CHAPTER 4: Toxicity of Botulinum Neurotoxin by Inhalation: Implications in Bioterrorism¹ Check Access

Exposure to botulinum neurotoxin (BoNT) results in botulism, a neuroparalytic illness characterized by cranial nerve palsies, generalized muscle weakness, autonomic dysfunction and respiratory depression. BoNT gains entry into the nerve terminal cytoplasm and inhibits the release of acetylcholine by cleaving specific SNARE proteins required for neurotransmitter release. BoNT is the most lethal substance known and exposure to even minute quantities can cause incapacitation and death. Outbreaks of botulism have decreased over the last half century owing to advances in food preservation techniques and survival has increased dramatically owing to improvements in surveillance, critical care and availability of antitoxin. The ability of BoNT to impair selectively cholinergic transmission and its long duration of action have led its use in the treatment of neurological conditions stemming from imbalances in muscle tone such as spasticity, dystonia and movement disorders. In contrast to its use in clinical medicine, the extreme potency and persistence of BoNT also enable this toxin to be used in biological warfare and bioterrorism. In this capacity, it is widely believed that BoNT would be disseminated as a respirable aerosol or possibly as a food contaminant. The potency of BoNT is greater by aerosol delivery than by ingestion, but less than by parenteral administration. The latency and progression of inhalation botulism are comparable to those of foodborne botulism and the signs and symptoms are comparable except for the absence of early gastrointestinal signs in the former. Inhalation botulism in nonhuman primates can be effectively treated with equine antitoxins, suggesting that these may also be effective in human botulism outbreaks. In the absence of critical care, intoxication with high doses of BoNT (>25 LD₅₀ units) is lethal if treatment by antitoxin is delayed until the appearance of the first signs of exposure. The limitations imposed by the time window of antitoxin efficacy necessitate a search for therapeutic agents that can inhibit the internalized toxin and promote survival and recovery.