FACT SHEET-JULY 1997

RESEARCH RELEVANT TO GULF WAR VETERANS ON THE
HEALTH EFFECTS OF NERVE AGENTS AND MUSTARD AGENTS
FUNDED BY THE DEPARTMENTS OF DEFENSE AND VETERANS AFFAIRS

 

This fact sheet summarizes the ongoing health research related to chemical warfare agent exposure, which is relevant to illnesses in Gulf War veterans. In addition, the relevant research which DOD and VA plans to fund in 1997 is outlined.

Most of the information in this fact sheet has been summarized from the Annual Report to Congress: Federally Sponsored Research on Persian Gulf Veterans' Illnesses. This report was published in April 1997 by the Persian Gulf Veterans Coordinating Board, and it can be obtained from the Department of Veterans Affairs.

Ongoing Research Funded by the DOD and VA on the Health Effects of Nerve Agents and Related Organophosphates


1. Chronic Organophosphorous Exposure and Cognition (DOD Project 22)

Location: Medical College of Georgia, Augusta, Georgia
Project Timeline: April 1995 to May 1998
Total Funding: $375,000
Publications, to date: Prendergast, M., Terry, A., and Buccafusco, J. Chronic, low-level
exposure to diisopropylfluorophosphate causes protracted impairment of spatial navigation learning. Psychopharmacology 129:183-191, 1997.

Overall Objective: Chronic exposure to organophosphate insecticides or chemical weapon nerve agents can produce abnormalities in brain function in experimental animals. The objective of this project is to evaluate the cognitive effects of exposure to an organophosphorous (OP) chemical in rats and monkeys. The long-term goal is to identify the underlying biochemical mechanisms of brain damage due to OP exposure. In this study, rats and monkeys are injected with diisopropylfluorophosphate (DFP), an OP chemical which is not a military nerve agent. Animals, that are trained to perform various memory tasks, are exposed to DFP for two or more weeks to determine if exposure causes learning or memory deficits. In addition, the animals will be given drugs that are being developed for Alzheimer's disease patients, to determine if the memory impairment caused by an OP chemical can be reversed.

Preliminary Results: The results of the first experiments are available. Their purpose was to identify the severity of impairment in learning in rats and monkeys following exposure to DFP. Rats were treated with DFP for 14 days, at doses that caused suppression of spontaneous activity and olfactory behavior. 40% of the rats in the highest dosage group died, after showing classic signs of OP toxicity. After withdrawal from DFP treatment, the rats' performances on a standard water maze test were impaired for as long as 21 days, the maximum period before they were sacrificed. Three rhesus monkeys, that were well trained in the performance of a delayed response test, were treated with DFP at a dosage that caused severe toxicity and task impairment, after 8 weeks of treatment. However, by 6 to 8 days after stopping the DFP, the monkeys' task performances were at near control levels. These preliminary results with rats and monkeys show that exposure to DFP may compromise memory at dosages that cause signs of toxicity, but there is no impairment of memory at dosages of DFP that do not cause toxicity. These early results cannot be extrapolated directly to Gulf War veterans who may have been exposed to OP nerve agents or pesticides. This is because of the much higher dosages, route of administration (injection), and severe toxicity observed in the animal experiments.

2. Molecular Targets for Organophosphates in the Central Nervous System (Funded by DOD)

Location: University of Maryland School of Medicine, Baltimore, Maryland
Project Timeline: April 1995 to August 1998
Total Funding: $229,000
Publications, to date: None

Overall Objective: This research is designed to improve the understanding of potential chronic effects of nerve agents and potential effects seen at low doses. Most research in the past has focused on the effects of nerve agents on only one neurotransmitter system in the brain, the cholinergic system. Previous research has found that nerve agents have effects on the brain, that cannot be explained solely on the basis of effects on cholinergic transmission. The objective of this project is to look beyond the effects of nerve agents on the cholinergic system to see how they perturb other brain systems, including the effects on the glutamate neurotransmitter system.

Preliminary Results: None

3. Toxicokinetics of O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) in Rats, Hairless Guinea Pigs, and Marmosets-Identification of Metabolic Pathways (DOD Project 50)

Location: TNO Prins Maruits Laboratory, Rijswijk, Netherlands
Project Timeline: October 1996 to April 1998
Total Funding: $699,136
Publications, to date: None

Overall Objective: The objective of this project is to determine the toxicokinetics of the nerve agent VX in rats, guinea pigs, and marmosets, a type of monkey. The toxicokinetic experiments are designed to study how animals metabolize and eliminate VX from the body. Among military nerve agents, VX is the most toxic, and it is also the most persistent in the environment. The hypothesis is that the toxicokinetics of VX differ from other military nerve agents. Iraq did not have weapons containing VX during the Gulf War, but information about VX is important for future deployments. This is because of uncertainties in the current pretreatment strategies, related to differences between VX and other nerve agents. O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate is the technical name for VX.

Preliminary Results: None

4. Transgenic Engineering of Cholinesterases: Tools for Exploring Cholinergic Responses (DOD Project 51)

Location: Hebrew University of Jerusalem, Israel
Project Timeline: October 1996 to February 2000
Total Funding: $864,026
Publications, to date: None

Overall Objective: Nerve agents interact with a group of blood chemicals called cholinesterases (ChE). This project will use transgenic frogs and mice to determine the responses of different types of ChE to nerve agent poisoning. These animals are called transgenic, because they have been implanted with a human gene that manufactures the human type of ChE inside the frogs or mice. Previous research has shown that elevated levels of ChE can protect animals from nerve agent poisoning. The objective of this project is to determine the contribution of different types of ChE toward protection against nerve agents, within specific cell and tissue types. Another objective of this study is to develop animal models which have predetermined susceptibilities to nerve agents.

Preliminary Results: None

Ongoing Research Funded by the DOD and VA on the Health Effects of Mustard Agents

1. Diagnosis and Dosimetry of Exposure to Sulfur Mustard: Development of Standard Operating Procedures and Exploratory Research on Protein Adducts (DOD Project 49)

Location: TNO Prins Maruits Laboratory, Rijswijk, Netherlands
Project Timeline: October 1996 to February 2000
Total Funding: $926,983
Publications, to date: None

Overall Objective: The objective of this project is to develop methods to assess mustard agent exposure in individual humans. Mustard agent is highly reactive and it shows little persistence in the body. Exposure levels will therefore be determined indirectly by quantifying levels of sulfur mustard adducts to DNA and protein, in samples of human blood and skin. These types of DNA and proteins (adducts) have been damaged by mustard agent and can be detected in the laboratory. The hypothesis is that the assessment of DNA and protein adducts can be used to determine exposure levels at short- and long-term intervals after exposure to mustard agent.

Preliminary Results: None

2. Retrospective Verification of Mustard Gas Exposure (VA Project 47)

Location: VA Medical Center, Louisville, Kentucky
Project Timeline: January 1997 to January 2000
Total Funding: Part of a research center which includes 5 projects, which together total $950,000
Publications, to date: None

Overall Objective: The objective of this project is to determine if there is a relationship between mustard gas exposure and human reproductive problems. Mustard gas can damage hemoglobin and cause a type of damaged hemoglobin called an adduct. First, a method of analysis will be developed to detect the mustard gas adduct with human hemoglobin. Then, blood samples will be taken from two populations to perform this test for hemoglobin adducts: Gulf War veterans who had potential exposure to chemical agents, and military personnel from the Bluegrass Army Depot who work with chemical agents. These populations will also be surveyed for reproductive difficulties and for developmental problems in their children. The correlation between verified exposure to mustard gas and reproductive and developmental problems will be investigated.

Preliminary Results: None

3. DNA Damage from Chemical Agents and Its Repair (Project VA-6D)

Location: VA Medical Center, Portland, Oregon
Project Timeline: October 1994 to September 1999
Total Funding: Part of a research center which includes 5 projects, which together total $2,572,500
Publications, to date: None

Overall Objective: The objective of this project is to determine the effects of nitrogen mustard on the DNA of human skin tissue and rodent brain tissue. Nitrogen mustard is used as a surrogate for sulfur mustard chemical weapon agents. Tissue cultures made from human skin, mouse brain, and rat brain are treated with nitrogen mustard. DNA is then isolated from the tissue cultures, and the DNA is analyzed for a form of damage called DNA adducts. This project is designed to investigate a possible relationship between nitrogen mustard exposure, DNA damage, and cell damage in nervous tissue.

Preliminary Results: The results of the first experiments are available. Two types of rodent brain cells, glial cells and neurons, were treated with nitrogen mustard. Glial cells were less sensitive than neuronal cells to damage from the nitrogen mustard. Nitrogen mustard is also acutely toxic to human skin tissue within 24 hours at high concentrations, and at much lower concentrations, if the skin is exposed for 7 days. DNA adducts can be repaired by a protein called APE. Nitrogen mustard modulated the concentration and activity of APE in rodent nervous tissue and human skin tissue. Alterations in APE concentrations and activity may be an indication of DNA damage induced by nitrogen mustard. These early results cannot be extrapolated directly to Gulf War veterans, because tissue cultures are being used instead of living animals. In addition, only one individual soldier is known to have had a documented exposure to mustard agent during the Gulf War, to date.

Research on Nerve Agents and Mustard Agents, Planned for 1997 by DOD and VA

In 1996, DOD announced that demolitions at the ammunition storage facility at Khamisiyah, Iraq may have lead to the low level exposure of U.S. troops to the nerve agents sarin and cyclosarin. In November 1996, the Persian Gulf Veterans Coordinating Board revised its research priorities and added the following recommendations:



DOD has responded to these research recommendations by funding both internal and external projects. For example, DOD plans to fund several external projects related to the effects of low level exposure to chemical warfare agents. In early 1997, DOD released three Broad Agency Announcements (BAA) for new research projects. Two of the three BAA focused on the following topics:



As of July, 1997, the research proposals submitted in response to the BAA have been reviewed. A number of projects related to chemical warfare agents have been selected for funding, which total several million dollars. The final funding decisions will be made by September 30, 1997. At that time, there will be a public announcement of the selected projects.

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