Nickel carbonyl delivers nickel atoms to the target organ (lung) in a manner that is probably different from that of other nickel species. After nickel carbonyl inhalation, removal of nickel from the lungs occurs by extensive absorption and clearance. The alveolar cells are covered by a phospholipid layer, and it is the lipid solubility of nickel carbonyl vapor that is of importance in its penetration of the alveolar membrane. Extensive absorption of nickel carbonyl after respiratory exposure has been demonstrated. Highest nickel tissue concentrations after inhalation of nickel carbonyl have been found in the lungs, with lower concentrations in the kidneys, liver, and brain. Urinary excretion of nickel increases in direct relationship to exposure to nickel carbonyl (Sunderman et al., 1986).
Acute toxicity is of paramount importance in controlling risks associated with exposure to nickel carbonyl. The severe toxic effects of exposure to nickel carbonyl by inhalation have been recognized for many years. The clinical course of nickel carbonyl poisoning involves two stages. The initial stages are characterized by headache, chest pain, weakness, dizziness, nausea, irritability, and a metallic taste in the mouth (Morgan, 1992; Vuopala et al., 1970; Sunderman and Kincaid, 1954). There is then generally a remission lasting 8-24 hours followed by a second phase characterized by a chemical pneumonitis but with evidence, in severe cases, of cerebral poisoning. Common clinical signs in severe cases include tachypnoea, cyanosis, tachycardia, and hyperemia of the throat (Shi, 1986). Hematological results include leukocytosis. Chest X-rays in some severe cases are consistent with pulmonary edema or pneumonitis, with elevation of the right hemidiaphragm. Shi reported three patients with ECG changes of toxic myocarditis.
The second stage reaches its greatest severity in about four days, but convalescence is often protracted. In ten patients with nickel carbonyl poi- soning, there were initial changes in pulmonary function tests consistent with acute interstitial lung disease (Vuopala et al., 1970). However, these results returned to normal after several months.
The mechanism of the toxic action of nickel carbonyl has never been adequately explained, and the literature on the topic is dated (Sunderman and Kincaid, 1954). Some researchers have held the view that nickel carbonyl passes through the pulmonary epithelium unchanged (Amor, 1932). However, as nickel carbonyl is known to be reactive to a wide variety of nitrogen and phosphorous compounds, as well as oxidizing agents, it is not unreasonable to assume that it is probably reactive with biological materials (Sunderman and Kincaid, 1954). It is known to inhibit the utilization of adenosine triphosphate (ATP) in liver cells and brain capillaries (Joo, 1969; Sunderman, 1971). Following acute exposure to nickel carbonyl, sections of lung and liver tissue have been shown to contain a granular, brownish-black, noniron-staining pigment (Sunderman et al., 1959). It has not been established, however, whether these dark granules represent metallic nickel or the compound, itself. Sunderman et al. (1959) proposed that nickel carbonyl may dissociate in the lung to yield metallic nickel and carbon monoxide, each of which may act singly, or in combination with each other, to induce toxicity.
Evidence of chronic effects at levels of exposure below those which produce symptomatic acute toxicity is difficult to find. The only epidemiological study that investigated specifically the possible carcinogenic effect of nickel carbonyl (Morgan, 1992) was limited in power and confounding factors–such as exposures to certain oxidic and sulfidic nickel species–thereby clouding any interpretation regarding the contribution of nickel carbonyl, per se, to the carcinogenic risk.
In animals, as in humans, the lung is the primary target organ for exposure to nickel carbonyl regardless of route of administration, and the effects in animals are similar to those observed in humans. Experimental nickel carbonyl poisoning in animals has shown that the most severe pathological reactions are in the lungs with effects in brain and adrenal glands as well. Acute toxicity is of greatest concern. The LD50 in rats is 0.20 mg Ni/liter of air for 15 minutes or 0.12 mg/rat. Effects on the lung include severe pulmonary inflammation, alveolar cell hyperplasia and hypertrophy, and foci of adenomatous change.
With respect to carcinogenic effects, studies on the carcinogenicity of nickel carbonyl were performed prior to present day standardized testing protocols, but because of the extreme toxicity of this material, more recent studies are not likely to be conducted. Studies by Sunderman et al., (1959) and Sunderman and Donnelly (1965) have linked nickel carbonyl to respiratory cancer, but high rates of early mortality in these studies preclude a definitive evaluation. It would be desirable to have additional studies with less toxic levels of exposure permitting a higher proportion of the animals to survive. This would provide a more complete understanding of the spectrum of lung pathology produced by nickel carbonyl. Nevertheless, the deficiencies in these early studies preclude reaching any definitive conclusions regarding the carcinogenicity of nickel carbonyl via inhalation. Possible developmental toxicity effects are also of concern for nickel carbonyl. In a series of studies, Sunderman et al. (1979, 1980) demonstrated that nickel carbonyl, administered by inhalation (160-300 mg Ni/m3) or injection (before or a few days after implantation) produced various types of fetal malformations in hamsters and rats.