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POSSIBLE LONG-TERM HEALTH EFFECTS OF SHO=-TERN EXPOSURE TO CHEMICAL AGENTS Volume 1 Anti choline s t erases and Anti choline rglcs prepared by the Panel on Anticholinesterase Chemicals Panel on Antic}~olinergic Chemicals Commi ttee on Toxicology Board on Toxicology and Environeental Health Hazards Assembly of Life Sciences . National Academy Press Washington, D.C. June 1982

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NOTI(:E:: The pro Ject that i 8 the subject of this report was approved by the Go~rerntug Board of the llatlor~al Research Council, whose members are drawn from the Councils of the National Academy of Sciences, the National Academy of Engineering' and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Englneering, and the Institute of ^dicine. The National Research Council was established by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and of advising the federal government. The Council operates in accordance with general policies determined by the Academy-under the authority of its Congressional charter of IR63, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. It is administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Hedicine were established in 1964 and 1970, re spectively, under the charter of the National Academy of Sciences. This study was supported by funds provided by the Department of the Army through a contract between the Office of fla~ral Research and the National Academy of Sciences under contracts N00014-BO~C~0815 and MA 903-82-C~0328 ii ,

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PANEL ON ANTICHOLINESTE"SE MILLS Peter S. Spence., Albert Einstein College of Medicine, New York, New York, Cha i roan Etson X. Albuquerque, University of Maryland School of Medicine, Bal t loo re, Ma ryland Wolf O. Dettbarn, Vanderbilt IJniversity School of Itedici-ne, Nashville, Tennessee Daniel B. Drachman, Johns Hopkins University School of Medicine, Bal timore, Ma rylant Waidemar H. Generoso, Oak Ridge National Laboratory, Oak Ridge, Tennessee Alexander. G. Karezmar, Loyola University Medical Center, Maywood, Illinoi s , George Koelle, University of Pennsylvania School of Medicine, Philade lphia, Pennsylvania Frank S. Standaert, Georgetown University Hedical School, Washi ngton, D . C. Technical Consultants: "- ._~ Frank H. Duffy, Children's Hospital, Brookline, Massachusetts Ronald J. Kassel, U. S . Aney Chemical Systems Laboratory, Aberdeen, Ma ry land Stephen Krop, McLean, Virginia Joseph S . Wiles, Baltimore, Maryland PANEL ON ANTI CHOL INERG IC ClIEMI CALS H. George Handel, George Washington University School of Medicine, Washington, D.C. ~ Chairman Leo G. Abood, University of Rochester Medical Center, Rochester, New York Virginia C. Dunkel, U.S. Food and Drug Administration, Washington, D .C. Max Fink, State University of New York at Stony Brook, School of Medicine, Long Island, New York Leo E. Hollister, Veterans' Administration Medical Center, Palo Alto, California John J. O'Neill, Temple University Medical School, Philadephia, Pennsylvania Norman Weiner, University of Colorado School of Medicine, Denver, Colorado Technical Consultants: . David L. Bazelon, U. S. Court House, Washington' D.C. Ronald J. Kasse I, U. S . Amy Chemical Systems Laboratory, Aberdeen Pro vi ng Ground, Ma ry land James S. Ketchum, University of California at Los Angeles School of Medicine, Los Angeles, California Joseph S . Wiles, Baltimore, Maryland J. Henry Wilis, Uniformed Service c University of the Health Sciences Be the sda, Mary land

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National Research Council Staf f Francis N. Marsulli, Pro Sect Officer, Panel on Antlcholinerglc ~emlcals and Panel on Anticholinesterase Chemicals Gordon W. Newell, ProJect Officer, Panel on Anticholinergic Chemicals and Pariel on Ar`ticholinesterase Chemicals Robert Tardiff, Executive Director, Board on Tc~xicolo~v and Environmental Health Hazards ~ BOTEHE) ~ OF Seymour Jablon, Director, Medical Follow-up Agency Robert J. Keehn, Statistician, Medical Follow-up Kenny Thomas L. Preston, Chief of Operations, Medical Follow~up Agency Karen M. Rao~polla$ Project Coordinator, Hetical Follow-up Agency Barbara B. Jaffe, Manager, Toxicology Information Center (BOMBER) Edna WO Paulson, Chemical Information Specialist, Toxicology Information Center (BOTEHE) Edna Millard, Reference Verifier, Toxicology Information Center ~ BOTEHH) Joyce R. Russell, Secretary, Panel on Anticholinergic Chemicals and Panel on Anti choliaest erase Chemicals Norman Grossblatt, Editor iv

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COMMI TTEE ON 'rOX ICOLOGY Roger O . McClellan, Lovelace Inhalation Toxicology Research Institute, Albuquerque, New Hexico, Chairman Donald Eco bi chon, McGill [Jniversi fly, Montreal, Que bee, Canada David W. Gaylor, National Center for Toxicological Research. Jef f erson, Arkansas Peter Greenwald, National Cancer Institute, Bethesda, Maryland Ian T. Higgins, University of Mtct2igan Medical Center, Ann Arbor, M! chi Ban Wendell W. Kilgore, University of California, Davis, California Leonard T. Kurland, Mayo Clinic, Rochester, .Hinnesota Howard I. Maibach, University of California, San Francisco, Calif ornia H. George Handel, George Washington University School of Medicine, Washi ngton, D . C. - Joseph V. Rodricks, Clement Associates, Inc., Arlington, Virginia Ronald C. Shank, University of California, Irvine, California Edward A. Smuckler, University of California, San Francisco, Calif ornia Ro bert Snyder, Rutgers Universi~cy College of Pharmacy, Pi scataway, flew Jersey Pe ter S . Spencer, Albert Einstein College of Medicine, New York, flew York Phi lip G. Watanabe , [)ow Chemical U. S.A., Midland , Michigan ~ ~ , National Research Council Staff Gory on W. Newell, Pro jec t Direc tor Gary R. Keilson, Staf f Scientist v r

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BOARD ON TOXICOLOGY A-ND ENVIRONMENTAL HEALTH HAZARDS Ronald W. Estabrook, University of Texas Medical Dallas, Texas, ~a iman Philip Landri~an N^t1~--l Towed a.. =__ no School ~ Southwestern) 9 -V- ,____ -e EVA uccupaclona1 Safety and Health, Cincinnati, Ohio, Vice-Chaiman Edward Bresr~ielt, Unt~ersity of Vermont 9 Burlington, Vermont Theodore Callus, DuPont Chemical Co. ( retired), Greenville, Delaware Victor Cohn, George Washington Uniu-~-V lA^A4~1 I__ .~--~. O.C. A. Myri ok Freeman, Bowtoin College, Brunswick,, Maine Ronald W. Hart, National Center for Toxicological Research, Jefferson, Arkansas Michael Lieberman, Washington University School of Medicine, St. Louis, Missouri _~__~ ..- cd Fencer, wasnt~ton, Richard Merrill, University of Virginia Law Virginta Robert A. Neal Oh - ~~, 7~ ~_ a___ School ~ Charlottesville 9 , _o~- ^~~ flute of Toxicology. Research Triangle Park' North Carolina Ian Nisbet9 Clement Associates' Inc., ArIt~gton, Virglsia John Peters, Univeraity of Southern California School of Medicine, Loa Ang eles, Ca llf ornia Liane Russell, Oak Ridge National Laboratory, Oak Ridge, Tennessee Charle ~ R e Schuster, Jr., University of Chicago ~ Chicago ~ Illinois National Research Council Staff . Robert G. Tardiff, Executive Director Gordon W. Newell, Associate Executive Direc tar vi

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AC~OWLEDGEME~S The following persons provided technical assistance: Samuel Gershon, Wayne State University Medical School, Detroit, Hi chigan Pe ter Kelleway, Baylor University Medical School. Houston, Texas Herbert Vaughn, Albert Einstein College of Medicine, Nest York, New York Hans Luders, Cleveland Clinic, Cleveland, Ohio James Lewis, University of Tennessee Medical School, Memphis, Te nnessee Lloyd Matter and Laurence Bedard, U.S. Army Chemical Systems Laboratory, Aberdeen Proving Ground, Maryland Nursing Staff, U.S. Army Metical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland $ vii

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PREFACE The Department of the Army asked the Committee on Toxicology (COT) of the National Research Council (Nat) Assembly of Life Sciences to conduct a study of the possible chronic adverse health effects on servicemen of experimental exposure to various chemicals at U.S. Army Laboratories at Edgewood, Maryland, in about 1958-1975. The Etgewoot tests were conducted to learn how specific chemicals may affect humans. Some 6,720 soldiers took part in the program; 254 chemicals were administered by various routes. Chemicals were tester for various military applications. Among them were acutely toxic anticholinesterase chemicals; incapacitating; agents, which included the glycolates, atropine-like anticholinergic compounds of which BZ (3-quinuclidinyl benzilate) is a prototype; the indoles, represented by EA 1729 (iSD-25); the cannabinols, or mariJuana-like compounds; and the sedative, or "tranquilizer," group. Review of the Edgewood tests included interviews with key administrators, investigators; nurses, ant technicians. The account of practices and procedures undertaken at Edgewood comes from a wide spectrum of sources, both documents and interviews. They represent a wide spectrum of attitudes, but are essentially in agreement. Committees were formed at Edgewood to review classified chemicals and reports for declassification and use by NRC panels. Extensive extracts were prepared of preclinical animal and human protocols and technical reports at Edgewood Libraries and other Edgewood facilities where records of subjects and details of exposure conditions and clinical findings are maintained. A repository was established at Edgewood Arsenal (August 1980) for storing the reports and information obtained from other sources. The NRC staff organized the test chemicals into several pharmacologic classes; the first two classes consisted of 15 nticholinesterase (Appendix A) and 24 anticholinergic (Appendix B) chemicals. Two expert panels were established (on anticholinesterase~ and on anticholinergics) with chairmen aelec ted from the COT and members drawn from the scientific community on the basis of familiarity with some aspect of the pharmacologic class involved or expertise in a discipline needed for proper evaluation of potential adverse health effects. Research and experimental case files on volunteers were extracted and summarized. Digests of the literature were prepared. The charge of the two panels was to determine whether, on the basis of the data available, it is possible to demonstrate the likelihood of long-tenm health effects or delayed sequelae and, if so, whether the involved chemicals, as tested, are likely to produce long-tenm health effects or delayed sequelae. The charge did not include policy recommendations regarding human testing. This report is the first of two on the Edgewood tests. In presents the two panelst tentative conclusions which are based on a review of data obtained from Edgewood in nine documents provided by NRC staff (listed in Appendixes C and D), on mortality data organized by the NRC Medical Follow-Up Agency, and on separate discussions and papers generated nisi

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by the panel member s. Specific issues addressed were based on thi is~f ormation and relevant items from the published literature. ~ second report will contain an evaluation of most of the remaining chemicals tented at Edgewood and an evaluation of the effects on mc~rbldity state of the test subjects. The information on morbidity may permit finger conclusions than are presented here.

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EXECUTIVE SUMMARY In response to a request from the Department of the Army, the Committee on Toxicology (COT) of the Nations Research Council Assembly of Life Sciences conducted a study to evaluate the possibility of loDg-term or delayed at~rerae health effects of chemical agents tested on military volunteers during the 1960s and 1970~. The task was-begun about 2 years ago, with interviews of key people who had been associated with the soldier-volunteer test program of the Army Chemical Center ( Edgewood Arsenal), Haryland . Initial efforts included a thorough review of the Army's laboratory and clinical records and of reporter in the scientific literature. Some 69720 soldiers took part tn the Edgewood program as test subjects in about 1958-1975, and 254 chemicals were administered in an experimental setti ~8 ~ The chemicals were divided into eight Major pharmacologic classes and organized ^thin each class according to structure. The good extenst~ely studied classes are the an~cicholinergic and the anticholinesterase chemicals 9 and these are the sub Sects of this report9 the other classes will be- reported on later. Panels were then formed to study these two main classes. The chained were selected from the COT, and the members were selected for expertise in some aspect of the review of the pharmacologic class in question. The anticholinest.erases are generally organophosphates; these are nerve agent ~ resembling pare fashion. Major symptoms of low-level anticholinesterase exposure include salivation, increased sweatlag, contracted pupils, and bronchospasm. The anticholinergics are generally "glycolates", (substituted glycolic and tropic acid esters) of which the representative and best-known member is atropine. MaJor symptoms of low-level atropinization include dry mouth, di lated pupils, and tachycardia. There were 24 acticholinergics tested on about I, 800 sub Sects. There were 15 anticholinesterases tested on about 1,400 subjects. These two classes are readily paired, in that members of each are used as treatment for overexposure to members of the 0 ther . The next step involved organization of Edgewood data and reports. Some of this material had to be declassified before use by the panels. Digests of the entire available literature, classified and unclassified, were prepared by consultant pharmacologists, and various documents were made available to the pasel-s for their use in investigating the possibility that the Edgewood test experience resulted in persistent adverse effects. The panels met several times, beginning In June 1980. The specific charge to the two panels was to determine: o Whether the data available are sufficient to estimate the likelihood that the test chemicals have long-term health effects or delayed sequelae. O Whether the involved chemicals, as tested, are likely to produce long-term adverse health effects or delayed sequelae in ache test subjects. x

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ANTICHOLINESTERASE CHEMICALS The panel concludes that although no evidence has been developed (to date) that any of the anticholinesterase test compounds surveyed carries long-range adverse human health effects in the toses used, the results of an ongoing NAS/NRC morbidity study may shed further light on this issue. The panel therefore is unable to rule out the possibility that some anti-ChE agents producer long-term adverse health effects in some individuals. Exposures to low dosea of OF compounds have been reported (but not confirmed) to produce subtle changes in EEG, sleep pattern, and behavior that persist for at lesat a year. Whether the subjects at Edgewood incurred these changes ant to what extent they might now show these effects are not known. If such changes occurred ant persisted, they would be difficult to detect now. They could be determined scientifically only by a new study in which BEG, sleep state, and psychologic-test scores were compared with those from nonexposed control subjects. This might be considered, if reasonable suspicion develops, based on responses obtained in the referenced morbidity study, that selected subjects experienced behavioral changes traceable in onset to experimental exposure to the anti-ChE agents e ANTICHOLINERGIC CHEMICALS No firm evidence has been seen that any of the anticholinergic test compounds surveyed produced long-range adverse human health effects in the doses used at Edgewood Arsenal. More intensive study is required to confirm this conclusion. The high frequency of uncontrolled variables makes evaluation of behavioral effects difficult. On the basis of available data, in the judgment of the panel, it is unlikely that administration of these anticholinergic compounds will have long-term toxicity effects or delayed sequellae. An ongoing morbidity study should provide more definitive information once it is completed. MORTALITY Standardized mortality ratios were derived from mortality data for the soldiers (all males) who participated in the Edgewood Tests and from U.S. mortality rates. For each class of chemicals, the mortality rates among the soldiers were not significantly higher than the rates of the U.S. population, categorized by age and calendar year. MORBIDITY An ongoing morbidity study among the test subjects is expected to provide a more complete understanding of the long-term consequences of exposure to anticholinergic and anticholinesterase chemicals. xi

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CONTENTS EXECUTIVE SUMMERY CHAPTER 1 INTRODUCTION History of the Edgewood Testing Program Procedures Used at the Edgewood Chemical Testing Program CHAPTER 2 ANTICHOLINESrERASES Chemistry of Anti~CHEs Absorption, Fate, and Exeretion of Anti-ChEs Mechanisms of Action P. 2 Biologic and Clinical Effects 16 Immediate ant Delayed Effects in Volunteera after Single or Repeated Exposure to Anti-ChEa at Etgewood 29 Mortality Data . 30 Evaluation of the Likelihood of LongoTer3 Atverae Health Effects 30 Conclusions Tables References 33 34 39 CHAPTER 3 ANTICHOLINERGICS Atropine, Scopolamine, and Related Therapeutic Anticholinerglc Chemicals Pharmacologic Properties of Synthetic Atropine Derivatives Role of Drug Disposition in Explaining Differences among Anticholinergic Compounds Animal Toxicology of Anticholinergic Compounds Human Toxicology of Anticholinergics Summary Conclusions Tables References CHAPTER 4 MORTALITY Method of Analysis Results Tables Reference APPENDIX A - MASTER FILE--ANTICHOLINESTERASE CHEMICALS AN PENDIX B - ASTER FI=--~ICHOLINERGIC C~MI"LS APPEN1:)IX C - LIST OF DOCUMENTS SUPPLIE1) TO ANTICHOLINESTERASE PANEL 51 51 S4 55 57 60 68 69 70 74 77 77 78 81 87 AM B-1 C-1 APPENDIX D - LIST OF DOCUMENTS SUPPLIED TO ANTICHOLI~GIC D-1 PANEL xil

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APPENDIX E - CASE-FILE DATA ON EDGEWOOD SUBJECTS AP PENDIX F - EXCESS FROM BZ DATA, CONTACT DA-18-108- 405- ~tL-8 26 AT PENDIX G - SONY 0E A=TE- ~ C~ONIC-TOXICI~ DATA IN VARIOUS MAMMALIAN SPECIES WITH THE ANTICHOL~ERGIC TEST AGENTS (DITBAN, BElIAC:YZINE9 EA 2545, EA 3167, EA 3443 9 EA 3392, EA 3580, EA 3834, 226,086)-- by Leo G. Abood, Ph.D. APPENDIX H - EVALUATION OF DATA FROM SHORT-TERM TESTING 0E ~ICIlOL INERG IC CHEMI CALS-- by Virginia C. Dunkel, Ph.D. APPENDIX I - DIGEST REPORI--ANTICHOLINERGIC CHEfICALS-- by J. -Henry Wllls' Phel)o APPE:.~IX J - ANTICHOLI.NERGIC DRUGS h~ THE EEG- by Hax Fink, Ph.D. APPENDI X K - BIOC~I CAL ASPECTS OF AN'rICHOL INERGIC CHEMICALS by John J. O'Neill, Ph.D. APPE~IX L - STRUCTI:RE-ACTIVITY RELATIONS OF THE CENTRALLY ACTIVE AN'rICHOLINERGIC AGENTS-- by Leo G. Abood, Ph.D. xiii E-1 F-l G-l H-1 I-1 J-l R-l L-1

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