Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review

Abstract

Sarin (GB, O-isopropyl methylphosphonofluoridate) is a potent organophosphorus (OP) nerve agent that inhibits acetylcholinesterase (AChE) irreversibly. The subsequent build-up of acetylcholine (ACh) in the central nervous system (CNS) provokes seizures and, at sufficient doses, centrally-mediated respiratory arrest. Accumulation of ACh at peripheral autonomic synapses leads to peripheral signs of intoxication and overstimulation of the muscarinic and nicotinic receptors, which is described as “cholinergic crisis” (i.e. diarrhea, sweating, salivation, miosis, bronchoconstriction). Exposure to high doses of sarin can result in tremors, seizures, and hypothermia. More seriously, build-up of ACh at neuromuscular junctions also can cause paralysis and ultimately peripherally-mediated respiratory arrest which can lead to death via respiratory failure. In addition to its primary action on the cholinergic system, sarin possesses other indirect effects. These involve the activation of several neurotransmitters including gamma-amino-butyric acid (GABA) and the alteration of other signaling systems such as ion channels, cell adhesion molecules, and inflammatory regulators. Sarin exposure is associated with symptoms of organophosphate-induced delayed neurotoxicity (OPIDN) and organophosphate-induced chronic neurotoxicity (OPICN). Moreover, sarin has been involved in toxic and immunotoxic effects as well as organophosphate-induced endocrine disruption (OPIED). The standard treatment for sarin-like nerve agent exposure is post-exposure injection of atropine, a muscarinic receptor antagonist, accompanied by an oxime, an AChE reactivator, and diazepam.

Keywords:

• Neurotoxicity
• organophosphates
• sarin
• toxicity
• oximes
• OPIDN
• OPICN
• AChE
• NTE
• BChE
• LD50

Declaration of interest

This manuscript was prepared by the authors who are affiliated with Duke University, aimed at engaging scientists from academia, government, industry, research institutes, and the public to identify and resolve health and environmental issues related to OP compounds and sarin exposure in particular. This is a significant issue considering that an estimated 200 000 American military personnel were suspected to have been exposed to low-level sarin that was released following the destruction of Iraqi weapon stockpile in Khamisiyah, Iraq in 1991. Many of these soldiers still complain of symptoms of the Gulf War illness. Recent attacks against civilian populations by terrorists ranging from fanatic religious cult members in Japan and dictators in Iraq and Syria have resulted in the death of thousands of people, including children. The authors have sole responsibility for this paper that reflects their views and of the writing and content of the paper. The views and opinions expressed in the paper do not necessarily reflect the views of the author’s employers. Mention of trade names does not constitute endorsement. The senior author, MBA investigated health effects of sarin through the Department of Defence grants. He testified of its involvement of chemical exposure, including sarin in the Gulf War illness before the U.S. Senate Veterans’ Committee and presented his research in DOD meetings. None of the authors has recently or is currently been involved as an expert witness in litigation on the subject of this paper. The authors declare that there is no conflict of interest.