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Kinetics of 70ZN Differs with Respect to Route of Exposure: Intratracheal Instillation Versus Oral Gavage
Citation:
WALLENBORN, G., K. KOVALCIK, J. K. MCGEE, M. S. LANDIS, AND U. P. KODAVANTI. Kinetics of 70ZN Differs with Respect to Route of Exposure: Intratracheal Instillation Versus Oral Gavage. Presented at Southeastern Pharmacology Society Meeting, Charleston, SC, October 13 - 14, 2008.
Impact/Purpose:
This abstract evaluates the kinetics of zinc systemic translocation from pulmonary and oral exposure using mass spectroscopy to detect stable isotope and provides evidence that metals translocate from lung to systemic organs.
Description:
Zinc (Zn) is often added to drugs before pulmonary delivery, and is also a major component of ambient air pollution. While Zn is an essential element, inhalation of Zn has been shown to have adverse respiratory and extrapulmonary health effects. We hypothesized that kinetics of Zn would differ with respect to route of exposure, likely playing a role in toxicity. To test this we used high resolution magnetic sector field inductively coupled plasma mass spectrometry to measure levels of five stable isotopes of Zn (64Zn, 66Zn, 67Zn, 68Zn, 70Zn) and copper (Cu) in healthy male Wistar Kyoto rats (12 wks old, 300 g) following a single intratracheal instillation (IT) or oral gavage of saline or 50 µg/rat of 70Zn (as ZnSO4), using a solution enriched with 76.6% 70Zn. Natural abundance of 70Zn is 0.6%, making it an easily detectable tracer following exposure. Levels were measured 1, 4, 24, and 48 hrs post exposure (pe) in lungs, plasma, heart, liver, spleen, and kidney. 70Zn was detected in the lungs of IT rats with levels highest 1 hr pe and lowest 48 hr pe. 70Zn was detected in all extrapulmonary organs, in higher amounts following IT than following gavage. Plasma 70Zn peaked 1 hr pe following IT or gavage. Heart 70Zn was elevated in both exposure groups. By 1 hr pe, cardiac 70Zn in IT rats was significantly higher compared with gavage rats. Cardiac 70Zn levels following gavage of Zn reached a plateau after 1 hr, whereas following IT of Zn, levels continued to rise from each time point to the next. Hepatic accumulation of 70Zn peaked 4 hr pe following gavage, whereas liver 70Zn was highest 24 hr pe following IT. Similar patterns of 70Zn kinetics were observed in spleen and kidney. Liver endogenous zinc was increased 24 and 48 h post IT. IT Zn exposure elicited increases in Cu in all tissues except kidney, where a decrease was seen. These data demonstrate that systemic translocation of zinc is greater following pulmonary exposure than following oral gavage. Pulmonary exposure to Zn results in selectively higher cardiac Zn exposure relative to oral exposure, which may be important to consider before the use of Zn in pulmonary drug delivery. [Abstract does not reflect USEPA policy. Funded in part by UNC/EPA CT829471.]