Respiratory Tract Deposition, Absorption and Retention

Toxicologically speaking, inhalation is the most important route of nickel exposure in the workplace, followed by dermal exposure. Deposition, absorption, and retention of nickel particles in the respiratory tract follow general principles of lung dynamics. Hence, factors such as the aerodynamic size of a particle and ventilation rate will largely dictate the deposition of nickel particles into the nasopharyngeal, tracheobronchial, or pulmonary (alveolar) regions of the respiratory tract.

Not all particles are inhalable. As noted in Section 2, many primary nickel products are massive in form and hence inherently not inhalable. However, even products which are “dispersible” may not necessarily be inhalable unless the particles are sufficiently small to enter the respiratory tract. Humans inhale only about half of the particles with aerodynamic diameters >30 µm, and it is believed that this efficiency may decline rapidly for particles with aerodynamic diameters between 100 and 200 µm. Of the particles inhaled, only a small portion with aerodynamic diameters larger than 10 µm are deposited in the lower regions of the lung, with deposition in this region predominantly limited to particles =4 µm (Vincent, 1989).

Factors such as the amount deposited and particle solubility, surface area, and size will influence the behavior of particles once deposited in the respiratory tract and will probably account for differences in retention and clearance via absorption or through mechanical means (such as mucociliary clearance). Physiological factors such as age and general health status may also influence the process. Unfortunately, little is known about the precise pharmacokinetics of nickel particles in the human lung.

Based largely upon experimental data, it can be concluded that the more soluble the compound, the more readily it is absorbed from the lung into the bloodstream and excreted in the urine. Hence, nickel salts, such as sulfate and chloride, are rapidly absorbed and eliminated. The half-life of nickel in the lungs of rats exposed by inhalation has been reported to be 32 hours for nickel sulfate (mass median aerodynamic diameter [MMAD] 0.6 µm) (Hirano et al. 1994), 4.6 days for nickel sub- sulfide (63Ni3S2 activity median aerodynamic diameter [AMAD] 1.3 µm), and 120 days for green nickel oxide (63NiO, AMAD 1.3 µm) (Benson et al., 1994). Elimination half-times from the lung of rats of 7.7, 11.5, and 21 months were calculated for green nickel oxide with MMADs of 0.6, 1.2, and 4.0 µm, respectively (Tanaka et al., 1985, 1988).

The relatively insoluble compounds, such as nickel oxides, are believed to be slowly absorbed from the lung into the bloodstream, thus, resulting in accumulation in the lung over time (see Section 6.3). Dunnick et al. (1989) found that equilibrium levels of nickel in the lungs of rodents were reached by 13 weeks of exposure to soluble NiSO4 (as NiSO4•6H2O) and moderately soluble Ni3S2, but levels continued to increase with exposure to NiO. There is also evidence that some of the nickel retained in lungs may be bound to macromolecules (Benson et al., 1989).

In workers presumably exposed to insoluble nickel compounds, the biological half-time of stored nickel in nasal mucosa has been estimated to be several years (Torjussen and Andersen, 1979). Some researchers believe that it is the accumulated, slowly absorbed fraction of nickel which may be critical in producing the toxic effects of nickel via inhalation. This is discussed in Section 5 of this Guide.

Workers occupationally exposed to nickel have higher lung burdens of nickel than the general population. Dry weight nickel content of the lungs at autopsy was 330±380 µg/g in roasting and smelting workers exposed to less-soluble compounds, 34±48 µg/g in electrolysis workers exposed to soluble nickel compounds, and 0.76±0.39 µg/g in unexposed controls (Andersen and Svenes 1989). In an update of this study, Svenes and Andersen (1998) examined 10 lung samples taken from different regions of the lungs of 15 deceased nickel refinery workers; the mean nickel concentration was 50 µg/g dry weight. Nickel levels in the lungs of cancer victims did not differ from those of other nickel workers (Kollmeier et al., 1987; Raithel et al., 1989). Nickel levels in the nasal mucosa are higher in workers exposed to less soluble nickel compounds relative to soluble nickel compounds (Torjussen and Andersen 1979). These results indicate that, following inhalation exposure, less- soluble nickel compounds remain deposited in the nasal mucosa.

Acute toxicokinetic studies of NiO or NiSO4•6H2O in rodents and monkeys and sub- chronic repeated inhalation studies in rodents have been conducted to determine the effects of nickel compounds on lung clearance (Benson et al., 1995). Clearance of NiO from lungs was slow in all species. Impairment of clearance of subsequently inhaled radiolabled NiO was seen in rodents, particularly at the highest concentrations tested (2.5 mg NiO/m3 in rats and 5.0 mg NiO/m3 in mice). In contrast to the NiOexposed animals, clearance of NiSO4•6H2O was rapid in all species, and no impaired clearance of subsequently inhaled radiolabeled NiSO4•6H2O was observed.

Measurements of deposition, retention, and clearance of nickel compounds are lacking in humans.