Toxicology

Mechanism of Action

Knowledge of the pathogenic mechanisms of Clostridium botulinum can provide insight into the potential adverse effects associated with administration of the botulinum toxoid vaccine. The signs and symptoms of botulism are due to the action of neurotoxins that are synthesized during cell growth of C. botulinum and released prior to or after lysis of the bacteria.

There are seven immunologically distinct types of botulinum neurotoxins: types A through G. Human botulism is caused principally by types A, B, E, and F toxins, and animal botulism is principally caused by types C and D (Sellin, 1984). In horses, the Clostridium botulinum that colonizes the intestinal tract produces type B toxin, causing the symptoms of shaker foal syndrome.

The mechanism of action of botulinum neurotoxins has recently been reviewed (Simpson, 1989; Brin, 1997). The seven neurotoxins are all metalloenzymes that cleave various components of the proteins involved in the release of the neurotransmitter, acetylcholine. Botulinum toxins share a number of structural features with tetanus toxins, even though the clinical symptoms of poisoning are quite different. The toxin molecule has three functional domains. The carboxy terminal portion of the molecule mediates binding of the toxin to the presynaptic nerve terminal at the neuromuscular junction. The central third of the molecule acts to internalize the neurotoxin inside the nerve ending. After internalization and disulfide cleavage, the light chain or amino terminal section then translocates the toxin to the cytosol where it inhibits the binding of synaptosomal vesicles to the axon terminal membrane, thus inhibiting the release of acetylcholine. Inhibiting the release of acetylcholine significantly affects nerve transmission between motor nerves and the voluntary muscles, causing paralysis and loss of respiration, a process that occurs at doses lower than required to affect the autonomic nervous system. All ganglionic synapses require acetylcholine and thus are disrupted. In addition, the postganglionic parasympathetic nervous system requires acetylcholine. The clinical effect of the toxin is thought to be due primarily to its effects on the peripheral nervous system because the botulinum neurotoxin does not cross the blood–brain barrier (Simpson, 1993). Extreme cases of poisoning with botulinum toxin result in total paralysis, with the patient incapable of moving or breathing.

To produce the toxoid, toxins are partially purified from culture supernatants and exposed for prolonged periods to formaldehyde. After exposure to formaldehyde they are tested for toxicity in mice and guinea pigs to ensure that the neurotoxin was inactivated.

Animal Studies

As noted earlier in this chapter, adverse health outcomes can result either from toxic effects of the injected toxoid preparation or from stimulation of the immune system. Toxic effects of the vaccination itself could be due to traces of



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