986: 1.20 µg/m3 1987: 0.46 µg/m3 1988: 0.19 µg/m3 Hoover et al. 1990 Sawing and milling of beryllium metal and alloys Area General work area: 0.07 µg/m3 Ventilation shroud: >7,000 µg/m3 Sawing, milling, and grinding produced large particles (50-300 µm) PCAM Kriebel et al. 1988 Extraction and manufacturing facility Daily weighted average 1935-1954: 0.2-80 µg/m3 1955-1964: 0.2-51 µg/m3 1965-1976: 0.1-33 µg/m3 1977-1983: 0.1-0.7 µg/m3 1935-1983 historical data Assume range of means Cullen et al. 1987 Precious-metal refining Personal Mean: 1.2 ± 0.96 9 μg/m3 (n = 114) Range: 0.22-42.3 µg/m3 Crusher: 2.7 ± 7.2 μg/m3 Ball-mill operators: 2.1 ± 1.6 μg/m3 Samples collected in 1983 Cotes et al. 1983 Ore refining Area 1952: 0.8 µg/m3 (mean) 1960: 0.4 µg/m3 (mean) Highest samples collected in final hydroxide plant in 1952 (2 µg/m3) Only 9% of 3,000 samples exceeded 2 µg/m3 Donaldson and Stringer 1980 Beryllium production facilities Daily weighted average Mean in powdered-metal products area: 1.55 ± 1.97 µg/m3 (n = 105) Mean in extraction oxide area: 1.75 ± 2.16 μg/m3 (n = 144) Mean in ceramics area: 1.03 ± 1.43 μg/m3 (n = 36) Mean in alloy area: 2.93 ± 3.44 μg/m3 (n = 54) Mean in maintenance area: 19.19 ± 66.36 μg/m3 (n = 18) Samples collected in 1974
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Health Effects of Beryllium Exposure: A Literature Review Personal total dust Mean in powdered-metal productsarea: 1.02 ± 1.63 µg/m3 (n = 105) Mean in extraction oxide area: 1.40 ± 1.26 μg/m3 (n = 144) Mean in ceramics area: 0.75 ± 1.36 μg/m3 (n =36) Mean in alloy area: 1.58 ± 1.90 μg/m3 (n = 54) Mean in maintenance area: 3.59 ± 9.85 μg/m3 (n =18) Personal respirable dust Mean in powedered-metal products area: 5.2 ± 10.73 µg/m3 (n = 105) Mean in extraction oxide area: 2.63 ± 1.88 μg/m3 (n = 144) Mean in ceramics area: 1.69 ± 3.06 μg/m3 (n = 36) Mean in alloy area: 5.09 ± 6.75 μg/m3 (n = 54) Mean in maintenance area: 12.96 ± 35.74 μg/m3 (n = 18) Campbell 1961 High-explosives test facility Area Mean concentration inside bunker range: 0.08-0.14 µg/m3 Mean in control room: 0.07 µg/m3 Mean in office: 0.04 µg/m3 Test explosions produced soil contamination extending up to 200 ft from test site. Breathing zone Mean concentration outside bunker: 0.11-2.4 µg/m3 Mitchell and Hyatt 1957 Department of Energy Los Alamos National Laboratory Area 98% of samples were <1.0 µg/m3 2% of samples were 1.0-25 µg/m3 Machine shop sampling from 1952 to 1956, highly controlled environment Shop stack samples 6% of samples were 1.0-25 µg/m3 Sussman et al. 1959 Non-occupational Ambient air sampling Median around plant: 0.004 µg/m3 Median around steel mill collected for comparison: 0.0002 µg/m3 500 2-day samples collected around a beryllium plant in PA Eisenbud et al. 1949 Non-occupational Ambient air sampling and modeling Concentrations 0.75 miles from the plant ranged from 0.004 to 0.02 µg/m3 Based on investigations of berylliosis case near a beryllium processing plant in Lorain, OH Note: GM = geometric mean, GSD = geometric standard deviation, PCAM = portable continuous aerosol monitor, TWA = time-weighted average.
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Health Effects of Beryllium Exposure: A Literature Review Skin-Exposure Studies A consistent inhalation-response relationship for CBD has been difficult to establish. Additional exposure matrices that have not been measured may contribute to the inconsistency. One possible additional exposure route is through the skin (Tinkle et al. 2003). Penetration of the skin by poorly soluble beryllium particles could provide an immunologic route to sensitization, as shown by earlier study with soluble beryllium salts (Curtis 1951). To determine whether skin could be a route of exposure to particles, such as beryllium, Tinkle et al. (2003) demonstrated that 0.5- and 1.0-μm particles in conjunction with motion, as at the wrist, penetrated the stratum corneum of human skin and reached the epidermis and, occasionally, the dermis. In separate experiments, cutaneous application of beryllium oxide and beryllium sulfate generated a beryllium-specific, cell-mediated immune response in exposed susceptible mice. Day et al. (2006) proposed that skin exposure may be sufficient to cause beryllium sensitization (BeS) but that inhalation exposure, even at concentrations below 2 μg/m3, may be necessary for manifestation of CBD. In a study to evaluate the efficacy of an improved particle-migration control program, beryllium was measured in workplace air, on work surfaces, on cotton gloves worn by employees over nitrile gloves, and on the necks and faces of employees after implementation of the program (Day et al. 2007). The geometric mean beryllium concentration in all general-area air samples was 0.003 μg/m3 (range, 0.0007-0.02 μg/m3). In production, production-support, and office areas, the geometric mean beryllium concentrations were, respectively, 0.95, 0.59, and 0.05 μg/100 cm2 on work surfaces; 42.8, 73.8, and 0.07 μg/sample on cotton gloves; 0.07, 0.09, and 0.003 μg on necks; and 0.07, 0.12, and 0.003 μg on faces. Strong correlations were found between beryllium in air and on work surfaces (r = 0.79) and between beryllium on cotton gloves and on work surfaces (0.86), necks (0.87), and faces (0.86). The study showed that even with the implementation of control measures to reduce skin contact with beryllium as part of a comprehensive workplace-protection program, measurable beryllium continues to reach the skin of workers in production and production-support areas. Skin exposure is probably an important exposure pathway that can lead to sensitization and the development of CBD (see Chapter 3 for further discussion). Only three studies, in addition to the study by Day et al. (2007), have reported measures of surface beryllium contamination and skin exposure (see Table 2-6). Sanderson et al. (1999) reported extensive beryllium contamination inside vehicles and on the hands of machine-shop workers. The systemic toxicity of ingested insoluble forms (metal, alloy, and oxide) is thought to be low, but the role of ingested beryllium in sensitization is not clear. The following can be tentatively concluded from the limited literature: Even in workplaces with stringent exposure controls, measurable amounts of beryllium on surfaces and the skin of workers can be detected. Surface and skin contamination appears to correlate with airborne beryllium concentration. Surface contamination can result in the spread of beryllium from primary production or use areas. Skin exposure is an important and underassessed route of exposure. Biomarkers of Exposure Two studies, one in workers (Apostoli and Schaller 2001) and one in the general population (Paschal et al. 1998), reported inconsistent results of using beryllium in urine as a biomarker of exposure (see Table 2-7). Metallurgy workers investigated by Apostoli and Schaller had urinary concentrations similar to those in the general population—on the basis of the National Health and Nutrition Examination Survey (NHANES)—reported by Paschal et al., whereas nonexposed controls in the Apostoli and Schaller population had exposures below detection and about one-tenth that in the NHANES sample. Urinary beryllium is not commonly used as a biomarker and is of uncertain utility.
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Health Effects of Beryllium Exposure: A Literature Review TABLE 2-6 Summary of Beryllium Skin-Exposure and Surface-Exposure Studies Reference Jobs or Worker Area Sample Type Summary of Key Findings Comments Emond et al. 2007 Recycling facility Body surface sample Postexposure samples of skin ranged from below the limit of detection to 0.26 μg/100 cm2 Postexposure samples for coverall surfaces ranged from 1.6 to 2.6 μg/100 cm2 Skin concentrations were estimated to be 10−3 to 10−7 inhalation concentrations Day et al. 2007 Alloy strip and wire finishing Surface wipe GM: 0.77 μg/100 cm2 GM range: 0.05 μg/100 cm2 (administrative area) to 13.6 μg/100 cm2 (wire annealing and pickling area) Large variability, GSDs range from 2.1 to 7.8 n = 252 Cotton glove Overall GM: 13.4 μg/glove GM range: 0.07 μg/glove (administrative area) to 196.5 μg/glove (rod and wire production area) Strong positive correlations between air and surface, surface and glove, glove and skin Skin wipes Overall GM on neck: 0.04 μg Overall GM on face: 0.04 μg GM range: 0.05 μg (administrative area) to 13.6 μg (wire annealing and pickling area) Sanderson et al. 1999 Machine shop Wipe samples in vehicles GM range: below detection limit (child car seat) to 19.0 μg/ft2 (driver’s floor) Machine-shop worker private vehicles Hand wipe GM range: 1.0 μg/ft2 (office worker) to 30.0 μg/ft2 (E-cell worker) Campbell 1961 High-explosives test facility Clothing samples Maximum coverall contamination range: <19-159 μg/coverall Maximum sock contamination: 178 μg/sock Maximum shoe sample: 1.6 μg/cm2 Surface samples 97% of samples in bunker (n = 145) were <0.01 μg/cm2 Mean of four detectable samples was 3.5 μg/cm3 Note: GM = geometric mean, GSD = geometric standard deviation. TABLE 2-7 Summary of Beryllium Biomonitoring Exposure Studies Reference Jobs or Worker Area Sample Type Summary of Key Findings Comments Apostoli and Schaller 2001 Metallurgy workers Spot urine Electric steel-plant furnace workers: 0.09 μg/L (median) Electric steel-plant casting workers: 0.06 μg/L (median) Copper-alloy foundry furnace workers: 0.25 μg/L (median) Copper-alloy foundry casting workers: 0.125 μg/L (median) Controls: <0.03 μg/L End of shift Airborne and urinary beryllium strongly correlated Paschal et al. 1998 General population Urine Median: 0.13 μg/L Mean: 0.22 μg/L Creatinine-adjusted NHANES sample
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Health Effects of Beryllium Exposure: A Literature Review REVIEW OF AIR-SAMPLING AND ANALYTIC METHODS Beryllium-aerosol exposure-assessment methods have changed (Kolanz et al. 2001). The first air samples for beryllium were collected with electrostatic precipitators (Mitchell and Hyatt 1957). In the early 1950s, filter-based sampling was initiated (Hyatt et al. 1959). Area or task-based area sampling strategies initially used high-volume pumps and filter-collection substrates, but more recent methods have adopted personal sampling techniques. Three types of samples have been described in the literature: fixed-airhead samples, high-volume samples, and personal samples (Hyatt and Milligan 1953; Campbell 1961; Lindeken and Meadors 1960; Kolanz et al. 2001). Fixed-airhead samples were collected at 10-100 L/min with open-faced samplers at fixed locations. High-volume samples were collected to estimate general area concentrations and to simulate personal exposures by placing a sampler in an employee’s breathing zone and combining the results with time-activity information. High-volume samples were collected at 200-400 L/min on filter media. More recently, personal samples have been collected from the lapels of workers at 1-2 L/min. Size-selective air sampling has not been generally used for beryllium exposure assessment. Most samples would have historically been considered as total dust samples, but it is important to recognize that all samplers have an inlet bias, and the use of the term total dust is now considered to be a misnomer. A comparison of respirable and total dust samples collected by Donaldson and Stringer (1980) indicated that total dust samples were 2-5 times more concentrated than respirable dust samples. In the 1940s, beryllium was analyzed with spectrography (Cholak and Hubbard 1948). That technique had a relatively poor sensitivity of about 0.25 μg of beryllium. In the early 1950s, it was replaced with fluorometry that had a sensitivity of about 0.05 μg (Mitchell and Hyatt 1957). Modern atomic-absorption spectroscopic methods of detecting beryllium were introduced in the 1970s and improved sensitivity to about 0.005 μg of beryllium. EXPOSURE METRICS The precise dose-response relationship between exposure to beryllium and development of CBD has remained unclear, probably because of both the uncertainty regarding beryllium exposure and the immune nature of CBD. Furthermore, the poor characterization of beryllium exposures makes comparison between studies difficult. Understanding of the role of dose in CBD is complicated by several exposure measures, including the airborne concentration of beryllium, the duration of exposure, and the solubility, particle size, and type of beryllium being manufactured or machined. Particle size, surface area, number, and concentration—particularly of submicrometer particles—are the most important dimensions to be determined. Because of the low density of beryllium, large particles would be aerodynamically smaller than other metal particles. It is important to characterize the size of airborne particles aerodynamically, and this should be followed by their chemical characterization. The solubility of beryllium compounds in skin, interstitial lung fluid, and phagolysosomes may also influence the bioavailability of beryllium. Physical and Chemical Properties Table 2-8 shows the physical and chemical properties of beryllium and commonly used beryllium compounds. Most beryllium compounds are poorly soluble in water. The most common compound used in industry is beryllium oxide; its solubility in water decreases as the temperature at which it is calcined increases (Spencer et al. 1968; Novoselova and Batsanova 1969; Eidson et al. 1984). Beryllium carbonate and beryllium hydroxide are practically insoluble in water. Beryllium chloride, beryllium fluoride, beryllium nitrate, beryllium phosphate (trihydrate), and beryllium sulfate (tetrahydrate) are
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Health Effects of Beryllium Exposure: A Literature Review TABLE 2-8 Physical and Chemical Properties of Beryllium and Beryllium Compounds Name Chemical Formula Molecular Weight Melting Point (°C) Boiling Point (°C) Density (g/cm3) Solubility in Water Beryllium metal Be 9.012 1,287-1,292 2,970 1.846 Insoluble Beryllium oxide BeO 25.01 2,508-2,547 3,787 3.016 Insoluble Beryllium sulfate BeSO4 105.07 550-600 (decomposes) Not applicable 2.443 Insoluble Beryllium carbonate (basic) Be(CO3)2 112.05 No data No data No data Cold, insoluble; hot, decomposes Beryllium hydroxide Be(OH)2 43.03 Decomposes (loses H20) Not applicable 1.92 3.44 mg/L Beryllium nitrate (tetrahydrate) Be(NO3)2 205.08 60.5 142 (decomposes) 1.557 1.66 × 106 mg/L Beryllium phosphate (trihydrate) Be3(PO4)2 271.03 100 (decomposes, loses H20) No data No data Soluble Beryllium fluoride BeF2 47.01 555 1,175 1.986 Very soluble Beryllium chloride BeCl2 79.92 405 520 1.899 Very soluble SOURCE: ATSDR 2002. soluble in water. Beryllium carbonate and beryllium sulfate are formed in a step during the extraction of beryllium hydroxide from ore. Beryllium ammonium fluoride and beryllium fluoride are formed in steps of processing beryllium hydroxide to beryllium metal. Concentration and Types of Beryllium in the Workplace In this section, the concentrations and types of beryllium exposure in workplaces are described. Much of this information was ascertained as part of epidemiologic studies of BeS and CBD. More detailed discussion of these studies and the relationships found between BeS and CBD and specific exposures are discussed in Chapter 3. Beryllium concentrations in a workplace vary substantially according to the production process and differ from location to location within a factory at any given time. Workers are exposed not only to freshly generated particles from production processes but also to mechanically resuspended particles from work surfaces and clothing fabric. Other factors, such as the ventilation system and use of local exhaust hoods, also influence exposure concentrations. A cross-sectional study in a beryllium-ceramics plant and a multifaceted beryllium production facility confirmed that the risk of BeS or CBD is process-related (Kreiss et al. 1997). However, no association between BeS and cumulative or average exposure to beryllium was found. It is possible that other physicochemical factors that potentially can influence bioavailability of beryllium—including particle size, specific surface area (SSA), and chemical composition—were more important than exposure concentration in determining disease outcomes. Exposure concentration can be measured with a personal sampler (usually on the lapel of work clothing) to sample for a full workshift and to collect samples of different atmospheres to which a worker is exposed during a shift. When that information is combined with results of a simultaneous time and motion study of the worker, one can obtain an estimated time-weighted average (TWA). An average ratio of about 3:1 was found when exposure measured with personal lapel monitors was compared with exposure estimated using area monitoring and time-motion studies. Placement of the monitors, fluctuations in flow rate of the sampling pumps, and resuspension of dust from work clothing into lapel monitors contributed to the discrepancy (Cohen 1991).
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Health Effects of Beryllium Exposure: A Literature Review The dose of inhaled dust in an industrial setting can be influenced by several factors, such as exposure concentration, particle size distribution, and breathing pattern. Because the biologic effects of inhaled aerosols depend on particle size and because many occupational diseases are associated with deposition of materials in particular regions of the respiratory tract, the American Conference of Governmental Industrial Hygienists has recommended particle-size selective Threshold Limit Values for dozens of chemical substances (ACGIH 2007). Cohen et al. (1983) used a multicyclone sampler to measure the size mass distribution of the beryllium aerosol at a beryllium-copper alloy casting operation. The mass median aerodynamic diameter (MMAD) ranged from 3 to 6 μm during most of the sampling period. For two measurement periods during which the furnace was being “charged,” the MMAD was considerably larger (6-16 μm), probably because of resuspension of settled dust. Hoover et al. (1990) reported that milling at a depth of 50 μm, compared with sawing, produced a smaller MMAD of beryllium particles. The milling process also produced a higher proportion of particles with MMAD smaller than 5 μm than did sawing (9% and 0.3%, respectively). In addition, the peak concentrations of beryllium particles captured by ventilation shrouds exceeded 7 mg/m3 when beryllium metal was processed, whereas the concentrations were lower by a factor of 10 when beryllium alloys were used. Several cross-sectional studies have demonstrated that some industrial processes are strongly associated with the development of CBD. A prevalence of 16% was associated with ceramics dry pressing (Kreiss et al. 1993a), 14% with ceramics machining (Kreiss et al. 1996), and 19% with beryllium-metal production (Kreiss et al. 1997); all those were higher than the prevalence of 5% in machinists in the nuclear industry (Kreiss et al. 1993b). Those data imply that the compositions of beryllium-containing aerosols derived with different processes or based on measures other than mass concentration may be responsible for the development of CBD. To investigate risk factors other than mass concentration, Martyny et al. (2000) characterized particle size distribution associated with a number of beryllium-machining processes during normal operating procedures in a precision beryllium-machining plant that used cascade impactors. Table 2-9 shows the concentrations and particle sizes obtained with different operations in the plant. There were large differences between sampling locations. The data show that beryllium machining as performed in industry today produces a large number of fine respirable beryllium particles with more than 50% of the mass in the breathing zone of the worker consisting of particles smaller than 10 μm and more than 30% smaller than 0.6 μm. Using the Andersen cascade impactor, Thorat et al. (2003) found similar size distribution with the mean MMAD of beryllium particles observed in various operations ranging from 5.0 to 9.5 μm. Kent et al. (2001) used an Andersen impactor for personal sampling and a micro-orifice uniform deposition impactor (MOUDI) for area sampling; the prevalences of CBD and BeS were significantly associated with the mass concentration of particles smaller than 10 and 3.5 μm (collected with a MOUDI) but not associated with particles collected with the Andersen impactor. The placement of the monitors, fluctuations in flowrate of the sampling pumps, and resuspension of dusts from work clothing into lapel monitors might have contributed to the discrepancies (Cohen 1991). The estimated number and surface area concentration (with the MOUDI) of particles smaller than 10 μm deposited in the alveoli also showed significant relationships with CBD. That no other exposure measures showed significant relationships with CBD or BeS suggests that size-selective characterization of exposure concentrations may provide more relevant exposure metrics for predicting the incidence of CBD or BeS than does the total mass concentration of airborne beryllium. McCawley et al. (2001) tested the hypothesis that particle number would be more reflective of target organ dose than would particle mass and be a more appropriate measure of exposure in connection with CBD. Area mass-based and number-based size distribution measurements were taken with a MOUDI and a scanning mobility particle sizer, respectively. Both the particle number and the mass distribution were weighted heavily with ultrafines for several processes; the fluoride-furnace area had the greatest number concentration (up to 109 particles/cm3). There was no correlation between any measure
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Health Effects of Beryllium Exposure: A Literature Review TABLE 2-9 Comparison of Beryllium Concentrations and Particle Size Obtained with Different Operations in a Precision Machining Plant Point of Operationa Near Worker Locationa Personal Impactorb Total Bec Process Median Concentration (μg/m3) MMAD (μm) Median Concentration (μg/m3) MMAD (μm) Median Concentration (μg/m3) MMAD (μm) Median Concentration (μg/m3) Deburring 0.58 3.2 0.26 1.2 0.74 1.6 1.42 Grinding 2.21 4.1 0.65 2.3 0.34 3.1 0.47 Lapping 0.32 0.11 1.2 0.13 2.3 0.31 Lathe operation 4.08 0.27 0.6 0.60 0.6 1.01 Milling 0.18 0.18 0.6 0.25 2.7 0.52 aSamples were taken with Lovelace Multijet Impactors. bSamples were taken with Series 290 Marple Personal Cascade Impactor. cSamples were taken with lapel samplers: closed-face 37-mm cassette with a 0.8-μm pore-size cellulose ester filter. SOURCE: Adapted from Martyny et al. 2000. Reprinted with permission; copyright 2000, Journal of Occupational and Environmental Medicine. of particle-mass dose and particle-number dose. Because the majority of the epidemiologic studies of health risk of beryllium only measured mass concentration of beryllium, more rigorous investigation is needed to establish the particle number hypothesis. In a case-control analysis of workers in a contemporary precision beryllium-machining plant, Kelleher et al. (2001) used personal sampling with total and particle-size fractions to investigate the relationship between beryllium exposure and health effects. Cases were more likely than controls to have worked as machinists (odds ratio of 4.4; 95% confidence interval: 1.1, 17.6). The exposure concentrations at which workers developed CBD and BeS were mostly below OSHA’s current permissible exposure limit of 2 μg/m3; that suggests that the current limit does not completely protect workers from beryllium-related health effects. Although this is not statistically significant, the median cumulative total exposure was consistently higher in the cases (2.9 μg/m3-years) than in the controls (1.2 μg/m3-years). Median cumulative exposure of cases and controls to particles smaller than 6 μm in diameter was 1.7 μg/m3-years and 0.5 μg/m3-years, respectively. Stefaniak et al. (2003b) investigated the contribution of particle structure and surface area as risk factors in CBD. Particles (powder and process-sampled) of beryllium metal, beryllium oxide, and copper-beryllium alloy were separated by aerodynamic size. Their chemical compositions and structures were determined with x-ray diffraction and transmission electron microscopy, respectively. The beryllium-metal powder consisted of compact particles, whereas the beryllium oxide powder and particles were clusters of smaller primary particles. SSA of all samples varied by a factor of 37, from 0.56 m2/g (the 0.4- to 0.7-μm fraction of the process-sampled reduction-furnace particles) to 20.8 m2/g (the ≤0.4-μm fraction of the metal powder). Large relative differences in SSA were observed as a function of particle size of the beryllium-metal powder, from 4.0 m2/g (particles <6 μm) to 20.8 m2/g (particles ≤0.4 μm). In contrast, little relative difference (<25%) in SSA was observed as a function of particle size of the beryllium oxide powder and particles collected from the screening operation. The SSA of beryllium-metal powder decreases with increasing particle size, as expected for compact particles, and the SSA of the beryllium oxide powders and particles remains constant as a function of particle size, which might be expected for clustered particles. Those associations illustrate how process-related factors can influence the structure and SSA of beryllium materials. Structure and SSA may be important determinants of the bioavailability of beryllium and the associated risk of CBD. Schuler et al. (2005) examined the prevalences of BeS and CBD and relationships between BeS and CBD and work-area processes and found that among 185 employees (153, or 83%, of whom participated), the prevalences of BeS and CBD were 7% (10 of 153) and 4% (six of 153), respectively.
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Health Effects of Beryllium Exposure: A Literature Review The prevalence of sensitization among employees with 1 year or less since first exposure was higher (13%); none of them had CBD. CBD risk was highest in rod and wire production workers; their air concentrations were highest. The area of wire annealing and pickling had the highest airborne beryllium concentrations and may have been a source of exposure of workers in other rod and wire processes nearby. During the wire annealing process, the formation and removal of a loose oxide scale could disperse beryllium into the air and onto surfaces in work areas. Bioavailability Several studies have shown that the solubility and toxicity of the beryllium oxide particles is inversely proportional to the temperature of calcination. To elucidate the role of solubility in the expression of beryllium toxicity, Finch et al. (1988) measured the dissolution kinetics of beryllium compounds calcined at different temperatures in either 0.1 N HCl or simulated serum ultrafiltrate (SUF). Beryllium oxide calcined at 500°C had 3.3 times greater SSA than beryllium oxide calcined at 1,000°C, even though there was no difference in size or structure of the particles as a function of calcination temperature. The beryllium-metal aerosol, although similar to the beryllium oxide aerosols in aerodynamic size, had an SSA about 30% that of the beryllium oxide calcined at 1,000°C. HCl increased the beryllium dissolution rate from what it was in SUF, and the beryllium oxide aerosol calcined at 500°C was more soluble than the 1,000°C-calcined aerosol in both solvents. The aerosols were much more soluble in HCl than in SUF over the 31-day study. Less than 10% of any of the beryllium forms dissolved in SUF, whereas more than 99% of the 500°C-calcined beryllium oxide aerosol, 50% of the 1,000°C-calcined beryllium oxide aerosol, and 64% of the beryllium-metal aerosol dissolved in HCl. On the basis of those data, the solubility constant (k, in grams per square centimeter-day) in SUF of beryllium metal, beryllium oxide calcined at 500°C, and beryllium oxide calcined at 1,000°C was estimated at (1.5 ± 0.8) × 10−9, (2.2 ± 0.5) × 10−9, and (3.7 ± 1.2) × 10−9, respectively. In a later study, beryllium oxide calcined at 1,000°C elicited little local pulmonary immune response, because of its low solubility, whereas the much more soluble beryllium oxide calcined at 500°C produced a beryllium-specific, cell-mediated immune response in dogs (Haley 1991). In a study of beryllium cellular dosimetry, Eidson et al. (1991) found that soluble beryllium sulfate was not taken up by beagle macrophages, whereas 60% of added insoluble beryllium oxide was taken up, with maximal uptake after 6 h. The uptake was independent of calcining temperature. About 22% of 500°C beryllium oxide dissolved within 48 h after addition to cell culture; 39% of cells died in that period. Dissolved beryllium remained associated with cells until a cytotoxic concentration was reached (2.2 × 10−5 M; 15 nmol of beryllium per 106 cells), at which time the beryllium was released into the medium. There was no significant dissolution of the 1,000°C beryllium oxide within 48 h and no significant cell death. The results indicate that beryllium dissolved from phagocytized beryllium oxide was more cytotoxic than soluble beryllium added extracellularly. Similar results were observed in a murine monocyte cell line (Day et al. 2005). At the cellular level, beryllium dissolution must occur for the macrophage to present beryllium as an antigen to induce the cell-mediated CBD immune reactions (Kreiss et al. 2007). In a phagolysosomal-simulating fluid with a pH of 4.5, dissolution of both beryllium metal and beryllium oxide was greater than that previously reported in water or SUF (Stefaniak et al. 2006), and the rate of dissolution for the multiconstituent arc-furnace particles was greater than that for the single-constituent beryllium oxide powder. The authors speculated that copper in the particles rapidly dissolves, exposing the small inclusions of beryllium oxide, which have higher SSA and therefore dissolve at a higher rate. The higher rate of dissolution of beryllium in the copper-beryllium alloy could increase the risk of CBD in workers exposed to these types of aerosols. Because an oxide layer may form on beryllium metal surfaces upon exposure to atmosphere (Mueller and Adolphson 1979), Harmsen et al. (1984) have suggested that a sufficient rate of dissolution
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Health Effects of Beryllium Exposure: A Literature Review of small amounts of poorly soluble beryllium compounds might occur in the lungs to allow persistent low-level beryllium presentation to the immune system. It is clear from these studies that more efforts are required to evaluate the role of intrapulmonary dissolution in beryllium-induced immune system stimulation and subsequent development of CBD. SUMMARY It is important to consider several exposure parameters in understanding the dose-response relationship between exposure to beryllium and the development of CBD. These parameters include airborne concentration, particle size, particle composition, and particle solubility. In addition, there is now evidence that skin exposure is probably an important contributor to sensitization. Thus, in the second report, the committee will focus its attention on characterizing inhalation and skin exposure contributions to risk of BeS and CBD, and whether differences in the physiochemical properties and bioavailability of beryllium compounds warrant the development of different chronic inhalation exposure levels for different beryllium compounds.
Representative terms from entire chapter: