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Title: Ricin toxicokinetics and its sensitive detection in mouse sera or feces using immuno-PCR

Author
item He, Xiaohua
item Patfield, Stephanie
item Henderson, Thomas
item GRIFFEY, STEPHEN - University Of California
item Cheng, Luisa

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/23/2010
Publication Date: 9/22/2010
Citation: He, X., Mcmahon, S.A., Henderson II, T.D., Griffey, S.M., Cheng, L.W. 2010. Ricin toxicokinetics and its sensitive detection in mouse sera or feces using immuno-PCR. PLoS One. 5(9):e12858. doi:10.1371/journal.pone.0012858.

Interpretive Summary: Ricin is a toxin derived from the seeds of the castor plant. The large quantities of raw materials left after oil extraction that can be used to extract toxin pose major bio-terror concerns. Currently, there is no effective medical treatment available for ricin poisoning. There are also no good diagnostic methods to detect ricin in biological samples such as blood and feces, and consequently, very little knowledge is available on the fate and distribution of ricin toxin in an animal’s body following poisoning. In this study, we used the mouse as an animal model to imitate human ricin poisoning. We developed a novel immuno-PCR test that is able to detect much lower amounts of toxin than other current tests. We applied this test to monitor concentrations of ricin in blood and feces after ricin poisoning by injection or ingestion. This study provides proof of principle for the use of immuno-PCR tests in the detection of ricin in mouse blood and feces, providing a framework for developing test kits in real human biological samples. Increased knowledge of the fate of ricin following poisoning and improved methods for its detection is valuable in the assessment of toxin risks and in the design of new medical interventions.

Technical Abstract: Ricin (also called RCA-II or RCA60), one of the most potent toxins and documented bioweapons, is derived from castor beans of Ricinus communis. Several in vitro methods have been designed for ricin detection in complex food matrices in the event of intentional contamination. Recently, a novel Immuno-PCR (IPCR) assay was developed with a limit of detection of 10 fg/ml in a buffer matrix and about 10-1000-fold greater sensitivity than other methods in various food matrices. In order to devise a better diagnostic test for ricin, the IPCR assay was adapted for the detection of ricin in biological samples collected from mice after intoxication. The limit of detection in both mouse sera and feces was as low as 1 pg/ml. Using the mouse intravenous (iv) model for ricin intoxication, a biphasic half-life of ricin, with a rapid t1/2 alpha of 4 min and a slower t1/2 beta of 86 min were observed. The molecular biodistribution time for ricin following oral ingestion was estimated using an antibody neutralization assay. Ricin was detected in the blood stream starting at approximately 6-7 h post- oral intoxication. Whole animal histopathological analysis was performed on mice treated orally or systemically with ricin. Severe lesions were observed in the pancreas, spleen and intestinal mesenteric lymph nodes, but no severe pathology in other major organs was observed. The determination of in vivo toxicokinetics and pathological effects of ricin following systemic and oral intoxication provide a better understanding of the etiology of intoxication and will help in the future design of more effective diagnostic and therapeutic methods.