Arsine is an important toxicant which has received little study despite its extensive use in the semiconductor industry. In addition to its industrial use, it can be formed when acid or base contracts inorganic arsenic and elemental metals like aluminum, tin, zinc and others. Thus, we predict that it can be formed in the environment in such places as hazardous waste dumpsites. The major route of toxicity for arsine is massive hemolysis. Arsine exposure ia a serious problem because there is no treatment except total blood exchange. Thus, a large scale accident would deplete the blood reserves of even the largest of blood banks. It is surprising that arsine has not received more attention because it is in widespread use and there is no good treatment after exposure. This proposal will study the mechanism of arsine-based hemolysis and characterize the changes which occur in the arsine molecule as a means to eventually design an effective treatment. The primary hypothesis is that arsine binds hemoglobin as first step and then reacts to form an oxidized arsine product and active oxygen species. Active oxygen species then go on to react with cellular components to cause hemolysis in a manner similar to other hemolytic agents. A second hypothesis is also considered in which hemoglobin reacts in a similar manner to P-450 and forms a reactive arsine metabolite which then could attack important cellular constituents. The studies proposed here combine a chemical approach using nuclear magnetic resonance and electron spin resonance spectroscopy to characterize the arsine-hemoglobin interaction with biological studies which characterize the oxidant stress on the red blood cell.
Other aims i nclude the characterization of the arsine species formed and an examination of the role of oxygen saturation on hemolysis. Our objective is to use these results to design a rational treatment for arsine toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES006644-01A1
Application #
2155448
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1994-07-15
Project End
1997-06-30
Budget Start
1994-07-15
Budget End
1995-06-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Peraza, Marjorie A; Cromey, Douglas W; Carolus, Barb et al. (2006) Morphological and functional alterations in human proximal tubular cell line induced by low level inorganic arsenic: evidence for targeting of mitochondria and initiated apoptosis. J Appl Toxicol 26:356-67
Rael, L T; Ayala-Fierro, F; Carter, D E (2000) The effects of sulfur, thiol, and thiol inhibitor compounds on arsine-induced toxicity in the human erythrocyte membrane. Toxicol Sci 55:468-77
Mitchell, R D; Ayala-Fierro, F; Carter, D E (2000) Systemic indicators of inorganic arsenic toxicity in four animal species. J Toxicol Environ Health A 59:119-34
Ayala-Fierro, F; Carter, D E (2000) LLC-PK1 cells as a model for renal toxicity caused by arsine exposure. J Toxicol Environ Health A 60:67-79
Ayala-Fierro, F; Baldwin, A L; Wilson, L M et al. (2000) Structural alterations in the rat kidney after acute arsine exposure. Lab Invest 80:87-97
Ayala-Fierro, F; Barber, D S; Rael, L T et al. (1999) In vitro tissue specificity for arsine and arsenite toxicity in the rat. Toxicol Sci 52:122-9
Hatlelid, K M; Carter, D E (1997) Reactive oxygen species do not cause arsine-induced hemoglobin damage. J Toxicol Environ Health 50:463-74
Winski, S L; Barber, D S; Rael, L T et al. (1997) Sequence of toxic events in arsine-induced hemolysis in vitro: implications for the mechanism of toxicity in human erythrocytes. Fundam Appl Toxicol 38:123-8
Klimecki, W T; Carter, D E (1995) Arsine toxicity: chemical and mechanistic implications. J Toxicol Environ Health 46:399-409