title: Pulmonary immunotoxic potentials of metals are governed by select physicochemical properties: chromium agents.
abstract: Increasing the understanding of how metal ions/complexes react in situ will allow for the improved specificity and controlled toxicity of novel synthetic metallocompounds that will be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of select metals (e.g., chromium, vanadium, nickel, iron) caused alterations in lung immune cell function and in local bacterial resistance. The data also suggested that variations in the degree of immuno-modulation induced were not solely dependent on the amount of metal deposited in the lung, but also on the specific compound. If specificity governs immunomodulatory potential, it follows that physicochemical properties inherent to the metal may have a role in the elicited effects. We hypothesize that major determinants of any metal compound's immunomodulatory potential in situ are its redox behavior, valency, and/or solubility. Using changes in local bacterial resistance as an endpoint, differences in immunotoxic potential in the lungs were quantified for a range of chromium agents (insoluble calcium chromate(VI), and soluble sodium chromate(VI), potassium bis(dipicolinato)chromate(III) and sodium bis(dipicolinato)chromate(II)). Results indicated that among the latter three forms of Cr, strongly oxidizing hexavalent Cr (Cr[VI]) had the greatest impact on resistance, while reducing divalent and fairly unreactive trivalent forms of Cr had no effect at an equal exposure level (i.e., 100 microg Cr/m(3), 5 hr/d, for 5 d). Insoluble Cr(VI) had a greater effect than its soluble form. When data was analyzed in the context of pre-infection lung Cr burdens, it was seen that immunomodulatory potentials for both Cr(VI) agents did not differ significantly; however, complexes with different oxidation states did induce varying responses, suggesting that differences in potential might be attributed to redox behavior. From this it was concluded that for Cr, certain physicochemical properties are likely more important to any in situ pulmonary immunotoxicity than others (i.e., redox behavior is more critical than solubility). Our findings, in part, will help provide a basis for understanding why certain metals could be a greater health risk than others, even when encountered in equal amounts. This, in turn, will help researchers in the design of inhalable diagnostic/therapeutic metallopharmaceuticals by pre-empting the selection of certain metal ions/complexes for potential use in these products.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA. cohenm@env.med.nyu.edu
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Cohen
authors.forename: Colette
authors.initials: C
authors.lastname: Prophete
authors.forename: Maureen
authors.initials: M
authors.lastname: Sisco
authors.forename: Lung-Chi
authors.initials: LC
authors.lastname: Chen
authors.forename: Judith T
authors.initials: JT
authors.lastname: Zelikoff
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Smee
authors.forename: Alvin A
authors.initials: AA
authors.lastname: Holder
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Crans