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OCR for page 111
APPENDIX G SUMMARY OF ACUTE- AND CHRONIC-TOXICITY DATA IN VARIOUS MAMMALS WITH THE A=ICHOL INERG IC TEST AGENTS (I)ITRAN, BENACTYZINE, EA 2545, EA 3167, EA 3443, EA 3392, EA 3580, EA 3834, ant 226,086) by Leo G. Abood, Ph.~. * Studies were carries out by Lakeside Laboratories (now Incorporated into Merrill Dow Pharmaceuticals, Inc. ~ in rodents and dogs. The results can be summarized as f allows. TOXIC ITY - Acute. The intravenous LD,o for male rats was 28 mg/kg, and that for . male mice was 45 mg/kg. Chronic . At ~ mg/kg ~ twice a day) for ~ wk. there was no change in weight of rats; at 300 mg/k8, there was a 12% decrease in weight, compared with controls. In dogs there was no significant change at 3. 75 mg/kg . 81~00D (RATS) At 300 mg/kg, hemoglobin was reduced by B%, compared with controls. Sedimentation rates increased by a factor of 3. There was a slight shif t in the lymphocyte-to-neutrophil ratio. Leukocyte count increased by about 50: over ~ wk. Terminal red cell count was reduced by 21%e HISTOPATHOLOGY At 3QO mg/k~, very few abnormalities were observed in rats. An increase in heart weight occurred in some rats; other organ weights remained normal. There were no histopathologic signs at 300 mg/kg; occasional slight changes were due to infection. In dogs, there were no histopathologic signs attributable to Ditran at 37.5 mg/kg (highest dose). The blood picture was essentially unch ang ed . OTHER DRUGS Acute- and chronic-toxicity tests were performed by various qualified laboratories at Edgewood laboratories on the various test agents used in the Edgewood study in human volunteers. Acute toxicity was usually studied in mice, rats, cats, dogs, and monkeys to determine the LD50 and to observe pharmacologic effects, such as autonomic changes, changes in motor activity, ataxia, pros Oration, and convulsions. All the compounds were similar in the spectrum of their pharmacologic effects and differedmainly in relative potency and *Professor, Center for Brain Research, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642. G 1
OCR for page 111
- ~ ~ ~ ~ - LD:o. For the most part, their LDSOa corresponded to central nervous system potency. Chronic toxicity was usually studied over a period of a month, with single daily infections of at least 3 doses of the test agent, the largest dose being near the LDso. Essentially no gross pathologic effects were noted at any of the doses. Occasionally, at nearly lethal doses, sI1ght changes were observed in the weights of some organs--liver , heart, spleen, and thrum . There were also slight changes in blood cells (e.g., increased leukocyte county) and the Paneth cells of the intestine (decreased counts). CONCLUSI ON . On the basi s of the acute- and chronic-toxicity data, the agents were deemed to be safe for human trials, particularly for acute studies of the type performed at Edgewood. It should be noted, however, that no attempt was mate to observe any long-ter~ behavioral effects, after either acute or chronic drug administration. Behavioral studies are difficult to perform, ~ <~ psychophysical measuring devices. Even with behavioral testing, it is questionable whether subtle long-range behavioral changes could be detected in animals, part icu3-arly in acute studies. requiring a battery of complex octane and G 2