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Health Effects of Beryllium Exposure: A Literature Review (2007)

Chapter:4 Genotoxicity and Carcinogenicity

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Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
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4
Genotoxicity and Carcinogenicity

The carcinogenic potential of beryllium and beryllium compounds has been assessed by various agencies in the last decade. The International Agency for Research on Cancer (IARC 1993) classifies beryllium and beryllium compounds as carcinogenic in humans, the U.S. Environmental Protection Agency (EPA 1998a,b) considers them probable human carcinogens, and the National Toxicology Program (NTP 1999, 2005) lists them as reasonably expected to be carcinogens. As noted in Chapter 1, EPA has performed a dose-response analysis of the cancer data to estimate an air unit risk of 2.4 ×10−3 per μg/m3. This chapter examines the literature used in the previous assessments, more recent reviews, and relevant new studies. First, information on the genotoxic potential of beryllium and beryllium compounds is presented. The literature on carcinogenicity, including the epidemiologic literature and animal bioassays, is then reviewed.

GENOTOXICITY

Compounds of beryllium have tested positively in nearly 50% of the genotoxic studies conducted without exogenous metabolic activation, but were nongenotoxic in most bacterial tests. Beryllium chloride, beryllium nitrate, beryllium sulfate, and beryllium oxide have been shown to be nongenotoxic in the Ames plate incorporation assay and assays with Escherichia coli pol A, E. coli WP-2 uvr A, and Saccharomyces cerevisiae (Table 4-1) (reviewed in EPA 1998a,b; ATSDR 2002; Gordon and Bowser 2003). Beryllium sulfate also did not induce unscheduled DNA synthesis in primary rat hepatocytes (Williams et al. 1982, 1989), was not mutagenic when injected intraperitoneally into adult mice in a S. typhimurium host-mediated assay (Simmon et al. 1979a), and failed to increase the incidence of micronucleated polychromatic erythrocytes in bone marrow (Ashby et al.1990). Lung tumors in F344/N rats treated with beryllium sulfate did not have mutations of the p53 or c-raf-1 gene, but weak mutations were detected in the K-ras gene (Nickell-Brady et al. 1994).

Positive genotoxic results have been reported for beryllium sulfate in the B. subtilis rec assay (Kada et al. 1980; Kanematsu et al. 1980) and the E. coli rec assay (Dylevoi 1990), for beryllium nitrate in the B. subtilis rec assay (Kuroda et al. 1991), and for beryllium chloride in the B. subtilis rec assay with spores (Kuroda et al. 1991), the E. coli forward-mutation assay (Zakour and Glickman 1984), and the Photobacterium fischeri assay (Ulitzur and Barak 1988). Gene mutations have been observed in

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
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TABLE 4-1 Genotoxicity Studies of Beryllium Compounds

Assay or End Point

Species

Compound

With Activation

Without Activation

Reference

In vitro

Plate incorporation assay

Salmonella typhimurium

BeSO4

Negative

Negative

Rosenkranz and Poirier 1979; Simmon 1979a; Simmon et al. 1979; Dunkel et al. 1984; Arlaukas et al. 1985; Ashby et al. 1990

S. typhimurium

Be(NO3)2

Negative

Negative

Arlaukas et al. 1985; Kuroda et al. 1991

S. typhimurium

BeO

Negative

Negative

Kuroda et al. 1991

S. typhimurium

BeCl2

Negative

Negative

Kuroda et al. 1991

Eschericia coli WP-2 uvrA

BeSO4

Negative

Negative

Dunkel et al. 1984

Rec assay

Bacillus subtilis

BeSO4

Positive

Kada et al. 1980; Kanematsu et al. 1980

B. subtilis

BeCl2

Positive

Kuroda et al. 1991

B. subtilis

BeCl2

Negative

Nishioka 1975

B. subtilis

Be(N03)2

Positive

Kuroda et al. 1991

B. subtilis

BeO

Negative

Kuroda et al. 1991

E. coli

BeSO4

Positive

Dylevoi 1990

DNA modification

E. coli pol A+/A

BeSO4

Negative

Rosenkranz and Poirier 1979

Bioluminescence test

Photobacterium fischeri

BeCl2

Positive

Ulitzur and Barak 1988

Recombogenic activity

Saccharomyces cerevisiae

BeSO4

Negative

Negative

Simmon 1979b

Host-mediated assay

S. cerevisiae

BeSO4

Negative

Simmon et al. 1979

S. typhimurium

BeSO4

Negative

Simmon et al. 1979

Chromosomal aberration

Swine lymphocytes

BeCl2

Positive

Vegni-Talluri and Guiggiani 1967

Syrian hamster embryo cells

BeSO4

Positive

Larramendy et al. 1981

Human lymphocytes

BeSO4

Positive

Larramendy et al. 1981

Chinese hamster ovary cells

BeSO4

Negative

Brooks et al. 1989

Cytogenetic assay

Chinese hamster lung cells

BeSO4

Negative

Negative

Ashby et al. 1990

Sister chromatid exchange assay

Chinese hamster V79 cells

BeCl2

Positive

Kuroda et al. 1991

Chinese hamster V79 cells

Be(NO3)2

Positive

Kuroda et al. 1991

Chinese hamster V79 cells

BeO

Negative

Kuroda et al. 1991

Syrian hamster embryo cells

BeSO4

Positive

Larramendy et al. 1981

Human lymphocytes

BeSO4

Positive

Larramendy et al. 1981

Human lymphocytes

BeSO4

Negative

Andersen 1983

Mouse macrophage P388D1 cells

BeSO4

Negative

Andersen 1983

DNA repair

Rat hepatocytes

BeSO4

Negative

Williams et al. 1982, 1989

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
×

Assay or End Point

Species

Compound

With Activation

Without Activation

Reference

Transformation assay

Syrian hamster embryo cells

BeSO4

Positive

DiPaolo and Casto 1979

Rat respiratory epithelial cells

Rocket exhaust residue

Mixed

Steele et al. 1989

Rat respiratory epithelial cells

BeO (low fired)

Positive

Steele et al. 1989

Rat respiratory epithelial cells

BeO (high fired)

Mixed

Steele et al. 1989

BALB/c-3T3 cells

BeSO4

Positive

Keshava et al. 2001

DNA damage

Rat respiratory epithelial cells

Rocket exhaust residue

Mixed

Steele et al. 1989

Rat respiratory epithelial cells

BeO (low fired)

Positive

Steele et al. 1989

Rat respiratory epithelial cells

BeO (high fired)

Mixed

Steele et al. 1989

Mutation of HGPRT gene

Chinese hamster ovary

K1-BH4 cells

BeSO4

Positive

Hsie et al. 1979

Chinese hamster V79 cells

BeCl2

Positive

Miyaki et al. 1979

Mutation of lacI gene

E. coli

BeCl2

Positive

Zakour and Glickman 1984

Mutation of K-ras gene

Rat lung tumors

Be

Weak positive

Nickell-Brady et al. 1994

Mutation of p53 gene

Rat lung tumors

Be

Negative

Nickell-Brady et al. 1994

Mutation of c-raf-1 gene

Rat lung tumors

Be

Negative

Nickell-Brady et al. 1994

In vivo

Transformation assay

Syrian hamsters (embryo cells evaluated after maternal exposure)

BeSO4

Positive

DiPaolo and Casto 1979

Micronucleus assay

CBA mice

BeSO4

Negative

Ashby et al. 1990

Note: Be = beryllium, BeCl2 = beryllium chloride, Be(NO3)2 = beryllium nitrate, BeO = beryllium oxide, BeSO4 = beryllium sulfate.

SOURCE: Adapted from ATSDR 2002.

mammalian cells cultured with beryllium chloride (Vegni-Talluri and Guiggiani 1967; Hsie et al. 1979; Miyaki et al. 1979) and beryllium sulfate (Larramandy et al. 1981; Brooks et.al. 1989); beryllium nitrate has resulted in clastogenic alterations (Kuroda et al. 1991). Overall, mutation and chromosomal-aberration assays of beryllium compounds have yielded somewhat contradictory results. Although the bacterial assays have been largely negative, the mammalian test systems exposed to beryllium compounds have shown evidence of mutations, chromosomal aberrations, and cell transformations. Further studies would confirm the mutagenic or genotoxic properties of the various beryllium compounds.

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
×

CARCINOGENICITY

Epidemiologic Studies

Several studies and reviews are available on cancer in relation to beryllium exposure in humans. Two worker cohorts involved in beryllium extraction, production, and fabrication have been extensively studied and are the primary basis of conclusions drawn to date on cancer in humans. One cohort is in Lorain, Ohio, and the other in Reading, Pennsylvania. The original study (Mancuso 1979) reported a lung-cancer standardized mortality ratio (SMR) for the two plants combined of 1.42 (95% confidence interval [CI], 1.1-1.8). The study involved 1,222 workers at the Ohio plant and 2,044 workers at the Pennsylvania plant who had been employed for at least 3 months during 1942 through 1948. No analysis by job title or by exposure category was performed, and the excess-lung-cancer finding was limited to workers who were employed for less than 5 years. The exposures of the workers were often at high concentrations. For example, a study at the Lorain plant in 1947-1948 by the U.S. Atomic Energy Commission measured beryllium at concentrations ranging from 411 μg/m3 in the mixing area to 43,300 μg/m3 in the breathing zone of alloy operatives (Zielinski 1961). Control limits at U.S. plants were introduced in 1949 (Wagoner et al. 1980). Mancuso (1980) reanalyzed the same two cohorts but expanded the period of employment of the study cohorts to 1937 through 1948 and used workers at the rayon plant for comparison purposes. The comparison between the two types of industrial workers found a significant relative SMR for lung cancer of 1.40 for the beryllium-worker cohort.

Wagoner et al. (1980) expanded the cohort in the Pennsylvania plant to include workers employed during 1941 through 1967. The group of 3,055 workers was found to have a lung-cancer SMR of 1.25 (95% CI, 0.9-1.7). When the analysis was adjusted for latency, there was a significant SMR of 1.68 for the group that had a latency of 25 years or longer. However, there was no relationship with duration of employment. The results of a 1968 medical survey of smoking histories of the workers showed that differences in smoking habits were sufficient to increase the cancer risk among beryllium workers by 14%. However, if the working population’s risk is compared with lung-cancer mortality in the county where the plant was instead of using the U.S. rates, the SMR is underestimated by 19% (Wagoner et al. 1980).

The National Institute for Occupational Safety and Health (NIOSH) conducted a retrospective cohort mortality study of seven beryllium production facilities that included the Pennsylvania and Ohio cohorts previously studied by Mancuso and Wagoner. In the study, Ward et al. (1992) developed a cohort of 9,225 male workers who had worked for at least 2 days during 1940 through 1969 and were followed through 1998. The SMR for lung cancer was 1.26 (95% CI, 1.12-1.42) on the basis of 280 lung-cancer deaths. The researchers also observed an SMR for nonmalignant respiratory disease of 1.48 (95% CI, 1.21-1.80). Ward et al. (1992) reported that SMR increased with latent period, with a significant SMR of 1.46 for a latent period greater than 30 years among the workers at the combined seven plants. The SMR for lung cancer was a significant 1.42 for those hired before 1950 and less than l for those hired during 1960 through 1969.

IARC (1993) has provided a detailed description and critique of the cohort studies. It pointed out that the risk of lung cancer was consistently higher in plants in which there was an excess mortality from nonrespiratory disease. IARC also concluded that the association between lung-cancer risk and beryllium exposure did not appear to be confounded by smoking.

A second line of investigation is embodied in the Beryllium Case Registry, which was established in 1952 to follow the clinical aspects and complications of people with beryllium-related diseases, including both chronic beryllium disease (CBD) and acute beryllium-related pneumonitis. The data were analyzed first by Infante et al. (1980) and more recently by Steenland and Ward (1991). In the Steenland and Ward study, the cohort consisted of 689 people who entered the registry during 1952 through 1980 and were followed through 1988. The researchers reported an SMR of 2.00 (95% CI, 1.33-2.89) on the basis of 28 observed lung-cancer deaths. The lung-cancer SMR was greater among people who had acute beryllium pneumonitis (SMR, 2.32) than among those who had CBD (SMR, 1.57); the former was

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
×

statistically significant. IARC (1993) concluded that the studies of cases in the Beryllium Case Registry provided indirect evidence that beryllium, rather than smoking, explained the increase in lung cancer under the assumption that people with acute pneumonitis were unlikely to smoke more than workers with CBD.

With respect to other cancer end points, Carpenter et al. (1988) conducted a nested case-control study of cancers of the central nervous system among workers at facilities in Oak Ridge, Tennessee. There were 72 male and 17 female deaths due to central-nervous-system cancer. Using job titles, the investigators considered the potential exposure to each of 26 chemicals, including beryllium. There was a weak association with exposure to beryllium with an odds ratio (OR) of 1.5 (95% CI, 0.6-3.9). The authors concluded that their study did not support the hypothesis that occupational exposures to the chemicals they studied appreciably increased the risk of cancer of the central nervous system. IARC (1993) noted that there was an increasing risk of cancer of the central nervous system with longer duration of employment in jobs with greater exposure to beryllium.

On the basis of the studies described above, IARC concluded that there is sufficient evidence in humans of the carcinogenicity of beryllium and beryllium compounds. That was based on the cohort studies, which showed

  • A large number of lung-cancer cases with a stable estimate of the SMR.

  • Consistency among locations.

  • A greater excess of lung cancer among workers hired before 1950, when exposures were greater.

  • The highest lung-cancer risk at the plant that had the greatest proportion of acute beryllium pneumonitis cases in the Beryllium Case Registry.

  • High lung-cancer risks at plants with the greatest risk of pneumoconiosis and other respiratory diseases.

  • A greater lung cancer risk observed in the Beryllium Case Registry cohort.

  • Increasing risks with increasing latency.

IARC pointed out the following limitations:

  • Absence of individual exposure measurements.

  • Relatively low excess lung-cancer risks.

  • Absence of any mention of exposures to other lung carcinogens in the workplace.

A series of letters and papers issued after the IARC report raised concerns and objections about the basis of its conclusions. Some raised concerns about the IARC procedures, the information available to the IARC working group, and possible conflicts of interest (Kotin 1994a,b; Vainio and Kleihues 1994). Others questioned the validity of the Ward et al. study. Questions were raised about the dataset used to estimate background lung-cancer rates, how to combine data from multiple plants, and how to adjust for cigarette-smoking (MacMahon 1994; Levy et al. 2002). Levy et al. (2002) have reported that making alternative adjustments and comparisons to address those issues resulted in no statistical association between beryllium exposure in the workers and lung cancer.

Since the IARC evaluation in 1993, there have been two additional studies. Sanderson et al. (2001b) conducted a nested case-control study of plant workers at the Reading, Pennsylvania, facility. The cohort of 3,569 male workers was the same cohort in the Ward et al. study in 1992. The lung-cancer cases numbered 142 on the basis of a followup of the cohort through 1992, each of which was age- and race-matched to five controls. In addition to assessment of beryllium exposures, the potential for confounding by smoking was evaluated. The cases had lower lifetime exposures to beryllium. However, when a 10-year lag and a 20- year lag were applied, the exposure metrics were higher for cases. Furthermore, significant positive trends with the log of exposure metrics were observed, and the authors concluded that smoking did not confound the exposure-response analysis.

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
×

Methodologic concerns have been raised about the Sanderson et al. study. Deubner et al. (2001c) suggested that concomitant exposure to acid mists and vapors was a possible confounder, noted difficulties with the adjustment for tobacco-smoking, and raised issues about the selection of control subjects. The study results were reanalyzed with different methods for summarizing exposure histories and for matching controls to cases (Levy et al. 2007). Each alternative method resulted in lower exposure ORs that were nonsignificant.

Brown et al. (2004) published a study of lung cancer and internal doses of plutonium among workers at the Rocky Flats plant in Colorado. The case-control study obtained information on smoking histories and on cumulative exposures to four lung carcinogens: asbestos, beryllium, hexavalent chromium, and nickel. In their analysis, none of the exposures to the four carcinogens was significantly associated with lung-cancer mortality.

Animal Studies

This section focuses on studies of inhalation exposure to beryllium and its compounds and the later development of neoplasms in laboratory animals (see Table 4-2). Lung neoplasms have been found in rats and monkeys exposed to beryllium compounds via inhalation.

Albino Sherman and Wistar rats (male and female) were exposed via inhalation to an aqueous aerosol of beryllium sulfate tetrahydate (which contained beryllium at 35.7 μg/m3) for 8 h/day, 5.5 days/week, for 6 months (Schepers et al. 1957). The rats were observed for 18 months after exposure. Lung neoplasms (18 adenomas, five squamous-cell carcinomas, 11 papillary adenocarcinomas, and seven alveolar-cell adenocarcinomas) were observed in the treated rats but not in the control rats.

A study by Vorwald and Reeves (1959) reported the development of lung neoplasms in Sherman rats (number and sex not reported) exposed via inhalation to beryllium sulfate at 6 and 54.7 μg/m3 for 6 h/day, 5 days/week, for up to 18 months. The neoplasms observed were primarily adenomas and squamous-cell cancers.

A study by Reeves et al. (1967) exposed male and female Sprague-Dawley rats to beryllium sulfate at 34.25 μg/m3 for 7 h/day, 5 days/week. The mean particle size of the beryllium sulfate aerosol was 0.118 μm. Exposure lasted up to 72 weeks. After 13 months of exposure, all the exposed rats developed alveolar adenocarcinomas; the control rats had no lung neoplasms. The neoplasia was preceded by a proliferative response that progressed from hyperplasia to neoplasia.

In another study in which particle size was calibrated, Charles River CD rats were exposed to beryllium sulfate at 35.16 μg /m3, with a mean particle size of 0.21 μm, for 35 h/week (Reeves and Deitch 1969). The exposure durations were 800, 1,600, and 2,400 h. The lung- tumor incidence in young rats exposed for 3 months (86%, 19 of 22 rats) was the same as that in older rats exposed for 18 months (86%, 13 of 15 rats). However, older rats that were exposed to beryllium sulfate for 3 months had fewer lung neoplasms than rats that were exposed when they were younger. The pulmonary neoplasms were typically observed after a latency of 9 months. Preneoplastic lesions were described as epithelial hyperplasia at 1 month, metaplasia at 5 to 6 months, and anaplasia by 7 to 8 months.

Male and female rhesus monkeys (Macaca mulatta) were exposed to beryllium sulfate at 35 μg/m3 for 6 h/day, 5 days/week (Vorwald 1968). Exposure was often interrupted for considerable periods to prevent the monkeys from developing acute beryllium pneumonitis (four monkeys died of acute chemical pneumonitis during the first 2 months of the study). The longest exposure was for a total of 4,070 h, and most of the exposure periods occurred during the first 4.5 years of the study. A 6-month exposure occurred 2.5 years after the initial 4.5-year exposure period. The authors reported that pulmonary anaplastic carcinomas (adenomatous and epidermoid patterns) were observed in eight of 12 monkeys; the first tumor was observed in a monkey that had been exposed for 3,241 h. The neoplasms metastasized to mediastinal lymph nodes and other areas of the body.

Lung tumors were observed in male white random-bred rats exposed to beryllium fluoride (at 0.4 or 0.04 mg/m3) or beryllium chloride (at 0.2 or 0.02 mg/m3) for 1 h/day, 5 days/week, for 4 months

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
×

TABLE 4-2 Inhalation Carcinogenicity Studies of Beryllium

Reference

Species

Route

Dose

Findings

Acute Exposures

Sanders et al. 1978

Rat

Inhalation

1.0-91 μg of Be from BeO (single, alveolar deposition)

Particle size: 1.10 ± 0.17 μm (GSD, 2.17 ± 0.17 μm)

Alveolar half-life of Be in lungs was 325 d; 1 of 184 rats had lung tumors after 2 years

Groth et al. 1980

Rat

Intratracheal

Be at 0.5 or 2.5 mg/m3 as passivated metal (Be-Cr), alloys (Al, Cu, Ni, Cu/Co)

Particle size: 1-2 μm

Lung adenomas, adenocarcinomas found in 2 of 21 and 9 of 16 treated with Be, 7 of 20 and 9 of 26 treated with Be-Cr, 1 of 21 and 4 of 24 treated with Be-Al, respectively; no tumors with other alloys

Litvinov et al. 1983

Rat

Intratracheal

BeO at 0.036, 0.36, 3.6, or 18 mg/kg (low- and high-fired)

Malignant epithelial lung tumors found;.

after low-fired BeO, 0 of 76, 0 of 84, 2 of 77, 2 of 103, respectively;

after high-fired BeO,: 3 of 69, 7 of 81, 18 of 79, 8 of 26

Nickell-Brady et al. 1994

Rat

Inhalation

Be at 410, 500, 830, 980 mg/m3 (single exposure; lung burdens, 110, 40, 360, 430 μg)

Particle size: 1.4 μm (GSD, 1.9 μm)

64% of rats developed lung tumors (primarily adenocarcinomas) after 14 months

Short-term and Subchronic Exposures

Schepers et al. 1957

Rat

Inhalation

Be at 35.7 μg/m3 as BeSO4 (8 h/day, 5.5 days/week for up to 6 months)

Lung-cancer rates higher in exposed rats than in controls

Vorwald and Reeves 1959

Rat

Intratracheal

4.5 mg of Be as BeO, 0.1071 mg of Be as BeSO4 (three injections over 3 weeks)

Lung tumors began to appear after 8 months; percentage of rats affected not specified in paper

Ishinishi et al. 1980

Rat

Intratracheal

1 mg of BeO (low-fired) (once a week for 15 weeks)

1 adenocarcinoma, 1 squamous-cell carcinoma, 4 adenomas

Chronic Exposures

Dutra et al. 1951

Rabbit

Inhalation

BeO at 1, 6, 30 μg/L (5 h/day, 5 days/week, for 9-13 months)

Particle size: 0.285 μm (mean), 0.11-1.25 μm (range)

6 of 9 rabbits developed osteosarcomas after 1 year

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
×

Reference

Species

Route

Dose

Findings

Vorwald and Reeves 1959

Rat

Inhalation

Be at 0.0547 mg/m3 as BeSO4, at 0.006 mg/m3 as BeO (6 h/day, 5 days/week, for various durations up to 18 months)

Lung tumors began to appear after 9 months; percentage of rats affected not specified, but later report (Vorwald et al. 1966) describes incidence of cancer as “almost 100%” in “large number” of surviving rats

Reeves et al. 1967

Rat

Inhalation

Be at 34.25 μg/m3 (mean) as BeSO4 (7 h/day, 5 days/week, for 72 weeks)

Particle size: 0.118 μm

All rats developed lung tumors (adenocarcinomas) by 13 months

Vorwald 1968

Monkey

Inhalation

Be SO4 at 35 μg/m3 (6 h/day, 5 days/week, with various interruptions and variable durations up to 4,070 h)

8 of 12 monkeys had pulmonary anaplastic carcinomas (adenomatous and epidermoid patterns); first tumor observed after 3,241 h of exposure

Reeves and Deitch 1969

Rat

Inhalation

BeSO4 at 35.16 μg/m3 (35 h/week for 800, 1,600, 2,400 h)

Particle size: 0.21 μm (mean)

19 of 22 young rats and 13 of 15 older rats developed lung tumors after 3 and 18 months, respectively; at 3 months, older rats had fewer lung neoplasms than younger rats

Wagner et al. 1969

Rat, hamser, squirrel monkey

Inhalation

Bertrandite dust at 15 mg/m3 (Be at 210 μg/m3) or beryl ore at 15 mg/m3 (Be at 620 μg/m3) (6 h/day, 5 days/week, for up to 23 months)

Particle size: bertrandite, 0.27 μm (mean); beryl ore, 0.64 μm (mean)

18 of 19 rats exposed to beryl ore had lung tumors (bronchial alveolar cell tumors, adenomas, adenocarcinomas, or epidermoid tumors); no increased incidence of tumors in rats from dust or in other species from either compound

Litvinov et al. 1975

Rats

Inhalation

BeF2 at 0.04 or 0.4 mg/m3or BeCl2 at 0.02 or 0.2 mg/m3 (1 h/day, 5 day/week, for 4 months)

Lung tumors found in treatment groups

Litvinov et al. 1984

Rats

Inhalation

BeO or BeCl2 at 0.8, 4, 30, or 400 μg/m3 (1 h/day, 5 days/week, for 4 months)

Malignant lung tumors found in 3 of 44, 4 of 39, 6 of 26, 8 of 21 in BeO group and in 1 of 44, 2 of 42, 8 of 24, 11 of 19 in BeCl2 group, respectively

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
×

Reference

Species

Route

Dose

Findings

Finch et al. 1998b

Mouse (p53+/− knockout and p53+/+ wild-type)

Inhalation

15 or 60 Be μg (60 μg achieved over 3 days)

Particle size: 1.4 μm (mean) (GSD, 1.8 μm)

4 of 28 p53+/− mice in high-dose group developed lung tumors; no lung tumors found in low-dose group or in p53+/− mice

Mode-of-Action Studies

Skilleter et al. 1991

Rat hepatic BL9L cells

In vitro

50 μM BeSO4

BeSO4 inhibited cell division during G1 phase of cell cycle, but expression of c-myc was maintained in serum-stimulated cells

Nickell-Brady et al. 1994

Rat

Inhalation

Be at 410, 500, 830, 980 mg/m3 (single exposure; lung burdens, 110, 40, 360, 430 μg)

Particle size: 1.4 μm (GSD, 1.9 μm)

Analysis of p53 and c-raf-1 genes in neoplasms did not indicate genetic alterations; weak evidence of mutation of K-ras gene

Swafford et al. 1997

Rat primary lung tumors and cells lines from Nickell-Brady et al. (1994) study

 

 

Aberrant methylation status of p16INK4a , leading to loss of expression

Joseph et al. 2001

Mouse BALB/c-3T3 cells

Transformed cells injected into nude mice, cell lines derived from resulting tumors

BeSO4 at 50-200 μg/mL

Analyses of gene expression indicate that cell transformation and tumorigenesis are associated with upregulated expression of genes related to cancer (such as c-fos, c-jun, c-myc, R-ras) and downregulation of genes involved in DNA synthesis, repair, recombination (such as MCM4, MCM5, PMS2, Rad23, DNA ligase I)

Keshava et al. 2001

Mouse BALB/c-3T3 cells

In vitro

BeSO4 at 50-200 μg/mL

Results show that cells transformed by BeSO4 are potentially tumorigenic; transformation might involve gene amplification of K-ras, c-jun; some transformed cells have neoplastic potential because of genomic instability

Belinsky et al. 2002

Rat

Inhalation

40, 110, 360, 430 μg of Be (single dose; mean lung burdens)

Tumors induced in part through inactivation of p16 and ER genes

Misra et al. 2002

Mouse peritoneal macrophages

In vitro

1-5 nM BeF2

Phosphorylation increased for kinases MEK1, ERK1, p38 MAPK, JNK; increases also seen in NF-κB, CREB transcription factors, c-fos, and c-myc

Note: Al = aluminum, Be = beryllium, BeCl2 = beryllium chloride, BeF2 = beryllium fluoride, BeO = beryllium oxide, BeSO4 = beryllium sulfate, Co = cobalt, Cr = chromium, Cu = copper,; GSD = geometric standard deviation, Ni = nickel.

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
×

(Litvinov et al. 1975). The first neoplasms were observed after 16 months in rats exposed to beryllium fluoride at 0.4 mg/m3 and beryllium chloride at 0.2 mg/m3. Neoplasms also developed in the lungs of rats exposed at the lower concentrations, but not in the lungs of the control rats.

Litvinov et al. (1984) exposed female albino rats to beryllium oxide or beryllium chloride at 0.8, 4, 30, and 400 μg/m3 for 1 h/day, 5 days/week, for 4 months. Malignant lung neoplasms developed in a dose-related manner after exposure to either beryllium oxide or beryllium chloride, but none was found in the controls. The carcinogenicity of two beryllium ores, bertrandite and beryl, was evaluated in male squirrel monkeys (Saimiri sciurea), male Charles River-CD rats, male Greenacres Controlled Flora (GA) rats, and male Golden Syrian hamsters (Wagner et al. 1969). The rats and hamsters were exposed to bertrandite or beryl at 15 mg/m3 for 6 h/day, 5 days/week, for 17 months, and the monkeys were exposed for 23 months. Beryllium from bertrandite was present in the test atmospheres at 210 μg/m3 and from beryl at 620 μg/m3; the geometric means of the particles were 0.27 μm and 0.64 μm, respectively. In the beryl-exposed rats, squamous metaplasia or small epidermoid tumors were identified in the lungs of five of 11 rats killed after 12 months of exposure and 18 of 19 rats after 17 months of exposure. Eighteen of the rats had bronchiolar alveolar-cell tumors, nine had adenocarcinomas, seven had adenomas, and four had epidermoid tumors. Although granulomatous lesions were observed in the bertrandite-exposed rats, no neoplasms were identified in the rats exposed for 6, 12, or 17 months. Neither neoplasms nor granulomas developed in the control rats.

Atypical proliferations were observed in the lungs of hamsters 12 months after exposure to bertrandite or beryl. The lesions were reported to be larger and more adenomatous in the beryl group after 17 months. No pulmonary lesions occurred in the control hamsters. No tumors were observed in either the bertrandite- or beryl-treated monkeys.

The carcinogenicity of beryllium metal has also been investigated. In one study, male and female F344/N rats were received a single, nose-only exposure to a beryllium metal aerosol at 500 mg/m3 for 8 min, at 410 mg/m3 for 30 min, at 830 mg/m3 for 48 min, or at 980 mg/m3 for 39 min (Nickell-Brady et al. 1994). The latent period for development of neoplasms was about 14 months; tumor incidence was 64% over the lifetime of the rats. Most of the neoplasms were adenocarcinomas, although multiple tumor types were observed.

In another study of beryllium metals (Groth et al. 1980), lung adenomas and adenocarcinomas were observed in nine of 16 female Wistar rats that received a single intratracheal instillation of 2.5 mg of beryllium metal, nine of 26 rats treated with 2.5 mg of passivated beryllium metal, and four of 24 rats given 2.5 mg of beryllium-aluminum alloy. No neoplasms were observed in the lungs of the controls.

Pulmonary neoplasms developed in inbred albino rats that were given single intratracheal deposits of beryllium oxide (fired at high and low temperatures) at 0.036, 0.36, 3.6, or 18 mg/kg (Litvinov et al. 1983). The neoplasms were adenomas, adenocarcinomas, and squamous-cell carcinomas.

Wistar rats received intratracheal instillations of 1 mg of beryllium oxide (low-fired) once a week for 15 weeks (Ishinishi et al. 1980). An adenocarcinoma, a squamous-cell carcinoma, and four adenomas were observed in the lungs of 30 beryllium-treated rats and no neoplasms in the 16 controls.

SUMMARY

Genotoxicity studies of beryllium have yielded conflicting results that appear to be somewhat compound dependent. The committee will critically evaluate the literature in its next report and consider how the information should be factored into the carcinogenic assessment of beryllium.

There is evidence from controlled studies that exposure to beryllium can cause lung cancer in both sexes of rats, and one study reported lung tumors in monkeys. Epidemiologic studies have reported increases in lung-cancer risk in two worker cohorts exposed to beryllium. Those studies were instrumental in forming the basis of the current cancer classifications by such agencies as the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, and the National Toxicology Program. In its second report, the committee will focus on assessing the collective evidence in characterizing the carcinogenic potential of beryllium and estimating carcinogenic risks.

Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
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Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
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Suggested Citation:"4 Genotoxicity and Carcinogenicity." National Research Council. 2007. Health Effects of Beryllium Exposure: A Literature Review. Washington, DC: The National Academies Press. doi: 10.17226/12007.
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Beryllium is an important metal that is used in a number of industries—including the defense, aerospace, automotive, medical, and electronics industries—because of its exceptional strength, stability, and heat-absorbing capability. It is found in a variety of technologies, including nuclear devices, satellite systems, missile systems, radar systems, bushings and bearings in aircraft and heavy machinery, x-ray machines used for mammography, cellular telephone components, computer components, and connectors for fiber optics. To help determine the steps necessary to protect its workforce from the adverse effects of exposure to beryllium used in military aerospace applications, the U.S. Air Force requested that the National Research Council's Committee on Toxicology (COT) conduct an independent evaluation of the scientific literature on beryllium, provide risk estimates for cancer and noncancer health end points, and make recommendations about specific tests for surveillance and biomonitoring of workers.

The request specified that two reports be produced to accomplish those tasks. The first is to provide a review of the scientific literature on beryllium, and the second will expand more critically on the review in considering the maximum chronic inhalation exposure levels that are unlikely to produce adverse health effects, in estimating carcinogenic risks, and in providing guidance on testing methods for surveillance and monitoring of worker populations and other specific issues detailed in the statement of task. In response to the U.S. Air Force request, COT convened the Committee on Beryllium Alloy Exposures, which prepared this first report. Health Effects of Beryllium Exposure : A Literature Review identifies the available toxicologic, epidemiologic, and other literature on beryllium that is most relevant for addressing the statement of task, focusing primarily on beryllium sensitization, CBD, and cancer.

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