Beryllium: An etiologic agent in the induction of lung cancer, nonneoplastic respiratory disease, and heart disease among industrially exposed workers

doi:10.1016/0013-9351(80)90004-3

Environmental Research

Volume 21, Issue 1, February 1980, Pages 15-34

https://doi.org/10.1016/0013-9351(80)90004-3 Get rights and content

Abstract

On the basis of the clear demonstration of the carcinogenicity of beryllium in several animal species along with the suggestion of an increased risk of lung cancer mortality in humans exposed to beryllium, an epidemiologic study of workers exposed to beryllium at one production facility was undertaken. Within the limitations imposed by the selection of data for calculation of cause-specific expected mortality (use of U.S. white male cause-specific mortality rates with linear extrapolation of 1965–1967 to 1968–1975 vs use of cause-specific mortality rates for the county in which the study facility and the majority of its workers resided), the study demonstrated a statistically significant increased risk of respiratory disease (neoplastic and nonneoplastic) and of heart disease mortality. A possible explanation other than in terms of beryllium was sought for this excessive risk of cause-specific mortality among beryllium-exposed workers. The excessive risk of lung cancer mortality could not be related to an effect of age, chance, self-selection, study group selection, exposure to other agents in the study facility, or place of residence. On the basis of the frequency of cigarette smoking among those cohort members employed in 1967–1968 and the distribution of histologic types of lung cancer among deceased cohort members, it seems unlikely that cigarette smoking per se could have accounted for the increased risk of lung cancer among beryllium-exposed workers in the study cohort. Lifetime employment histories for members of the study cohort were not available, so that definitive statements about the role of other occupational exposures cannot be made. However, information on usual occupations as indicated on death certificates suggests that it is unlikely that some undefined occupational or environmental exposure other than to beryllium could account per se for the excessive lung cancer mortality. This interpretation is further supported by the residential stability of the study cohort in a county having a lung cancer rate significantly lower than that of the entire United States. The findings of a statistically significant excess of lung cancer mortality among cohort members in general (P < 0.05) and among workers observed 25 or more years since onset of beryllium exposure in particular (P < 0.01), when taken in context with the results of earlier animal bioassay and recent epidemiologic studies, are supportive of the hypothesis that beryllium is carcinogenic to man.

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Cited by (81)

Carcinogenicity of metal compounds
2021, Handbook on the Toxicology of Metals: Fifth Edition
Compounds of four metals including nickel, chromium, cadmium, and beryllium, and one metalloid and its compounds—arsenic, have been confirmed as human carcinogens by International Agency for Research on Cancer (IARC). Most of these epidemiological studies were done retrospectively in humans occupationally exposed to compounds of these metals. There are only a few environmental studies in humans exposed to any of these metal compounds in which possible speciation of the metal compound is considered. The carcinogenicity of these compounds has been confirmed in vitro and in vivo. This chapter gives the background of metal carcinogenicity. Epidemiological studies, experimental models, and mechanism of carcinogenicity are summarized for each metal. In addition, mechanical information about the carcinogenicity of air pollution is briefly discussed in this chapter. The reader is referred to more detail in the individual metals chapters in Volume II and to Chapter 11, Volume I, Selected Molecular Mechanisms of Metal Toxicity and Carcinogenicity, and to Chapter 6, Volume I, Metals and Air Pollution, for more detail in air pollution.
Beryllium
2021, Handbook on the Toxicology of Metals: Fifth Edition
Beryllium is a critical material for many strategic industries, and it is produced in three primary forms: copper-beryllium alloy, pure beryllium metal, and beryllium oxide ceramics.
At present, the time-weighted average (TWA) concentrations are in the range of 0.01–1 μg/m³ (work environment limits).
Exposures to beryllium are much more hazardous by the inhalation route than by the ingestion route. Inhalation exposure to beryllium compounds results in the long-term storage of beryllium in lung tissue, particularly in pulmonary lymph nodes, and in the skeleton, which is the ultimate site of beryllium storage.
Exposure to beryllium compounds has caused dermatitis, acute and chronic beryllium disease (CBD, chronic pulmonary granulomatosis, berylliosis). Exposure to soluble beryllium salts may cause skin reactions such as edematous, erythematous, and papulovesicular dermatitis. Granulomatous necrotic changes and ulcerations due to skin penetration by insoluble beryllium salts were also observed. These pathological changes are based on delayed allergic hypersensitivity. Acute toxicity of beryllium at concentrations usually above 25 μg/m³ is manifested by skin, eye, nose, and throat irritation, followed by upper and lower airway inflammation, pulmonary edema, and chemical pneumonitis.
CBD is the best-known negative health effect caused by exposure to beryllium. CBD is a T-cell-mediated disorder. Beryllium linked to HLA-DP2/peptide complex interacts with T-cell antigen receptors in the lungs. The beryllium blood lymphocyte proliferation test (BeLPT) is used as a medical surveillance tool for the assessment of persons at risk of developing clinical and subclinical CBD. It is generally accepted that sensitization occurs among a subset of workers. An increased incidence of lung cancer was found in populations occupationally exposed to beryllium. In their carcinogenicity rating, the International Agency for Research on Cancer classified beryllium as a group 1 substance (carcinogenic to humans).
Carcinogenicity of metal compounds
2021, Handbook on the Toxicology of Metals: Volume I: General Considerations
Compounds of four metals including nickel, chromium, cadmium, and beryllium, and one metalloid and its compounds—arsenic, have been confirmed as human carcinogens by International Agency for Research on Cancer (IARC). Most of these epidemiological studies were done retrospectively in humans occupationally exposed to compounds of these metals. There are only a few environmental studies in humans exposed to any of these metal compounds in which possible speciation of the metal compound is considered. The carcinogenicity of these compounds has been confirmed in vitro and in vivo. This chapter gives the background of metal carcinogenicity. Epidemiological studies, experimental models, and mechanism of carcinogenicity are summarized for each metal. In addition, mechanical information about the carcinogenicity of air pollution is briefly discussed in this chapter. The reader is referred to more detail in the individual metals chapters in Volume II and to Chapter 11, Volume I, Selected Molecular Mechanisms of Metal Toxicity and Carcinogenicity, and to Chapter 6, Volume I, Metals and Air Pollution, for more detail in air pollution.
Characterization and distribution of metal and nonmetal elements in the Alberta oil sands region of Canada
2016, Chemosphere
Citation Excerpt :
Much less focus has been on the metals despite their being on the United States Environmental Protection Agency (USEPA) list of priority pollutants (PPE) and known risks towards the health of many species (Kelly et al., 2010; Gueguen et al., 2011; Puttaswamy and Liber, 2012). Toxicological effects have been reported for currently considered metal elements including Hg (Sweet and Zelikoff, 2001; Clarkson and Magos, 2006; Rooney, 2007), Pb (Hsu, 2002; Canfield et al., 2003; Flora et al., 2012), As (Hindmarsh, 2000; Xia et al., 2009; Hughes et al., 2011), Cd (Perfus-Barbeoch et al., 2002; Nordberg, 2009), Cr (Katz and Salem, 1993; Levina et al., 2002), Be (Wagoner et al., 1980), Sb (Gebel, 1997), Se (Spallholz, 1994), Tl (Cerwenka and Cooper, 1961), Cu (Welsh et al., 1996), Ni (Oller et al., 1997), Ag (Hollinger, 1996), and Zn (Eisler and Gardner, 1973). Among these, Hg, Pb, and As have received the most attention, while enhanced synergistic toxicological effects have been reported in the presence of multiple elements (Leber, 1976; Pillai et al., 2003; Hu et al., 2013).
This review covers the characterization and distribution of metals and nonmetals in the Alberta oil sands region (AOSR) of Canada. The development of the oil sands industry has resulted in the release of organic, metal and nonmetal contaminants via air and water to the AOSR. For air, studies have found that atmospheric deposition of metals in the AOSR decreased exponentially with distance from the industrial emission sources. For water, toxic metal concentrations often exceeded safe levels leading to the potential for negative impacts to the receiving aquatic environments. Interestingly, although atmospheric deposition, surface waters, fish tissues, and aquatic bird eggs exhibited increasing level of metals in the AOSR, reported results from river sediments showed no increases over time. This could be attributed to physical and/or chemical dynamics of the river system to transport metals to downstream. The monitoring of the airborne emissions of relevant nonmetals (nitrogen and sulphur species) was also considered over the AOSR. These species were found to be increasing along with the oil sands developments with the resultant depositions contributing to nitrogen and sulphur accumulations resulting in ecosystem acidification and eutrophication impacts. In addition to direct monitoring of metals/nonmetals, tracing of air emissions using isotopes was also discussed. Further investigation and characterization of metals/nonmetals emissions in the AOSR are needed to determine their impacts to the ecosystem and to assess the need for further treatment measures to limit their continued output into the receiving environments.
Beryllium
2015, Handbook on the Toxicology of Metals: Fourth Edition
Beryllium is a critical material for many strategic industries. It is widely used despite its relatively high cost because it performs better in certain critical applications than its alternatives. The beryllium industry produces three primary forms of beryllium: copper-beryllium alloy is the largest, followed by pure beryllium metal and beryllium oxide ceramics.
As a result of the increasing industrial use of beryllium, occupational exposure to the metal may be an important issue. Prior to 1950 when exposure levels of ≤ 2 μg/m³ were mandated by the Atomic Energy Commission, beryllium levels were very high. The estimated daily weighted average beryllium exposure levels for some workers in a plant that extracted and produced beryllium metal were 1000 μg/m³ in the 1940s and 1950s, > 50 μg/m³ during the mid-1960s, and > 30 μg/m³ during the mid-1970s. At present, the time-weighted average (TWA) concentrations are in the range of 0.01-1 μg/m³.
Exposures to beryllium are much more hazardous by the inhalation route than by the ingestion route. Beryllium and its compounds are poorly absorbed from the gastrointestinal tract. In general, inhalation exposure to beryllium compounds results in the long-term storage of appreciable amounts of beryllium in lung tissue, particularly in pulmonary lymph nodes, and in the skeleton, which is the ultimate site of beryllium storage. Urinary beryllium concentrations are below the detection limits of 0.03-0.06 μg/L.
Exposure to beryllium compounds has caused dermatitis, acute pneumoconiosis, and chronic beryllium disease (CBD, chronic pulmonary granulomatosis, berylliosis). Exposure to soluble beryllium salts may cause skin reactions such as edematous, erythematous, and papulovesicular dermatitis. These changes usually disappear after the cessation of exposure. Granulomatous necrotic changes and ulcerations due to skin penetration by insoluble beryllium salts were also observed. These pathological changes are based on delayed allergic hypersensitivity. Acute toxicity of beryllium at concentrations usually above 25 μg/m³ is manifested by skin, eye, nose, and throat irritation, followed by upper and lower airway inflammation, pulmonary edema, and (above 100 μg/m³) chemical pneumonitis.
CBD is the best-known negative health effect caused by exposure to beryllium. CBD is a T cell-mediated disorder. Beryllium, acting as a hapten, interacts with antigen-presenting cells in the lungs. The beryllium blood lymphocyte proliferation test (BeLPT) is used as a medical surveillance tool for the assessment of persons at risk of developing clinical and subclinical CBD. It is generally accepted that sensitization occurs among a subset of workers. Several reports suggest that sensitization and CBD were associated with beryllium air TWA levels exceeding 0.2 μg/m³. A threshold limit value (TLV)-TWA of 0.05 μg/m³ recommended in 2008 by American Conference of Governmental Industrial Hygienists is expected to be protective for the beryllium-sensitive population.
An excess incidence of lung cancer was found in populations occupationally exposed to beryllium, and was higher for individuals with acute beryllium disease than those with CBD. In their carcinogenicity rating, the International Agency for Research on Cancer (IARC, 1993, IARC, 2012) classified beryllium as a group 1 substance (i.e. sufficient evidence for carcinogenicity in humans). The U.S. Environmental Protection Agency (EPA) inhalation unit risk is 2.4 × 10×³ per μg/m³. In general, it seems that the lung cancer risk related to occupational exposure to beryllium is linked to the higher exposure levels that were associated with acute beryllium pneumonitis and predominated prior to the 1950s. The risk of additional lung cancer caused by 40 years of occupational exposure to beryllium or its compounds at the present TLV-TWA of 0.05 μg/m³ amounts to 1.5 × 10⁻⁵.
Cardiovascular Disease
2015, Handbook on the Toxicology of Metals: Fourth Edition
There is strong epidemiological and mechanistic evidence for a causal association between exposure to arsenic and lead and development of cardiovascular disease. There is relatively strong but less conclusive evidence for a causal relationship between cadmium and mercury exposure and cardiovascular disease. All of these metals are suspected of inducing pathophysiological changes relevant to atherogenic disorders, including increased oxidative stress, inflammatory response, and coagulation activity.
Cardiomyopathy has been associated with excessive intake of arsenic, cobalt, and iron. Deficiency of selenium has been related to dilated cardiomyopathy.
Airborne beryllium exposure has been associated with heart disease, including both ischemic heart disease and cor pulmonale. Signs of cor pulmonale have also been observed after cobalt exposure among hard-metal workers. Pulmonary fibrosis with increased blood pressure in the pulmonary circulation is a likely mechanism in the development of cor pulmonale.
Ionizing irradiation may explain the suggested relation between uranium exposure and cerebrovascular disease.

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Present knowledge of the toxic effect of berylliumBeryllium: An etiologic agent in the induction of lung cancer, nonneoplastic respiratory disease, and heart disease among industrially exposed workers

Abstract

Lancet

Environ. Res.

Chest

Environ. Res.

Environ. Res.

Environ Res.

Environ. Res.

Toxicol Appl. Pharmacol.

Mortality experience of a cohort of rubber workers, 1964–1973

J. Occup. Med.

Patterns of lung dysfunction in chronic beryllium disease

Amer. Rev. Resp. Dis.

Experimental studies on beryllium-induced malignant tumors of rabbits

Gann

Respiratory disease mortality among uranium miners

Ann. N. Y. Acad. Sci.

Frequency of different histologic types of bronchogenic carcinoma as related to radiation exposure

Cancer

Cancer Patient Survival

Beryllium bone sarcoma in rabbits

Brit. J. Cancer

Chronology of beryllium cohort studies

NIOSH memorandum to Wagoner

Mortality Patterns in Beryllium Production Workers

Letter from Kawecki Berylco Industries to D. L. Bayliss

National Institute for Occupational Safety and Health

Health Hazard Evaluation Determination Report No. 75-87-280

Bone changes observed following intravenous injection of beryllium

Amer. J. Pathol.

Some statistical considerations in the study of cancer in industry

Amer. J. Pub. Health

Health hazards from beryllium

A survey of occupational cancer in the rubber and cablemaking industries: Analysis of deaths occuring in 1972–1974

Brit. J. Ind. Med.

Osteosarcoma from intravenous beryllium compounds in rabbits

Lung-cancer mortality as related to residence and smoking histories. I. White males

J. Nat. Cancer Inst.

Inhalation of benzpyrene and cancer in man

Ann. N. Y. Acad. Sci.

Beryllium poisoning—Lessons in control of man-made disease

N. Engl. J. Med.

United States Beryllium Case Registry (1952–1966): Review of its methods and utility

J. Occup. Med.

Progress report U.S. Beryllium Case Registry 1972

Amer. Rev. Resp. Dis.

Beryllium and growth. I. Beryllium-induced osteogenic sarcoma

Cancer Res.

IARC Monograph Programme on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Preamble

IARC Internal Technical Report No. 77/002

Evidence for the carcinogenicity of beryllium

Beryllium-induced osteogenic sarcoma in rabbits

J. Bone Joint Surg.

Present knowledge of the toxic effect of beryllium
Beryllium: An etiologic agent in the induction of lung cancer, nonneoplastic respiratory disease, and heart disease among industrially exposed workers