Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM) 

Beryllium Toxicity
How Does Beryllium Induce Pathogenic Changes?

Learning Objectives

Upon completion of this section, you will be able to

• describe two mechanisms of injury resulting from beryllium exposure, and
• describe the health conditions associated with beryllium exposure.

Acute versus Chronic Disease

Two distinct mechanisms of injury can result from beryllium exposure. In acute disease, high levels of beryllium exposure can result in inflammation of the upper and lower respiratory tract and airways, bronchiolitis, pulmonary edema, and chemical pneumonitis. (Kim 2004). Acute beryllium disease occurs less commonly than chronic beryllium disease (CBD).

CBD, sometimes called berylliosis, is primarily a pulmonary disorder in which granulomatous inflammation develops after exposure and subsequent sensitization to beryllium. The lungs and thoracic lymph nodes are the primary sites involved. In addition, beryllium exposure can cause skin disease. Rarely, CBD can involve the liver, myocardium, salivary glands, and bones (Glazer and Newman 2003).

The terms acute and chronic, used to describe beryllium disease, refer to disease processes rather than types of exposure. Acute beryllium disease manifests as an acute chemical pneumonitis, whereas CBD is typically a progressive pulmonary granulomatous lung disease (Sawyer et al. 2002). Table 2 shows possible human health effects of beryllium exposure.

Respiratory Tract

• Bronchiolitis
• Acute pneumonitis
• Chronic beryllium disease
• Lung cancer
• Pulmonary hypertension*
• Pneumothorax*

Skin

• Contact dermatitis
• Subcutaneous granulomatous nodules
• Ulceration
• Delayed wound healing

Lymphatic/ Hematologic

• Hilar and mediastinal lymphadenopathy*
• Beryllium sensitization

*Occurs in association with chronic beryllium disease.

Respiratory Effects: Acute

Acute beryllium lung disease has been almost completely eliminated in the United States through use of exposure controls. Acute disease manifests as inflammation of the upper or lower respiratory tract or both. The most serious complication is chemical pneumonitis. Acute disease appears suddenly after short exposure to high concentrations or progresses slowly after longer exposure to lower concentrations. Pneumonitis or bronchitis induced by (Kress and Crispell 1944).

Respiratory Effects: Chronic

CBD (also known as berylliosis) continues to occur in industries where beryllium and its alloys are processed, smelted, fabricated, and machined—resulting in respirable beryllium particles. CBD is a disorder in which a delayed type IV hypersensitivity response to a persistent antigen (beryllium) leads to noncaseating granuloma formation (Tinkle et al. 1999). This interstitial mononuclear cell inflammation and granuloma formation are the primary processes that occur in the lungs and airways of beryllium exposed workers (Sawyer et al. 2002). The most common manifestation is chronic interstitial pneumonitis with infiltration of lymphocytes, histiocytes, and plasma cells (Saltini and Amicosante 2001).

Beryllium sensitization (BeS) and CBD can occur within 50 days of first exposure in modern industry. Some cases of CBD, however, do not develop until 30 - 40 years after exposure has ceased. On average, CBD usually takes at least 6 - 15 years after exposure to develop into clinically significant respiratory disease (Glazer and Newman 2003; Newman et al. 2001).

Dermal Effects

Beryllium-containing particles that lodge in a worker’s skin can cause BeS, and lead to ulcerations and delayed wound healing. Biopsy reveals noncaseating granulomas at the site of injury (Berlin et al. 2003). Soluble beryllium compounds may cause contact dermatitis. Conjunctivitis, periorbital edema, or upper respiratory tract involvement may occur along with facial contact dermatitis. The use of beryllium-containing dental prostheses can cause the equivalent of oral contact dermatitis and hand lesions in individuals making oral prostheses (Grimaudo 2001).

Carcinogenic Effects

The National Toxicology Program (1999, 2002) lists beryllium and certain beryllium compounds (beryllium-aluminum alloy, beryllium chloride, beryllium fluoride, beryllium hydroxide, beryllium oxide, beryllium phosphate, beryllium sulfate, beryllium zinc silicate, and beryl ore) as substances reasonably anticipated to be carcinogens. The International Agency for Research on Cancer (1993, 2001) has classified beryllium and beryllium compounds in Group 1, carcinogenic to humans, and the U.S. Environmental Protection Agency classifies inhaled beryllium in Group B1, a probably human carcinogen (IRIS 2002). (Sanderson et al. 2001, ATSDR 2002).

Epidemiological studies have shown an increased risk of lung cancer among beryllium-exposed workers and among workers with acute and CBD. The excess incidence of lung cancer was more pronounced among those with acute beryllium disease (SMR = 2.32) than among those with CBD (SMR = 1.57) (Steenland and Ward 1991). Increased lung cancer among workers with higher beryllium exposures and lack of evidence for confounding by cigarette smoking, provide further evidence that beryllium is a human lung carcinogen (Sanderson et al. 2001).

Some researchers have disputed reported increased risk of lung cancer in beryllium workers in published epidemiologic studies (Levy et al. 2002). In addition, mutation and chromosomal aberration assays have yielded somewhat contradictory results. Only a limited number of studies have addressed the underlying mechanisms of the carcinogenicity and mutagenicity of beryllium.

It is likely that the different chemical forms of beryllium have different effects on mutagenicity and carcinogenicity, causing some confusion as to mechanisms of carcinogenesis and the cancer risk to humans (Gordon and Bowser 2003).

Key Points

• The most common histology in CBD is granulomatous inflammation on lung biopsy.
• Skin contact with beryllium can cause ulceration and subcutaneous granulomas.
• Epidemiological studies have shown an increased risk of lung cancer among beryllium-exposed workers and among workers with acute and CBD.

Progress Check