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IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Arsenic, Metals, Fibres and Dusts. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 100C.)

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Arsenic, Metals, Fibres and Dusts.

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BERYLLIUM AND BERYLLIUM COMPOUNDS

Beryllium and beryllium compounds were considered by previous IARC Working Groups in 1971, 1979, 1987, and 1993 (IARC, 1972, 1980, 1987, 1993). Since that time, new data have become available, these have been incorporated in the Monograph, and taken into consideration in the present evaluation.

1. Exposure Data

1.1. Identification of the agents

Synonyms and molecular formulae for beryllium, beryllium–aluminium and beryllium–copper alloys, and certain beryllium compounds are presented in Table 1.1. The list is not exhaustive, nor does it comprise necessarily the most commercially important beryllium-containing substances; rather, it indicates the range of beryllium compounds available.

Table 1.1. Chemical names (CAS names are in italics), CAS numbers, synonyms, and molecular formulae of beryllium and beryllium compounds.

Table 1.1

Chemical names (CAS names are in italics), CAS numbers, synonyms, and molecular formulae of beryllium and beryllium compounds.

1.2. Chemical and physical properties of the agents

Beryllium (atomic number, 4; relative atomic mass, 9.01) is a metal, which belongs to Group IIA of the Periodic Table. The oxidation state of beryllium compounds is +2. Selected chemical and physical properties of beryllium, beryllium–aluminium and beryllium–copper alloys, and various beryllium compounds can be found in the previous IARC Monograph (IARC, 1993).

Beryllium is the lightest of all solid chemically stable substances, and has an unusually high melting-point. It has a very low density and a very high strength-to-weight ratio. Beryllium is lighter than aluminium but is greater than 40% more rigid than steel. It has excellent electrical and thermal conductivities. Its only markedly adverse feature is relatively pronounced brittleness, which restricts the use of metallic beryllium to specialized applications (WHO, 1990).

Because of its low atomic number, beryllium is very permeable to X-rays. Neutron emission after bombardment with α or γ rays is the most important of its nuclear physical properties, and beryllium can be used as a neutron source. Moreover, its low neutron absorptiveness and high-scattering cross-section make it a suitable moderator and reflector in structural materials in nuclear facilities; where most other metals absorb neutrons emitted during the fission of nuclear fuel, beryllium atoms only reduce the energy of such neutrons, and reflect them back into the fission zone (Ballance et al., 1978; Newland, 1984; WHO, 1990).

The chemical properties of beryllium differ considerably from those of the other alkaline earths, but it has several chemical properties in common with aluminium. Like aluminium, beryllium is amphoteric and shows very high affinity for oxygen; on exposure to air or water vapour, a thin film of beryllium oxide forms on the surface of the bare metal, rendering the metal highly resistant to corrosion, to hot and cold water, and to oxidizing acids (Newland, 1984; Petzow et al., 1985; WHO, 1990).

1.3. Use of the agents

Beryllium is primarily used in its metallic form, in alloys, or in beryllium oxide ceramics. Its physical and mechanical properties make it useful for many applications across a range of industries. These properties include: outstanding strength (when alloyed), high melting-point, high specific heat, excellent thermal properties, electrical conductivity, reflectivity, low neutron absorption, and high neutron-scattering cross-sections, and transparency to X-rays (WHO, 1990; USGS, 2007).

Industries using beryllium and beryllium products include: aerospace (e.g. altimeters, braking systems, engines, and precision tools), automotive (e.g. air-bag sensors, anti-lock brake systems, steering wheel connecting springs), biomedical (e.g. dental crowns, medical laser components, X-ray tube windows), defence (e.g. heat shields, missile guidance systems, nuclear reactor components), energy and electrical (e.g. heat exchanger tubes, microwave devices, relays and switches), fire prevention (e.g. non-sparking tools, sprinkler system springs), consumer products (e.g. camera shutters, computer disk drives, pen clips), manufacturing (e.g. plastic injection moulds), sporting goods (e.g. golf clubs, fishing rods, naturally occurring and man-made gemstones), scrap recovery and recycling, and telecommunications (e.g. mobile telephone components, electronic and electrical connectors, undersea repeater housings) (Kreiss et al., 2007).

1.3.1. Beryllium metal

Some typical applications of beryllium metal include: aerospace technology (structural material, inertia guidance systems, additives in solid propellant rocket fuels, aircraft brakes, mirror components of satellite optical systems, gyroscopes), nuclear technology (moderator and reflector of neutrons in nuclear reactors, neutron source when bombarded with α particles), X-ray and radiation technology (special windows for X-ray tubes), computer technology and alloys (e.g. beryllium–copper alloys; hardening of copper, and developmental brass alloys) (WHO, 1990; Petzow et al., 2007).

1.3.2. Beryllium-containing alloys

Approximately 75% of manufactured beryllium is used in alloys, 95% of which is copper alloy (Jakubowski & Palczynski, 2007). Because of the properties it confers on other metals (i.e. low density combined with strength, high melting-point, resistance to oxidation, and a high modulus of elasticity), beryllium alloys are light-weight materials that can withstand high acceleration and centrifugal forces (WHO, 1990). Beryllium–copper alloys are commonly used in the electronics (e.g. switch and relay blades, electronic connector contacts, control bearings, magnetic sensing device housings, and resistance welding systems), automotive (e.g. air-bag sensors), military (e.g. electro-targeting and infrared countermeasure devices, missile systems, advanced surveillance satellites, and radar systems), and aerospace industries (e.g. landing gear bearings, weather satellites). Other applications include computers, oil exploration equipment, medical appliances, sporting equipment (e.g. golf clubs), and non-sparking tools (e.g. in petroleum refineries) (WHO, 1990; Kaczynski, 2004; Jakubowski & Palczynski, 2007).

1.3.3. Beryllium oxide

The ceramic properties of sintered beryllium oxide make it suitable for the production or protection of materials to be used at high temperatures in corrosive environments. It is used in lasers and electronics (e.g. transistor mountings, semiconductor packages, microelectronic substrates, microwave devices, high-powered laser tubes), in aerospace and military applications (e.g. gyroscopes and armour), refractories (e.g. thermocouple sheaths and crucibles), nuclear technology (reactor fuels and moderators), and medical/dental applications (e.g. ceramic crowns). It is also used as an additive (to glass, ceramics, and plastics) in the preparation of beryllium compounds, and as a catalyst for organic reactions (WHO, 1990; Taylor et al., 2003).

1.3.4. Other beryllium compounds

Other important beryllium compounds include the beryllium halides (beryllium chloride and beryllium fluoride), beryllium hydroxide, and beryllium sulfate. Beryllium chloride has been used as a raw material in the electrolytic production of beryllium, and as the starting material for the synthesis of organo-beryllium compounds (O’Neil, 2006; Petzow et al., 2007). Beryllium fluoride is used as an intermediate in the preparation of beryllium and beryllium alloys. It is used in nuclear reactors and glass manufacture, and as an additive to welding and soldering fluxes (O’Neil, 2006; Petzow et al., 2007). Beryllium hydroxide is used as an intermediate in the manufacture of beryllium and beryllium oxide (O’Neil, 2006). Beryllium sulfate tetrahydrate is used as an intermediate in the production of beryllium oxide powder for ceramics (Kaczynski, 2004).

1.4. Environmental occurrence

Beryllium occurs naturally in the earth’s crust, and is released in the environment as a result of both natural and anthropogenic activities. The environmental occurrence of beryllium has been reviewed extensively (WHO, 1990; ATSDR, 2002; Taylor et al., 2003).

1.4.1 Natural occurrence

The 44th most abundant element in the earth’s crust, beryllium occurs in rocks and minerals (mica schist, granite, pegmatite, and argillite), although the most highly enriched beryllium deposits are found in granitic pegmatites, in which independent beryllium minerals crystallize. Some 50 beryllium-containing minerals have been identified. Only ores containing beryl (3BeO.Al2O3.6SiO2) and bertrandite (4BeO.2SiO2.H2O) have achieved economic significance. The average terrestrial abundance of beryllium is 2–5.0 mg/kg. (IARC, 1993; Jakubowski & Palczynski, 2007; USGS, 2007).

1.4.2 Air

Beryllium particulates are released in the atmosphere from both natural and anthropogenic sources. Windblown dust is the most important natural source of atmospheric beryllium (approximately 95%), with volcanic activity accounting for the remainder. The major anthropogenic source of atmospheric beryllium is the combustion of coal and fuel oil. Other sources include: municipal waste incineration, beryllium alloy and chemical use (includes ore processing, production, use and recycling), and the burning of solid rocket fuel (WHO, 2001; ATSDR, 2002). Ambient concentrations of atmospheric beryllium are generally low. Based on measurements at 100 locations, an average daily concentration of less than 0.5 ng/m3 was reported in the United States of America (Jakubowski & Palczynski, 2007). Atmospheric concentrations of beryllium in the vicinity of beryllium-processing plants are often higher than those measured elsewhere (IARC, 1993).

1.4.3 Water

Beryllium is released in the aquatic environment from both natural and anthropogenic sources. Weathering of beryllium-containing rocks and soils is the primary source of release, although leaching of coal piles may also contribute to beryllium entering surface water. Anthropogenic sources include industrial waste water effluents (e.g. from electric utility industries). The deposition of atmospheric fall-out (of anthropogenic and natural sources) is also a source of beryllium in surface waters. However, the relative importance of this contribution to aquatic concentrations of beryllium is difficult to assess (ATSDR, 2002).

Beryllium concentrations in surface waters are usually in the range of 0.01–0.1 μg/L (WHO, 1990). The concentration of beryllium in deep ocean waters tend to be fairly uniform worldwide, and are estimated to be approximately three orders of magnitude lower than that of surface river water (Jakubowski & Palczynski, 2007). Beryllium concentrations in drinking-water are on average 0.19 μg/L, with a range of 0.01–1.22 μg/L (Kolanz, 2001).

1.5. Human exposure

1.5.1. Exposure of the general population

The primary route of beryllium exposure for the general population is via the ingestion of contaminated food or water. The daily intake of beryllium by non-occupationally exposed persons in the USA from drinking-water is estimated to be 1 μg per day (assuming an average concentration of 0.5 μg/L, and a drinking-water consumption rate of 2 L/day). In the 1980s, the Environmental Protection Agency in the USA estimated the daily intake of beryllium in food to be approximately 0.12 μg per day (based on an arbitrary value of 0.1 ng beryllium per gram of food, and an assumption that a normal adult consumes 1200 g of food per day). Other studies have estimated the daily intake of beryllium in food to be in the range of 5–100 μg per day (ATSDR, 2002).

The inhalation of beryllium via ambient air or smoking is considered to be a minor exposure route for the general population. Assuming an average airborne concentration of less than 0.03 ng/ m3 beryllium per day, and a breathing rate of 20 m3 of air per day, the estimated daily intake for an adult in the USA is approximately 0.6 ng of beryllium, or less, per day. This estimated intake is likely to be higher for for persons living near point sources of beryllium emission (ATSDR, 2002).

1.5.2 Occupational exposure

The occupational environment is the predominant source of beryllium exposure for humans. Inhalation of beryllium dust and dermal contact with beryllium-containing products are the main routes of occupational exposure, although there may be the potential for in-home exposure if contaminated work garments are worn at home (ATSDR, 2002; NTP, 2004). Industries using or producing beryllium include: aerospace; automotive; biomedical; defence; energy and electrical; fire prevention; instruments, equipment and objects; manufacturing; sporting goods and jewellery; scrap recovery and recycling; and telecommunications (Kreiss et al., 2007).

Based on data obtained from the primary beryllium industry and government agencies, Henneberger et al. (2004) estimated that 134000 workers were potentially exposed to beryllium in the USA (1500 in the primary beryllium industry, 26500 in the Department of Energy or Department of Defence, and between 26400 and 106000 in the private sector, outside of the primary industry). This figure may be an underestimate because of the limited data on potential beryllium exposures in military and nuclear weapons workplaces, and in many others where beryllium is a minor or unsuspected component (e.g. aluminium smelting, scrap recovery, and electronics recycling). The number of workers in the USA ever exposed to beryllium is likely to be far higher than 134000, as it does not include approximately 250000 construction workers that are employed at nuclear weapons reclamation sites alone (Kreiss et al., 2007).

Estimates of the number of workers potentially exposed to beryllium and beryllium compounds have been developed by CAREX in Europe. Based on occupational exposure to known and suspected carcinogens collected during 1990–93, the CAREX (CARcinogen EXposure) database estimates that 66069 workers were exposed to beryllium and beryllium compounds in the European Union, with over 80% of workers employed in the manufacture of machinery, except electrical (n = 38543); manufacture of fabricated metal products except machinery and equipment (n = 5434); manufacture of electrical machinery, apparatus and appliances (n = 4174); manufacture of professional, scientific, measuring and controlling equipment not elsewhere classified (n = 3708); and manufacture of transport equipment (n = 3328). CAREX Canada estimates that 4000 Canadians (86% male) are exposed to beryllium in their workplaces (CAREX Canada, 2011). These industries include: building equipment contractors, medical equipment and supplies manufacturing, residential building construction, motor vehicle parts manufacture, automotive repair and maintenance, non-residential building construction, commercial/industrial machinery repair and maintenance, architectural and structural metals manufacturing.

Data on early occupational exposures to beryllium were summarized in the previous IARC Monograph (IARC, 1993), and data from studies on beryllium exposure published since are summarized below.

(a) Processing and manufacturing

Sanderson et al. (2001a) investigated historical beryllium exposures in a beryllium-manufacturing plant in the USA during 1935–92 for the purpose of reconstructing exposures for an epidemiological study. Daily weighted average (DWA) exposure estimates ranged from 1.7–767 μg/m3 for 1935–60; 1.0–69.9 μg/m3 for 1961–70; 0.1–3.1 μg/m3 for 1971–80; and 0.03–1.4 μg/m3 for 1981–92 (range of geometric means).

Seiler et al. (1996a, b) investigated historical beryllium exposure data (n = 643) collected in five beryllium-processing facilities in the USA during 1950–75. Descriptive data for representative job titles in November 1974 indicated that DWA beryllium exposures ranged from a minimum of 0.3 μg/m3 for a ceramics machine operator to a maximum of 111.4 μg/m3 for a vacuum cast furnace operator. Approximately 73% of the maximum breathing zone DWA exposures exceeded the 2 μg/m3 standard; only 18% of the general air DWA beryllium exposures exceeded the standard.

Deubner et al. (2001a) analysed 34307 airborne beryllium measurements (general air, breathing zone, and personal lapel) collected during 1970–99 at a beryllium mining and extraction facility in Delta, UT, USA, and compared them to a mixed beryllium products facility and a beryllium ceramics facility located in Elmore, OH and Tucson, AZ, respectively. DWAs (n = 1519) were calculated to estimate task-specific, time-weighted average (TWA) exposures for workers at the Delta facility. The general area and breathing zone sampling data indicated that average annual beryllium concentrations at the Delta plant declined over the study period. The range of annual median general area sample concentrations at the mining and milling plant was comparable to that at the beryllium ceramics facility (0.1–0.6 μg/m3 versus 0.1–0.4 μg/m3, respectively). These data were lower than those observed at the mixed beryllium products facility (range of annual median general area sample concentrations, 0.1–1.0 μg/m3). At the mining and milling facility, the highest exposures were observed in jobs involving beryllium hydrolysis and wet-grinding activities. This observation was independent of the exposure assessment method used.

Kreiss et al. (1997) analysed 106218 airborne beryllium measurements collected during 1984–93 at a beryllium-manufacturing plant producing pure metal, oxide, alloys, and ceramics. Of these, 90232 were area samples (30-minute samples: n = 30872; full-shift, continuous samples: n = 59360), and 15986 were personal samples (1–15 minute breathing zone samples: n = 15787; full-shift personal lapel samples: n = 179). Using these data, DWA exposures were calculated for most jobs. Median area concentrations were 0.6 μg/m3 and 0.4 μg/m3 for full-shift and short-term samples, respectively. Median personal concentrations were 1.4 μg/m3 and 1.0 μg/m3 for short-term and full-shift samples, respectively. The highest median area concentrations were observed in the alloy arc furnace and alloy melting-casting areas, and the highest median breathing zone concentrations were observed in the beryllium powder and laundry areas.

Kent et al. (2001) collected full-shift particle-size-specific personal samples (n = 53) and area samples (n = 55) in five furnace areas at a beryllium-manufacturing facility. Personal samples were collected with Anderson impactors and general area samples were collected with micro-orifice uniform deposit impactors (MOUDIs). The median total mass concentration of beryllium particles (in μg/m3) was reported by work process area and particle size. Median personal aerosol concentrations ranged from 0.8−5.6 μg/m3 for total particle mass, and 0.05−0.4 μg/m3 for alveolar-deposited particle mass. Median area concentrations ranged from 0.1−0.3 μg/m3 for total particle mass, and 0.02−0.06 μg/m3 for alveolar-deposited particle mass.

(b) Beryllium oxide ceramics

As part of a study to examine the relationship between sensitization and beryllium exposure in a beryllium ceramics plant in the USA, Kreiss et al. (1996) reviewed all general area (n = 5664) and personal breathing zone (n = 4208) samples collected during 1981–92. Of the area samples collected, 14% (n = 774) were full-shift samples collected from 1983 onwards; of the personal breathing zone samples, 1.7% (n = 75) were full-shift samples collected from 1991 onwards. Using average general area, full-shift area and breathing zone measurements, DWA exposures for most occupations were calculated. Of the full-shift area samples, 76% were reported to be at or below the detection limit of 0.1 μg/m3. The median general area concentration was at or below the detection limit, with measured concentrations ranging as high as 488.7 μg/m3. Median personal breathing zone concentrations were 0.3 μg/m3 (maximum, 1931 μg/m3) and 0.20 μg/m3 (range, 0.1−1.8 μg/m3) for the short-term and full-shift samples, respectively. Machinists were observed to have the highest exposures, with breathing zone concentrations of 63.7 μg/m3, and a median DWA exposure of 0.9 μg/m3.

Henneberger et al. (2001) conducted a follow-up to the Kreiss et al. (1996) study, screening workers at a US beryllium ceramics plant to determine whether the plant-wide prevalence of beryllium sensitization and disease had declined in the 6-year interval since first screening, and to explore exposure–response relationships. Historical airborne beryllium measurements (task- and time-specific) were combined with individual work histories to compute worker-specific beryllium exposures (mean, cumulative, and peak). A total of 18903 beryllium measurements were collected during 1981–98, of which 43% were short-term (1–15 minute), task-specific personal breathing zone samples, and 57% were short-term (30 minute) general area samples. Mean calculated exposures for all workers ranged from 0.05 μg/m3 (i.e. less than the limit of detection) to 4.4 μg/m3. When duration of employment was taken into account, short-term workers (i.e. those hired since the previous survey) had lower mean (median value: 0.28 μg/m3 versus 0.39 μg/m3) and peak concentrations (median value: 6.1 μg/m3 versus 14.9 μg/m3) than long-term workers.

Cummings et al. (2007) conducted a follow-up study in the same beryllium oxide ceramics manufacturing facility considered by Henneberger et al. (2001) to assess the effectiveness of an enhanced preventive programme to reduce beryllium sensitization. Sensitization for newly hired workers was compared with that for workers hired from 1993–98, and tested in the 1998 survey. Full-shift personal exposure data collected by the facility from 1994–2003 (n = 1203 measurements) was grouped into two time periods (1994–99 and 2000–03), and three work categories (production, production support, and administration). For the period 1994–99, median beryllium levels were 0.20 μg/m3, 0.10 μg/m3, and less than the limit of detection in production, production support and administration, respectively (n = 412, full-shift personal lapel samples). For the later period, median beryllium levels were 0.18 μg/m3, 0.04 μg/m3, and 0.02 μg/m3 in production, production support, and administration, respectively (n = 791, full-shift personal lapel samples).

(c) Machining and use

Martyny et al. (2000) conducted particle-size selective sampling on five mechanical processes (milling, deburring, lapping, lathe operations, and grinding) to examine the particle size distribution of beryllium machining exposures. Two sets of stationary samples were collected using Lovelace Multijet Cascade Impactors mounted to the machines at ‘point of operation’ and at ‘nearest worker location’, two sets of personal samples were collected in the breathing zone of workers operating the machines (one personal pump-powered lapel sampler, one personal cascade impactor), as well as ambient air samples from four fixed locations in the facility. In total, 336 measurements were collected (79 personal pump samples, 87 personal impactor samples, 71 nearest worker location samples, 87 point of operation samples, and 12 ambient air samples. Of these, 243 were samples of the five target processes (64 personal pump samples, 59 personal impactor samples, 64 nearest worker location samples, and 56 point of operation samples). For the stationary area samples, median TWA concentrations were in the range of 0.20 μg/m3 for the ‘nearest worker location’ samples to 0.60 μg/m3 for the ‘point of operation’ samples. For the personal breathing zone samples (collected by the personal impactors), median TWA concentrations were in the range of 0.13 μg/m3 for lapping processes to 0.74 μg/m3 for deburring operations. The range of 48-hour median ambient concentration was 0.02−0.07 μg/m3.

To evaluate the effectiveness of a beryllium exposure control programme at an atomic weapons facility in Wales, United Kingdom, Johnson et al. (2001) analysed 585438 air monitoring records (367757 area samples collected at 101 locations, and 217681 personal lapel samples collected from 194 workers during 1981–97). Across all departments, the range of annual personal concentrations was 0.11−0.72 μg/m3 (mean) and 0.08−0.28 μg/m3 (median). The highest levels of exposure were observed in foundry workers, with a mean exposure level of 0.87 μg/m3 and a median exposure level of 0.22 μg/m3 (over all years). For the area samples, mean annual concentrations ranged from a high of 0.32 μg/m3 in 1985 to a low of 0.02 μg/m3 in 1997.

(d) Alloy facilities

Schuler et al. (2005) analysed airborne beryllium measurements collected in 1969–2000 at a beryllium–copper alloy strip and wire finishing facility. Of the 5989 available measurements, 650 were personal samples, 4524 were general area samples, and 815 were short-duration, high-volume (SD-HV) breathing zone samples. Data were grouped and analysed on the basis of work category (production, production support, administration), and by process or job within each work category. For example, ‘rod and wire’ production is a subcategory of ‘production’; jobs within ‘rod and wire’ production include: wire annealing and pickling, wire drawing, straightening, point and chamfer, rod and wire packing, die grinding, and, historically, wire rolling. Median plant-wide exposure levels were 0.02 μg/m3 (personal), 0.09 μg/m3 (general area), and 0.44 μg/m3 (SD-HV breathing zone). Among work categories, the highest levels of beryllium exposure were found in ‘rod and wire’ production (median, 0.06 μg/m3), with the most highly exposed process or job being ‘wire annealing and pickling’ (median, 0.12 μg/m3).

In a study in a beryllium alloy facility, Day et al. (2007) measured levels of beryllium in workplace air (n = 10), on work surfaces (n = 252), on cotton gloves worn over nitrile gloves (n = 113), and on necks and faces of workers (n = 109). In production, geometric mean levels of beryllium were 0.95 μg/100 cm2 (work surfaces), 42.8 μg per sample (cotton gloves), 0.07 μg per sample (necks), and 0.07 μg per sample (faces). In production support, geometric mean levels of beryllium were 0.59 μg/100 cm2 (work surfaces), 73.8 μg per sample (cotton gloves), 0.09 μg per sample (necks), and 0.12 μg per sample (faces). The lowest levels were measured in the administration section, with geometric mean levels of beryllium of 0.05 μg/100 cm2 (work surfaces), 0.07 μg per sample (cotton gloves), 0.003 μg per sample (necks), and 0.003 μg per sample (faces). Strong correlations were observed between beryllium in air and on work surfaces (r = 0.79), and between beryllium on cotton gloves and on work surfaces (r = 0.86), necks (r = 0.87), and faces (r = 0.86).

Yoshida et al. (1997) studied airborne beryllium levels at two beryllium–copper alloy manufacturing factories in Japan during 1992–95. General area samples were collected in the beryllium–copper alloy process (n = 56) and the beryllium–copper metal mould manufacturing process (n = 41) of Factory A, and in the beryllium–copper cold rolling, drawing and heat-treatment process (n = 16) and beryllium–copper slitting treatment process (n = 8) of Factory B. In all years studied, the highest geometric mean beryllium levels were observed in the beryllium–copper alloy process of Factory A (range, 0.16–0.26 μg/m3).

Stanton et al. (2006) studied beryllium exposures among workers at three beryllium–copper alloy distribution centres in the USA in 2000–01. For the period 1996–2004, company records of full-shift personal lapel breathing zone samples for airborne beryllium (n = 393) were examined. A total of 54% of all samples were at or below the limit of detection. The overall median beryllium concentration was 0.03 μg/m3 (arithmetic mean, 0.05 μg/m3). When examined by work category (production – bulk products, production – strip metal, production support, administration) and process or job within work category, concentration ranges were 0.01–0.07 μg/m3 (median), and 0.02–0.07 μg/m3 (geometric mean). The highest concentrations were measured in heat-treating (bulk products) and tensioning (strip metal) processes, with levels of 1.6 μg/m3 and 1.4 μg/m3, respectively.

(e) Nuclear facilities

Stange et al. (1996a) studied beryllium exposures in the Rocky Flats Nuclear Facility in the USA. Fixed airhead (i.e. area) samples (n = 102) and personal breathing zone samples (n = 102) were collected from the main beryllium production building. The mean beryllium concentration from the area samples was 0.16 μg/m3, and from the personal samples, 1.04 μg/m3. No correlation (r2 = 0.029) was observed between fixed airhead and personal breathing zone beryllium samples.

Stefaniak et al. (2003a) investigated historical beryllium exposure conditions at the Los Alamos Nuclear Laboratory in the USA. A total of 4528 personal breathing zone and area samples were analysed. For all technical areas, the geometric mean concentration for the period 1949–89 was 0.04 μg/m3. Average beryllium concentrations per decade were less than 1 μg/m3, and annual geometric mean concentrations in the area that was the largest user of beryllium were generally below 0.1 μg/m3.

(f) Other

Meeker et al. (2006) compared occupational exposures among painters using three alternative blasting abrasives (specular hematite, coal slag, steel grit) on a footbridge painting project during 2002–04 in New Jersey, USA. Over the 3-year project, personal breathing zone samples were collected outside the respirators of two or three abrasive blasters. The range of beryllium concentrations measured outside personal protective equipment (n = 18 samples) was 2.5−9.5 μg/m3, with a geometric mean exposure level of 5.0 μg/m3. Beryllium was also measured in bulk paint chips collected from each bridge.

Bauxite, from which aluminium is derived, may contain beryllium in varying degrees. In 965 personal samples collected during 2000–05 in four aluminium smelters, beryllium concentrations varied in the range of 0.002–13.0 μg/m3 (arithmetic and geometric means were 0.22 and 0.05 μg/m3, respectively) (Taiwo et al., 2008).

1.5.3 Dietary exposure

There is a lack of reliable data on the concentration of beryllium in food (WHO, 1990; ATSDR, 2002). Measured concentrations of beryllium have been reported for 38 foods, fruit and fruit juices from around the world (number of samples, 2243; 2209 foods + 34 fruit and juices). Concentrations in the foods have been reported in the range of < 0.1–2200 μg/kg fresh weight, with the highest concentrations measured in kidney beans, crisp bread, garden peas, parsley and pears (2200, 112, 109, 77, and 65 μg/kg fresh weight, respectively), and with a median concentration of 22.5 μg/kg fresh weight (kidney beans were excluded from this calculation). Concentrations in the fruits and juices ranged from not detected to 74.9 μg/L, with an average concentration of 13.0 μg/L (ATSDR, 2002). Beryllium has also been measured in rice, head lettuce, and potatoes at 80 μg/kg, 330 μg/kg, and 0.3 μg/kg, respectively (Kolanz, 2001).

1.5.4 Biomarkers of exposure

Several analytical methods are available and have adequate sensitivity for measuring beryllium in biological samples. These include gas chromatography-electron capture (GC-ECD), graphite furnace atomic absorption spectrometry (GF-AAS), inductively coupled plasma atomic emission spectrometry (ICP-AES), and inductively coupled plasma mass spectrometry (ICP-MS). Biological matrices in which these methods can measure beryllium include: blood, urine, faeces, fingernails, hair, and lung tissue. Urinary beryllium is an indicator of current exposure, but is of uncertain utility for quantitative exposure assessment. Beryllium levels in blood, serum or plasma are indicators of the intensity of current exposure (ATSDR, 2002; NTP, 2004; NRC 2007).

The average burden of beryllium in the general population is 0.20 mg/kg in the lung and is below 0.08 mg/kg in other organs (Kolanz, 2001).

The mean concentration of beryllium in urine measured in about 500 non-occupationally exposed individuals in the USA during the Third National Health and Nutrition Examination Survey (NHANES III) was 0.22 μg/g of creatinine (Paschal et al., 1998). Other studies reported mean urinary beryllium concentrations in the range of < 0.03–0.4 μg/L for non-occupationally exposed individuals (Apostoli & Schaller, 2001).

2. Cancer in Humans

The previous IARC Monograph on beryllium and beryllium compounds was based largely on evidence of elevated lung cancer mortality among 689 individuals (predominantly workers) entered into the US Beryllium Case Registry (Steenland & Ward, 1991; Table 2.1 available at http://monographs.iarc.fr/ENG/Monographs/vol100C/100C-02-Table2.1.pdf), and in a cohort of 9225 workers employed at seven beryllium-processing plants in the USA (Ward et al., 1992). The cohort study included two plants that had been previously studied (Mancuso, 1979, 1980; Wagoner et al., 1980) and Infante et al. (1980) had reported earlier on mortality in the Beryllium Case Registry cohort.

2.1. Cohort studies and nested case–control studies

The body of evidence available for the current evaluation of the carcinogenicity of beryllium in humans includes the two previously evaluated cohort studies and a nested case–control study initially reported by Sanderson et al. (2001b), and reanalysed with adjustment for temporal confounders by Schubauer-Berigan et al. (2008).

The Beryllium Case Registry study included 689 individuals entered alive into the registry and followed for mortality through to 1988 (Steenland & Ward, 1991); 34% were from the fluorescent tube industry, and 36% were from basic manufacturing. There were 158 deaths from pneumoconiosis and other respiratory disease, the category that included beryllium disease (Standard Mortality Ratio [SMR], 34.2; 95%CI: 29.1–40.0). The overall SMR for lung cancer was 2.00 (95%CI: 1.33–2.89), based on 28 deaths. Among those with acute beryllium disease, there were 17 lung cancer deaths (SMR 2.32; 95%CI: 1.35–3.72), and among those with chronic beryllium disease, ten lung cancer deaths (SMR 1.57; 95%CI: 0.75–2.89).

The cohort study included workers at seven beryllium-processing plants in the USA involved in various phases of beryllium processing with exposure to many forms of beryllium and beryllium compounds (Ward et al., 1992). The study found a significantly elevated SMR of 1.26 (95%CI: 1.12–1.42) for lung cancer in the cohort overall, with significant excesses observed for the two oldest plants located in Lorain, Ohio, and Reading, Pennsylvania.

The SMR for lung cancer at the Lorain plant was 1.69 (95%CI: 1.28–2.19), and at the Reading plant, 1.24 (95%CI: 1.03–1.48). The Lorain plant, in operation during 1935–48, is thought to have had very high beryllium exposures. The majority of workers (84.6%) were employed for less than 1 year. Ninety-eight of the 1192 individuals employed at the Lorain plant (8.2%) were identified in the Beryllium Case Registry as having beryllium disease; 91 were of the acute form which has only been associated with very high beryllium exposure, six individuals had chronic beryllium disease, and one was of unknown type. A total of 11 lung cancer deaths occurred among the 98 individuals with beryllium disease (SMR, 3.33; 95%CI: 1.66–5.95), and 46 lung cancer deaths occurred among the remaining 1094 Lorain workers (SMR, 1.51; 95%CI: 1.11–2.02). All but one of the 57 lung cancer deaths occurred in latency categories < 15 years; for 15–30 years’ latency, the SMR was 2.09 [95%CI: 1.30–3.21]; and for over 30 years’ latency, 1.66 [95%CI: 1.16–2.31].

The plant in Reading, Pennsylvania, in operation during 1935–2001, employed 3569 workers during 1940–69. Among those, 53.8% were employed for less than 1 year, and only 17.2% were employed for more than 10 years. When the SMRs for lung cancer at the Reading plant were analysed by latency and duration of exposure, the highest SMR was observed for the category with less than 1 year of employment and duration and more than 30 years’ latency (SMR = 1.42; [95%CI: 1.01–1.93]). Further analyses by decade of hire revealed that 92/120 lung cancer deaths occurred among workers hired before 1950 (SMR, 1.26; [95%CI: 1.02–1.55]). None of the newer plants included in the study had a significantly elevated SMR for lung cancer. However, non-significantly elevated SMRs were observed for four out of five plants operating in the 1950s for workers hired during that decade. The results were adjusted for smoking based on comparing smoking histories of 1466 (15.9%) of cohort members surveyed in 1968 with a survey of the US population conducted in 1965, resulting in SMRs of 1.12, 1.49 and 1.09 for the total cohort, the Lorain plant, and the Reading plant, respectively. [The Working Group noted that it is unclear that adjustment for differences in smoking patterns between cohort members and the US population in the late 1960s would accurately reflect patterns in the 1940s that would be most relevant to interpreting the lung cancer excess. It is possible that using data from the 1960s would overestimate the impact of smoking.] SMRs based on county referent rates were also presented and for the cohort as a whole, the SMR was slightly increased to 1.32, the SMR declined for the Lorain plant to 1.60, and increased for the Reading plant to 1.42.

Subsequent to the publication of the Ward et al. (1992) study, the Beryllium Industry Scientific Advisory Committee suggested that the excess of lung cancer observed at the Lorain plant might be attributable to exposure to sulfuric acid mist and fumes rather than exposure to beryllium (BISAC, 1997). A reanalysis of the cohort study used alternative referent rates (for cities in which the two oldest plants were located) to compute expected number of lung cancers, alternative smoking risk factor estimates to adjust for differences in smoking habits between the cohort and the US population, and an alternative methodology to calculate the SMR for all plants combined (Levy et al., 2002). The net effect of the reanalysis was to reduce the magnitude and statistical significance of the SMRs in the Ward et al. (1992) study. [The Working Group noted that there are several potential methodological limitations of this reanalysis. For instance, the city referent rates used for the calculation were not published, whereas Ward et al. (1992) used only published rates.]

Sanderson et al. (2001b) conducted a nested case–control study of lung cancer within one of the beryllium processing plants studied by Ward et al. (1992). This plant was selected for study because it was one of the two older plants in which an elevated lung cancer SMR was observed, and because industrial hygiene measurement data were available from as early as 1947. Details of the job–exposure matrix are provided in Sanderson et al. (2001a). Mortality was followed-up through 1992, and 142 lung cancer cases were identified. Cases were age- and race-matched to five controls through incidence-density sampling (Sanderson et al., 2001b). The main findings of the Sanderson et al. (2001b) study were positive associations with average and maximum exposure lagged 10 and 20 years. This association did not appear to be confounded by smoking in an analysis that excluded professional workers.

Following some letters and critiques of the Sanderson et al. (2001b) study (Deubner et al., 2001b, 2007; Sanderson et al., 2001c; Levy et al., 2007), a reanalysis of the study was carried out that adjusted for year of birth and an alternative minimal exposure value (the lowest detectable exposure level divided by two) in continuous exposure–response analyses (Schubauer-Berigan et al., 2008; see Table 2.2 available at http://monographs.iarc.fr/ENG/Monographs/vol100C/100C-02-Table2.2.pdf). After controlling for year of birth, significantly elevated odds ratios for 10-year lagged average beryllium exposure were found in the middle two exposure quartiles. The choice of an alternative minimal exposure value decreased the trend statistic for cumulative exposure but increased it for average exposure. In the continuous analysis of average 10-year lag dose, the parameter estimates and P-values were highly significant with control for year of birth. [The Working Group noted that several methodological articles were published regarding the incidence-density sampling methods used in the nested case–control study (Deubner & Roth, 2009; Hein et al., 2009; Langholz & Richardson, 2009; Wacholder, 2009). Three of these articles affirmed the methodology used to select controls in the study (Hein et al., 2009; Langholz & Richardson, 2009; Wacholder, 2009). The Working Group noted that the issues raised in the Deubner & Roth (2009) commentary did not undermine confidence in the results of the Schubauer-Berigan et al. (2008) reanalysis.]

2.2. Synthesis

A large body of evidence was evaluated by the Working Group and, in conclusion, elevated lung cancer mortality was observed in a study of individuals with beryllium disease and in a cohort study of workers at seven beryllium-processing plants. The association of the elevated lung cancer risks with beryllium exposure is supported by a large number of lung cancer cases and stable rate ratios, a consistency in findings among plants, higher risks of lung cancer among workers hired before 1950 (when exposures were at their highest), a greater risk of lung cancer in the US Beryllium Case Registry cohort (especially among those highly exposed who were diagnosed with acute pneumonitis), and greatest risks for lung cancer in the plants with the highest risk for acute pneumonitis and other respiratory disease. In addition, the nested case–control studies found evidence for an exposure–response relationship that was strongest when using the 10-year lag average-exposure metric. All of the epidemiological studies involved potential exposure to metallic beryllium as well as other beryllium compounds, and were unable to discern the specific effects of beryllium metal or specific beryllium compounds.

3. Cancer in Experimental Animals

Beryllium compounds have been tested for carcinogenicity by inhalation in rats and mice, by intratracheal or intrabronchial administration in rats, by intravenous administration to rabbits, by intraperitoneally administration to mice, and by intramedullary bone administration in rabbits.

To date, by all routes of exposure and in all species tested, all beryllium compounds examined have been shown to be carcinogenic (IARC, 1993).

3.1. Inhalation exposure

3.1.1. Mouse

In p53 heterozygous mice, lung tumours occurred after a single series of three consecutive daily inhalation exposures to beryllium metal (Finch et al., 1998a).

3.1.2. Rat

The first inhalation study published on beryllium was with beryllium sulfate in rats, which induced lung tumours and chronic lung disease (Schepers et al., 1957). Inhalation of single doses of beryllium metal (Nickell-Brady et al., 1994), and exposure to beryllium sulfate for 6 months (Schepers et al., 1957) or 72 weeks (Reeves et al., 1967) caused lung tumours in rats. Beryl ore dust induced lung tumours in rats (Wagner et al., 1969).

3.1.3. Hamster

A study of inhalation of beryl ore for 17 months in hamsters resulted in excess atypical lung proliferative lesions, some of which described as tumours (Wagner et al., 1969). It is noteworthy that similar doses caused tumours in rats (Wagner et al., 1969).

See Table 3.1.

Table 3.1. Studies of cancer in experimental animals exposed to beryllium (inhalation exposure) .

Table 3.1

Studies of cancer in experimental animals exposed to beryllium (inhalation exposure) .

3.2. Intratracheal administration

3.2.1. Rat

A single intratracheal administration of beryllium metal, beryllium oxide, and beryllium hydroxide once per week for 15 weeks caused lung tumours in rats (Groth et al., 1980). Beryllium oxide caused lung tumours in rats (Ishinishi et al., 1980; Litvinov et al., 1983).

See Table 3.2.

Table 3.2. Studies of cancer in experimental animals exposed to beryllium (intratracheal or intrabronchial exposure) .

Table 3.2

Studies of cancer in experimental animals exposed to beryllium (intratracheal or intrabronchial exposure) .

3.3. Intravenous administration

3.3.1. Mouse

A mouse study reported bone tumours after intravenous injection of zinc beryllium silicate (Cloudman et al., 1949).

3.3.2. Rabbit

Multiple intravenous injections of beryllium metal (Barnes & Denz, 1950), beryllium oxide (Gardner & Heslington, 1946; Dutra & Largent, 1950; Araki et al., 1954; Komitowski, 1967; Fodor, 1977), beryllium silicate, beryllium phosphate (Araki et al., 1954), and zinc beryllium silicate (Gardner & Heslington, 1946; Cloudman et al., 1949; Barnes & Denz, 1950; Hoagland et al., 1950; Janes et al., 1954; Kelly et al., 1961) caused osteosarcomas in rabbits, which were reviewed by Groth (1980).

See Table 3.3.

Table 3.3. Studies of cancer in experimental animals exposed to beryllium (intravenous exposure) .

Table 3.3

Studies of cancer in experimental animals exposed to beryllium (intravenous exposure) .

[The Working Group noted that although many of these studies had defficiency in reporting methods, the rarity of the induced tumours was considered to be compelling enough to consider them as a group.]

3.4. Other routes of exposure

3.4.1. Mouse

Beryllium sulfate injected intraperitoneally caused an increased incidence and multiplicity of lung tumours in A/J mice (Ashby et al., 1990).

3.4.2. Rabbit

Intramedullary bone administration of beryllium oxide (Yamaguchi, 1963; Komitowski, 1974; Hiruma, 1991), beryllium silicate (Tapp, 1966), zinc beryllium silicate (Tapp, 1969; Mazabraud, 1975), beryllium carbonate (Matsuura, 1974), and beryllium acetylacetonate (Matsuura, 1974) caused osteosarcomas or other bone tumours in rabbits.

See Table 3.4.

Table 3.4. Studies of cancer in experimental animals exposed to beryllium (other routes of exposure) .

Table 3.4

Studies of cancer in experimental animals exposed to beryllium (other routes of exposure) .

3.5. Synthesis

Lung tumours were induced in rats by inhalation of beryllium sulfate, beryllium metal, and beryl ore dust. In mice, lung cancer occurred after inhalation of beryllium metal. In hamsters, inhalation of beryl ore induced adenomatous hyperplasia of the lung. Intratracheal instillation of beryllium metal, beryllium hydroxide, and beryllium oxide in rats induced lung tumours. Intraperitoneal injection of beryllium sulfate induced lung tumours in mice. Intravenous injection or intramedullary injection/implantation of various beryllium compounds induced osteosarcoma in various studies in rabbits, and in one study in mice.

4. Other Relevant Data

4.1. Absorption, distribution, metabolism, and excretion

The bioavailability of beryllium particles as a function of size (geometric mean diameter), chemical composition, and specific surface area has been studied extensively. The agglomeration of beryllium particles does occur but the agglomerates dissociate again in fluid, with a corresponding decrease in particle mean diameter (Kent et al., 2001; Stefaniak et al., 2003b, 2004, 2007). Highly significant associations of chronic beryllium disease (CBD) and beryllium sensitization with particle-mass concentration for particles of less than 10 μm have been observed. The particle-mass concentration of alveolar-deposited particles (< 10 μm) correlates significantly with the occurrence of CBD. In a simulated phagolysosomal fluid, dissolution rate constants (k) for metallic beryllium particles and multiconstituent particles from arc-furnace processing of a beryllium–copper alloy were greater than those observed for beryllium oxide materials (Stefaniak et al., 2006). Beryllium has been detected in CBD-associated granulomas of beryllium-exposed workers by secondary ion mass-spectroscopy at an average of 9 years post exposure (Sawyer et al., 2005a). These data indicate that beryllium is retained in granulomatous lesions for extended periods of time in exposed humans with CBD. Verma et al., (2003) also reported elevated concentrations of beryllium in lung tissue from a person with CBD.

Acute inhalation dose–response studies in mice with a follow-up period of 350 days showed that high-dose exposures produced granulomatous beryllium lesions, which impeded the clearance of beryllium from the lungs (Finch et al., 1998b).

Accidental exposure of 25 people to beryllium dust produced a mean serum concentration of 3.5 μ/L measured one day later, which decreased to a mean concentration of 2.4 μ/L after 6 days (Zorn et al., 1986). These data indicate that beryllium from beryllium metal is biologically available from the lung. Exposure to beryllium metal (Williams, 1977) and beryllium alloys (Lieben et al., 1964) have been reported to produce beryllium disease.

4.2. Genetic and related effects

4.2.1. Direct genotoxicity

A large number of mutagenicity studies for beryllium compounds have been published (for reviews see IARC, 1993; Gordon & Bowser, 2003). In general, results of these studies have been either negative or weakly positive, depending on the test system used.

Joseph et al. (2001) studied gene expression patterns in BALB/c-3T3 cells transformed with beryllium sulfate, and reported a general upregulation of several cancer-related genes. Because no toxicity data were provided in these studies, the relevance of these findings to cancer cannot be interpreted. The same authors also reported the downregulation of several genes involved in DNA synthesis, repair and recombination in the tumour cells relative to controls.

Fahmy et al. (2008) studied the genotoxicity of beryllium chloride in mice exposed to oral doses of 93.75–750 mg/kg body weight for 3 weeks. Starting with the second lowest concentration (187.5 mg/kg bw; 1/8 of the LD50), chromosomal aberrations (excluding gaps) and aneuploidy were observed both in bone-marrow cells and in spermatocytes, as a function of dose and time.

4.2.2. Indirect effects related to genotoxicity

(a) Oxidative stress

Palmer et al. (2008) demonstrated upregulation of the protein PD-1 (programmed death-1) in beryllium-specific CD4+ T-cells derived from broncho-alveolar lavages from beryllium-sensitized persons or CBD patients. Upregulation of PD-1 was closely correlated with the severity of T-cell alveolitis.

Subsequent studies by Sawyer et al. (2005b) in mouse macrophages demonstrated beryllium-induced formation of reactive oxygen species in vitro, with marked increases in apoptosis and activation of caspase 8. These effects were attenuated by the addition of the antioxidant manganese(III)meso-tetrakis(4-benzoic acid)porphyrin (MnTBAP).

The inflammatory processes associated with the development of acute or chronic beryllium disease could plausibly contribute to the development of lung cancer by elevating the rate of cell turnover, by enhancing oxidative stress, and by altering several signalling pathways involved in cell replication.

(b) Epigenetic mechanisms

Studies by Belinsky et al. (2002) in beryllium-induced rat lung tumours demonstrated hypermethylation of the p16 and estrogen-receptor-α genes, and their attendant inactivation.

4.3. Synthesis

Several molecular mechanisms, possibly interrelated, operate in beryllium-induced carcinogenesis. Whereas mutagenicity tests with beryllium have shown only weakly positive or negative results, chromosomal aberrations and aneuploidy were observed in vivo in mice, at non-toxic concentrations. Like many other carcinogenic metals, beryllium is capable of producing oxidative stress, which can lead to cell injury in the form of DNA damage, activation of proto-oncogenes, and apoptotic mechanisms. In addition, the toxicity of beryllium in the lung may lead to cell killing and compensatory cell proliferation. Furthermore, the beryllium-induced chronic inflammatory response with attendant release of cytokines from beryllium-reactive CD4+ T-cells could also play a role in the development of a carcinogenic response in lung tissue.

In addition to beryllium-mediated generation of reactive oxygen species, inflammatory processes induced by beryllium may also cause an increase in reactive oxygen species, mediate cell turnover, and alter cell-signalling pathways. Furthermore, downregulation of genes involved in DNA synthesis, repair and recombination also occurs. Thus, the processes underlying beryllium-induced carcinogenesis are clearly complex, with several possible interactive mechanisms.

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of beryllium and beryllium compounds. Beryllium and beryllium compounds cause cancer of the lung.

There is sufficient evidence in experimental animals for the carcinogenicity of beryllium and beryllium compounds.

Beryllium and beryllium compounds are carcinogenic to humans (Group 1).

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© International Agency for Research on Cancer, 2012. For more information contact publications@iarc.fr.
Bookshelf ID: NBK304379

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