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.

Effects of metal compounds with distinct physicochemical properties on iron homeostasis and antibacterial activity in the lungs: chromium and vanadium

“…Listeria was grown 16 hr in trypticase soy (TS) broth at 37°C, its concentration was determined spectrophotometrically at 540 nm, and an aliquot then diluted with saline to the needed concentration for intratracheal instillation (110 μl/rat) under light halothane anesthesia. Extrapolation to predict Listeria concentration is known to be within 90% of predicted values (Cohen et al, 2002, 2006). …”

“…Atmospheres of each soluble agent were generated by nebulizing a dilute solution (pH 7.2–7.4) via a Collison nebulizer (BGI, Waltham, MA) as described previously (Cohen et al, 2006, 2007). Insoluble Cr particle atmospheres were similarly generated using CaCrO 4 bought in the appropriate size; insoluble V 2 O 5 atmospheres were generated via a Wright dust feeder.…”

“…NIEHS Center Analytical Core procedures used earlier (Cohen et al, 2006, 2007) were applied to determine the amount of each metal in the lungs at Day 0 and at 72 hr post-infection. Each final isolate was analyzed using inductively coupled plasma optical emission spectroscopy (ICPOES-Model Optima 4300-DV; Perkin Elmer, Norwalk, CT).…”

Toxicity of Vanadium Compounds: Pulmonary and Immune System Targets

“…In some cases, it seems that solubility may be most critical for effects in the lungs as insoluble materials often persist after entrainment. For example, a recent study reported that solubil ity had a dramatic effect on the in situ immunomodulating effects of inhaled chromium compounds (114). Valency and redox behavior also likely impact on the immunotoxicity of metals that can exist in several oxidation states.…”

“…Whether the effects observed with each dipic agent (i.e., as a chelate form of V) was representative of all soluble V ,v and V 1 " agents will require comparison of immunotoxic potentials of the each dipic form vs. other V m or V ,v complexes, as well as against their free salts. To see if the differing solubility-related effects among the V compounds were not simply due to differences in how they were generated and admin istered, comparative analyses of data obtained here with that from studies with other metal agents (i.e., chromium, lead, and zinc; [114] and unpublished data) of varied solubility was performed. As netiher all soluble nor all insoluble agents induced equivalent immunomodulating effects, this meant that the means of atmosphere generation here was not a factor dictating differences in effects from each V compound.…”