Cr (III) is an essential trace mineral in human nutrition.
Chromium's nutritional role has not been thoroughly delineated, but it appears to potentiate insulin action, probably in the form of glucose tolerance factor (GTF). The estimated safe and adequate daily intake of chromium for adults is in the range of 50 to 200 µg/day, although data are insufficient to establish a recommended daily allowance.
Because Cr (VI) is a powerful oxidizing agent, exposure can cause irritation and corrosion.
Dietary chromium deficiency is reactively uncommon; most cases occur in persons with special problems such as total parenteral nutrition, diabetes, or malnutrition. Chromium deficiency is characterized by glucose intolerance, glycosuria, hypercholesterolemia, decreased longevity, decreased sperm counts, and impaired fertility. In one patient receiving total parenteral nutrition, a peripheral neuropathy was corrected after chromium supplementation.
The target organ of inhaled chromium is the lung; the kidneys, liver, skin, and immune system may also be affected. Cr (III), an essential dietary element, plays a role in maintaining normal metabolism of glucose, fat, and cholesterol.
Major factors governing the toxicity of chromium compounds are oxidation state and solubility. Cr (VI) compounds, which are powerful oxidizing agents and thus tend to be irritating and corrosive, appear to be much more toxic systemically than Cr (III) compounds, given similar amounts and solubilities. Although mechanisms of biological interaction are uncertain, this variation in toxicity may be related to the ease with which Cr (VI) can pass through cell membranes and its subsequent intracellular reduction to reactive intermediates.
Severe dermatitis and skin ulcers can result from contact with Cr (VI) salts.
Chromic acid, dichromates, and other Cr (VI) compounds are not only powerful skin irritants, but they can also be corrosive. On broken skin, a penetrating round ulcer may develop. Common sites for these persistent ulcers ("chrome holes") include the nail root, knuckles and finger webs, backs of the hands, and forearms. The characteristic chrome sore begins as a papule, forming an ulcer with raised hard edges. Ulcers can penetrate deep into soft tissue or become the site of secondary infection, but are not known to lead to malignancy. The progression to ulceration is generally painless, suggesting toxicity to peripheral sensory nerves. The lesions heal slowly and can persist for months.
Chromium compounds can be sensitizers as well as irritants.
At concentrations below those resulting in irritation, skin sensitivity is the most common effect after exposure to chromium compounds, especially Cr (VI) compounds. Up to 20% of chromium workers develop contact dermatitis (dermatitis toxicosis). Allergic dermatitis with eczema has been reported in printers, cement workers, metal workers, painters, and leather tanners. Data suggest that a Cr (III)-protein complex is responsible for the allergic reaction, with Cr (III) acting as the hapten.
When inhaled, Cr (VI) is a respiratory tract irritant and can cause pulmonary sensitization.
Human occupational experience clearly indicates that, when inhaled, Cr (VI) is a respiratory tract irritant, resulting in airway irritation, airway obstruction, and possibly lung cancer. Dose, exposure duration, and the specific compound involved determine chromium's effects.
Chronic chromium inhalation increases the risk of lung cancer.
Pulmonary irritant effects following prolonged inhalation of chromate (VI) dust can include chronic irritation, congestion and hyperemia, chronic rhinitis, polyps of the upper respiratory tract, tracheobronchitis, chronic pharyngitis, ulceration of the nasal mucosa with possible septal perforation, and chronic bronchitis. Radiograph abnormalities reflect enlargement of the hilar region and lymph nodes, increased peribronchial and perivascular lung markings, and adhesions of the diaphragm. Consistent associations have been found between employment in the primary chromium industries and higher risk for respiratory cancer (see Carcinogenic Effects).
Pulmonary sensitization resulting in an asthmatic response is more common in exposure to Cr (VI) than to Cr (III). A delayed anaphylactoid reaction was reported in a male worker occupationally exposed to chromium vapors from Cr (VI) trioxide baths and chromium fumes from steel welding. A subsequent inhalation challenge with sodium chromate resulted in a reaction including late-onset urticaria, angioedema, and bronchospasm accompanied by tripling of plasma histamine levels.
Many cases of nasal mucosa injury (inflamed mucosa, ulcerated septum, and perforated septum) have been reported in workers exposed to Cr (VI) in chrome-plating plants and tanneries. A 1983 study of 43 chrome-plating plants in Sweden, where workers were exposed almost exclusively to chromic (VI) acid, revealed that all workers with nasal mucosa ulceration or perforation were periodically exposed to at least 20 micrograms per cubic meter (µg/m3) when working near the plating baths. (The current U.S. permissible exposure level in the workplace for chromates and chromic acid is 100 µg/m3 as a ceiling.) The period of exposure for workers experiencing nasal mucosal ulceration varied from 5 months to 10 years.
Studies of welders and chromium platers have found that workers with higher levels of exposure to airborne chromium (typically greater than 20 µg/m3) show damage to renal tubules. Adverse renal effects have been reported in humans after inhalation, ingestion, and dermal exposure to chromium. Renal effects in animals occurred only after parenteral administration of large doses.
Low-dose, chronic chromium exposures generally cause only transient renal effects.
Acute Cr (VI) exposure can result in renal tubular necrosis.
Although glomerular injury has been noted in chromium workers, the predominant renal injury is tubular, with low doses acting specifically on the proximal convoluted tubules. Low-dose, chronic chromium exposure typically results only in transient renal effects. Elevated urinary β2-microglobulin levels (an indicator of renal tubular damage) have been found in chrome platers, and higher levels have generally been observed in younger persons exposed to higher Cr (VI) concentrations. However, in a study of tannery workers (Cr [III] exposure) whose duration of employment ranged from 1 month to 30 years, urinary β2-microglobulin levels were within normal limits, even though urinary chromium levels clearly indicated chromium exposure. A suggested urinary threshold for nephrotoxic effects is 15 µg chromium/g creatinine.
Cr (VI) can cause mild to moderate liver abnormalities.
Acute chromium exposure can result in hepatic necrosis. In one case, external chromic acid burns over 20% of a worker's body resulted in severe liver damage and acute renal failure. Limited data indicate that chronic inhalation of chromium compounds also can cause hepatic effects. Acute hepatitis with jaundice was reported in a woman who had been employed for 5 years at a chromium-plating factory. Tests revealed large amounts of urinary chromium, and liver biopsy showed abnormalities. Three co-workers exposed to chromic acid mists from the plating baths for 1 year to 4 years also had mild to moderate liver abnormalities, as determined by liver function tests and liver biopsies.
Occupational exposure to Cr (VI) has long been associated with increased lung cancer mortality.
Latency for chromium-induced lung cancer is greater than 20 years; exposure duration can be as short as 2 years.
Epidemiological studies of occupational cohorts exposed to chromium aerosols provide clear evidence of carcinogenicity. In one key epidemiologic study involving workers at a chromate production plant who had worked at the plant for more than 1 year from 1931 to 1949, the percentage of deaths due to lung cancer was 18.2%; the percentage expected was 1.2%. For the 322 workers first employed from 1931 to 1937, the percentage of deaths due to lung cancer was close to 60%, with a latency period of approximately 30 years. Studies of workers in the chromium pigment, chrome-plating, and ferrochromium industries also suggest a statistically significant association between worker exposure to chromium and lung cancer. Increased lung cancer mortality has been associated with occupational exposures as short as 2 or 3 years. On the basis of these and other studies, EPA and the International Agency for Research on Cancer (IARC) have classified inhaled Cr (VI) as a known human carcinogen.
Because it is an essential nutrient and it exhibits low acute and chronic toxicity, and because no evidence exists to indicate that Cr (III) can cause cancer in animals or humans, Cr (III) has not been classified as a human carcinogen by the National Toxicology Program, EPA, or IARC.
Although epidemiologic evidence strongly points to Cr (VI) as the agent in carcinogenesis, solubility and other characteristics of chromium compounds might be important in determining cancer risk. Data from animal studies have not resolved the issues of identities and potencies of various chromium-containing compounds as respiratory carcinogens. No chromium compound has been unequivocally shown to cause a significant increase in the number of neoplasms in experimental animals after exposure by natural routes (inhalation, ingestion, or dermal absorption), unless the animals were exposed until death. (Standard protocols for animal experiments involve termination after 24 months.) However, intratracheal instillation, intrabronchial implantation, or injection of various chromium-containing compounds have produced tumors in some cases at the site of application.
No cancers, other than lung cancer, are associated with occupational chromium exposure. All pathologic cell types have occurred in chromium-induced lung cancers; however, small-cell and poorly differentiated cancers predominate. Findings of some epidemiologic studies and animal experiments suggest that chromium is also associated with nonrespiratory cancers, but the evidence is insufficient to consider the nonrespiratory cancers to be of a causal nature.
Data indicate that chromium has effects on reproductive organs and is teratogenic in animals.
Potential reproductive effects of chromium in humans have not been adequately investigated.
Cr (III) is an essential element that is transported to the developing fetus. Less than 0.5% of Cr (III) was found to cross the placenta in mice when the chromium was administered as an inorganic salt, but concentrations of 20% to 25% were found in litters when chromium was administered in a biologically active form (brewer's yeast). Adverse developmental effects in animals include cleft palate, hydrocephalus, delayed ossification, edema, and incomplete neural tube closure. Data implicating chromium in adverse human reproductive or developmental effects are unavailable.
