Statement of Jerry J. Buccafusco PhD.
Professor of Pharmacology and Toxicology
Medical College of Georgia

at the Annual Press Conference of the
Chemical Weapons Working Group
Washington, DC
April 21, 1997

Organophosphorus agents have a wide use in medicine, agriculture, and
unfortunately in the arsenal of chemical weapons. However, it is the
latter two uses that have been associated with significant toxicity and
lethality to humans. With the demise of the chlorohydrocarbon
insecticides such as DDT, the use of the organophosphorus insecticides
which are chemically-related to chemical warfare agents, has become
prevalent. Along with the manufacture and deployment of the more
lethal nerve agents this class of drug has prompted concern regarding not
only their acute toxicity, but also the possibility that low-level, chronic
exposure to these compounds is associated with subtle forms of chronic
illness. The most recent event to bring such concern to the forefront was
the Persian Gulf conflict wherein significant numbers of returning
veterans continue to complain of the cluster of symptoms termed the
Persian Gulf Illness.

Gulf War personnel had ample opportunities to undergo repeated
exposure to drugs related to the organophosphate cholinesterase
inhibitors. These included the liberal use of personal insecticides, the
use and over-use of pyridostigmine bromide--a potential nerve agent
protectant, and the direct exposure to Iraqi chemical nerve agents. But
it is the agricultural setting that has provided the little that is known
regarding the consequence of chronic sub-toxic exposure to the
organophosphorus pesticides. In fact, many of the symptoms reported by
agricultural workers who had been subjected to repeated low-level
intoxication are similar to those reported by Gulf War veterans.

One of the more prevalent and troubling of the symptoms reported by
both groups is the subtle cognitive impairment characterized by
forgetfulness and difficulty concentrating. Our research at the MCG has
focused on human disorders of cognition, or thinking, and memory, and
it was the memory loss attributed to Persian Gulf Illness that we initially
chose to address. Funded by a grant from the US Army over the past two
years, we have developed a rat model in which chronic low-level exposure
to an organophosphorus agent produced a subtle but reproducible
memory impairment for as long as 3 weeks after termination of the
exposure. Moreover, this protracted memory impairment was
accompanied by a delayed recovery of the enzyme acetylcholinesterase,
which is targeted by chemical warfare agents.

These changes were shown to occur specifically in the hippocampus, a
portion of the brain that is critical for new memory formation.
Additionally, there was a loss of a specific class of neurotransmitter
receptors for acetylcholine--a brain substance that helps solidify new
memories. The number of acetylcholine receptors had declined by over 50% and
even after 3 weeks, the level had only slightly returned towards
normal. The relevance of these findings is based on the facts that (1) the
dementia and memory loss associated with Alzheimer's disease is
accompanied by loss of acetylcholinesterase and acetylcholine receptors
in the hippocampus, (2) that the hippocampus is a brain structure that
is intimately involved in normal memory processes, and (3) that the
neurochemical changes that took place after chronic low-level
organophosphorus exposure appeared to parallel the memory loss in the
animals. Our data go on to show that only a particular form of memory-
-working memory (but not reference memory) is affected by OP agents.

Our continuing studies are directed at more fully characterizing the
behavioral and neurochemical, and perhaps the neuropathological
change associated with chronic OP exposure. With this knowledge, we
anticipate the development of novel approaches to the treatment of the
cognitive symptoms related to OP exposure whether it occurs on the
peanut field, or the battle field.

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