(7)
Background and Exposure (1) :
Beryllium occurs in nature, but most exposures to beryllium that cause disease are related to beryllium processing. Beryllium is a strategic and critical material for many industries resulting in occupational exposures. It is widely used despite the high cost because it performs better than alternatives in some situations (2). The major source of its emission into the environment is through the combustion of fossil fuels (primarily coal), which releases beryllium-containing particulates and fly ash into the atmosphere. Toxic exposures can result in symptoms similar to pneumonia or bronchitis. Beryllium is not crucial for humans and in fact one of the most toxic elements we know.
Biotransformation and Mechanism of Action (2):
Target Organs (8):
- 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.
- Skeletal system:
- Rickets in young animals appeared to be the result of the binding of phosphate to beryllium in the gut.
- Skin, liver, spleen, lymph nodes, myocardium, skeletal muscles, kidney, bone, and salivary glands may exhibit granulomas, similar to those of the lungs.
Target Organ MoA and Effects: The lungs
The primary exposure pathway for beryllium is inhalation, but beryllium is not well absorbed by any route. The major toxicological effects of beryllium are on the lung (3). Beryllium interacts with the antigen-presenting cells in the lungs. Beryllium peptide associated with the major histocompatibility (MHC) class II molecule is recognized by the T-cell receptor with the help of CD4+ molecules. This interaction triggers CD4+ T lymphocyte activation and proliferation.
Beryllium and its compounds are not biotransformed however, soluble beryllium salts are converted to less soluble forms in the lung. About half of inhaled beryllium is cleared in ∼2 weeks. The remainder is cleared slowly and the residual becomes fixed in the lung (granulomata) (3).
In general, inhalation exposure to beryllium results in 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.
(6)
Toxicokinetics in Humans (2):
The most common health effects associated with overexposure to beryllium in the workplace include beryllium sensitization, chronic beryllium disease (CBD), and lung cancer (4).
May cause skin reactions such as:
- Edematous
- Erythematous
- Papulovesicular dermatitis
May also cause:
- Conjunctivitis in occupationally exposed workers.
- Gingivitis in persons with dental implants made from alloys including beryllium.
- Granulomatous necrotic changes and ulcerations caused by skin penetration by insoluble beryllium salts.
*These pathological changes are due to delayed allergic hypersensitivity, which has been proven in-vitro and in-vivo.
Inhalation exposure may cause irritation in:
- Skin
- Eyes
- Nose
- Throat
- Upper and lower airway inflammation
- Pulmonary edema
- Chemical pneumonitis
*The pathogenesis of inflammatory changes is probably connected with the acidity of beryllium salts
Systemic effects
There are acute systemic effects, following acute exposure, reported in studies with animals that resulted in death. Chronic systemic effects include chronic Beryllium disease (CBD) which includes pulmonary granulomatosis and Berylliosis. Other Chronic systemic effects include
- Cardiovascular effects (severe cases of chronic beryllium disease can result in right ventricle hypertrophy),
- Endocrine system effects ( In a study of workers at a plant manufacturing fluorescent lamps, 1 of 17 workers exposed to beryllium who died from chronic beryllium disease had marked hyperemia and vacuolization in the histology of adrenal glands)
Carcinogenic Effects:
The International Agency for Research on Cancer (IARC) classified beryllium as a group 1 carcinogen. IARC 2001, noted that 1. the epidemiological data generally showed increases in observed lung cancers at most of the beryllium processing plants, 2. these increases were generally associated with high exposure levels that occurred before 1950, and 3. the highest risk of lung cancer occurred in individuals with acute beryllium disease. Beryllium is recognized as a known carcinogen in many other health organizations across the world.
Biomarkers (2):
BLTP:
The beryllium blood lymphocyte proliferation test (BLTP) is used as a medical surveillance tool for the assessment of persons at risk for developing clinical and subclinical CBD however, we have to consider its negative result is not the evidence for the absence of beryllium exposure.
Inflammation markers:
For the assessment of CBD progression, some nonspecific inflammation markers (cytokines) or basic fibroblast growth factor (bFGF) have been used.
Genetics:
Blood biomarkers of CBD susceptibility include class II major histocompatibility complex (MHC) genes: HLA-DP, HLA-DR.
Signs and Symptoms (5):
Patient-reported symptoms:
- Nonproductive cough
- Fatigue
- Exertional dyspnea
- Weight loss
- Fever
- Myalgia
Clinical Signs in radiograph findings:
- Nodular diffuse infiltrates
- Diffusely linear infiltrates
- Hilar adenopathy in 30-40%
Treatments (2):
- Remove affected workers from exposure to beryllium (however, no epidemiological studies have examined whether removal from exposure brings changes to the clinical course).
- Systemic glucocorticosteroid (GCS) use in improving the symptoms and/or pulmonary function.
- Immunosuppressive agents such as methotrexate and cyclosporine may be used in individuals nonresponding to GCS.
- Supportive therapy including oxygen, bronchodilators, and immunization against respiratory pathogens.
(5)
References:
(1) https://www.cancer.gov/about-cancer/causes-prevention/risk/substances/beryllium#:~:text=Hand%2Dto%2Dmouth%20exposures%20and,fly%20ash%20into%20the%20atmosphere. Accessed June 16th, 2020
(2) https://www.sciencedirect.com/science/article/pii/B9780123694133500768 Accessed June 16th, 2020
(3) https://www.sciencedirect.com/science/article/pii/B9780123864543008204 Accessed June 16th, 2020
(4) https://www.osha.gov/SLTC/beryllium/healtheffects.html#:~:text=The%20most%20common%20health%20effects,CBD)%2C%20and%20lung%20cancer. Accessed June 16th, 2020
(5) https://www.youtube.com/watch?v=CdYOYFDunsM Accessed June 16th, 2020
(6) https://www.jimmunol.org/content/196/1/22 Accessed June 16th, 2020
(7) https://www.livescience.com/28641-beryllium.html Accessed June 16th, 2020
(8) https://rais.ornl.gov/tox/profiles/beryllium.html#t2 Accessed June 16th, 2020