SAFE USE OF NICKEL IN THE WORKPLACE
Last Revised: 5/1997
4. PHARMACOKINETICS OF NICKEL
COMPOUNDS
4.1 INTAKE
4.2 ABSORPTION 4.2.1 RESPIRATORY TRACT DEPOSITION,
ABSORPTION AND RETENTION
4.2.2 DERMAL ABSORPTION
4.2.3 GASTROINTESTINAL ABSORPTION 4.3 DISTRIBUTION
4.4 EXCRETION
4.5 FACTORS AFFECTING METABOLISM
4.6 REFERENCES
4. PHARMACOKINETICS OF NICKEL COMPOUNDS
Factors of biological importance to nickel, its compounds, and alloys include solubility, chemical form (species), physical form (e.g. massive versus dispersible), particle size, surface area, concentration, and route and duration of exposure. Where possible, the relationship of these factors to the intake, absorption, distribution, and elimination of nickel is discussed in this section. Independent factors that can also affect the biokinetic activity of nickel species, such as disease states and physiological stresses, are briefly noted.
The major routes of nickel intake are dietary ingestion and inhalation. In most individuals, even some who are occupationally exposed, diet constitutes the main source of nickel intake. Recent studies indicate that average dietary intake is approximately 0.15 mg Ni/day (Federal Register, July 17, 1992, 31784). However, consumption of foodstuffs naturally high in nickel, such as oatmeal, cocoa, chocolate, nuts, and soy products, may result in higher nickel intake (Nielsen and Flyvolm, 1984; Grandjean et al., 1989).
Nickel in potable water also is generally quite low, averaging from < 0.001 to < 0.010 mg Ni/L (Grandjean et al., 1989). Assuming an intake of 1.4 L/day, either as drinking water or water used in beverages, nickel in water may add 0.0014 to 0.014 mg Ni to total daily intake.
For individuals who are not occupationally exposed to nickel, nickel intake via inhalation is considerably less than dietary intake. Levels of nickel in ambient air typically range from ~ 1 to 20 ng Ni/m3 at rural sites and from ~ 10 to 60 ng Ni/m3 at urban sites (ATSDR, 1993). Higher values have been recorded in heavily industrialized areas and larger cities (IPCS, 1991). An average urban dweller (70 kg man breathing 20 m3 of 20 ng Ni/m3/day) would inhale around 0.0004 mg Ni/day (Bennet, 1984). For rural dwellers, daily intake of airborne nickel would be even lower.
For occupationally exposed individuals, total nickel intake is likely to be higher than that of the general populace. Whether diet or workplace exposures constitute the main source of nickel intake in workers depends upon a number of factors. These factors include the aerodynamic size of the particle and whether it is inhalable, the concentration of the nickel that is inhaled, the minute ventilation rate of a worker, whether breathing is nasal or oronasal, the use of respiratory protection equipment, personal hygiene practices, and general work patterns.
B ased upon the exposure estimates presented in Section 2 and assuming that a total of 10 m3 of air is inhaled in an eight-hour work day (the assumption being that industrial workers have a higher inhalation rate than the average citizen), the approximate amount of nickel likely to be inhaled in non-refining, nickel-producing industries would range from 0.1 to 0.25 mg Ni/day. The average amount of nickel likely to be inhaled in nickel refining operations may be somewhat higher, ranging from 0.3 to 0.8 mg Ni/day or higher in the case of matte handling or grinding. The average amount of nickel likely to be inhaled in most nickel-using industries would range from < 0.02 to 1.0 mg Ni/day depending upon the industry. Powder metallurgy operations are an exception, with average airborne nickel concentrations that have occasionally been reported to be greater than 1.0 mg Ni/m3.
Other sources of exposure include contact with nickel-containing items (e.g. jewelry), medical applications (e.g. prostheses), and tobacco smoke. Dermal exposure to nickel-containing articles constitutes one of the most important routes of exposure for the general public with respect to allergic contact dermatitis. Likewise, tobacco smoking may also be a source of nickel exposure. Some researchers have suggested that smoking a pack of 20 cigarettes a day may contribute up to 0.004 mg Ni/day (Grandjean, 1984). While this would contribute little to total nickel intake, smoking cigarettes with nickel-contaminated hands can significantly increase the potential for oral nickel exposures.
4.2.1 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, 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, with a urinary half-time from hours to just a few days. Conversely, 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 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 the Guide.
Recently, acute toxicokinetic studies of NiO or NiSO4·6H2O in rodents and monkeys and subchronic 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 NiO-exposed animals, clearance of NiSO4·6H2O was rapid in all species, and no impaired clearance of subsequently inhaled radiolabeled NiSO4·6H2O was observed.
As measurements of deposition, retention, and clearance of nickel compounds are lacking in humans, it is hoped that results from the aforementioned animal studies and chronic inhalation studies recently conducted by the National Toxicology Program (NTP, see Section 5) can ultimately be extrapolated to humans.
Divalent nickel has been shown to penetrate the skin fastest at sweat ducts and hair follicles where it binds to keratin and accumulates in the epidermis. However, the surface area of these ducts and follicles is small; hence, penetration through the skin is primarily determined by the rate at which nickel is able to diffuse through the horny layer of the epidermis (Grandjean et al., 1989). Nickel penetration of skin is enhanced by many factors including sweat, solvents, detergents, and occlusion, such as wearing gloves (Malten, 1981; Fischer, 1989; Wilkinson and Wilkinson, 1989).
Although dermal exposure to nickel-containing products constitutes an important route of exposure for the general public, the amount of nickel absorbed from such products is unknown. In a study using excised human skin, only 0.23 percent of an applied dose of nickel chloride permeated non-occluded skin after 144 hours, whereas 3.5 percent permeated occluded skin in the same period (i.e., skin with an airtight seal over the test material on the epidermal side). Nickel ions from a chloride solution passed through the skin approximately 50 times faster than nickel ions from a sulfate solution (Fullerton et al., 1986).
4.2.3 GASTROINTESTINAL ABSORPTION
Gastrointestinal absorption of nickel is relevant to workplace safety and health insofar as the consumption of food or the smoking of cigarettes in the workplace or without adequate hand washing can result in the ingestion of appreciable amounts of nickel compounds.
Intestinal absorption of ingested nickel varies with the type of food being ingested and the type and amount of food present in the stomach at the time of ingestion (Solomons et al., 1982; Foulkes and McMullen, 1986). In a study with human volunteers, Sunderman and coworkers (1989) showed that if nickel is consumed in drinking water on an empty stomach, the rate of nickel absorption can be as high as 25%. In contrast, only 1 percent of nickel was absorbed by these same volunteers when they fasted overnight and then were fed a nickel-containing breakfast in the morning. The rate constants for absorption, transfer, and elimination did not differ significantly between nickel ingested in drinking water and food.
Clearly, good industrial hygiene practices should include the banning of food consumption and cigarette smoking in areas where nickel compounds are used and should include requirements for hand washing upon leaving these areas.
The kinetic processes that govern transport and distribution of nickel in the body are dependent on the site of absorption, rate and concentration of nickel exposure, solubility of the nickel compound, and physiological status of the body. Nickel is mainly transported in the blood through binding with serum albumin and, to a lesser degree, histidine. The nickel ion may also bind with body proteins to form a nickel-rich metalloprotein (Sunderman et al., 1986).
Postmortem analysis of tissues from ten individuals who, with one exception, had no known occupational exposure to nickel, showed highest nickel concentrations in the lungs, thyroid gland, and adrenal gland, followed by lesser concentrations in the kidneys, heart, liver, brain, spleen and pancreas (Rezuke et al., 1987). These values are in general agreement with other autopsy studies that have shown highest concentrations of nickel in lung, followed by lower concentrations in kidneys, liver, heart, and spleen (Nomoto, 1974; Zober et al., 1984a; Seemann et al., 1985).
The distribution of various nickel compounds to tissues has been studied in animals. Such studies reveal that the route of exposure can alter the relative amounts of nickel deposited in various tissues. Recent animal studies indicate that inhaled nickel is deposited primarily in the lung and that lung levels of nickel are greatest following inhalation of relatively insoluble NiO, followed by moderately soluble Ni3S2 and soluble NiSO4 (as NiSO4·6H2O) (Dunnick et al., 1989). Following intratracheal administration of Ni3S2 and NiSO4, concentrations of nickel were found to be highest in the lung, followed by the trachea, larynx, kidney, and urinary bladder (Valentine and Fisher, 1984; Medinsky et al., 1987). Kidney nickel concentrations have been shown to increase in proportion to exposure to NiSO4 via inhalation, indicating that a significant portion of soluble nickel leaving the respiratory tract is distributed to the kidneys (Benson et al., 1988). There is also some evidence that the saturation of nickel binding sites in the lung or saturation or disruption of kidney reabsorption mechanisms in rats administered NiSO4 results in more rapid clearance (Medinsky et al., 1987).
Not surprisingly, predictions of body burden have varied depending upon the analytical methods used and the assumptions made by investigators to calculate burden. Bennett (1984) estimates the average human nickel body burden to be about 0.5 mg (0.0074 mg/kg x 70 kg). In contrast, values of 5.7 mg have been estimated by Sumino et al. (1975) on the basis of tissue analyses from autopsy cases.
Once absorbed into the blood, nickel is predominantly extracted by the kidneys and excreted in urine. Urinary excretion of nickel is thought to follow a first-order kinetic reaction (Christensen and Lagesson, 1981).
Urinary half-times in workers exposed to nickel via inhalation have been reported to vary from 17 to 39 hours in nickel platers who were largely exposed to soluble nickel (Tossavainen et al., 1980).
Relatively short urinary half-times of 30 to 53 hours have also been reported in glass workers and welders exposed to relatively insoluble nickel (Raithel et al., 1982; cited in IARC, 1990; Zober et al., 1984b). It should be noted, however, that in these cases the insoluble nickel that workers were exposed to - probably NiO or complex oxides - was likely in the form of welding fumes or fine particles (Zober et al., 1984b; Raithel et al., 1981). Such particles may be absorbed more readily than large particles. Difference in particle size may account for why other researchers have estimated much longer biological half-times of months to years for exposures to presumably relatively insoluble nickel compounds of larger particle size (Torjussen and Andersen, 1979: Boysen et al., 1984; Åkesson and Skerfving, 1985). The precise role that particle size or dose may play in the absorption and excretion of insoluble nickel compounds in humans is still uncertain (Sunderman et al., 1986).
Reported urinary excretion half-times following oral exposures are similar to those reported for inhalation (Christensen and Lagesson, 1981; Sunderman et al., 1989). Christensen and Lagesson (1981) reported that maximal excretion of nickel in urine occurred within the first 8 hours of ingesting soluble nickel compounds. The highest daily maximum renal excretion reported by the authors was 0.5 mg Ni/day.
Excretion via other routes is somewhat dependent on the form of the nickel compound absorbed and the route of exposure. Unabsorbed dietary nickel is lost in feces. Insoluble particles cleared from the lung via mucociliary action and deposited in the gastrointestinal tract are also excreted in the feces.
Sweat constitutes another elimination route of nickel from the body; nickel concentrations in sweat have been reported to be 10 to 20 times higher than concentrations in urine (Cohn and Emmett, 1978; Christensen et al., 1979). Sunderman et al. (1986) state that profuse sweating may account for the elimination of a significant amount of nickel.
Bile has been shown to be an elimination route in laboratory animals, but its importance as an excretory route in humans is unknown.
Hair is also an excretory tissue of nickel. However, use of hair as an internal exposure index has not gained wide acceptance due to problems associated with external surface contamination and non-standardized cleaning methods (IPCS, 1991).
Nickel may also be excreted in human breast milk leading to dietary exposure of breast-fed infants. On a body weight basis, such exposures are believed to be similar to average adult dietary nickel intake (Grandjean, 1984).
4.5 FACTORS AFFECTING METABOLISM
Some disease states and physiological stresses have been shown to either increase or decrease endogenous nickel concentrations. As reviewed by Sunderman et al. (1986) and the U. S. Environmental Protection Agency (U. S. EPA, 1986), serum nickel concentrations have been found to be elevated in patients after myocardial infarction, severe myocardial ischemia, or acute stroke. Serum nickel concentrations are often decreased in patients with hepatic cirrhosis, possibly due to hypoalbuminemia (McNeely et al., 1971). Physiological stresses such as acute burn injury have been shown to correspond with increased nickel serum levels in rats. Animal studies also indicate that nickel may be an endogenous vasoactive substance and that low concentrations (0.1 µM) of nickel chloride can induce coronary vasoconstriction in the perfused hearts of rats (Edoute et al., 1992).
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