An Assessment of Health Status among Medical Research Volunteers Who Served in the Project Whitecoat Program at Fort Detrick, Maryland

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1 MILITARY MEDICINE, 170, 3:183, 2005 An Assessment of Helth Sttus mong Medicl Reserch Volunteers Who Served in the Project Whitecot Progrm t Fort Detrick, Mrylnd Gurntor: COL Phillip R. Pittmn, MC USA Contributors: COL Phillip R. Pittmn, MC USA*; Srh L. Norris, MPH ; Kevin M. Coonn, MD* ; Kelly T. McKee, Jr., MD MPH Between 1954 nd 1973, more thn 2,000 men entering militry service s conscientious objectors prticipted in Project Whitecot s medicl reserch volunteers for the Army s biologicl wrfre defense progrm. An ssessment of self-reported, current helth sttus mong 358 exposed individuls nd 164 unexposed control subjects found no conclusive evidence tht receipt of investigtionl gents ws relted to dverse helth outcomes. No differences in current overll helth, current exercise levels, self-reported symptoms, nd self-reported medicl conditions were seen between the study groups. Possible ssocitions were seen between exposure to ntibiotics or other biologicl gents nd self-reported sthm (13.0% vs. 2.4%, reltive risk [RR] 6.00, 95% confidence intervl [CI] , p 0.050), s well s between receipt of tulremi vccine(s) nd self-reported sthm (13.3% vs. 2.4%, RR 6.15, 95% CI , p 0.049) nd incresed frequency/severity of hedches (35.6% vs. 18.3%, RR 2.46, 95% CI , p 0.074). However, the size of the popultion under study ws insufficient to ssert with confidence tht these sttisticl ssocitions re rel. *USAMRIID, Fort Detrick, MD Science Applictions Interntionl Corp./USAMRIID, Fort Detrick, MD Cmber Corp./USAMRIID, Fort Detrick, MD Current ddress: Deprtment of Medicl Informtics, University of Uth School of Medicine, Slt Lke City, UT. The opinions expressed re those of the uthors nd should not be construed to represent those of Cmber Corp., Science Applictions Interntionl Corp., the Deprtment of the Army, or the Deprtment of Defense. Reprints: COL Phillip R. Pittmn, U.S. Army Medicl Reserch Institute of Infectious Diseses, 1425 Porter St., Fort Detrick, MD ; e-mil: phillip.pittmn@medd.rmy.mil. This mnuscript ws received for review in Februry 2004 nd ws ccepted for publiction in Mrch Introduction nited Sttes government efforts to counter the thret of U biologicl wepons hve their genesis in the Wr Bureu of Consulttion, commission of the Ntionl Acdemy of Sciences tht ws formed t the request of Secretry of Wr Hrold Stimson in ,2 This group recommended the urgent cretion of progrm of reserch to ddress the problem of biologicl wrfre nd, in 1942, President Roosevelt uthorized Mr. Stimson to estblish the Wr Reserch Service s unit of the Federl Security Agency for this purpose. The Wr Reserch Service, heded by George Merck (president of Merck Phrmceuticls), immeditely undertook progrm of study of biologicl gents, conducted with utmost secrecy. 3 With incresing pprecition of the scope nd complexity of lrge-scle progrm of reserch nd development in this re, the Wr Reserch Service requested tht the U.S. Army Chemicl Wrfre Service ssume responsibility. The initil site selected for the progrm ws Edgewood Arsenl, ner Aberdeen, Mrylnd. In 1943, smll Ntionl Gurd irfield (Detrick Field) just outside Frederick, Mrylnd, ws purchsed by the Wr Deprtment, nd the hub of the opertion ws moved to the renmed Cmp Detrick. The Office of the Army Surgeon Generl ws involved in the biologicl wrfre reserch nd development progrm from the time of its inception in 1941, but it ws not directly responsible for ny ctivities until 1956, when the U.S. Army Medicl Unit t Cmp Detrick ws ctivted with mission to evlute the thret of biologicl wrfre nd to develop pproprite countermesures. 4 During the sme yer, Cmp Detrick becme Fort Detrick. From tht time to the present, Fort Detrick hs been the home of the ntion s biologicl wrfre defense progrm. The Army Medicl Unit ws redesignted the U.S. Army Medicl Reserch Institute of Infectious Diseses (USAMRIID) in The contributions of USAMRIID nd its predecessor to militry medicl reserch nd ntionl security re legion, nd the plnned integrtion of USAMRIID with Ntionl Institutes of Helth nd Deprtment of Homelnd Security progrms through the formtion of ntionl biodefense cmpus t Fort Detrick 5 ensures its future ledership role in this re. Project Whitecot ws the title given to n Army reserch progrm to use humn volunteers in medicl studies to evlute the effect of certin biologicl pthogens upon humns in n effort to determine the vulnerbility to ttck with biologicl gents (W.S. Augerson, 1976, cited in Ref. 4, p 20). The objectives of the studies involved were to develop medicl defenses ginst biologicl wrfre nd included techniques for rpid dignosis, improved therpeutic nd prophylctic gents, nd development of vccines ginst biologicl wepons nd endemic disese threts. The progrm evolved fter series of meetings in between representtives of the Army Surgeon Generl nd the Seventh Dy Adventist Church. With the bckground of the Church s philosophy nd prctice of medicl service nd encourgement of noncombtncy nd its longstnding coopertion with the militry in helth nd medicl prctice, Project Whitecot becme n ccepted nd respected vehicle by which conscientious objectors could serve the ntion. 4 From its inception in 1954 to its termintion in 1973, pproximtely 2,300 individuls prticipted in this progrm, more thn 90% of whom were Seventh Dy Adventists. The group prticipted in more thn 135 clinicl reserch studies involving exposure to live gents, receipt of investigtionl vccines, nd studies of metbolic nd psychologicl effects of environmentl- nd infection-induced stress. 4,6 Most volunteers prticipted in t lest one project, wheres some prticipted in severl. The current study Downloded from by guest on 12 November Militry Medicine, Vol. 170, Mrch 2005

2 184 Helth Sttus mong Project Whitecot Volunteers ws designed to ssess the long-term effects on the helth of these men resulting from their involvement in this vitl progrm. Methods Design This ws controlled, unblinded, retrospective, cohort study to ssess the helth sttus of individuls who volunteered to prticipte in Project Whitecot t Fort Detrick, Mrylnd, during Popultion Approximtely 2,300 men who entered militry service nd were clssified s conscientious objectors prticipted in Project Whitecot. Most were ssigned to Fort Detrick, Mrylnd, nd individuls there were ssigned vriety of duties in support of the medicl reserch efforts t the fcility. Some worked s technicins in reserch lbortories, some worked s hospitl corpsmen, nd others were ssigned predominntly dministrtive duties nd responsibilities. Periodiclly, the group membership ws pproched regrding interest in prticipting s volunteers for clinicl reserch studies. Most studies were relted to exposure to infectious diseses, for which volunteers would receive proven therpies nd occsionlly investigtionl prophylctic gents (e.g., vccines). Subjects for this study were recruited from mong the membership of the Project Whitecot lumni group. A totl of 358 men who were exposed to n infectious gent or vccine (study group) nd 164 men who prticipted in reserch studies s unexposed control subjects (control group) greed, fter signing written informed consent greement, to complete self-dministered questionnire tht inquired bout helth sttus, ongoing clinicl symptoms nd signs, reproductive outcomes, nd diseses or conditions dignosed by competent medicl uthorities. The study ws reviewed nd pproved by the institutionl review bord t USAMRIID, s well s by the Humn Subjects Reserch Review Bord of the U.S. Army Surgeon Generl. Exposure Histories Records for prticiption in clinicl protocols, including receipt of vccines nd disese-cusing gents, were obtined by reviewing rchives t USAMRIID. The nme nd type of study in which ech volunteer prticipted were extrcted from these records nd entered into n utomted dtbse for nlysis. A totl of 197 volunteers received investigtionl vccines. The vilble dt did not llow distinction between live vccines nd killed/toxoid products, nor did they llow enumertion of the numbers of different vccine cndidtes involved in testing. Two hundred eleven individuls were exposed to disese-cusing gents (some of which might hve involved exposure to different strins of given pthogen), nd 46 received ntibiotics or other therpeutic gents (in physiologicl or other studies seprte from tretment for exposures in other protocols). Sttisticl Anlyses The 2 nd Fisher exct tests were used to compre proportions nd the t test ws used to compre men differences between the exposed (study) nd control groups. Rte differences between groups were compred with Fisher exct tests djusted for multiple comprisons using resmpling bootstrp pproch (SAS MULTTEST) for sets of relted vribles (e.g., symptoms, diseses nd conditions, nd reproductive outcomes). To exmine the effect of multiple exposures in the exposed (study) group by itself, logistic regression nlysis of the number of studies in which subjects were enrolled ws used. To exmine the possibility tht confounder vribles could explin group differences, further nlysis ws done using logistic regression nlysis of demogrphic vribles. Subgroup nlysis ws conducted bsed on clss of exposure (vccine, pthogen, or therpeutic gent). Effects of individul gents were ssessed; however, smple sizes were insufficient for conclusive results. All nlyses used SAS version 8.2 (SAS Institute, Cry, North Crolin). The sttisticl power of this study to detect rte differences between groups ws ssessed using power nlysis progrm. 7 With the smple sizes of 358 control subjects nd 164 study subjects, with testing t the 5% level of significnce (one-tiled), miniml difference in reltive risk (RR) of twofold could be detected with t lest 80% probbility for rtes of helth-relted outcomes, over rnge of bckground helth condition rtes for the control subjects. Results Popultion Chrcteristics subjects were mle nd predominntly (91.0%) Cucsin. The medin durtion of ssignment t Fort Detrick ws 2.0 yers (rnge, 0 8 yers). The men ge of the popultion t the time tht the survey ws performed ws 58.4 yers (rnge, yers); the mjority of study subjects were highly educted (58.2% possessed college or grdute degrees). Although 12.8% of those completing surveys were retired t the time of the study, less thn one-hlf (47.9%) were fully employed. No demogrphic differences were found between subjects who hd been exposed to test gents in the course of prticiption in clinicl reserch studies nd those who hd served s control subjects for the sme studies (Tble I). Eighty-seven percent of the study prticipnts reported their current stte of helth s good or excellent, nd 72.6% climed to engge in t lest some exercise every week. Exposed nd control subjects did not differ with regrd to current overll helth sttus or current exercise level (Tble II). A reltively smll proportion of individuls reported tobcco nd/or lcohol use. Only 14.9% of survey respondents dmitted to hving ever smoked cigrettes, 7.7% to hving ever smoked cigrs, 7.9% to hving ever smoked pipe, nd 1.1% to hving ever used chewing tobcco or snuff. Aside from slightly higher percentge of subjects who hd been exposed to test gents climing to hve quit smoking cigrettes, no differences between the exposed nd control groups with regrd to tobcco nd lcohol consumption were evident (Tble II). Exposures Among the 358 exposed subjects, 303 prticipted in one study while ssigned to Fort Detrick, 75 prticipted in two studies, 17 prticipted in three studies, nd 1 prticipted in four studies. Vccine exposures included Venezueln equine encephlitis (73 persons), tulremi (45 persons), yellow fever Downloded from by guest on 12 November 2018 Militry Medicine, Vol. 170, Mrch 2005

3 Helth Sttus mong Project Whitecot Volunteers TABLE I DEMOGRAPHIC DATA (n 164) p Rce (%) Cucsin Africn Americn Other Mle NT Men ge, yers (rnge) 58.4 (47 74) 58.5 (46 79)0.822 Men time spent t Fort Detrick, yers (rnge) 1.5 ( 1 8) 1.5 ( 1 3) Served in militry (%) NT College degree or higher (%) Current employment sttus (%) Retired Employed full-time Employed prt-time Not working becuse of disbility Tests re two-tiled. NT, not tested. TABLE II HEALTH AND BEHAVIORAL CHARACTERISTICS (n 164) p Current helth sttus (%) Excellent Good Fir Poor Current exercise level (%) None More thn 5 times/week Up to 5 times/week Disbled Tobcco history Ever smoked cigrettes (%) No. of pcks/dy (men) No. of yers smoked (men) Quit (mong those ever smoked) (%) Yers since quitting (men) Ever smoked pipe (%) Ever smoked cigrs (%) Ever dipped snuff/used chewing tobcco (%) Alcohol use, ever drink (%) Tests re two-tiled. (31 persons), Estern equine encephlitis (29 persons), Western equine encephlitis (28 persons), plgue (13 persons), Q fever (11 persons), Rift Vlley fever (8 persons), nthrx (7 persons), chikunguny (six persons), nd denovirus (4 persons). Virulent gent exposures included Coxiell burnetii (Q fever) (58 persons), snd fly fever (30 persons), stphylococcl enterotoxin B (20 persons), Frncisell tulrensis (tulremi) (11 persons), Venezueln equine encephlitis (7 persons), nd Pseudomons endotoxin (2 persons). Antibiotic nd other therpeutic gent exposures included tetrcycline (25 persons), mino cids (15 persons), chlormphenicol (4 persons), nd tyrosine (4 persons). Subjects who volunteered to prticipte in virulent bcteril gent exposure studies (e.g., Q fever or tulremi) lso received curtive ntibiotics during, or t the conclusion of, ech project. Outcomes Most (87%) study prticipnts reported hving hd children. The proportions of exposed nd control subjects with children were similr (87.4% nd 86.0%, respectively). A totl of 1,052 children were reported to hve been sired by the 522 study prticipnts. The vst mjority (92.3%) of these children were reported s norml nd helthy. No differences between exposed nd control groups in the numbers of children per individul, children with congenitl bnormlities, or children with mentl retrdtion were seen (Tble III). No differences between exposed subjects nd control subjects were seen with regrd to self-reported clinicl signs nd symptoms or diseses (or other medicl conditions) (Tbles IV nd V). When symptoms nd diseses mong individuls who hd received ll vccines nd those who hd received ll virulent gents were exmined seprtely, there remined no differences between the groups. Asthm ws reported more frequently mong the group of subjects exposed to ll ntibiotics or other nongents thn mong control subjects (13.0% vs. 2.4%, RR 6.00, 95% confidence intervl [CI] , p 0.050, fter djustment for multiple comprisons). Attempts to ssess frequencies of clinicl signs nd symptoms or diseses by individul vccine, individul virulent gent, nd individul ntibiotic/other gent exposure yielded numbers too smll for meningful nlysis for ll except recipients of Venezueln equine encephlitis vccine(s), tulremi vccine(s), or virulent C. burnetii. Among these exposures, possible ssocition between sthm nd receipt of tulremi vccine(s) ws observed (13.3% of vccinees vs. 2.4% of control subjects, RR 6.15, 95% CI , p 0.049, fter djustment for multiple comprisons). In the sme cohort, n ssocition with n incresed frequency of hedches (never or rrely problem vs. occsionlly or more frequently problem) mong tulremi vccinees ws suggested (35.6% vs. 18.3%), but the difference from control subjects did not rech sttisticl significnce (RR 2.46, 95% CI , p 0.074, fter djustment for multiple comprisons). There were no differences in ny outcome vribles (generl helth, exercise levels, reproductive outcomes, reported symptoms, or reported medicl conditions) between subjects prticipting in one study nd those prticipting in two or more studies (dt not shown). TABLE III REPRODUCTIVE OUTCOMES (n 164) p No. of children, men (rnge) 2.0 (0 7) 2.0 (0 6) Hd ny children 313 (87.4%) 141 (86.0%) Hd children with birth defects 25 (7.0%) 15 (9.1%) or mentl retrdtion No. of children (N 1,052) Norml/helthy 698 (95.6%) 306 (95.0%) With birth/congenitl defects 24 (3.3%) 14 (4.3%) With mentl retrdtion 8 (1.1%) 2 (0.6%) Tests re two-tiled. 185 Downloded from by guest on 12 November 2018 Militry Medicine, Vol. 170, Mrch 2005

4 186 Helth Sttus mong Project Whitecot Volunteers TABLE IV SELF-REPORTED DISEASES AND CONDITIONS Condition No. % No. % p Amyloidosis Anemi Anemi of chronic disese Aplstic nemi Arthritis Asthm Atopic dermtitis Cncer Dibetes mellitus Eczem Erythem nodosum Frequent colds Glomerulonephritis Goodpsture s syndrome Guillin-Brré syndrome Hy fever Hemolytic nemi Hodgkin s disese Hypertension Immune complex disese Iron deficiency nemi Kidney disese Leukemi Low white blood cell count Lupus Multiple myelom Multiple sclerosis Neuritis Prkinson s disese Pltelet problems Pneumoni Pneumonitis Reiter s syndrome Rheumtoid rthritis Srcoidosis Serum sickness Sjögren s syndrome Temporl rteritis Thyroid disese Ulcers Uveitis Vsculitis Vitmin B 12 deficiency Wegener s grnulomtosis Totl One-tiled Fisher exct test djusted for multiple comprisons (bootstrp). Discussion Symptom TABLE V SELF-REPORTED SYMPTOMS, No., No., %, % p Arthrlgi Severe Moderte Mild/none Ftigue Severe Moderte Mild/none Mylgi Severe Moderte Mild/none Insomni Severe Moderte Mild/none Depression Severe Moderte Mild/none Memory loss Severe Moderte Mild/none Abdominl pin Severe Moderte Mild/none Hedche Severe Moderte Mild/none Mlise Severe Moderte Mild/none Tremors Severe Moderte Mild/none Fevers Severe b Moderte Mild/none Rshes Severe Moderte Mild/none Comprisons by 2 test except s noted. b Two-tiled Fisher exct test. Men entering militry service between 1955 nd 1973 who volunteered to serve t Fort Detrick in Project Whitecot prticipted in wide vriety of clinicl reserch studies involving exposure to investigtionl vccines, pthogenic gents, other biologicls (such s ntibiotics), nd environmentl stresses, for the purpose of prepring our ntion ginst the thret of biologicl wrfre. Most, but not ll, Project Whitecot prticipnts were members of the Seventh Dy Adventist Church. Individuls were recruited from the rnks of enlisted soldiers (predominntly drftees) with 1-A-O (conscientious objector) clssifiction who were engged in bsic or dvnced individul trining t the Medicl Trining Center, Fort Sm Houston, Texs. Upon rrivl t Fort Detrick, personnel underwent complete series of medicl evlutions (including detiled history, physicl exmintion, nd lbortory studies) nd then were ssigned to vriety of duties within the Medicl Reserch Downloded from by guest on 12 November 2018 Militry Medicine, Vol. 170, Mrch 2005

5 Helth Sttus mong Project Whitecot Volunteers Unit/USAMRIID, such s lbortory technicin, niml cretker, medic, or supply clerk. All duties were noncombtnt in nture. All remined full-time soldiers, nd most remined t Fort Detrick for the durtion of their service obligtions. No specil considertion or privileges were ccorded Project Whitecot prticipnts. When volunteers were needed for specific reserch studies, briefing to n ssembly of Project Whitecot personnel ws provided by the commnding officer, regrding the nture nd purpose of the project, the risks involved, nd the requirements for ech prticipnt. Questions were then entertined. Those expressing interest in prticipting were subsequently interviewed individully; detils of the study were recounted, individuls were llowed to sk questions, nd, if the individul gin expressed interest in prticipting, signed consent ws obtined (USAMRIID 1969 Fct Sheet, cited in Ref. 8). During the course of the progrm, Project Whitecot volunteers prticipted in pproximtely 150 studies. 8 Although some of the projects remin clssified, the vst mjority of the work ws conducted openly nd ws reported in the scientific nd medicl literture. No ftlities directly ttributble to prticiption in these clinicl trils occurred. Although the trils met nd often exceeded the ethicl stndrds of the dy for reserch involving humn subjects, the current clinicl reserch climte would preclude repetition of mny of these studies tody. The dt obtined from reserch involving Project Whitecot volunteers therefore stnd s unique nd represent the only humn dt vilble in mny res. To dte, there hs been no systemtic ttempt to ssess the long-term impct of these exposures on the helth of Project Whitecot volunteers. In , questionnire designed to cpture reflections on their experiences, the resons behind their interest in prticipting in the progrm, nd demogrphic profiles ws completed by pproximtely 200 former prticipnts. 4 One question in this survey ddressed potentil residul effects of progrm prticiption on helth. At tht time, only one individul in the progrm hd been wrded service-connected disbility designtion. A few other Project Whitecot prticipnts cited progrm prticiption s cuse of current medicl problems; none ws confirmed by medicl review. 4,8 The current study ws n ttempt to objectively ssess the impct of prticiption in clinicl reserch studies by the Project Whitecot popultion by compring questionnire responses from those who were exposed to gents, biologicls, or other potentil stressors nd those in the progrm who served s control subjects for the experiments. Anlyses of questionnires completed by volunteers for this study provided no evidence tht exposures sustined by prticipnts in Project Whitecot were ssocited with dverse helth outcomes. The exposed nd control groups were comprble in most demogrphic nd lifestyle prmeters. No differences were reported in overll helth sttus between the two groups, nd there were no evident effects on reproductive outcomes. Asthm ws reported more frequently mong subjects exposed to ntibiotics or other inert substnces thn mong control subjects, nd similr borderline higher frequencies were observed for reported sthm nd hedches mong subjects exposed to tulremi vccines. However, the size of the popultion under study proved insufficient to conclude tht these sttisticl ssocitions were rel. This study hs number of shortcomings. Mortlity rtes could not be ssessed becuse of incomplete reporting for the totl Project Whitecot popultion. There re selection nd other bises inherent in volunteer study of this nture, which might hve ffected our findings. The smple sizes vilble were insufficient to detect rre helth effects. Furthermore, no lbortory studies were performed s prt of the study, nd no review of medicl records ws ttempted. Therefore, helth consequences from exposures experienced by Project Whitecot prticipnts might hve been missed. However, the derth of evidence suggesting dverse helth effects reported by the volunteers who greed to prticipte rgues ginst such possibility. Project Whitecot represents n importnt chpter in the history of medicl defense ginst biologicl wepons nd in humn experimenttion. The men who volunteered to prticipte in the seminl studies tht provided proof of concept in so mny criticl res should be herlded for their contributions to science nd medicine in both the militry nd civilin sectors. It is grtifying tht no dverse impct on the overll helth of Project Whitecot volunteers could be conclusively ttributed to their prticiption in these importnt reserch studies. References Clendenin RM: Science nd Technology t Fort Detrick Wshington, DC, U.S. Army, Smrt JK: History of chemicl nd biologicl wrfre: n Americn perspective. In: Medicl Aspects of Chemicl nd Biologicl Wrfre, pp Edited by Sidell FR, Tkfuji ET, Frnz DR. Wshington, DC, Borden Institute, Wlter Reed Army Medicl Center, Cole LA: Clouds of Secrecy: The Army s Germ Wrfre Tests over Populted Ares. Totow, NJ, Rowmn nd Littlefield, Mole RL, Mole DM: For God nd Country: Opertion Whitecot: Brushton, NY, Rech Services, Deprtment of Homelnd Security: 2004 Deprtment of Homelnd Security Appropritions Act (HR 2555), October 1, Anderson AO: A brief history of militry contributions to ethicl stndrds for reserch involving humn subjects Avilble t com/rtnscience/jm4-primr.html. 7. Borenstein M, Rothstein H, Cohen J: Power nd Precision. Englewood, NJ, Biostt, Moreno JD: Undue Risk: Secret Stte Experiments on Humns. New York, NY, W.H. Freemn nd Co., Downloded from by guest on 12 November 2018 Militry Medicine, Vol. 170, Mrch 2005