title: Macrophage solubilization and cytotoxicity of indium-containing particles as in vitro correlates to pulmonary toxicity in vivo.
abstract: Macrophage-solubilized indium-containing particles (ICPs) were previously shown in vitro to be cytotoxic. In this study, we compared macrophage solubilization and cytotoxicity of indium phosphide (InP) and indium-tin oxide (ITO) with similar particle diameters (∼ 1.5 µm) and then determined if relative differences in these in vitro parameters correlated with pulmonary toxicity in vivo. RAW 264.7 macrophages were treated with InP or ITO particles and cytotoxicity was assayed at 24 h. Ionic indium was measured in 24 h culture supernatants. Macrophage cytotoxicity and particle solubilization in vitro were much greater for InP compared with ITO. To correlate changes in vivo, B6C3F1 mice were treated with InP or ITO by oropharyngeal aspiration. On Days 14 and 28, bronchoalveolar lavage (BAL) and pleural lavage (PL) fluids were collected and assayed for total leukocytes. Cell differentials, lactate dehydrogenase activity, and protein levels were also measured in BAL. All lavage parameters were greatly increased in mice treated with InP compared with ITO. These data suggest that macrophage solubilization and cytotoxicity of some ICPs in vitro are capable of predicting pulmonary toxicity in vivo. In addition, these differences in toxicity were observed despite the two particulate compounds containing similar amounts of indium suggesting that solubilization, not total indium content, better reflects the toxic potential of some ICPs. Soluble InCl3 was shown to be more cytotoxic than InP to macrophages and lung epithelial cells in vitro further suggesting that ionic indium is the primary cytotoxic component of InP.
authors.affiliation: *NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences; and Alion Science and Technology Corporation, Research Triangle Park, North Carolina 27709, USA gwinnwm@niehs.nih.gov.
authors.forename: William M
authors.initials: WM
authors.lastname: Gwinn
authors.affiliation: *NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences; and Alion Science and Technology Corporation, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Qu
authors.affiliation: *NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences; and Alion Science and Technology Corporation, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Bousquet
authors.affiliation: *NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences; and Alion Science and Technology Corporation, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Herman
authors.initials: H
authors.lastname: Price
authors.affiliation: *NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences; and Alion Science and Technology Corporation, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Cassandra J
authors.initials: CJ
authors.lastname: Shines
authors.affiliation: *NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences; and Alion Science and Technology Corporation, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Genie J
authors.initials: GJ
authors.lastname: Taylor
authors.affiliation: *NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences; and Alion Science and Technology Corporation, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
authors.affiliation: *NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences; and Alion Science and Technology Corporation, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Morgan
mesh_terms: D000395:Air Pollutants, Occupational / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007204:Indium / Q000737:chemistry / Q000633:toxicity*; D019570:Inhalation Exposure; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D010316:Particle Size; D010587:Phagocytosis; D010720:Phosphines / Q000737:chemistry / Q000633:toxicity*; D000067996:RAW 264.7 Cells; D012995:Solubility; D013997:Time Factors; D017971:Tin Compounds / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000395:Air Pollutants, Occupational; D010720:Phosphines; D017971:Tin Compounds; D007204:Indium; C020758:indium trichloride; C109984:indium tin oxide; D007770:L-Lactate Dehydrogenase; C090882:indium phosphide
keywords: InP; indium; macrophage cytotoxicity; pulmonary toxicity; sintered ITO; solubilization