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Guidelines for Chemical Warfare Agents in Military Field Drinking Water 2 Guidelines for 3-Quinuclidinyl Benzilate INTRODUCTION The chemical 3-quinuclidinyl benzilate (BZ) is a bicyclic ester and exists as a crystalline solid. At high doses, it has pronounced hallucinogenic effects. BZ was produced in the United States between 1962 and 1964, but production was terminated because of the realization that BZ 's effects on front-line troops could be varied and unpredictable (thus the term “buzz” or Agent BZ). In the United States, existing amounts of BZ are thought to equal only a few grams (Compton, 1988). Field drinking-water-quality standards for BZ have been proposed by Palmer (1990). Studies regarding the solubility and hydrolysis of BZ indicate that BZ can hydrolyze in alkaline solution (pH > 11) to benzylic acid and 3-quinuclidinyl within minutes (Sass et al., 1960; Yurow et al., 1963; Rosenblatt et al., 1977). This reaction is depicted below:
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Guidelines for Chemical Warfare Agents in Military Field Drinking Water TOXICITY Sim (1961) and Ketchum et al. (1967) have described the toxic manifestations of BZ in humans. Like atropine, it inhibits the action of acetylcholine by binding to the acetylcholinesterase receptor. However, it is more potent. There is evidence that antimuscarinic drugs, such as BZ, cause hallucinogenic effects by binding to a serotonin receptor subtype (Battaglia and De Souza, 1989). Atropine-like effects include rapid pulse, dry mouth, blurred vision due to pupillary dilation, inability to solve problems or remember numbers, poor coordination, stupor, confusion, and disorientation. Paresthesia of the legs, weakness and tightness, speech difficulty, tremor of the face and arms, and tachycardia are also common symptoms. BZ is hydrolyzed in alkaline solutions to benzylic acid and 3-quinuclidinyl. Studies in mice indicate that BZ is much more toxic than its hydrolysis products. LD50s in mice for BZ, benzylic acid, and 3-quinuclidinyl were found to be 18-25 mg/kg, >400 mg/kg, and 179 mg/kg, respectively (McNamara, 1963a). BZ has similar effects in humans and animals. With increased doses, there is increased heart rate, impaired performance, prostration, convulsion, and death rate. In a 42-day exposure of dogs administered BZ intravenously at 100 µg/kg, slight pathological changes were observed in the gastrointestinal tract (ulceration and bloody stool) in 50% of the exposed dogs and 25% of the controls. There was a slight increase in kidney weight and a slight decrease in liver and spleen weights. There were no changes in white-blood-cell or sodium measurements (McNamara, 1963b). FIELD DRINKING-WATER STANDARDS There are sufficient human data on BZ to establish field drinking-water standards. In several studies, humans were administered BZ either in drinking water or by intramuscular (i.m.) injection; the doses ranged from 2 to 7 µg/kg of body weight (Sim, 1961; Avellino, 1963; Ketchum, 1963; McNamara, 1963b; Kitzes and Vancil, 1965; Ketchum et al., 1967). Animal data support human findings. For purposes of establishing field drinking-water-quality standards for BZ, the most pertinent investigations are those of Avellino (1963) and
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Guidelines for Chemical Warfare Agents in Military Field Drinking Water Ketchum (1963). Avellino examined the available literature for data regarding potability standards for BZ in water supplies. Avellino also examined the unpublished reports (“Human Studies with BZ and Related Compounds,” March, 1963) of Major James S. Ketchum, who personally supervised the administration of BZ to healthy male volunteers (Avellino, 1963). In those investigations, four subjects were administered BZ i.m. in daily doses of 0.5 µg/kg on days 1 through 5 and on day 8, for a total of six doses in 8 days. Changes in heart rate or blood pressure (objective criterion) and symptoms of disorientation or delirium (subjective criterion) were evaluated. It was the opinion of all medical and nursing personnel who supervised the four subjects that at no time during or after the study were there any additional signs or symptoms beyond the usual BZ effects. At the termination of the study, the subjects had certain mild medical conditions that might or might not have been related to BZ administration. Those medical conditions included dermatosis (subject Je), dysphagia with mild malaise (subject We), rash (subject Ba), and low-grade fever (subject Mc) (Avellino, 1963). Ketchum stated that the highest dose that can be absorbed without noticeable effects is 0.5 µg/kg (Avellino, 1963). Thus, the 0.5-µg/kg dose can be considered a no-observed-adverse-effect level (NOAEL). Ketchum also compared an oral dose of BZ to an i.m. injection in adult males and determined that the effectiveness of the oral route is approximately 75% that of an i.m. injection (Avellino, 1963). It should be noted that the number of subjects receiving the 0.5-µg/kg i.m. dose of BZ was small (four subjects). There were mild flu-like clinical symptoms noted in the study. Neither the investigator nor the nurse felt that the symptoms resulted from the drug administration. Furthermore, because the likely route of exposure to BZ for military personnel is drinking water, as opposed to an i.m. injection, the dose of 0.5 µg/kg via the oral route should be less adverse because 25% less BZ is absorbed (Avellino, 1963). SUMMARY There is no information in the literature concerning the in vivo half-life of BZ. As mentioned previously, BZ can hydrolyze in alkaline
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Guidelines for Chemical Warfare Agents in Military Field Drinking Water solutions. It is recommended that information be obtained about the fate of BZ in water. The Army's field drinking-water standards for BZ are based on human studies. The criterion set by the Army Medical Department assumes water consumption ranging from 5 to 15 L/day, depending on climatic conditions. The duration of exposure is set at 7 days or less. The “acceptable” dose (i.e., an apparent NOAEL) for BZ is 0.5 µg/kg, which, when normalized for a 70-kg soldier, is equivalent to 35 µg/day. Therefore, the Army's proposed standards for a water consumption of 5 L/day or 15 L/day (for no longer than 7 days) are 7 or 2.3 µg/L of water, respectively. No further allowance was made for individual variability because the military population is considered to be healthy with no preexisting health conditions. The allowable maximum total intake for 7 days would be 245 µg (7 days at 35 µg/kg/day). FIELD DRINKING-WATER GUIDELINE COMPUTATIONS 0.5 µg/kg × 70 kg = 35.0 µg. Assuming a water consumption of 5 or 15 L/day, the proposed field drinking-water standards are 5-L consumption = 35.0 µg/5 L = 7 µg/L. 15-L consumption = 35.0 µg/15 L = 2.3 µg/L. CONCLUSIONS AND RECOMMENDATIONS The subcommittee concludes that the Army's recommended field drinking-water standards of 2.3 µg/L for 15 L/day of water consumption and 7 µg/L for 5 L/day of water consumption are appropriate. The field drinking-water guidelines recommended by the subcommittee for BZ are the same as the Army's proposed standards. The subcommittee also recommends that further research be done to study the fate of BZ in water as well as the hydrolysis products of BZ after standard field-water treatment (e.g., chlorination, iodination, and boiling).
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