mals (n = 8) exposed to fresh air in an exposure chamber. At no time did sarin-exposed animals show signs of cholinergic toxicity, although AChE activity was inhibited by 27 percent (blood) and 19 percent (brain). A subsequent study in white leghorn hens (Gallus domesticus, n = 5) given subcutaneous doses of sarin (50 μg/kg, daily for 10 days) found moderate ataxia on the fourteenth day (Husain et al., 1995). The dose is reported to be one-tenth of the LD50 (Husain et al., 1995). NTE activity was inhibited in brain (53 percent), spinal cord (38 percent), and platelets (54 percent). Sarin caused moderate axonal degeneration and axonal swelling, while the effects of mipafox (n = 6) were much more severe (Husain et al., 1995). Platelet acetylcholinesterase activity was inhibited by 72 percent, but no indication is provided on whether cholinergic symptoms were observed. In summary, the findings of the studies reviewed indicate evidence that sarin can cause OPIDN in some animal species, particularly at doses that produce otherwise lethal effects.
In a comprehensive study of the genotoxicity of sarin, no mutagenesis, chromosomal damage, unscheduled DNA synthesis, or sister chromatid exchange was found. In vitro doses of sarin ranging from 0.2 to 200 μg/ml and in vivo exposures in rats at 360 μg/kg did not produce toxicity in any gene toxicity assays performed (Goldman et al., 1988). Klein and colleagues (1987) measured unscheduled DNA repair and synthesis in rat hepatocytes exposed to sarin. No increase in DNA synthesis was observed, but a decrease in repair synthesis was seen after administration of two different formulations of sarin (3.0 × 10−4–2.4 × 10−3 moles [M] sarin, with different stabilizers). This study did not control for the stabilizers, and variability between experiments casts doubt on these results.
A standard subchronic (90-day) toxicology study of sarin was performed at the National Center for Toxicological Research (Bucci and Parker, 1992; Bucci et al., 1992). Rats were administered sarin in two formulations (type I with tributylamine stabilizer and type II stabilized with diisopropylcarbodiimide) at three different doses: a maximum tolerated dose, MTD/2, and MTD/4 (corresponding to 300, 150, and 75 μg/kg per day, given by gavage). Both formulations produced profound inhibition of acetylcholinesterase and some deaths. No neoplastic lesions were detected after sarin (type I), but nonneoplastic lesions (necrosis in the cerebrum, related to hypoxia) were detected and were thought to be the cause of death in 3 of 36 female rats (1 at 75 μg/kg, 2 at 300 μg/kg.). Sarin (type II) was associated with one neoplastic lesion, a lymphoma, in one male in the high-dose group (n = 12). No studies have been conducted to catalog the effects of chronic exposure to sarin.