The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is no evidence that it causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxicity, the nerve agents are not likely to be carcinogens. The overreaching concern with regard to nerve agent exposure is the extraordinarily high acute toxicity of these substances. Furthermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent release, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs.

Toxicity of the Organophosphate Chemical Warfare Agents GA, GB, and VX: Implications for Public Protection.

1. The influences of ambient temperature (T(a)) on the thermoregulatory effector activities and the body temperature (T(b)) of intraventricular injections into the sheep, goat and rabbit of 5-hydroxytryptamine (5-HT), noradrenaline (NA), acetylcholine (ACh), carbachol and eserine, have been interpreted in terms of a simple neuronal model of the pathways between thermosensors and thermoregulatory effectors.2. In all three species 5-HT in minimal doses caused a rise in respiratory frequency (RF) and a fall in T(b) at high T(a), and a reduction in EMG activity and a fall in T(b) at low T(a). These effects could be interpreted as those of an excitatory transmitter acting on the warm receptor-heat loss pathway.3. In all three species NA caused a reduction in RF and a rise in T(b) at high T(a), and a reduction in EMG activity and a fall in T(b) at low T(a). These effects are interpreted as those of an inhibitory transmitter acting both on the warm sensor-heat loss pathways and on the cold sensor-heat production pathway.4. The effects of ACh and the cholinomimetic substances carbachol and eserine are complex and more difficult to interpret. In small doses the effects on the sheep and goat are those of an excitatory transmitter on the cold sensor-heat production pathway. There was an increase in EMG activity and a rise in T(b) at low T(a), and a reduction in RF and a rise in T(b) at high T(a). At higher dose levels in the goat and at all dose levels in the rabbit these substances had the reverse effects which are attributed to a synaptic block due to the excess of the excitatory substance.5. The effects of ambient temperature and injected substances upon ear temperature are consistent with the predictions of the model if it is assumed (a) that at high and low ambient temperatures direct thermal effects on ear vessels dominate those of the sympathetic innervation, and (b) that the warm sensor influence is to lower peripheral vasomotor tone, and the cold sensor influence is to increase it.6. The conclusion reached is that when consideration is given to species differences in the thermoneutral ambient temperature and to the possibility that excitatory substances have reversed effects at high dose levels, the effects of 5-HT, NA and ACh in the control of body temperature are very similar in the sheep, goat and rabbit: 5-HT is excitatory on the heat loss pathway, ACh is excitatory on the heat production pathway and NA has an inhibitory influence on both pathways.

Influence of ambient temperature on the thermoregulatory responses to 5-hydroxytryptamine, noradrenaline and acetylcholine injected into the lateral cerebral ventricles of sheep, goats and rabbits.

https://deepblue.lib.umich.edu/bitstream/handle/2027.42/26059/0000133.pdf?sequence=1

O.L. Wolthuis

Papers

The effects of cholinesterase inhibitors on the body temperature of the rat