Abstract
The work described in this thesis examines the renal excretion of nickel in humans and the Wistar Albino male rat. The renal clearance of nickel is characterized in two groups of electrolytic nickel-refinery workers. In the animal work, the mechanisms of nickel uptake in kidney tissue and its pathological consequences are investigated. Multi-void 24-h urine collections were obtained from 26 workers, as well as serum samples at the beginning and end of this sampling period. Nickel, ?[2]-microglobulin and creatinine concentrations were measured in both body fluids. In addition, specific gravity, protein and qualitative indices of kidney disfunction (by Dip Stick) were assessed in urine. Examination of the functional dependence in individuals of urinary nickel, creatinine and specific gravity on urine flow-rate indicates that specific gravity adjustment of spot-nickel voids is more appropriate than employing creatinine. The systematic strategy devised in this study to overcome concentration-dilution effects for nickel has wide application in biological monitoring. It is demonstrated that if the specific gravity values of spot urine voids in a group of 20 individuals are between 1.010 and 1.039, then the uncompensated uncertainty in specific-gravity adjusted urinary-nickel concentrations does not exceed +/- 10% (95% Confidence Level). Nickel clearance studies and the determination of nickel in serum ultrafiltrates indicated that 24 +/- 6% of serum nickel is available for renal filtration, of which 65% on average is reabsorbed in the human kidney. It is concluded for the nickel-refinery workers studied, that there was little evidence of kidney dysfunction. Studies with rat renal slices and isolated proximal tubules showed that the uptake of Ni[2+] and its histidine complexes is probably passive. Ni(His)[2] reduced the uptake of L-histidine and proline, but not of thymidine. The renal accumulation of nickel from nontoxic i.v. doses of [63]Ni(His)[2] (6 mug Ni kg[-1]) was followed by rapid subcellular clearance during the 24-h period after injection. Autoradiography of the nephron illustrated that only the S3 segment of the proximal tubule accumulated and retained nickel. There was no evidence of nephrotoxicity in the histopathological examination of these tissues. By contrast, high i.p. doses (3 and 6 mg Ni kg[-1] induced a decrease in Bowman's space and minor changes along the entire length of affected nephrons. Compartmentalization of nickel within subcellular fractions of the rat kidney is interpreted in terms of an "Equilibrium" model for metal- ion uptake under steady state conditions (i.e., at fixed pH, redox potential, intracellular and extracellular ligand concentrations). Effectively, nickel distribution is determined by thermodynamic parameters such as complex stability. The human and animal evidence support a passive mechanism of nickel reabsorption in the kidney. Simple pulmonary deposition and absorption considerations in man suggest that the dose of nickel acquired during an 8- h shift of work at a Threshold Limit Value (TLV) of 0.1 mg Ni m[-3] is roughly equivalent to the 6 mug Ni kg[-1] dose used in the rat study. Therefore, the absence of signs of significant nephrotoxicity in both the human and animal models appears to be consistent.