Some degree of uncertainty is present in every human health risk evaluation or risk assessment. For purposes of this evaluation, the uncertainties conveniently fall into three categories: (1) uncertainties associated with the agents’ toxicology, (2) uncertainties associated with human exposure, (3) and uncertainties inherent in the risk assessment process. While uncertainties clearly are associated with toxicological effects of sarin on the forces at Khamisiyah, the uncertainties associated with exposure are likely far greater.

A. Toxicological Uncertainties

Uncertainties exist in assessing the toxicology of any noxious chemical, including, among others, study design; data quality; endpoint selection; extrapolating from high to low doses, from animals to humans, and different exposure routes; and selecting uncertainty factors, database weaknesses, and intra- and inter-species differences. Results from a short-term, in vivo test may be different from results obtained in a longer-term in vivo study, and thus require substantiation. These uncertainties do not discount toxicological studies’ utility in predicting the likelihood of the occurrence of a given effect in humans; they simply suggest caution in interpretation.

Several toxicological uncertainties are of specific interest to this evaluation, most significantly the relative paucity of data related to low-dose asymptomatic exposure to sarin and cyclosarin. During vapor exposure studies and unintentional vapor exposures, the first signs and symptoms are usually miosis, rhinorrhea, and/or chest tightness. Early studies often defined an individual as exposed if at least one of these symptoms appeared. Persons in the same area without such symptoms or health complaints were not considered exposed (Sidell, 1992; Perrotta, 1996). Thus, only those who had clinical signs or symptoms, reflecting a higher exposure than those considered in this evaluation, would have been studied and documented. Ethically, studies on militarily incapacitating and/or lethal agents could not have been performed at higher doses. This difficulty also is present to a lesser degree when evaluating the effects of human exposure to organophosphorus pesticides. However, some significant possible effects of exposure to these nerve agents, such as OPIDN, have been shown to occur only with very high exposures, so this evaluation eliminates them from consideration.

A closely related uncertainty is the lack of long-term follow-up of exposed persons. Older doctrine had considered that if a victim recovered from the acute effects of nerve agent or organophosphorus pesticide poisoning, he or she would have no adverse health sequelae. As a result of studies showing alterations in EEGs and long term behavioral, psychological, and performance decrements resulting from organophosphate exposure, this doctrine has been called into question (Ecobichon, 1992). However, virtually all studies reporting these effects involved clearly symptomatic exposures, except the one examining long-term EEG changes in monkeys, whose authors were unclear as to exactly what symptoms were present (Burchfiel et al., 1976). More recent animal studies on behavioral and performance effects associated with exposure to organophosphorus pesticides and soman suggest a threshold is associated with percent reduction in ChE (Sheets et al., 1997). Generally, a threshold is assumed for the dose-response curve for most neurotoxicants, based on the known capacity of the nervous system to compensate for or repair a certain amount of damage at the cellular, tissue, or organ level (EPA, 1995). However, controlled studies of low-dose, asymptomatic agent exposures currently are unavailable.

Little toxicity data exist for cyclosarin. Toxicity studies on the effects of sarin and cyclosarin in combination suggest they do not act synergistically (Clement, 1994).

The appropriateness of using cholinesterase inhibition as an endpoint for organophosphate toxicity has been debated (EPA, 1995). Small ChE decreases and slight miosis, though not demonstrated as clinically adverse effects, reasonably can be used as early markers of exposure. In cases of several toxic effects, preventing the most sensitive effect generally is considered protective, based partly on the assumption that preventing the most sensitive effect prevents all other (toxic) effects (EPA, 1989). Recent studies in animals suggest percentage of ChE inhibition resulting from organophosphate exposure may prove a useful marker even for such subtle effects as EEG changes and psychological or behavioral effects (Blick et al., 1987, 1988; Sheets et al., 1997); however, sarin-specific data on this point are unavailable. No one obtained post-exposure ChE levels for forces at Khamisiyah because no symptoms were documented.

DoD is making a concerted effort to fill these data gaps. Studies are being undertaken on chronic organophosphorus exposure and cognition, organophosphates’ molecular targets in the CNS, biomarkers for exposure to low-level exposure to organophosphates, and the toxicology and epidemiology of the possible long-term health effects resulting from low-level, subclinical exposures to chemical agents, particularly organophosphate agents such as sarin (DHS, 1997b).

B. Exposure Determination

Determining whether an individual actually was exposed to a noxious chemical and, if so, to how much and for how long is difficult and involves considerable uncertainty. Estimating an exposure in combat situations is no trivial problem. Several factors can greatly influence the effective exposure a soldier receives. Temperature, humidity, skin moisture, exposed surfaces, fit of personal protective equipment, pretreatment, wind strength and direction, the agent’s form (liquid or vapor), soldier’s activity level (at rest or running), host susceptibility, and other factors make estimating field doses a complex problem (Perrotta, 1996).

Estimating the possible agent concentration in a vapor cloud from the Khamisiyah demolition required extensive field testing at Dugway Proving Ground (DPG) to accurately characterize the agents’ source and distribution and then extensive modeling of the data. Modeling itself has inherent uncertainties. The calculated areas covered by low level concentrations are best estimates based on most reasonable assumptions; however, the actual areas covered could have been greater or less than the model projections if different assumptions were used. Although both DPG and ERDEC laboratory tests and the DPG field tests helped reduce some of these uncertainties, others remain.

C. Risk Assessment Process

The risk assessment process, including using equations to develop risk estimates or conclusions, involves numerous general assumptions. For example, the RfDs identified in Section IV were developed from data points from the best available studies, with uncertainty factors included in their development. Regulatory programs have successfully used these factors for decades, but concerns exist that the resulting exposure guidelines may be overly conservative in some situations and possibly insufficiently conservative in others. In addition, some generalizations in a risk assessment involve the exposed individuals’ weight, their breathing rates, exposure routes, and duration of exposure. For example, EPA hazard quotient calculations assume an exposed adult weighs 70 kg and breathes 15 l/min of air. Comparing the RfDi and intake dose in developing a hazard quotient has unreconcilable uncertainties. Although EPA risk assessment methods generally are useful in establishing protective limits, they are inappropriate for assessing whether effects may have occurred. An exposure level designed to protect the most susceptible people does not necessarily predict health outcomes for healthy people or forces possibly exposed to nerve agent at Khamisiyah. Finally, it is clear confounders exist.

A comprehensive toxicity assessment for sarin and cyclosarin was performed, regulatory guidance and relevant data were reviewed, and a risk evaluation was completed. Reviewing existing toxicological data suggests it is unlikely exposure to sarin or cyclosarin at concentrations below those needed to cause acute signs, symptoms, or ChE inhibition will cause long-term adverse health effects to develop. However, human studies specifically designed to address chronic effects from low-level asymptomatic exposure to sarin are unavailable. OPIDN studies, clearly negative for a particular health effect at high, but below supralethal doses, provide confidence that no increased health risk exists for these effects at much lower doses. If an exposure is small enough not to cause significant hypoxia, GB’s and GF’s acute effects are readily reversible. The forces at Khamisiyah reported no symptoms. OPIDN, which is of concern with some organophosphorus pesticides, has been reported only in animals exposed to very high doses of nerve agents.

While evidence suggests possible psychological, behavioral, and EEG changes are fairly common with exposure to high doses of organophosphates, including nerve agents, data on lower doses are sparse or non-existent. No animal or human studies of sarin-induced EEG changes fully address the question of chronic effects from short-term, subclinical exposure. Whether the EEG changes occur in humans exposed to levels below those required to produce mild signs or symptoms or significant ChE depression is unknown. The CDC (1988) stated, "The EEG changes reported after intoxication with GB were considered to be of questionable significance, given the difficulty of demonstrating such changes and the absence of clinically significant effects even when EEG changes are present." The available organophosphate data on low doses, including the PEP monkey studies with soman and the recent, well-controlled studies of six organophosphates in rats, suggest these effects have a threshold correlating with percentage of ChE inhibition (Sheets et al., 1997; Blick et al., 1987, 1988). Collectively, these data suggest a threshold exists for organophosphate -induced neurobehavioral effects and low-level exposures to sarin or cyclosarin causing no symptoms or significant ChE inhibition are unlikely to produce any long-term neurobehavioral effects.

Multiple lines of evidence indicate GB does not have carcinogenic, mutagenic, or teratogenic properties. Therefore, no increases in birth defects or cancer would be expected from low-dose, asymptomatic exposure to GB. Available data suggest that exposure levels below those inducing convulsions do not cause cardiomyopathy. Other than sarin’s well-known neurotoxic effects, no general adverse health effects from low-level exposure to sarin have been evidenced, nor have any reports of immunotoxicity associated with sarin exposure been identified. Examining several follow-up measurements of the men exposed to anticholinesterase chemicals (including GB) during experiments at Aberdeen Proving Ground in Edgewood, Maryland, found no significant increases in hospital admissions, self-reported medical problems, impairments, malignancies, or other adverse health outcomes (NRC, 1985). The expected healthy soldier effect was observed in some of the standardized morbidity (or mortality) ratios calculated in this study. Reviewing current toxicological and medical data indicate long-term health effects from brief, low-level, asymptomatic sarin exposures are unlikely to significantly depress ChE.

Uncertainties remain; they include the lack of human data addressing the cholinergic and noncholinergic effects of very low-dose exposure to sarin and uncertainties inherent in modeling and retrospective exposure assessment. Some uncertainties will continue even though this analysis used the best available data and the best estimates and conservative modeling and risk assessment methods.

Based on available data on servicemembers’ apparent health status, modeling results, and toxicological data, this risk assessment concludes that the exposure dosages possibly received by forces at Khamisiyah were smaller than should cause acute health effects (e.g., as miosis) or long-term health effects (e.g., OPIDN). Although exposure to sarin itself at the estimated concentrations may not cause any adverse health effects, this finding does not preclude the possibility of adverse health effects resulting from any number of combinations of noxious chemicals and/or other stressors.

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