{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T19:53:36Z","timestamp":1778615616253,"version":"3.51.4"},"reference-count":63,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,1,25]],"date-time":"2017-01-25T00:00:00Z","timestamp":1485302400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000139","name":"U.S. Environmental Protection Agency","doi-asserted-by":"publisher","award":["SP0700\u201000\u2010D\u20103180\/CB\u201011\u20100232"],"award-info":[{"award-number":["SP0700\u201000\u2010D\u20103180\/CB\u201011\u20100232"]}],"id":[{"id":"10.13039\/100000139","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000993","name":"Battelle","doi-asserted-by":"publisher","award":["US001\u20100000318847"],"award-info":[{"award-number":["US001\u20100000318847"]}],"id":[{"id":"10.13039\/100000993","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Risk Analysis"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:p>Survival models are developed to predict response and time\u2010to\u2010response for mortality in rabbits following exposures to single or multiple aerosol doses of <jats:italic>Bacillus anthracis<\/jats:italic> spores. Hazard function models were developed for a multiple\u2010dose data set to predict the probability of death through specifying functions of dose response and the time between exposure and the time\u2010to\u2010death (TTD). Among the models developed, the best\u2010fitting survival model (baseline model) is an exponential dose\u2013response model with a Weibull TTD distribution. Alternative models assessed use different underlying dose\u2013response functions and use the assumption that, in a multiple\u2010dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this article. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high\u2010dose rabbit data sets. More accurate survival models depend upon future development of dose\u2013response data sets specifically designed to assess potential multiple\u2010dose effects on response and time\u2010to\u2010response. The process used in this article to develop the best\u2010fitting survival model for exposure of rabbits to multiple aerosol doses of <jats:italic>B. anthracis<\/jats:italic> spores should have broad applicability to other host\u2013pathogen systems and dosing schedules because the empirical modeling approach is based upon pathogen\u2010specific empirically\u2010derived parameters.<\/jats:p>","DOI":"10.1111\/risa.12688","type":"journal-article","created":{"date-parts":[[2017,1,25]],"date-time":"2017-01-25T12:46:52Z","timestamp":1485348412000},"page":"943-957","source":"Crossref","is-referenced-by-count":4,"title":["Modeling Rabbit Responses to Single and Multiple Aerosol Exposures of <i>Bacillus anthracis<\/i> Spores"],"prefix":"10.1111","volume":"37","author":[{"given":"Margaret E.","family":"Coleman","sequence":"first","affiliation":[{"name":"National Homeland Security Research Center U.S. Environmental Protection Agency  Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harry M.","family":"Marks","sequence":"additional","affiliation":[{"name":"National Homeland Security Research Center U.S. Environmental Protection Agency  Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy A.","family":"Bartrand","sequence":"additional","affiliation":[{"name":"National Homeland Security Research Center U.S. Environmental Protection Agency  Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darrell W.","family":"Donahue","sequence":"additional","affiliation":[{"name":"National Homeland Security Research Center U.S. Environmental Protection Agency  Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie A.","family":"Hines","sequence":"additional","affiliation":[{"name":"National Homeland Security Research Center U.S. Environmental Protection Agency  Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason E.","family":"Comer","sequence":"additional","affiliation":[{"name":"National Homeland Security Research Center U.S. Environmental Protection Agency  Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah C.","family":"Taft","sequence":"additional","affiliation":[{"name":"National Homeland Security Research Center U.S. Environmental Protection Agency  Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,1,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/0272-4332.00028"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003555"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2010.0491"},{"key":"e_1_2_7_5_1","volume-title":"Multiple daily low\u2010dose Bacillus anthracis Ames inhalation exposures in the rabbit. EPA\/600\/R\u201011\/145","author":"U.S. Environmental Protection Agency","year":"2012"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.2033"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1089\/bsp.2013.0067"},{"issue":"2","key":"e_1_2_7_8_1","first-page":"78","article-title":"Mathematically modeling inhalation anthrax","volume":"3","author":"Gutting BW","year":"2008","journal-title":"Microbe"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2013.03.020"},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","DOI":"10.17918\/etd-3426","volume-title":"Incorporating Time to Response into Dose\u2010Response Models Used in Quantitative Microbial Risk Assessment","author":"Huang Y.","year":"2010"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/0272989X08315245"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/es504422q"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2011.07.005"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1201\/b11523-7"},{"key":"e_1_2_7_15_1","volume-title":"Overcoming Challenges to Develop Countermeasures against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models","author":"National Research Council","year":"2006"},{"key":"e_1_2_7_16_1","first-page":"39","volume-title":"Medical Aspects of Biological Warfare","author":"Dembek ZF","year":"2007"},{"key":"e_1_2_7_17_1","volume-title":"Acute low dose Bacillus anthracis Ames inhalation exposures in the rabbit. EPA\/600\/R\u201011\/075","author":"U.S. Environmental Protection Agency","year":"2011"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1086\/429696"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.4161\/viru.1.2.10752"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2012.0843"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.038794-0"},{"issue":"4","key":"e_1_2_7_22_1","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1128\/IAI.72.4.2329-2337.2004","article-title":"Modulation of enteropathogenic Escherichia coli virulence by quorum sensing","volume":"72","author":"Sircili MP","year":"2004","journal-title":"Infection and Immunity"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.052694299"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1086\/382656"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1011490"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiq051"},{"issue":"5","key":"e_1_2_7_27_1","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1128\/iai.5.5.734-744.1972","article-title":"Pathogenesis of tularemia in monkeys aerogenically exposed to Francisella tularensis 425","volume":"5","author":"Schricker IL","year":"1972","journal-title":"Infection and Immunity"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00473-11"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.10.5831-5844.2003"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1833677100"},{"key":"e_1_2_7_31_1","volume-title":"Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World\u2014Told from Inside by the Man Who Ran It","author":"Alibek K","year":"1999"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1525\/california\/9780520222045.001.0001"},{"key":"e_1_2_7_33_1","volume-title":"Prepositioning Antibiotics for Anthrax","author":"Stroud C","year":"2012"},{"key":"e_1_2_7_34_1","volume-title":"September 11th Sourcebooks, v. 5; National Security Archive Electronic Briefing Book No. 61:1\u201316","author":"Wampler RA","year":"2001"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid0706.010604"},{"key":"e_1_2_7_36_1","volume-title":"Reopening Public Facilities after a Biological Attack","author":"National Research Council","year":"2005"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00292-12"},{"issue":"6","key":"e_1_2_7_38_1","first-page":"461","article-title":"Aerosolized Bacillus anthracis infection in New Zealand white rabbits: Natural history and intravenous levofloxacin treatment","volume":"60","author":"Yee SB","year":"2010","journal-title":"Comparative Medicine"},{"issue":"3","key":"e_1_2_7_39_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1128\/br.30.3.646-659.1966","article-title":"Industrial inhalation anthrax","volume":"30","author":"Brachman PS","year":"1966","journal-title":"Bacteriological Reviews"},{"issue":"5","key":"e_1_2_7_40_1","first-page":"691","article-title":"Pathology of experimental inhalation anthrax in the rhesus monkey","volume":"73","author":"Fritz DL","year":"1995","journal-title":"Laboratory Investigation"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2613.2008.00581.x"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00520-08"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.LAB.0000080599.43791.01"},{"key":"e_1_2_7_44_1","unstructured":"Pitt M Louise M (U.S. Army Medical Research Institute of Infectious Diseases [USAMRIID] Pathology Division Fort Detrick MD). Dataset \u201cInhalation anthrax in African green monkey\u201d to: Margaret E. Coleman (Coleman Scientific Consulting)."},{"key":"e_1_2_7_45_1","first-page":"416","article-title":"Pathology of experimental respiratory anthrax in Macaca mulatta","volume":"44","author":"Gleiser CA","year":"1963","journal-title":"British Journal of Experimental Pathology"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0022172400039279"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1354\/vp.44-5-716"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.52.4.632"},{"key":"e_1_2_7_49_1","volume-title":"Anthrax in Humans and Animals","author":"World Health Organization","year":"2008"},{"key":"e_1_2_7_50_1","first-page":"6","article-title":"An epidemic of inhalation anthrax: The first in the twentieth century","volume":"72","author":"Brachman PS","year":"1960","journal-title":"American Journal of Hygiene"},{"key":"e_1_2_7_51_1","first-page":"24","article-title":"Bacillus anthracis aerosols in goat hair processing mills","volume":"72","author":"Dahlgren CM","year":"1960","journal-title":"American Journal of Hygiene"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-144-4-200602210-00009"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/88.1.99"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2672.2009.04248.x"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1539-6924.2008.01195.x"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/risa.12122"},{"key":"e_1_2_7_57_1","volume-title":"R Statistical Programming Language","author":"R Core Development Team","year":"2013"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/76.2.297"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0022172400037827"},{"issue":"11","key":"e_1_2_7_60_1","first-page":"982","article-title":"The pathology of experimental anthrax in rabbits exposed by inhalation and subcutaneous inoculation","volume":"122","author":"Zaucha GM","year":"1998","journal-title":"Archives of Pathology and Laboratory Medicine"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2009.01281.x"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2008.04.011"},{"issue":"4","key":"e_1_2_7_63_1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/wsbm.131","article-title":"A multifaceted approach to modeling the immune response in tuberculosis","volume":"3","author":"Marino S","year":"2011","journal-title":"Systems Biology and Medicine"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.3.1951"}],"container-title":["Risk Analysis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Frisa.12688","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/risa.12688","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T10:38:46Z","timestamp":1696156726000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/risa.12688"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,25]]},"references-count":63,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,5]]}},"alternative-id":["10.1111\/risa.12688"],"URL":"https:\/\/doi.org\/10.1111\/risa.12688","archive":["Portico"],"relation":{},"ISSN":["0272-4332","1539-6924"],"issn-type":[{"value":"0272-4332","type":"print"},{"value":"1539-6924","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,25]]}}}