Mathematical modeling of the kinetics of nickel absorption, distribution, and elimination was performed in healthy human volunteers who ingested NiSO, drinking water (Experiment 1) or added to food (Experiment 2). Nickel was analyzed by electrothermal atomic absorption spectrophotometry in serum, urine, and feces collected during 2 days before and 4 days after a specified NiS0, dose (12 pg of nickel/kg, n = 4; 18 pg of nickel/kg, n = 4; or 50 pg of nickel/kg, n = 1). In Experiment 1, each of the subjects fasted 12 hr before and 3 hr after drinking one of the specified NiSO, doses dissolved in water; in Experiment 2, the respective subjects fasted 12 hr before consuming a standard American breakfast that contained the identical dose of NiS0, added to scrambled eggs. Kinetic analyses, using a compartmental model, provided excellent goodness-of-fit for paired data sets from all subjects. Absorbed nickel averaged 27 2

Measurements of nickel in body fluids, excreta, and tissues from humans with occupational, environmental, and iatrogenic exposures to nickel compounds are comprehensively reviewed. Correlations between levels of human exposures to various classes of nickel compounds via inhalation, oral, or parenteral routes and the corresponding concentrations of nickel in biological samples are critically evaluated. The major conclusions include the following points: Measurements of nickel concentrations in body fluids, especially urine and serum, provide meaningful insights into the extent of nickel exposures, provided these data are interpreted with knowledge of the exposure routes, sources, and durations, the chemical identities and physical-chemical properties of the nickel compounds, and relevant clinical and physiological information, such as renal function. Nickel concentrations in body fluids should not, at present, be viewed as indicators of specific health risks, except in persons exposed to nickel carbonyl, for whom urine nickel concentrations provide prognostic guidance on the severity of the poisoning. In persons exposed to soluble nickel compounds (e.g., NiCl2, NiSO4), nickel concentrations in body fluids are generally proportional to exposure levels; absence of increased values usually indicates non-significant exposure; presence of increased values should be a signal to reduce the exposure. In persons exposed to less soluble nickel compounds (e.g., Ni3S2,NiO), increased concentrations of nickel in body fluids are indicative of significant nickel absorption and should be a signal to reduce the exposures to the lowest levels attainable with available technology; absence of increased values does not necessarily indicate freedom from the health risks (e.g., cancers of lung and nasal cavities) associated with exposures to certain relatively insoluble nickel compounds.

Recent investigations on possible mechanisms of nickel carcinogenesis are reviewed, emphasizing cellular uptake and intracellular translocation of nickel, morphological transformat ion of cells by nickel compounds, chromosomal damage, DNA strandbreaks and DNA-protein complexes produced by nickel compounds, mutagenic effects of nickel, influence of nickel on the helical transition of B-DNA to Z-DNA, nickel-inducedinfidelity of DNA synthesis. free radicals and lipid peroxidation induced by nickelexposures, nickel inhibition of DNA repair. nickel as a tumor promotor, nickel inhibition of natural-killer (NK) cell activity. manganese and magnesium antagonism of nickel carcinogenesis. and speculation that Nj2 + might replace Zn 2 + in finger-loop domains of transforming proteins. The weight of evidence support s the following tentative conclusions: differences in the carcinogenic activities of nickel compounds may reflect variations in their capacities to provide nickel ions (eg, Nj2 +) at critical sites within target cells; Ni 2 + can initiate carcinogenesis, possibly by mutagenesis, chromosome damage, formation of Z-DNA, inhibition of DNA excision-repair or epigenetic mechanisms; Ni 2+ can function as a tumor promotor; Ni 2 t can enhance tumor progression by inhibiting NK cell activity; and nickel carcinogenesis can be suppressed or modified by certain other metals (eg, manganese and magnesium).

Co, Cr, and Ni concentrations were determined by electrothermal atomic absorption spectrophotometry in serum and urine specimens collected from a group of 28 patients at intervals of from 1 day to 2.5 years after total knee or hip arthroplasty with porous-coated prostheses fabricated of Co-Cr alloy (ASTM F-75-82). Two control groups were also tested: (a) 42 healthy adults and (b) 16 orthopaedic patients after total knee or hip arthroplasty with porous-coated prostheses fabricated predominantly of Ti-Al-V alloy (ASTM F-136-84). All prostheses contained polyethylene components to avoid metal-to-metal contact. Mean Co concentrations in serum and urine were slightly increased in patients with Co-Cr knee implants at 6-120 weeks after surgery, compared with (a) preoperative values, (b) corresponding values in patients with Co-Cr hip implants, and (c) corresponding values in control patients with Ti-Al-V knee and hip prostheses. Substantially increased Co levels were observed in serum and urine of two patients at 7 weeks and 22 months postarthroplasty, associated with loosening of the prostheses; one of the patients also had elevated Cr levels in serum and urine. Although ASTM F-75-82 and F-136-84 alloys contain very little Ni (less than 1.0 and less than 0.2% Ni, respectively, by wt), mean Ni concentrations in serum and urine were greatly increased at 1-2 days after implantation of Ti-Al-V and Co-Cr prostheses, diminishing by 2 weeks. The postoperative hypernickelemia and nickeluresis may reflect contamination of the operative field with Ni-containing particles from the drills, cutting jigs, and drilling jigs, or it may represent a previously unrecognized pathophysiological response to surgery.

Experimental observations that pertain to mechanisms of metal carcinogenesis are summarized, with emphasis upon (a) interactions of metals with nucleic acids in vitro; (b) impairment by metals of the fidelity of DNA replication by DNA polymerase in vitro; (c) mutagenicity of metals in microorganisms; (d) cytogenetic aberrations induced by metals in tissue culture cells; (e) induction by metals of neoplastic transformation of tissue culture cells; and (f) nuclear uptake of metals in vivo and concomitant inhibitory effects of metals on synthesis of nucleic acids. Considered in toto, the experimental data support the somatic mutation hypothesis of chemical carcinogenesis. Sufficient experimental evidence is available regarding four carcinogenic metals (As, Be, Cr, and Ni) to permit speculations about the molecular reactions whereby these metals may induce somatic mutations.