title: Deviations from Haber's Law for multiple measures of acute lung injury in chlorine-exposed mice.
abstract: Chlorine gas is considered a chemical threat agent that can cause acute lung injury. Studies in the early 20th century on war gases led Haber to postulate that the dose of an inhaled chemical expressed as the product of gas concentration and exposure time leads to a constant toxicological effect (Haber's Law). In the present work, mice were exposed to a constant dose of chlorine (100 ppm-h) delivered using different combinations of concentration and time (800 ppm/7.5 min, 400 ppm/15 min, 200 ppm/30 min, and 100 ppm/60 min). Significant effects of exposure protocol on survival evaluated 6 h after exposure were observed, ranging from 0% for the 7.5-min exposure to 100% for the 30- and 60-min exposures. Multiple parameters indicative of lung injury were examined to determine if any aspects of lung injury were differentially affected by the exposure protocols. Most parameters (pulmonary edema, neutrophil influx, and levels of protein, immunoglobulin M, and the chemokine KC [Cxcl1] in lavage fluid) indicated that lung injury was most pronounced for the 15-min exposure and least for the 60-min exposure. In contrast, changes in pulmonary function at baseline and in response to inhaled methacholine were similar following the three exposure regimens. The results indicate that the extent of lung injury following chlorine inhalation depends not only on total dose but also on the specifics of exposure concentration and time, and they suggest that evaluation of countermeasures against chlorine-induced lung injury should be performed using multiple types of exposure scenarios.
authors.affiliation: Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky 40202, USA. Gary.Hoyle@louisville.edu
authors.forename: Gary W
authors.initials: GW
authors.lastname: Hoyle
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Chang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Connie F
authors.initials: CF
authors.lastname: Schlueter
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Rando
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000280:Administration, Inhalation; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002713:Chlorine / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D023381:Endpoint Determination; D019570:Inhalation Exposure; D008136:Longevity / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms
chemical_list: D002619:Chemical Warfare Agents; D002713:Chlorine
references.citation: Arch Toxicol. 1993;67(7):478-90
references.pmid: 8239997
references.citation: Am J Respir Crit Care Med. 2003 Sep 1;168(5):568-74
references.pmid: 12724121
references.citation: J Appl Toxicol. 1998 Jul-Aug;18(4):249-55
references.pmid: 9719424
references.citation: Toxicology. 2005 Nov 5;215(1-2):48-56
references.pmid: 16076519
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Nov;295(5):L733-43
references.pmid: 18708632
references.citation: J Appl Physiol (1985). 1999 Jun;86(6):1984-93
references.pmid: 10368365
references.citation: Public Health Rep. 2007 Nov-Dec;122(6):784-92
references.pmid: 18051671
references.citation: J Appl Physiol (1985). 1996 May;80(5):1841-9
references.pmid: 8727575
references.citation: J Appl Physiol (1985). 2007 Jan;102(1):221-30
references.pmid: 17008432
references.citation: Am J Clin Pathol. 1971 Oct;56(4):430-42
references.pmid: 5113398
references.citation: Eur Respir J. 1997 May;10(5):1100-7
references.pmid: 9163653
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Sep;299(3):L289-300
references.pmid: 20525917
references.citation: Toxicol Appl Pharmacol. 1979 Jun 15;49(1):77-88
references.pmid: 473205
references.citation: Inhal Toxicol. 2008 Jul;20(9):783-93
references.pmid: 18645717
references.citation: Am Ind Hyg Assoc J. 1978 Feb;39(2):129-38
references.pmid: 565136
references.citation: J Appl Physiol (1985). 2002 Jul;93(1):263-70
references.pmid: 12070213
references.citation: J Appl Toxicol. 1994 Nov-Dec;14(6):405-9
references.pmid: 7884144
references.citation: J Appl Physiol (1985). 2004 Jun;96(6):2019-27
references.pmid: 14660507
references.citation: Am Rev Respir Dis. 1969 Mar;99(3):374-9
references.pmid: 5765629
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Jun;298(6):L830-6
references.pmid: 20348278
references.citation: Toxicology. 2000 Aug 14;149(1):21-34
references.pmid: 10963858
references.citation: Respir Res. 2008 Jun 12;9:51
references.pmid: 18549493
references.citation: Lung. 2005 May-Jun;183(3):151-67
references.pmid: 16078037
references.citation: J Occup Med. 1962 Mar;4:152-4
references.pmid: 14452652
references.citation: J Appl Physiol (1985). 1992 Jan;72(1):168-78
references.pmid: 1537711