bolic rates. The levels of IMPA in urine correlated with the degree of clinical symptoms. They also found evidence of distribution of sarin to the human brain in 4 of the 12 people who died after exposure. Solubilized sarin-bound AChE from formalin-fixed cerebellar tissue of victims of the Tokyo attack contained a derivative of the sarin hydrolysis product methylphosphonic acid (MPA) (Matsuda et al., 1998). The estimated amounts of MPA ranged from 0.32 to 1.13 nmol/g tissue. Although no IMPA was found, it was assumed that IMPA had hydrolyzed to MPA in the formalin solution over 2 years of storage.

Biomarkers of Exposure

Biomarkers of acute sarin exposure can be detected in blood or urine. In blood, the extent of inhibition of RBC AChE is considered the best marker of acute exposure. Sarin preferentially inhibits RBC AChE more than BuChE; however, after high-level sarin exposure, complete inhibition of both esterases occurs (Sidell and Borak, 1992). Since inhibition of blood cholinesterases is a common feature of organophosphates and other anticholinesterases, this biomarker is not specific to sarin exposure. Further, its utility as a biomarker is limited to a short time after exposure, with a return to original blood esterase levels by about 1–3 months (Grob, 1963). The recovery times for blood esterases are somewhat different. BuChE is replaced after about 50 days following de novo synthesis in the liver. RBC AChE recovery is contingent upon the turnover rate of red blood cells, which is about 1 percent per day. This esterase is synthesized with the RBC (Sidell and Borak, 1992). Sensitive methods for detecting urinary metabolites as biomarkers of sarin exposure were recently developed by Japanese researchers in the aftermath of the Tokyo terrorism incident (Minami et al., 1997, 1998).

Black and colleagues (1999) recently found a sensitive biomarker that can specifically identify sarin at low concentrations in human plasma. The researchers found a novel phosphonylation site, presumably from human serum albumin, at which sarin interacts with a tyrosine residue. In contrast, the biomarkers noted above are indices of sarin exposure but do not uniquely identify sarin as opposed to other CW agents. The advantage of this potentially new method is that it can directly implicate sarin at low concentrations.

Animal Studies

This section summarizes the toxic effects of sarin in laboratory animals. Most animal studies of sarin did not examine low-level exposure, but instead focused on lethal, near-lethal, or maximum tolerated doses (MTDs).4 These high doses produced the acute cholinergic syndrome and in many cases necessitated

4  

The MTD is the highest dose used during a long-term study that will not alter the life span of the animal and slightly suppresses body weight gain (i.e., 10 percent) in a 90-day subchronic study.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement