title: Evaluation of tissue disposition, myelopoietic, and immunologic responses in mice after long-term exposure to nickel sulfate in the drinking water.
abstract: Female B6C3F1 mice were exposed to graded doses of nickel sulfate to determine a threshold response for myelotoxicity and immunotoxicity, and to identify which of the populations of lymphoreticular cells were most sensitive to the toxic effects of nickel. Animals were given free access to the chemical in the drinking water at 0, 1, 5, or 10 g/l for 180 d. Water consumption, blood and tissue nickel concentrations, body and organ weights, histopathology, immune responses, bone marrow cellularity and proliferation, and cellular enzyme activities were evaluated. There was no mortality. Mice in the 5-g/l and 10-g/l dose groups drank less water than controls; the responses measured in the 10-g/l group may have been due to a combination of dehydration and chemical toxicity. Decreases in body and organ weights were confined to mice in the 10-g/l dose group, except for the dose-related reductions in thymus weights. Blood nickel was measured at 4, 8, 16, and 23 wk of exposure. The mean blood nickel values showed increases between 4 and 8 wk that were proportional to time and dose; thereafter there was no substantial increase in blood nickel in any of the dose groups, except for an increase in the mean blood concentration in the 10-g/l group at 23 wk. The kidney was the major organ of nickel accumulation. The primary toxic effects of nickel sulfate were expressed in the myeloid system. There were dose-related decreases in bone marrow cellularity, and in granulocyte-macrophage and pluripotent stem-cell proliferative responses. In unfractionated bone marrow cells glucose-6-phosphate dehydrogenase enzyme activity from the hexose monophosphate shunt was more sensitive to nickel sulfate than were representative glycolytic or Krebs cycle enzymes, with 25-35% maximum inhibition at 5 g/l and 10 g/l. Aliquots of bone marrow cells were separated into enriched bands of lymphocytes, granulocyte-macrophages, and erythrocytes; enzyme inhibition that occurred in unfractionated bone marrow cell aliquots was only expressed after cell separation in the enriched granulocyte-macrophage cell population, suggesting that these committed stem cells were a primary target of nickel sulfate toxicity. There was one example of systemic immunotoxicity, reduction in the lymphoproliferative response to lipopolysaccharide, and it was regarded as secondary to the primary effect of nickel sulfate on the myeloid system, since this was the only significant change among a panel of seven immune parameters that were evaluated.
authors.affiliation: National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, North Carolina 27709.
authors.forename: M P
authors.initials: MP
authors.lastname: Dieter
authors.forename: C W
authors.initials: CW
authors.lastname: Jameson
authors.forename: A N
authors.initials: AN
authors.lastname: Tucker
authors.forename: M I
authors.initials: MI
authors.lastname: Luster
authors.forename: J E
authors.initials: JE
authors.lastname: French
authors.forename: H L
authors.initials: HL
authors.lastname: Hong
authors.forename: G A
authors.initials: GA
authors.lastname: Boorman
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000201:enzymology; D004326:Drinking; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007109:Immunity / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009532:Nickel / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D009532:Nickel