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POSSIBLE LONG-TERM HEALTH EFFECTS OF SHORT-TERM EXPOSURE TO CHEMICAL AGENTS Volume 2 Cho1inesterase Reactivators, Psychochemicals, and Irritants and Vesicants Prepared by the Panel on Cholinesterase Reactivator Chemicals Panel on Paychochemicale Pane' on Irritants and Vesicants Committee on Toxicology Board on Toxicology and Environmental Health Hazards Commission on Life Sciences National Research Council National Academy Press Washington, D. C. 1984

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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are draw 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 appro- priate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee con- sisting of members of the National Academy of Sciences, the National Academy of Engineerlng, and the Institute of Medicine. 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 lB63, which establishes the Academy as a private, nonprofit, se~f- goveraing membership corporation. The Counci1 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 Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences. This study was supported by funds provided by the Department of the Army through contract DAMDi7-83-C-3045 between the U.S. Army Research and Development Command and the National Academy of Sciences. Copies available from: National Academy Press 2101 Constitution Avenue, N.W. Washington, D.C. 20418

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PANEL ON CHOLLNESTERASE REACTIVATOR CHEMICALS Donald Ecobichon, McGill University, Quebec, Cantata, Chairman Mohamed Abou-Donia, Duke University Medical School, Durham, North Carolina Won Of D. Det~cbarn, Vanderbilt University School of Medicine, Nashville, Tennessee Walderico M. Generoso, Oak Ridge National Laboratory, Oak Ridge, Tennessee Wayland Hayes, Vanderbilt University School of Medicine, Nashville, Tennessee Richard Johns, Johns Hopkins University School of Medicine, Baltimore, Maryland Lewis H. Kuller, UP versity of Pittsburgh, Pittsburgh, Pennsylvania Frank S. Standaert, Georgetown University Medical School, Washington, D. C. Irwin Wilson, University of Colorado, Boulder, Colorado Technical Consultants Ronald J. Kassel, U. S. Army Chemical Systems Laboratory, Aberdeen Proving Ground, Maryland Joseph S . Wiles, Baltimore, Maryland J. Henry Wills, Uniformed Service s University of the Health Sciences, Bethesda, Maryland PANEL ON PSYCHOCHEMICALS Robert Snyder, Rutgers University, New Brunswick, New Jersey, Chairman Monique C. Braude, National Institute on Drug Abuse, Rockville, Maryland Sidney Cohen, Uni~reraity of California, Los Angeles, California Walter J. Decker, U=1 versity of Texas Medical Branch, Galveston, Texas Reese T. ~Jones, University of California, San Francisco, California Marvin S. Legator, University of Texas Medical Branch, Galore ston, Texas William R. Martin, University of Kentucky, Lexington, Kentucky A. Thomas McLellan, Veterans Administration Medical Center, Philadelphia, PennsylYa=1 a Charles P. O'Brien, University of PenneyI,rar~ia, Philadelphia, Penn Sylvania Wolfgang H. Vogel, Thomas Jefferson University, Philadelphia, Pennsylvania

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Technical Consultants Ronald J. Kassel, U. S . Army Chemical Systems Laboratory, Aberdeen Proving Ground, Maryland James S . Ketchum, University of Cal if ornia at Los Angeles, School of Medicine, Los Angeles, California S .N. Pradhan, Howard Urn versity, Washington, D. C. Fred Sidell, Biomedical Laboratories, Aberdeen Proving Ground, Maryland Jo seph S . Wi ~ es, Ba ~ t imore, Maryland PANEL ON IRRITANTS AND V-ESICANTS Howard I. Maibach, University of California, San Francisco, California, Chairman William J. Blot, National Institutes of Health, Bethesda, Maryland George Hoffmann, Holy Cross College, Worcester, Massachusetts Frederick Oehme, Ransas State University, Manhattan, Kansas Charles J. Stahl, E. Tennessee State University, Johnson City, Tennessee Marshall Steinberg, Hazleton Laboratories America, Vienna, Virginia Kim Thorbu`", University of California at Los Angeles, California John H. Weiaburger, American Health Foundation, Valhalla, New York William Willoughby, Johns Hopkins University Medical School, Bait imore, Maryland John Zapp, Kennett Square, Pennsylvania Technical Consultants . . Charles Hassett, Towson, Maryland Ronald J. Kassel, U.S. Army Chemical Systems Laboratory, Aberdeen Proving Groaned, Mary and National Research Council Staff Francis N. Marsulli, Project Officer, Panel on Cholinesterase Reactivator Chemicals, Panel on Paychochemicale, and Panel on Irritants and Vesicants

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Devra Lee Davis, Executive Director, Board on Toxicology and Environmental Health Hazards ( BOTEHH) Seymour Jablon, Director, Medical Follo~up Agency Robert J. Keehn, Statistician, Medical Follow-up Agency Edna Paulson, Manger, Toxicology Information Center (BOTEHH) Virginia Mite, Reference Verifier, Toxicology Information Cent er ~ BOTEHH) Jean E. Dent, Secretary, Panel on Cholinesterase Reacti~rator Chemica1 s, Panel on Paychochemicals, and Pane1 on Irritants and Vesicants Norman Grosablatt, Editor COMMITTEE ON TOXICOLOGY Roger O. McClellan, Lovelace Inhalation Toxicology Research Institute, Albuquerque, New Mexico, Chairman Richard R. Bates, Health Effects Institute, Cambridge, Massachusetts Donald Ecobichon, McGill University, Montreal, Quebec, Canada David W. Gaylor, National Center for Toxicological Research, Jef ferson, Arkansas Richard Griesemer, Oak Ridge Nationa1 Laboratory, Oak Ridge, Tennessee William Halperin, National Instiute for Occupational Safety and Health, Cincinnat i, Ohio Clark W. Heath, Jr., Emory University School of Medicine, Atlanta, Georgia Howard I. Maibach, University of California School of Medicine, San Francisco, California Robert E. Menzer, University of Maryland, College Park, Maryland Robert Snyder, Rutgers University School of Pharmacy, New Brunswick, New Jersey Ronald Spanggord, SRI International, MeDlo Park, Cal if ornia Peter S . Spencer, Albert Einstein College of Medicine, Bronx, New York Lloyd B. Tepper, Air Products and Chemica1 s, Inc., Allentown, Penn syl~rallia Clarence J. Terhaar, Eastman Kodak Company, Rochester, New York National Research Council Staff . Francis N. Marzul li, Pro ject Of ficer lbir S. Bakshi, Staff Officer

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BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS Gerald N. Wogan, Massachusetts Institute of Technology, Cambridge, Maseachusetts, Chainean Donald Hornig, Harvard University, Boston, Massachusetts, Co-Vice-Chairman Philip Landrigan, National Institute for Occupational Safety and Health, Cincinnati, Ohio, Co-Vice-Chairman Edward Bresnick, University of Nebraska Medical Center, Omaha, Nebraska Herman N. Elsen, Massachusets Institute of Technology, Cambridge, Massachuset to Ronald Estabrook, University of Texas Medical School (Southwestern), Dallas, Texas Emma Duel Farber, University of Toronto, Toronto, Canada David G. Hoel, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina Michael Lieberman, Washington Uni~reraity School of Medicine, St . Louis, Missouri Abraham M. Lilienfeld, Johns Hopkins Uni~reraity, Baltimore, Maryland Richard Merrill, University of Virginia, Charlottesville, Virginia Vaun A. Newill, Exxon Corporation, New York, New York John Peters, University of Southern Californ' a, School of Medicine, Los Angeles, California Joseph V. Rod~ricks, Environ Corporation, Washington, D.C. Llane B. Russell, Oak Ridge National Laboratory, Oak Ridge, Tennessee Ellen Silbergeld, Environmental Defense Fund, Washington, D.C. National Research Council Staff Devra Lee Davis, Executive Director

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ACKNOWT EDGlIENTS The following persons provided technical assis~cance: Gary Keilson, University of Virginia Medical School, Charlottesville, Virginia Lester Miller, U. S . Army Chemical Systems Laboratory, Aberdeen Proving Ground, Maryland Gordon Newell, EPRI, Palo Alto, California James Norman, Medical Fol~ow-up Agency, National Research Council Robert Tardiff, Environ Corporation, Washington, D.C. James Vick, Food and Drug Administration, Washington, D.C.

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PREFACE The Department of the Army asked the Committee on Toxicology, in the Board on Toxicology and Environmental Health Hazards of the Commission on Life Sciences, National Research Council (NRC) to conduct a study of the possible chronic adverse health effects on servicemen of experimental exposure to various chemicals at the U.S. Army Laboratories (formerly the Army Chemical Center), Edgewood, Md. The Edgewood tests were conducted over a 20-yr period ending in 1975, to learn how five major classes of chemicals tested for various military applications may affect humans. Some 6,720 soldiers took part in the programs, and 254 chemicals were administered by various routes. In 1982, the Committee reported (Volume I) on possible long-term effects of two pharmacologic classes of chemicals (anticho~inesterases and anticholinergica) tested at Edgewood. This volume reports on long-term effects of three additional classes of chemicals tested at Edgewood: ~ It_ _ _ ~ ~ ~ ~ ~ ~ . _ cholinesterase reactivators, psycnocnem~ca~s, ana ~rrz~ants and vesicants. Studies of these substances, including LSD (discussed in a separately prepared report), constituted the main thrust of the Edgewood experiments. After completion of Volume I, three new panels were established to identify and assess evidence on the possible long-term health effects or delayed sequelae of the three chemical classes tested. This wan done over a period of a year, during which each pane' met three times. Pertinent material was examined to evaluate the possibility that experimental exposure of soldiers may have resulted in untoward health effects. The three panels were separately concerned with four cholinesterase Deactivator chemicals (oximes); two types of paychochemd cals (phencyclidine and dimethylhepty~pyran and congenera), administered in pure form, as opposed to street drugs; and mustard gas and severe' lacrimatory and respiratory irritants (such as ON, CS, CR, and CA). The charges to each panel were as follows: ~ To determine whether there was sufficient evidence to assess the likelihood that the test chemicals had had long-term health effects or delayed sequelae.

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To determine, on the basis of this evidence, whether the chemicals, as administered, are likely to have produced such adverse effects in the test subjects. As part of aches undertaking, the MRC staff conducted interviews with administrators, irlves~cigators, nurses, and technicians and reviewed documents to identify practices and procedures followed in testing chemicals at Edgewood. The interviews included persons who had a wide spectrum of viewpoints, but who were essentially in agreement regarding the conduct of h'' - n testing. Committees were formed at Edgewood to retried classif fed chemicals and develop reports for deciaselfication and use by NRC panels. Extensive extracts were prepared of precli~cal animal and human protocols and of technical reports at Edgewood libraries and other facilities. A repository was established at Edgewood (August 1980) for storing selected reports and needed information obtained from other sources. Research and experimental case files on volunteers were extracted and summarized. Digests of the literature were prepared. This report presents the conclusions of the three panels based on available toxicologic and epidemiologic data, including specific information on the frequency, routes, and amounts of the substances administered and the known immediate and long-term effects of the substances under the prevailing experimental conditions. A third report is intended to provide a final evaluation of the chemicals tested. Volume 3 will report on ache current health status of the soldier participants on the basis of a recent questionnaire and interpret its impact on the conclusions reported in Volumes ~ and 2. The followup questionnaire to volunteer subjects may add descriptive data, but, because of the km] ted sample size, it is unlikely to protrude evidence of a cause-and~ef feet relation between exposure to these chemicals and development of delayed disease.

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EXECUTIVE SUMMARY In 1980, the Board on Toxicology and Environmental Health Hazards of the National Research Council's Commission on Life Sciences began a program to evaluate the long-term health effects of chemical agents administered to military volunteers at the Army Chemical Center, Edgewood, Md., during the 1950s, 1960s, and 1970~. This work was conducted at the request of the Department of the Army. The tests were conducted to find out how various potential chemical warfare agents affect human performance. It was felt that animal tests were inadequate for this type of evaluation and that only humans could provide d ef ini t ive inf orma t ion . The first report (Volume l) reviewed data on 15 anticholinesterase and 24 antichollnergic agents, to which almost half of some 6, 700 sub jects were exposed at Edgewood. The current report, prepared by three panels of the Board's Committee on Toxicology, evaluates possible delayed health ef fee to of three additional classes of compounds that were tested on most of the remaining volunteer subjects: cholinesterase reacti~rators, paychochemicals, and irritants and vesicants (blistering chemicals). The cholinesterase reactivators, of which there are four, are used as antidotes for antlchotinesterase poisoning. The paychochemlcals income phencyclidine, an anesthetic with substantial disorienting ef fects that is also available (with impurities) as the street drug PCP, and 10 related dibenz opyrans that are central nervous system depressants capable of producing orthostatic hypotension. The irritants include the well-known lacrimatory chemical ON, the riot-control agent CS, and other ocular and re spiratory irritants . Mustard gas was the vesicant whose ef fects were studied. The Committee established three panels to identify and assess evidence on the possible long-term health effects or delayed sequelae of the chemicals tested. As in the work that led to Volume I, the chairman of each panel was selected from the Committee on Toxicology. The specific charges to each panel were as follows: To determine whether there was sufficient evidence to assess the likelihood that the test chemicals had had long-term health effects or delayed sequelae. To determine on the basis of this evidence whether the chemicals, as administered, are likely to have produced such adverse ef fects in the test subjects.

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The conclusions in this volume are based on available epidemiologic, toxicologic, and mortality data that were reported in Volme l. They also rely on a review of teat-subJect exposure data obtained from Edgewood, an of which were available to pane] membere. Long-term clinical fo~owup was not conducted. The subjects tested were healthier than the control subjects with whom they were compared, an both groups were healthier than the general population, reflecting the better health status of those in mid ~ tary service. The analyses presented here necesearily reflect the limitations of the available data. These conclusions might change in the light of information gained through a study of morbidity, which will be based on a questionnaire arid an analysis of admissions to Army and Veterans' Administration hospitals (to be reported in Volume 3~. CHOLINESTERAS E REACTIVATORS On the basis of an examination of toxicologic literature, case reports from Edgewood volunteers, and a retried of mortality data conducted by the National Research Council Medical Follow~up Agency, the Committee fond no evidence of chronic disease in anir~=ts or humus associated with single or repeated doses of the cho t ~ nesterase reacti~ratore ~ oximes) . The lack of followup data on volunteers pretreats certainty in predicting occurence or absence of delayed effects. The compounds are eliminated very rapidly from the body, but they produce a variety of acute effects that are short-lived an reversible, such as gastrointestinal distress after oral administra~cion, pain at an injection site, dizziness, headache, and ocular dlacomfort. The Committee found no conclusive studies of carcinogeniclty, mutagenicity, teratogen~city, or reproductive anomalies associated with the four oxides and therefore did not reach a conclusion in this regard. PSYCHOCH~ICALS The Committee found the evidence on the long-tenm health ef facts of the tested psychochemicale to be sparse. The target organs that may be involved in prolonged or delayed effects of phencyclidine are the brain and cardiovascular system. Target mental or cardiovascular effects did not take place within a week of espo sure to the drug. No case reports have identified long-.cerm effects or mental or cardiovascular effects soon after first exposure.

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The margin of safety of a tested chemical is sometimes estimated by considering the ratio of the lethal dose to the pharmacologically effective 608e ~ the 608e at which some detectable biologic ef feet occurs) ~ On the basis of animal data on the psychochemlcals tested, the margin of safety for short-term effects is large for acute intravenous, inttagastric, intraperitoneal, and subcutaneous administration and somewhat amass er for inhalation of the aerosolized form. On the basis of the scientific literature alone, it is not possible to predict whether any long-term effects would be asoclated with the small exposures used. However, evaluation of thi ~ toxicity literature and the Edgewood studies led this Committee to conclude that, at the doses and frequencies of phencycl1dine used at Edgewood in a small number of test subjects, it is unlikely that detectable long-term or delayed effects have occurred or win occur. Acute administration of the dibenzopyrans (dimethy~hepty~pyran and congellera) produced various degrees of physical incapacitation in Edgewood subjects, mainly because of moderate to marked and prolonged or~chostatic hypotension. The duration and intensity of effects varied among most doses and subjects. Despite the variations, there is a large pharmacologic margin of safety in the use of these compounds in animals. The dibenzopyrans produced more potent long-lasting orthostatic hypotension and weaker (but otherwise similar) paychologic effects thand-9-tetrahydrocann~blool during the Edgewood experiments. There is no laformation on chromic effects of dibenzopyrane. IRRITANTS AND VESICANTS The Committee analyzed published studies describing the in viva and in vitro properties of the agents used and reviewed short-term data collected by the U.S. Army on volunteers. The ability to provide defluitlve answers to the questions raised by the charge to the Committee was limited by the absence of long-term for owup studies of the so1diere and by the sparsenese of chronic effects studies of these compounds in animate or in h''mAns after industrial exposure. In general, the Committee found insufficient evidence to evaluate these chemicals, except mustard gas. Mustard gas is an experimental mutagen and human carcinogen at high doses.

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Data on the irritan~cs are insufficient to evaluate their mutage~clty, carcinogenlcity, or other long-term ef feces. Tests of all theses chemicals involved few exposures and low doses. MUSTARD GAS ~ H) Mustard gas is highly reactive and has vesicant and systemic toxic effects. It is an alkylating agent that is mutagenic ire various laboratory test systems, including mammalian germ cells, but data are inadequate to predict the extent of its genetic risk in humans. Mustard gas is also carcinogenic in experimental animals and humans. Other possible long-term ef fects of mustard gas are related to its |~4t toxicity; specifically, it can cause blindness, po ssible skin tumors from some cases of permanent scarring of the skin, and chronic bronchitis . Reported ~ nstaneee of long-term injury, such as carcinogenesis in workers tn a Japanese mustard production plant, were associated with exposure at high, long-term dosages. Information is insufficient to project risks associated with smaller exposures to mustard gas; however, serious long-term adverse effects in the small number of soldiers who received one or a few low~dose exposures at Edgewood seem unit ikely (except for possible skin tumors and some cases of permanent scarring) . Some of those exposed at Edgewood suffered skin injuries that took several weeks to resolve. However, in view of the small number of persons tested (about 150 healthy men) and the very low dosages involved, it is unlikely that a statistically signif icant increase in the flak of cancer or other chronic disease can be detected in those exposed to mustard gas at Edgewood. Then exposed, the Edgewood subjects were wearing gas masks and impregnated clothing--an ensemble being tested for efficacy against toxic contamination. o-CHLOROBENZY[IDENE MALONONITRILE ~ CS ~ - Results of experimental studies in microorganisms and short-~cerm elopements in laboratory animals suggest that long-c erm medical abnormalities in soldiers exposed deco CS are unlikely. Acute tissue changes produced in animals and humans seem reversible and not likely to become chronic in the absence of recurrent exposures. Follownp information on the long-term state of health of exposed soldiers is not available, but no reports indicate that Edgewood subjects have experienced any long-term sequelae.

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CHLOROACETOPHENONE ( CN) ON, a moderately toxic irritant, has immediate effects on the eyes, skin, and respiratory tract. CN is a strong skin-sensitizing agent, but is rarely lethal. The Committee found no e~rldence of lasting ocular or respiratory effects in 99 volun~ceers exposed esperlmentally at Edgewood between 1958 and 1972 when subjects were evaluated 2 wk after cutaneous administration or inhalation of aerosol. Allergic contact dermatitis or hypersensitivity in these volunteers on re-exposure to CN in possible. There has been no systematic study of the possible mutagenic and s~eoplasm-promotir~g effects of CN with current scientific methods. DIBENZlb, f] [1,4]0XAZEPINE (CR) CR, a mild lacrimatory irritant, manifests less acute toxicity than CN and CS. At low doses, it causes transient effects. There are a few studlee on long-term health effects, including potential mutagenicity and teratogenicity. The available data are insufficient to predict long-term health effects. The small number of exposures and the Small number of subjects exposed to CR at low doses at Edgewood make the occurrence of demonstrable ef fects in these sub jects unlikely. CHLOROPICRIN ( PS ) PS is acutely toxic and has a variety of sensory effects in animals. It has not been evaluated thoroughly for mutagenicity or carcinogen city. Like those exposed to mustard gas, the subjects exposed to PS were wearing gas masks, and small numbers of soldiers were exposed to small doses. PS is unlikely to have produced detectable long-term hew th effect'' in volunteers exposed at Edgewood. BROMBENZYL CYANIDE (CA), DIPHENYI~IINOCHLORARSINE (DM), and 1-METHOXY-1 3 5-CYCLOHEPTATRIENE (CHT) . , CA, DM, and CHT are unlikely to have produced measurable long-term hew th effects in volunteers exposed at Edgewood. But there are no specific toxicologic data on the mutagenicity and carcinogenicity of these compounds. CH1 is less toxic than CN or DM when administered acutely.

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NONANOYL MORPHOLIDE The Committee does not expect long-ter~ health effects in volunteers tested with nonanoyl morpholide at the dosages used at Edgewood. As with CA, DM, and CHT, specific toxicologic data regarding its potential in this regard are not available. 123 IRRITANT CHEMICALS . A total of 123 irritant chemicals were tested on only two subjects each. There are no data on their mutagenicity, carcinoger~icity, or other long-term health effects. However, because the exposures were Small, detectable adverse effects seem unlikely. OVERVIEW . The Army~s studies on hen subjects were designed ent ire ly to evaluat e short-term physiologic and pharmacologic effects. A review of all available data reveals that these data are inadequate to provide defluiti~re answers regarding the likelihood that the test chemicals produced or did not produce long-term health effects or delayed sequelae. Information on long-term health effects of the teat chemicals on aMmals or humans is lacklug, as is followup information on the current health statue of the subjects. It therefore cannot be determined whether some subjects may have sustained long-ter~ or delayed effects. Analysis of a questionnaire and of admissions to Army and Veterans' Administration hospitals (Volume 3) may provide further information on the current health status of these subjects.