Toxicity Summary for BERYLLIUM

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

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EXECUTIVE SUMMARY

1. INTRODUCTION

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION
2.2 DISTRIBUTION
2.3 METABOLISM
2.4 EXCRETION

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES
3.2 INHALATION EXPOSURES
3.3 OTHER ROUTES OF EXPOSURE
3.4 TARGET ORGANS/CRITICAL EFFECTS

4. CARCINOGENICITY

4.1 ORAL EXPOSURES
4.2 INHALATION EXPOSURES
4.3 OTHER ROUTES OF EXPOSURE
4.4 EPA WEIGHT-OF-EVIDENCE
4.5 CARCINOGENICITY SLOPE FACTORS

5. REFERENCES

April 1992

Prepared by: Mary Lou Daugherty, M.S., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.

Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Beryllium is present in the earth's crust, in emissions from coal combustion, in surface water and soil, and in house dust, food, drinking water, and cigarette smoke (U.S. EPA, 1987a). However, the highest risk for exposure occurs among workers employed in beryllium manufacturing, fabricating, or reclamation industries (ATSDR, 1988). Workers encounter dusts and fumes of many different beryllium compounds; the current occupational standard for worker exposure to beryllium is 2 µg/m³ during an 8-hour workshift (OSHA, 1989).

Inhaled beryllium is absorbed slowly and localizes mainly in the lungs, bone, liver and kidneys (Stiefel et al., 1980; Reeves et al., 1967; Reeves and Vorwald, 1967; Zorn et al., 1988; Tepper et al., 1961; Meehan and Smyth, 1967). Ingested beryllium undergoes limited absorption and localizes in liver, kidneys, lungs, stomach, spleen and the large and small intestines (Crowley et al., 1949; Furchner et al., 1973; Watanabe et al., 1985). Significant absorption of beryllium or its compounds through intact skin is unlikely because of its chemical properties (U.S. EPA, 1987b). Beryllium per se is not biotransformed, but soluble salts may be converted to less soluble compounds in the lung (U.S. EPA, 1987b). Most orally administered beryllium passes through the gastrointestinal tract unabsorbed and is excreted in the feces (Reeves, 1965), whereas inhaled water-soluble beryllium salts are excreted mainly by the kidneys (Zorn et al., 1988).

Limited data indicate that the oral toxicity of beryllium is low. No adverse effects were noted in mice given 5 ppm beryllium in the drinking water in a lifetime bioassay (Schroeder and Mitchener, 1975a,b). The dose (converted to 0.54 mg/kg bw/day) was the no-adverse-effect level (NOAEL) used in the calculation of the chronic oral RfD for beryllium of 0.005 mg/kg/day (U.S. EPA, 1991a).

In contrast, the toxicity of inhaled beryllium is well-documented. Humans inhaling "massive" doses of beryllium compounds (such as the water soluble sulfate, fluoride, chloride, and oxide) may develop acute berylliosis (Constantinidis, 1978). ATSDR (1988) estimated that, based on existing data, the disease could develop at levels ranging from approximately 2-1000 µg Be/m³. This disease usually develops shortly after exposure and is characterized by rhinitis, pharyngitis, and/or tracheobronchitis, and may progress to severe pulmonary symptoms. The severity of acute beryllium toxicity correlates with exposure levels, and the disease is now rarely observed in the United States because of improved industrial hygiene (Zorn et al., 1988; Kriebel et al., 1988b).

Humans inhaling beryllium may also develop chronic berylliosis which, in contrast to acute berylliosis, is highly variable in onset, is more likely to be fatal, and can develop a few months to >=20 years after exposure (Constantinidis, 1978; Hall et al., 1959; Kriebel et al., 1988b). Chronic beryllium disease is a systemic disease that primarily affects the lungs and is characterized by the development of non-caseating granulomas. The disease most likely results from a hypersensitivity response to beryllium as evidenced by positive patch tests (Nishimura, 1966) and positive lymphocyte transformation tests (Williams and Williams (1983) in exposed individuals. Granulomas may also appear in the skin, liver, spleen, lymph nodes, myocardium, skeletal muscles, kidney, bone, and salivary glands (Kriebel et al., 1988b; Freiman and Hardy, 1970).

Epidemiologic studies have suggested that beryllium and its compounds could be human carcinogens. In a study that covered 15 regions of the U.S., Berg and Burbank (1972) found a significant correlation between cancers of the breast, bone and uterus and the concentration and detection frequency of beryllium in drinking water. However, imperfect analytical and sampling methods used in the study prompted the U.S. EPA (1986b) to conclude that these results are not proof of cause and effect relationships between cancer and beryllium in drinking water. Studies in workers exposed to beryllium, mostly via inhalation, have shown significant increases in observed over expected lung cancer incidences (Bayliss et al., 1971; Bayliss and Lainhart, 1972; Bayliss and Wagoner, 1977; Wagoner et al., 1980; Mancuso, 1970; 1979; 1980). The U.S. EPA (1986a), in evaluating the total database for the association of lung cancer with occupational exposure to beryllium, noted several limitations, but concluded that the results must be considered to be at least suggestive of a carcinogenic risk to humans. In laboratory studies, beryllium sulfate caused increased incidences of pulmonary tumors in rats and rhesus monkeys (Vorwald, 1953, 1962, 1968; Vorwald et al., 1955, 1966; Schepers et al., 1957; Reeves and Deitch, 1969).

Based on sufficient evidence for animals and inadequate evidence for humans, beryllium has been placed in the EPA weight-of-evidence classification B2, probable human carcinogen (U.S. EPA, 1991a). For inhalation exposure, the unit risk value is 2.4E-3 (µg/m³)^-1, and the slope factor is 8.4 (mg/kg/day)^-1 (U.S. EPA, 1991b). For oral exposure, the unit risk value is 1.2E-4 (µg/L)^-1 and the slope factor is 4.3 (mg/kg/day)^-1 (U.S. EPA, 1991a).

1. INTRODUCTION

Beryllium (Be), a metallic element, belongs to Group IIA of the periodic table and has an atomic weight of 9.012 and an oxidation state of +2 (U.S. EPA, 1987a; Budavari et al., 1989). Beryllium occurs naturally in the earth's crust at concentrations ranging from 2-10 ppm. It is also released into the atmosphere from coal combustion at concentrations of ~0.01-0.1 ng/m³, most likely as beryllium oxide (U.S. EPA, 1987a). Beryllium occurs in house dust (0.05-0.1 µg/g), surface water (0.01-1.0 ng/g), and soil (0.3-6.0 µg/g) (U.S. EPA, 1987a). Total daily intake values for beryllium in the general population are estimated at 1.6 ng/day in air, 120 ng in food, and 285 ng in water (U.S. EPA, 1987b). In addition, a smoker of one pack of cigarettes/day could inhale up to 700 ng of beryllium, depending on the type of tobacco used (U.S. EPA, 1987b).

Currently, beryllium has many industrial uses (e.g., in brake systems of airplanes, for neutron monochromatization, as window material for x-ray tubes, and in radiation detectors) (Zorn et al., 1988). The commercially important compound, beryllium oxide, is used in the electronics industry as a substrate for transistors and silicon chips, coil cores, and laser tubes (Zorn et al., 1988).

Although beryllium ore is relatively nontoxic, all other commercially important beryllium compounds exhibit significant pulmonary toxicity (ATSDR, 1988). Individuals employed in beryllium manufacturing, fabricating, or reclaiming industries are at highest risk for exposure and may encounter dusts and fumes of many different beryllium compounds. The current occupational standard for worker exposure to beryllium is 2 µg/m³ over an 8-hour workshift (OSHA, 1989). The U.S. EPA (1987b) reports that new cases of chronic beryllium disease are surfacing in industries where the OSHA standard is exceeded, but that few cases have been reported where levels do not exceed 2 µg/m³.

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

The gastrointestinal absorption of beryllium and its compounds is limited; instead, these compounds form insoluble precipitates at about pH 7 (Zorn et al., 1988) and pass out of the g.i. tract unabsorbed (Reeves, 1965; Furchner et al., 1973). Two studies in which beryllium was given orally to animals as ⁷Be in single or repeated doses demonstrated that <1% of the administered beryllium was absorbed (Crowley et al., 1949; Furchner et al., 1973). In another study, rats given beryllium sulfate (6.6 or 66.6 µg beryllium/day) in drinking water for up to 24 weeks eliminated 60-90% in the feces, suggesting at first that significant absorption had taken place; however, further analysis of the recovery data revealed that the metal was probably precipitated as the phosphate and was not available for absorption (Reeves, 1965).

The small amount of gastrointestinal absorption of beryllium that does occur depends on the specific compound administered. In hamsters, the absorption of soluble beryllium sulfate from the g.i. tract exceeded that of insoluble beryllium oxide and beryllium metal (Watanabe et al., 1985); and in rats, the absorption of beryllium oxide exceeded that of the hydroxide, and the absorption of beryllium fluoride exceeded that of the chloride, sulfate, nitrate, and hydroxide (Bugryshev et al., 1984). Reeves (1965) concluded from his studies that most of the beryllium found in the body was absorbed from the stomach at pH values (3.0-3.6 in the rat) that are favorable for maintaining beryllium salts in their ionized and soluble form.

Beryllium is slowly absorbed and retained by the lungs (Stiefel et al., 1980; Reeves et al., 1967; Reeves and Vorwald, 1967; Zorn et al., 1988). In one study, rats and guinea pigs were exposed for 3 hours to beryllium sulfate aerosol containing ⁷Be added as the chloride (Zorn et al., 1977). Of the <3 mg of beryllium that were inhaled, 10 ng were ⁷Be. Immediately after exposure, ~5 ng of ⁷Be were retained, 67% in the lungs and 15% in the skeleton. In another study, levels of beryllium reached steady state in the blood of rats and guinea pigs after 8 to 12 hours of exposure to beryllium nitrate (35 µg/m³ Be), and equilibrated in the lungs of rats after 32 weeks of exposure to beryllium sulfate (35 µg/m³ Be) (Stiefel et al., 1980).

Dermal absorption of water-soluble beryllium sulfate or beryllium chloride occurred at pH 3 in animal experiments (Zorn et al., 1988); however, U.S. EPA (1987b) concluded that significant absorption of beryllium or its compounds through intact skin is unlikely because of its chemical properties.

2.2. DISTRIBUTION

Watanabe et al. (1985) studied the distribution of beryllium in groups of hamsters given several different beryllium compounds in the diet for 3 to 12 months. The animals were sacrificed for tissue examination at various times. Beryllium administered as the soluble sulfate localized in liver, large intestine, small intestine, kidneys, lungs, stomach, and spleen; whereas beryllium administered as beryllium metal or beryllium oxide, both insoluble, localized mainly in the large and small intestines. Zorn et al. (1988) reported that a portion of beryllium or its compounds is stored in the liver and skeleton.

Analysis of tissues from workers exposed to beryllium via inhalation revealed that the highest levels of the metal were in the lungs, then bone, liver, and kidneys (Tepper et al., 1961; Meehan and Smyth, 1967).

2.3. METABOLISM

Beryllium is not biotransformed, but soluble salts may be converted to less soluble compounds in the lung (U.S. EPA, 1987b).

2.4. EXCRETION

Animal studies have shown that most orally administered beryllium passes through the gastrointestinal tract unabsorbed and is excreted in the feces. In one study, rats given beryllium sulfate (6.6 or 66.6 µg beryllium/day) in drinking water for up to 24 weeks eliminated 60-90% in the feces and <1% in the urine (Reeves, 1965). Another study demonstrated that urinary beryllium levels for rats fed beryllium sulfate doses of 5, 50, or 500 mg/kg for 2-years were proportional to intake (Morgareidge et al., 1977).

Inhaled water-soluble beryllium salts are excreted mainly by the kidneys, with a half-life of 2-8 weeks (Zorn et al., 1988). Stiefel et al. (1980) found increased levels of beryllium in the urine of cigarette smokers (2 µg/L compared with 0.9 µg/L, normal level); in animals, urinary elimination of beryllium peaked at 300 ng/g 10 hours after exposure ended. Stress, such as that brought on by pregnancy or major surgery, may mobilize beryllium in the body, and excretion of the metal in the urine may continue for years. Thus, urinary concentrations of beryllium at any point in time reflect only the amount released, and not the total body burden (Parkes, 1984).

Beryllium particles are cleared slowly from the lungs. Sanders et al. (1975) measured the clearance of beryllium oxide in rats and hamsters. Females of both species had slower clearance than did males. Reeves and Vorwald (1967) made similar observations in rats exposed to beryllium sulfate, and reported that the clearance half-time exceeded 63 days. Rhoads and Sanders (1985) reported that the half-time for removal of 50% of the initial lung burden of beryllium, following up to 3 hours of exposure to the metal, was 400 days.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Information on the acute toxicity of beryllium following oral exposure to humans was unavailable.

3.1.1.2. Animal

Acute oral LD₅₀ values for beryllium range from 18 mg Be/kg as beryllium fluoride in the mouse to 200 mg Be/kg as beryllium chloride in the rat (Reeves, 1986).

3.1.2. Subchronic Toxicity

Information on the subchronic toxicity of beryllium following oral exposure to humans and animals was unavailable.

3.1.3. Chronic Toxicity

3.1.3.1. Human

Information on the chronic toxicity of beryllium following oral exposure to humans was unavailable.

3.1.3.2. Animal

In early studies, chronic feeding of large doses of beryllium carbonate (0.1-0.5%, 1-5 g/kg of food) to young animals produced rickets (Guyatt et al., 1933; Jacobson, 1933; Kay and Skill, 1934). This effect was thought to be the result of the binding of phosphate to beryllium in the gut and the subsequent depletion of phosphorus in the body. In a two-year feeding study, rats were given dietary levels of 5, 50, or 5000 ppm beryllium (as beryllium sulfate) (Morgareidge et al., 1977). Animals of the 5000 ppm group (5 g/kg of food) had slightly decreased body weights. U.S. EPA (1991a) indicates that an unpublished dietary study by Cox et al. (1975) provided a NOEL of 25 mg/kg/day for beryllium.

Groups of approximately 50 male and female Long-Evans rats and Swiss mice received drinking water containing 5 ppm beryllium sulfate for life (Schroeder and Mitchener, 1975a,b). Body weights were measured throughout the study, and at the time of death, the animals were dissected and gross pathology recorded. Blood and urine samples were taken from the rats only. A slight depression in growth rate was observed for male rats at 2-6 months of age and glucose was detected in the urine of the female rats (p<0.025, compared with control values, Chi square analysis). No other consistent differences were noted between treated and control rats regarding urinalysis, or serum glucose, uric acid, and cholesterol. No differences were noted between treated and control mice.

3.1.4. Developmental and Reproductive Toxicity

Information on the developmental/reproductive toxicity of beryllium following oral exposure to humans or animals was unavailable.

3.1.5. Reference Dose

3.1.5.1. Subchronic

• ORAL RfD: 0.005 mg/kg/day (U.S. EPA, 1992)
• UNCERTAINTY FACTOR: 100
• NOAEL: 5 ppm in drinking water (0.54 mg/kg bw/day)
• COMMENT: The principal study (Schroeder and Mitchener, 1975) is the same for the subchronic and chronic RfD and is described in section 3.1.3.2.

3.1.5.2. Chronic

• ORAL RfD: 0.005 mg/kg/day (U.S. EPA, 1991)
• UNCERTAINTY FACTOR: 100
• NOAEL: 5 ppm in drinking water (0.54 mg/kg bw/day)
• CONFIDENCE:
  Study: Low
  Data Base: Low
  RfD: Low
• VERIFICATION DATE: 12/02/85
• PRINCIPAL STUDY: Schroeder and Mitchener, 1975
• COMMENTS: The NOAEL was based on no effects in rats in a lifetime bioassay. The uncertainty factor of 100 reflects a factor of 10 each for interspecies conversion and for the protection of sensitive human subpopulations. The RfD is limited to soluble beryllium salts.

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Acute beryllium diseases in humans result from the inhalation of high concentrations of highly dispersed forms of beryllium or its compounds (Zorn et al., 1988). Individuals inhaling massive doses of beryllium compounds (such as the water soluble sulfate, fluoride, chloride, and oxide) may develop acute berylliosis (Constantinidis, 1978). This disease usually develops shortly after exposure and is characterized by rhinitis, pharyngitis, and/or tracheobronchitis, and may progress to severe pulmonary disease. The severity of acute beryllium toxicity correlates with exposure levels (Zorn et al., 1988). Brief exposure to concentrations of beryllium in air above 100 µg/m³, may cause acute pneumonitis characterized by shortness of breath, malaise, anorexia, weight loss, coughing, cyanosis, tachypnea and tachycardia (U.S. EPA, 1987; Eisenbud et al., 1948). Lung volumes are reduced and diffuse or localized infiltrates are seen on the chest x-ray (Kriebel et al., 1988b). Although some cases of acute beryllium disease are fatal, most are resolved within a few months (Dutra, 1948). Sprince et al. (1983) reported that 17% of a group of patients with the acute disease developed chronic disease in 10 or more years. Acute beryllium disease is now rarely observed in the United States because of improved industrial hygiene (Kriebel et al., 1988b).

3.2.1.2. Animal

LC₅₀ values for beryllium were not found in the available literature. In rats, the lethal dose for acute inhalation of beryllium sulfate was 10 mg of the salt/m³ 6 hours/day for 5 days (Stiefel et al., 1980).

Brief exposures to beryllium can result in long-term effects. In a pulmonary toxicity study, male rats were exposed for one hour in a nose only chamber to an aerosol of 4.05 µg of Be/L (as beryllium sulfate) and were examined for toxicity for a year after exposure (Sendelbach et al., 1989). Parameters for lung toxicity included bronchoalveolar lavage, lung cell kinetics, and histopathologic analysis. The activities of alkaline phosphatase (Alk Pase), acid phosphatase (Ac Pase), and lactate dehydrogenase (LDH) in lavage fluids were elevated 3 weeks after exposure; Alk Pase and LDH levels peaked 3 months after. Microscopic examination revealed progressive focal interstitial pneumonitis with a prominent alveolar component of heteromorphic macrophages, neutrophils, and debris.

In a similar study, higher concentrations of beryllium (800 µg Be metal/m³ for 50 min; initial lung burden, 625 µg) caused severe, acute chemical pneumonitis that is followed by a quiescent period of minimal inflammation and mild fibrosis (Haley et al., 1990). Progressive, chronic-active, fibrosing pneumonitis appeared later.

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Information on the subchronic toxicity of beryllium following inhalation exposure to humans was unavailable.

3.2.2.2. Animal

The respiratory tract is the target for the subchronic inhalation toxicity of beryllium. Schepers et al. (1957) exposed 115 male and female Sherman and Wistar rats to 35 µg/m³ of beryllium (as beryllium sulfate) 8 hours/day, 5 days/week and 4 hours/day 1 day/week for 180 days. During exposure, 46 exposed rats died from a bacterial infection that affected the heart and lungs. At the end of exposure, 17 rats were sacrificed and examined for pulmonary effects. Foam-cell clusters, infiltration of macrophages, lobular septal-cell proliferation and peribronchial and alveolar-wall epithelialization were observed in the treated animals. Untreated controls had none of these effects. Fifty-two of the exposed rats were maintained in beryllium-free air for up to 18 months. These animals demonstrated a progressive increase in the frequency of pulmonary changes that included atrophic-vesicular emphysema and metaplasia of the bronchial epithelium.

A dose-response for pulmonary effects was suggested in a study of rats exposed to beryllium sulfate aerosol 7 hours/day for 1-560 days (Vorwald et al., 1966). The animals exhibited no specific inflammatory abnormalities at an aerosol concentration of 2.8 µg/m³, significant inflammatory changes at 21 µg/m³, chronic pneumonitis at 42 µg/m³, and acute berylliosis at 194 µg/m³. Durations of exposure associated with these effects were not clear.

Tumors developed in animals in both of the above studies; these are discussed in Section 4.

3.2.3. Chronic Toxicity

3.2.3.1. Human

Humans inhaling beryllium may develop chronic berylliosis which, in contrast to acute berylliosis, is highly variable in onset and can develop a few months to >=20 years after exposure (Constantinidis, 1978; Kriebel et al., 1988b). Exposure lasting for months to years is essential for the development of the disease (Kriebel et al., 1988b).

The risk of disease, estimated at 1 to 10% (Eisenbud and Lisson, 1983), is probably related to both the magnitude of the exposure and the type of beryllium compound. The more soluble compounds apparently cause the acute disease; whereas, the less soluble compounds are more likely to be associated with the chronic disease (Machle et al., 1948). This suggests that the risks are now much lower as a result of the increased effectiveness of current occupational and environmental controls (Kriebel et al., 1988b). In at least one exception to this, five workers developed lung granulomas after working in an area where beryllium fume concentrations were consistently <2 µg/m³, the OSHA standard (Cullen et al. 1987). However, the investigators suspect that exposure was underestimated because of the collection method used.

Chronic beryllium disease is a systemic, granulomatous disease that primarily affects the lungs (Kriebel et al., 1988b). Non-caseating granulomas may also be observed in the skin, liver, spleen, lymph nodes, myocardium, skeletal muscles, kidney, bone, and salivary glands (Freiman and Hardy, 1970). Other symptoms of the disease include dyspnea, weight loss, chest pain, cough, arthralgias, and fatigue (Kriebel et al., 1988b). Physical findings include bibasilar crackles, skin lesions, hepatosplenomegaly, clubbing of the nail beds, and lymphadenopathy, and in severe cases, right heart failure and cor pulmonale may occur (Kriebel et al., 1988b). X-rays may show diffuse infiltrates and hilar adenopathy. In addition, a cross-sectional study conducted on 297 white male workers employed for an average of 17 years in a large beryllium plant, revealed decrements in pulmonary function (Kriebel et al., 1988a).

Chronic pulmonary beryllium disease proceeds at one of the following three levels, as characterized by Zorn et al. (1988): (1) after the onset of lung function diminution, the pathological changes regress, leaving minimal fibrosis and respiratory impairment; (2) following an asymptotic period of 2-30 years, the disease "burns out" at a more advanced fibrotic stage with little effect on the overall life expectancy: or (3) a continuous activity with progressive inflammatory and fibrotic changes, resulting in increasing respiratory disability such as shortness of breath on exertion, chronic dry cough, and burning substernal pain. The progressive form of berylliosis is associated with decreased life expectancy.

The Beryllium Case Registry (BCR) at the Massachusetts General Hospital requires that at least four of the following six criteria be met for diagnosis of chronic beryllium disease: (1) epidemiologic evidence of significant beryllium exposure; (2) presence of beryllium in lung tissue, lymph nodes, or urine; (3) evidence of lower respiratory tract disease and a clinical course consistent with beryllium disease; (4) radiologic evidence of interstitial disease consistent with a fibronodular process; (5) evidence of a restrictive or obstructive ventilatory defect or diminished carbon monoxide diffusing capacity; (6) pathologic changes consistent with beryllium disease on examination of lung tissue and/or lymph nodes (Sprince and Kazemi, 1983).

The disease most likely results from a hypersensitivity response to beryllium as evidenced by positive patch tests (Nishimura, 1966) and positive lymphocyte transformation tests (Williams and Williams, 1983). Circulating humoral antibodies to beryllium have never been demonstrated, thus, the hypersensitivity to beryllium appears to be strictly cell-mediated (Reeves, 1979; Stiefel et al., 1980). A predisposition to the development of chronic beryllium disease, consistent with the inability of susceptible individuals to develop a sufficient number of suppressor cells to prevent the immune response from becoming excessive and destructive against autologous lung tissue, has been suggested (Zorn et al., 1988).

The chronic disease is more likely to be fatal than the acute disease. For example, in a study of 601 cases of berylliosis (61% were chronic), 31% of the patients with chronic disease died compared with 6% of the acute cases (Hall et al., 1959).

3.2.3.2. Animal

Rats exposed 7 hours/day, 5 days/week for 72 weeks to 34 µg/m³ of beryllium (as beryllium sulfate) had increased lung weights and inflammatory and proliferative changes and clusters of macrophages in the alveolar spaces (Reeves et al., 1967).

See also the section on subchronic exposure, inhalation effects (3.2.2.2).

3.2.4. Developmental and Reproductive Toxicity

Information on the developmental/reproductive toxicity of beryllium following inhalation exposure to humans and animals was unavailable.

3.2.5. Reference Concentration

A subchronic or chronic reference concentration for beryllium was not available.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Beryllium is a direct irritant and may cause edema and inflammation of any contacted tissue (Kriebel et al., 1988b). The eyes and skin are common targets of the acute irritant effects of beryllium (Kriebel et al., 1988b). Cutaneous injuries from beryllium metal, alloys, or oxide may require surgical excision of the foreign substance to promote healing (Zorn et al., 1988). In addition to primary dermatitis, beryllium may sensitize the skin to subsequent contact with the metal. Dermatitis usually abates after exposure stops, but ulceration can result from particles retained in the skin (Kriebel et al., 1988b).

3.3.1.2. Animal

Information on the acute toxicity of beryllium following exposure to animals by other routes was unavailable.

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of beryllium following exposure to humans or animals by other routes was unavailable.

3.3.3. Chronic Toxicity

3.3.3.1. Human

Chronic dermal contact by beryllium and its compounds may result in skin sensitization and contact dermatitis in predisposed persons (Zorn et al., 1988).

3.3.3.2. Animal

Information on the chronic toxicity of beryllium following exposure to animals by other routes was unavailable.

3.3.4. Developmental and Reproductive Toxicity

Information on the developmental/reproductive toxicity of beryllium following exposure to humans by other routes was unavailable.

3.3.4.2. Animal

Intratracheal injection of rats with 50 mg/kg of beryllium chloride or beryllium oxide on (one or more) days 3, 5, or 8 of gestation produced increases in fetal mortality, decreases in fetal weight, and increases in the percentages of pups with internal abnormalities (Selivanova and Savinova, 1986).

Rats, treated intratracheally with beryllium oxide (0.2 mg beryllium/rat) and allowed to mate repeatedly over 15 months, displayed no change in reproductive performance (Clary et al., 1975).

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organs

Skeletal system: Rickets in young animals appeared to be the result of the binding of phosphate to beryllium in the gut.

3.4.1.2. Other Target Organs

None

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organs

Lungs: Chronic beryllium disease is characterized as an immunologically mediated granulomatous lung disease in humans and appears to be the result of direct chemical toxicity and foreign-body-type reactions in rats.

3.4.2.2. Other Target Organs

Skin, liver, spleen, lymph nodes, myocardium, skeletal muscles, kidney, bone, and salivary glands may exhibit granulomas, similar to those of the lungs.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

In the late 1970's, epidemiological studies suggested that beryllium and its compounds could be human carcinogens. In a study that covered 15 regions of the U.S., Berg and Burbank (1972) found a significant correlation between cancers of the breast, bone, and uterus and the concentration and detection frequency of beryllium in drinking water. Mortality rates in areas with beryllium in the drinking water were excessive only for nonwhite males. The probability of a positive association ranged from 0.006-0.040. However, imperfect analytical and sampling methods used in the study prompted the U.S. EPA (1986b) to conclude that these results were not proof of cause and effect relationships between cancer and beryllium in drinking water.

4.1.2. Animal

Chronic oral administration of beryllium to animals produced equivocal carcinogenicity results in two studies. In one study, mice and rats treated with drinking water containing 5 ppm beryllium (as beryllium sulfate) had slightly higher incidences of leukemias and grossly observed tumors, but the increases were not statistically significant (Schroeder and Mitchener, 1975a,b). In the other study, male Wistar rats fed diets containing 0, 5, 50, or 500 ppm beryllium as beryllium sulfate for 104 weeks had statistically significant increases in the incidence of reticulum cell sarcoma at the two lowest doses, but no response at the highest dose (Morgareidge et al., 1975). The U.S. EPA (1986b) concluded that this study is suggestive of a carcinogenic response to ingested beryllium, but the lack of response at the high dose and the lack of peer review or publication of the study limits the interpretation as a positive study.

4.2. INHALATION EXPOSURES

4.2.1. Human

Infante et al. (1980) conducted a lung cancer mortality study of white males listed in the BCR using a retrospective cohort method. Of the cohort consisting of 421 individuals, 139 had died and 64 had no vital statistics; 15 of the 139 that died had no cause of death listed. In terms of total cancer, 19 deaths were observed vs. 12.41 expected for white males. In terms of lung cancer, 6 deaths were observed 15 or more years after exposure vs. 2.81 expected (p<0.01). However, the study used the NIOSH life table program which results in an 11% excess in the calculated expected number of lung cancer deaths (Wagoner et al., 1980). When the expected lung cancer deaths were adjusted for using the NIOSH program, the p value was reduced to <0.09, questionable or borderline significance. Further analysis of the data from this study revealed a positive correlation for increased cancer and acute (but not chronic) beryllium disease. However, the NIOSH life tables were used for some of the calculations and the results are therefore questionable (U.S. EPA, 1987).

Several epidemiological studies of lung cancer were conducted among beryllium workers from two plants (Bayliss et al., 1971; Bayliss and Lainhart, 1972; Bayliss and Wagoner, 1977; Wagoner et al., 1980; Mancuso, 1970; 1979; 1980). The studies, based on personnel records and social security quarterly earnings reports, were equivocal regarding the carcinogenicity of beryllium. For example, three studies revealed significant increases in observed over expected lung cancer cases in workers who were (a) employed from 1942-1967 and followed for ten additional years (p<0.05) (Bayliss and Wagoner, 1977; Wagoner et al., 1980); (b) employed from 1937-1948 and followed for 30 additional years (p<0.01) (Mancuso, 1980); and (c) combined workers of both plants who were employed from 1942-1948 and followed for an additional 28 years (P<0.01) (Mancuso, 1979). However, the studies were considered to be limited because of methodological constraints and deficiencies such as no correction for smoking (U.S. EPA, 1991a).

The U.S. EPA (1986a) evaluated the total database for the association of lung cancer with occupational exposure to beryllium, and noted several limitations. However, in spite of the limitations of the studies, U.S. EPA (1986a,b) concluded that the results must be considered to be at least suggestive of a carcinogenic risk to humans.

4.2.2. Animal

Inhalation studies have tested the carcinogenic potential of beryllium in various animal species. Table 1 shows that beryllium sulfate causes increased incidences of pulmonary tumors in rats and rhesus monkeys (Vorwald, 1953, 1962, 1968; Vorwald et al., 1955, 1966; Schepers et al., 1957; Reeves and Deitch, 1969). Rats exposed to concentrations of beryllium ranging from 1.8 to 180 mg/m³ exhibited increased incidences of pulmonary carcinomas that ranged from 20 to 100% (Vorwald 1953; 1962). The animals were exposed 33-38 hours/week for 3 to 24 months. The incidence of lung tumors exhibited a weakly positive correlation with exposure concentration and duration. Schepers et al. (1957) observed a 43% increase in the incidence of pulmonary carcinomas in rats exposed to 32-35 mg/m³ beryllium 44 hours/week for 6-9 months followed by an 18-month observation period. These investigators identified eight histologically distinct types of tumors in the lungs of exposed rats. The tumors were metasticizing and transplantable. Reeves and Deitch (1969) observed an approximate 100% incidence in lung tumors in rats exposed to 36 mg/m³ beryllium 35 hours/week for up to 18 months. The studies of these investigators indicated that tumor yield in rats was dependent upon age at exposure rather than on duration of exposure.

Tumor incidences were also increased in rats exposed to beryllium phosphate, beryllium fluoride, and beryl ore (Schepers, 1961; Wagner et al., 1969).

4.3. OTHER ROUTES OF EXPOSURE

Beryllium is carcinogenic when administered by intratracheal and intravenous injections and implantation into bone. Intratracheal injection of beryllium into rats induced cancer incidences ranging from 0-100%, with latency periods of at least 6 to 9 months (Vorwald and Reeves, 1959; Spencer et al., 1968; 1972; Ishinishi et al., 1980; Groth et al., 1972; 1976; 1980; Groth and MacKay, 1971). Several investigators have induced osteosarcomas in rabbits (Nash, 1950; Dutra and Largent, 1950; Yamaguchi and Katsura, 1963; Sissons, 1950; and others) and mice (Cloudman et al., 1949) with intravenous injection and subperiosteal or intraosseous implantation of beryllium and several of its compounds. The incidence of osteosarcoma ranged from 0-100% by either route of administration, with a latency period of >=9 months.

TABLE 1. Pulmonary Carcinoma from Inhalation Exposure of Animals to Beryllium
Compound/Species	Concentration (mg/m3 as Be)	Weekly Exposure Time (hours)	Duration of Exposure (months)	Incidence of Pulmonary Carcinoma	Reference
Beryllium sulfate
Rat	33-35	33-38	12-14	4/8 (females)	Vorwald, 1953
Rat	33-35	33-38	13-18	17/17	Vorwald et al., 1955
Rat	32-35	44	6-9, followed by 18-month observation	58/136	Schepers et al., 1957
Rat	55	33-38	3-18	55/74	Vorwald, 1962
Rat	180	33-38	12	11/27	Vorwald, 1962
Rat	18	33-38	3-22	72/103	Vorwald, 1962
Rat	18	33-38	8-21	31/63	Vorwald, 1962
Rat	18	33-38	9-24	47/90	Vorwald, 1962
Rat	18	33-38	11-16	9/21	Vorwald, 1962
Rat	1.8-2.0	33-38	8-21	25/50	Vorwald, 1962
Rat	1.8-2.0	33-38	9-24	43/95	Vorwald, 1962
Rat	1.8-2.0	33-38	13-16	3/15	Vorwald, 1962
Rat	21-42	33-38	18	almost all	Vorwald et al., 1966
Rat	2.8	33-38	18	13/21	Vorwald et al., 1966
Rat	34	35	13	43/43 (females)	Reeves et al., 1967
Rat	36	35	3	19/22 (both sexes)	Reeves and Deitch, 1969
Rat	36	35	6	33/33 (both sexes)	Reeves and Deitch, 1969
Rat	36	35	6	33/33 (both sexes)	Reeves and Deitch, 1969
Rat	36	35	9	15/15 (both sexes)	Reeves and Deitch, 1969
Rat	36	35	12	21/21 (both sexes)	Reeves and Deitch, 1969
Rat	36	35	18	13/15 (both sexes)	Reeves and Deitch, 1969
Rhesus monkey	35-200	42	8	0/4 (females)	Schepers, 1964
Rhesus monkey	38.8	15	36+	8/11	Vorwald, 1964
Guinea pig	35	NRa	12	0	Schepers, 1961
Guinea pig	36	35	12	2/20	Schepers, 1971
Guinea pig	3.7-30.4	35	18-24	0/58	Reeves et al., 1972
Beryllium phosphate
Rat	32-35	NRa	1-12	35-60/170b	Schepers, 1961
Rat	227	NRa	1-12	7/40b	Schepers, 1961
Rhesus monkey	200	42	8	0/4 (females)	Schepers, 1961
Rhesus monkey	1100	42	8	0/4 (females)	Schepers, 1964
Rhesus monkey	8300	42	8	0/4 (females)	Shepers, 1964
Beryllium fluoride
Rat	9	NRa	6-15	10-20/200	Schepers, 1961
Rhesus monkey	180	42	8	0/4 (females)	Schepers, 1964
ZnBEMnSiO3
Rat	700	NRa	9	4-20/220b	Schepers, 1961
Rabbit	700	NRa	24	0	Schepers, 1961
Guinea pig	700	NRa	22	0	Schepers, 1961
Beryl ore
Rat	620	30	17+	18/19	Wagner et al., 1969
Hamster	620	30	17+	0/48	Wagner et al., 1969
Squirrel monkey	620	30	17+	0/12	Wagner et al., 1969

^aNR = Not reported

^bNumber of tumors/Number of animals exposed

4.4. EPA WEIGHT-OF-EVIDENCE

4.4.1. Oral

Not assigned.

4.4.2. Inhalation

Classification -- B2, probable human carcinogen

Basis -- Inadequate evidence for humans; sufficient evidence for animals (U.S. EPA, 1991a). "Beryllium has been shown to induce lung cancer via inhalation in rats and monkeys and to induce osteosarcomas in rabbits via intravenous or intramedullary injection. Human epidemiology studies are considered to be inadequate."

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

• SLOPE FACTOR: 4.3 (mg/kg/day)^-1
• DRINKING WATER UNIT RISK: 1.2E-4 (µg/L)^-1
• VERIFICATION DATE: 02/01/89 (U.S. EPA, 1991a)
• PRINCIPAL STUDY: Schroeder and Mitchener (1975a)

4.5.2. Inhalation

• SLOPE FACTOR: 8.4 (mg/kg/day)^-1
• INHALATION UNIT RISK: 2.4E-3 (µg/m³)^-1
• VERIFICATION DATE: 05/04/88 (U.S. EPA, 1991a)
• PRINCIPAL STUDY: Wagoner et al. (1980)

5. REFERENCES

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