Nickel in Urine

Soluble nickel compounds are rapidly excreted from the body; consequently, they do not bioaccumulate (Hall, 1989). The biological halftime of soluble nickel in urine following inhalation has been reported to range from 17 to 39 hours in humans (Tossavainen et al., 1980). Reported urinary excretion of nickel following oral exposures is also quite rapid (Sunderman et al.).

Some attempts have been made to look at nickel in nasal tissue as a possible indicator of nickel exposure (Torjussen et al., 1979; Boysen et al., 1982). However, due to the problems associated with the invasiveness of the biopsy technique, the use of nasal tissue monitoring is not recommended as a routine procedure (Aitio, 1984). al., 1989). Because of this rapid clearance of soluble nickel from the body, regardless of route of exposure, levels in urine are indicative only of relatively recent exposures.

Relatively insoluble nickel, on the other hand, is known to accumulate in tissue such as lung, where, depending upon particle size, it may only slowly be absorbed over time. Nickel in urine, therefore, only reflects the fraction of insoluble nickel that has been absorbed. The smaller the particle, the more likely it is to be rapidly absorbed and excreted. This phenomenon may account for the relatively short half-times of nickel in urine, ranging from 30 to 53 hours, reported by Zober et al. (1984) and Raithel et al. (1982) for workers exposed to welding fumes and/or insoluble nickel particles of small diameter. Conversely, some have suggested that for workers presumably exposed to insoluble nickel of larger particle size, the biological half-time of stored nickel may be considerably longer, possibly ranging from months to years (Torjussen and Andersen, 1979; Boysen et al., 1984; Morgan and Rouge, 1984).

Urine samples for nickel analysis can be collected by spot sampling or by 24-hour sampling. The most sensitive method for correlating urinary nickel concentrations to air nickel concentrations is the 24-hour urine sample (Hall, 1989). A spot urinary sample tends to be more variable and, therefore, is not as informative. However, since collection of a 24-hour urine sample may be impractical in an occupational setting, post- shift or end-of-week spot sampling is the preferred method when 24-hour sampling cannot be carried out.

Due to variable urine dilution, spot samples are typically normalized on the basis of either creati-

Exposed To Nickel nine concentration or specific gravity. A study of 26 electrolytic nickel refinery workers suggests that specific gravity normalization of nickel concentration is more appropriate than creatinine adjustment (Sanford et al., 1988). However, drawbacks to both methods exist, depending upon factors such as the degree of dilution of the sample, the fluctuations of salt in the body, and the presence of glycosuria or proteinuria (Lauwerys and Hoet, 1993). Some evidence exists that on a group basis, there may be no difference between corrected and uncorrected samples (Morgan and Rouge, 1984). A recent study of Scandinavian nickel workers, however, suggests that corrected urinary samples (adjusted for creatinine concentrations) correlate better with measurements of nickel aerosol than do “raw” uncorrected samples (Werner et al., 1999). A study of urinary nickel levels at a nickel refinery in Russia showed lower urinary nickel values in females than in male workers with similar inhalation exposures (Thomassen et al., 1999).

It is important that urine samples be analyzed by a reputable laboratory accustomed to doing the required analyses (Hall, 2001). It is also important that the analyses be reported in appropriate units; in the case of urine, typically as mg Ni/gm creatinine or µmol Ni/mol creatinine. If a biological monitoring program is instituted, urine nickel samples should be collected quarterly or semi-annually (Hall, 2001).

Urinary nickel levels can vary considerably, even in non-occupationally exposed individuals. Because of this, they are of most use when interpreted on a group basis. Reported urinary nickel concentrations in non-exposed individuals range from approximately 0.2 to 10 µg Ni/L, depending upon the method of analysis (Sunderman et al., 1986; Sunderman, 1989).

As noted above, the only nickel compound for which a correlation between urinary nickel concentrations and adverse health effects has been found is nickel carbonyl. There is a close correlation between the clinical severity of acute nickel carbonyl poisoning and urinary concentrations of nickel during the initial three days after exposure (Sunderman and Sunderman, 1958). The correlations are as follows:

  • Mild Symptoms: 60 to 100 µg Ni/l (18-hour urine specimen).
  • Moderate Symptoms: 100 to 500 µg Ni/l (18-hour urine specimen).
  • Severe Symptoms: >500 µg Ni/l (18-hour urine specimen).

These values are only relevant, however, where urinary nickel is not elevated due to other exposures.

Recent experience at a nickel carbonyl refinery from 1992 to 2002 has shown that the clinical severity of the acute nickel carbonyl exposure can also be correlated to nickel levels in early urinary samples (within the first 12 hours of exposure). The use of an 8-hour post exposure urinary nickel specimen may also be helpful in categorizing cases and determining the need for chelation therapy. Of 170 potentially exposed cases, mild cases were defined as having <150 µg Ni/l, moderate cases as having 150-500 µg Ni/l, and severe cases as having >500 µg Ni/l (with 8 hours post exposure samples) (Dr. S. Williams, Inco, personal communication). Chelation therapy with disulfiram was considered with respect to the moderate and severe groups only.

Nickel carbonyl is also the only nickel compound for which information is available regarding treatment following acute exposure. The administra-

Exposed To Nickel tion of either sodium diethyldithiocarbamate (Dithiocarb) or its analogue, tetraethylthiuram disulfide (Disulfiram, which is marketed as the proprietary drug, Antabuse, and is more readily commercially available), has been recommended in the treatment of nickel carbonyl poisoning. Both agents work by chelating the metal in the blood and transporting it to the kidneys for rapid excretion in urine.

In summary, from the above discussions, it is evident that there are both advantages and disadvantages to using urinary nickel concentrations in biological monitoring programs. The disadvantages include fluctuating specific gravity, problems associated with dilute urine, matrix variability and possible dust contamination, and, with the exception of nickel carbonyl, the lack of any dose-effect relationship (Sunderman, 1989). The advantages are the non-invasiveness of the technique and convenience of collection. Also, urinary nickel concentrations are higher than concentrations in other biological media, improving sensitivity, analytical accuracy, and precision (Sunderman et al., 1986). When compared to other methods for estimating biological exposures (e.g., serum nickel), the advantages of collecting urinary nickel make it the preferred biological monitoring method.