A. Pesticides of Potential Concern (POPC)
Although all pesticides can be toxic to humans if they are taken in large doses, the pesticides sent to the Gulf were typical of products readily available in the US at the time. As indicated previously, they were considered safe for general unrestricted use within the US. The POPCs are categorized below by group or class. These groups include organophosphates, carbamates, pyrethroids, organochlorine, and repellents (DEET). This section provides a general overview of potential health effects for the POPCs reportedly used during the Gulf War deployment.
To help evaluate the possible health effects of pesticides on Gulf War veterans, OSAGWI commissioned RAND to review the existing scientific literature on the health effects of pesticides. The RAND report reviews the scientific literature on the active ingredients of the POPCs used during the Gulf War deployment. The objective of the report was "to examine the scientific literature pertaining to the potential health effects of pesticides available during ODS/DS as part of the ongoing effort to gain a better understanding of the possible causes of undiagnosed symptoms reported by veterans."[74] The report summarizes the relevant literature and includes reports of known pesticide exposures and doses and the related health outcomes. RAND investigators combined this review with information from the Environmental Protection Agency and other sources to produce a health effects analysis.
The scientific literature review is only one step in determining the potential contribution of pesticides to the undiagnosed symptoms reported by some Gulf War veterans; however, we hope that this information will be useful in subsequent efforts to further define or characterize the possible role of pesticides in undiagnosed symptoms of Gulf War veterans.
The RAND review is inconclusive on the role of pesticides, particularly acetylcholinesterase (AChE) inhibitors and their relationship with the undiagnosed illnesses reported by some Gulf War veterans. RAND also indicates that additional research is necessary in this area. The report concludes that:
Existing evidence in the literature is suggestive, but not conclusive, that pesticides, specifically AChE inhibitors such as organophosphates and carbamates, could be among the potential contributing agents to some of the undiagnosed illnesses seen in [Gulf War veterans].[75]
Conclusions reached in the RAND report are supported by information and evidence collected from a number of subject areas to include: epidemiology; genetic and biologic differences between ill and healthy subjects; physiological mechanisms of AChE inhibitors; and similarities between clinical findings of AChE inhibitor-exposed subjects and reported symptoms among Gulf War veterans. The report notes that significant uncertainties remain, especially in linking these lines of evidence with actual exposures to AChE inhibitors (including pesticides) during the Gulf War, and that more research is needed to confirm or deny a causal link between pesticides or other agents and illness among Gulf War veterans.[76]
Finally, the report states that although the scientific literature has implicated exposure to acetylcholinesterase-inhibiting pesticides as a contributing factor to some health problems similar to those experienced by Gulf War veterans, few symptoms are uniquely characteristic of pesticide exposure. Therefore:
[g]iven the evidence to date and the literature reviewed, it is inappropriate to rely upon exposure to pesticides, especially organophosphates and carbamates, as the [sole] explanation for the myriad health problems reported by [Gulf War veterans]; however, we think it equally inappropriate at this point to completely rule out pesticides as a potential contributing factor.[77]
Only one medically documented case of acute pesticide exposure has been found during the course of this investigation. On February 17, 1991, a US airman working around insecticide containers at Thumrait Air Base in Oman experienced burning in his lungs, nausea, stomach cramps, and dizziness. The airman inhaled fumes from containers of an unspecified insecticide that were apparently leaking. The airman was treated with intravenous fluids and oxygen, observed overnight, and returned to duty the following day. A follow-up interview with the veteran was conducted to verify information contained in the original medical record and to inquire into his current health status. The results of the interview indicate that the veteran is currently not suffering from any health symptoms associated with his exposure incident.[78]
The medical record that documented this exposure was found during a preliminary survey of hospitalization records from the Gulf War. At this time these records have not been cataloged to allow an automated search by diagnosis. When cataloging is complete, other instances of treatment for acute pesticide exposure may be found. In addition there have been some non-documented (i.e., not supported by hospital and medical records) reports by several Gulf War veterans that they required medical treatment due to pesticide exposures received while in the KTO (see Tab C-4, Symptomatic Pesticide Exposures Reported). Until such time as a searchable database is developed, however, these reports cannot be substantiated.
Organophosphates used during the Gulf War deployment include azamethiphos, chlorpyrifos, diazinon, dichlorvos, and malathion. Organophosphate pesticides, like carbamate pesticides, act by binding to and inhibiting acetylcholinesterase (AChE). AChE, an enzyme found in the blood, is critical to the normal functioning of the nervous system. It serves a critical role in regulating impulses between nerves, and between nerves and muscles. The body can withstand some inhibition of AChE with no ill effects.
Exposure to large amounts of organophosphorus pesticides can cause nerve and nerve/muscle disorders. Acute symptoms span a range from mild to severe depending upon the degree of AChE inhibition. Mild symptoms include narrowing of the pupil and runny nose; more severe symptoms may include additionally any or all of the following: dizziness, nausea, vomiting, rapid heart rate, breathing difficulty, and death. Acute symptoms of organophosphate poisoning usually appear within a few hours of exposure. Generally, reports of pesticide intoxication are associated with patients involved with accidental exposures or mishandling/misapplication of pesticides.
Organophosphate Induced Delayed Neurotoxicity (OPIDN) or Organophosphate Induced Delayed Polyneurotoxicity (OPIDP) is a form of delayed clinical and pathological response to organophosphates and requires significant acute exposure. Weak experimental evidence of an association between chlorpyrifos and OPIDN exists, but there is little or no evidence of an association for the other POPC organophosphates.
Some reports indicate that symptomatic exposures (i.e., exposure to excessive levels of organophosphate pesticides may cause runny nose, temporary cough, and burning eyes near the time of exposure) to organophosphates may result in lingering effects months or years later. Persistent symptoms may include fatigue, headache, joint and muscle pain, memory problems, upper and lower respiratory problems, gastrointestinal disturbance, dizziness, atrophy, and antibiotic sensitivity one to several years after exposure.[79]
The literature suggests that exposures to organophosphate pesticides levels that cause acute health effects at the time of exposure, and require medical treatment or reporting are associated with elevated rates of neurological or psychiatric symptoms and poorer performance on standardized neuropsychological tests several years after the exposure.[80] The literature also suggests, however, that in studies of low-level occupational exposures these and other long-term effects occur solely in the aftermath of severe and immediate organophosphate pesticide poisoning.[81]
Carbamates used during the Gulf War included bendiocarb, methomyl, and propoxur. Like organophosphates, carbamates act by inhibiting AChE and can cause similar immediate poisoning effects. Poisoning with carbamates tends to be much shorter duration compared with organophosphorus pesticides. While many organophosphates may irreversibly inhibit AChE, the effects of carbamates on AchE enzyme are always reversible.
The acute symptoms of carbamate exposure are similar to those described for organophosphates. Chronic symptoms resulting from exposure to AChE inhibitors may include fatigue, joint and muscle symptoms, sleep effects, headaches, skin effects, cognitive effects, mood effects, and neurological effects.[82] As with organophosphate pesticide poisoning, long-term effects occur solely in the aftermath of severe and immediate carbamates pesticide poisoning.[83]
Lindane was the only organochlorine pesticide reportedly obtained from the US military supply system for use during the Gulf War. Lindane also affects the nervous system, but in a manner different from organophosphates and carbamates. The effects of lindane are primarily neurotoxic and may result in convulsions. The main routes of exposure include dermal contact, ingestion, and inhalation. Mild symptoms of exposure following dermal contact include headache and nausea. The EPA considers lindane a cancer risk because it has been demonstrated to cause liver cancer in rats and mice when ingested.[84]
Lindane has been widely used for about 50 years as an insecticide on crops and in medicinal formulas to treat head lice and scabies, so there exists a fair amount of data on its efficacy, safety, and toxicity.[85]
The RAND literature review notes that acute symptoms in humans exposed to lindane include headache, nausea, vomiting, restlessness, ataxia (loss of muscular coordination), tremor, excitability, and coma. Seizure has been reported with more extensive exposures, although specific levels at the time of exposure are not available.[86] Many of these symptoms are reversible with supportive care. However, deaths have occurred reported following lindane ingestion.[87]
The RAND report also notes that few studies in the literature describe the effects of chronic dermal exposure because lindane treatments generally require only one application. Further, epidemiologic studies suggest the possibility of subtle long-term neurologic and reproductive health effects; however, subjects in these studies were exposed to a number of different potentially toxic substances, making it difficult to attribute findings specifically to lindane.[88]
Due to the risks associated with lindane use, it is no longer recommended as the first-line drug treatment for scabies and body lice.[89]
One service-connected claim involving exposure to lindane was submitted to the Department of Veterans Affairs (VA) Board of Veterans Appeals. The initial claim was denied but was subsequently appealed. The appellant, the surviving spouse of a veteran, contended that her husband was exposed to various toxic chemicals, particularly lindane, during the Gulf War, and as a result of exposure to lindane, the veteran developed pancreatic cancer from which he subsequently died.
In the appeal, the Board considered scientific opinions presented on behalf of the appellant and by the VA. The scientific opinion on the behalf of the appellant maintained that lindane likely caused the veteran’s cancer, while the VA did not recognize an association between lindane exposure in the Gulf and the veteran’s cancer. The Board concluded that the preponderance of the evidence presented favored the appellant’s claim. The Board found that it was "reasonably probable" that the veteran’s pancreatic cancer, which caused his death, resulted from his exposure to lindane during the Gulf War. Therefore, the Board granted service connection for the cause of the veteran’s death.[90]
Pyrethroids reported used during the Gulf War included permethrin and d-phenothrin. In general, pyrethroids are considered safe and effective when used as recommended; however, they are potentially toxic at extremely high exposures. Even when used properly, minor skin irritation in sensitive individuals may result.[91]
The literature contains a limited number of references for acute symptoms from permethrin exposure. With occupational exposure, individuals experienced facial skin sensations (burning or itching) within a few hours of exposure. With ingestion, digestive symptoms included stomach pain, nausea, and vomiting. Acute poisoning symptoms include dizziness, headache, nausea, loss of appetite, and fatigue. Symptoms are reversible and subside with discontinuance of exposure.[92]
RAND notes that the literature cites very few references for d-phenothrin, and those that are cited repeatedly address the relative safety of this insecticide, and of pyrethroids in general.[93]
Based on available data, EPA has recently concluded that DEET is of low acute toxicity and normal, intermittent use for days or weeks does not present a health concern to the general population. During the recent EPA review of DEET, the agency considered exposures to be brief, and long-term exposure was not expected. DEET has been classified as an EPA Group D carcinogen (i.e., not classified as a human carcinogen). Mutagenicity tests for DEET have been negative. With the exception of infrequent incidents of scarring, there have been no long-term effects from chronic exposure to DEET.
Most of the health effects reportedly caused by DEET are acute. DEET has been associated with a number of symptoms that may affect cardiovascular, dermatologic/allergic, and nervous systems. Reports of severe effects from DEET describe neuralgic symptoms and tend to occur in children. Severe DEET toxicity results in encephalopathies (brain diseases) in children.
Reviews of DEET toxicity generally indicate that the risk of adverse effects from using repellents as directed is low. Concerns have been raised regarding the interaction of DEET with other chemicals, such as PB and permethrin. However the available literature is incomplete.[94]
Pesticides contain "active" ingredients and "inert" ingredients. An "active" ingredient is the specific chemical in a pesticide responsible for repelling or killing the pest. For example, "DEET, 33 percent cream" means that 33 percent of the pesticide product is the active ingredient DEET and that other substances make up 67 percent of the product. Some of these other substances are added to make application easier. Inert ingredients are other components in the product that are not intended to affect pests but are used to help formulate, stabilize, or disperse the product. The designation "inert," as used by EPA, means that the chemical does not have recognized pesticidal activity, and is not regulated by EPA as a pesticide. Current laws and regulations do not require that inert ingredients be identified by name on the label.
EPA has categorized over 1600 inert ingredients found in registered pesticides into four groups. These groups include inerts of toxicological concern, inerts of potential toxicity with high priority for testing, inerts of unknown toxicity, and inerts of minimal concern.
According to EPA, most inert ingredients do not pose health or environmental concerns, however, some inert ingredients are not benign to human health and the environment, and may be more toxic or pose greater risks than the active ingredients.[95] The RAND literature review states that many of the inert ingredients in pesticide products may pose a hazard to human health and/or combine with active ingredients to produce an effect different from that predicted when using animal models.[96]
Due to the limited information available on the inert ingredients used during the Gulf War, this investigation has focused primarily on the potential health effects of the active ingredients. In most cases, the military-issued pesticides used during the Gulf War were mixed with water as an inert carrier. However, inert ingredients frequently include petroleum products and solvents. Investigators have been unable to obtain reliable information on the inert ingredients used by host nation contractors.
EPA has formed an Inert Disclosure Stakeholder Workgroup to provide advice on how to make information on inert ingredients more available to the public. As a result, additional detail on inert or other ingredients may be available in the future.
B. Pyridostigmine Bromide (PB)
In 1999, RAND prepared a literature review on the subject of pyridostigmine bromide (PB) use during the Gulf War. PB is a chemical taken orally to reduce the chance of death in the event of a chemical agent (soman) attack. Some researchers have suggested that, because PB is also an AChE inhibitor, interactions among PB, insecticides, and repellents may contribute to undiagnosed illnesses in Gulf War veterans.
The RAND report on PB notes that animal studies found that the toxicity of PB is enhanced with simultaneous exposures to other chemicals. These other exposures may include pesticides and insect repellents, as well as caffeine, stress, and perhaps nerve agents. But, the degree to which these interactions between PB and other factors may play a role in Gulf War veterans is unclear, as the RAND report indicates:
Data regarding who received which exposures is not available; this complicates performance of epidemiological studies looking for the effect of these interactions.
Data from animal studies are difficult to extrapolate to Gulf War veterans because extremely high doses of drugs were used in these animal studies--doses many times higher than those experienced by Gulf War veterans.
There is no good way of evaluating the importance of synergistic effects at the dose levels experienced by veterans.[97]
The RAND PB report concludes, however, that because evidence of synergistic toxicity exists -from animal studies using high doses and different routes of administration from those experienced by Gulf War veterans - interactions between PB and other agents cannot be ruled out as a possible avenue by which increased effect or toxicity of PB may have occurred in some veterans.[98]
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