title: Animal models that best reproduce the clinical manifestations of human intoxication with organophosphorus compounds.
abstract: The translational capacity of data generated in preclinical toxicological studies is contingent upon several factors, including the appropriateness of the animal model. The primary objectives of this article are: 1) to analyze the natural history of acute and delayed signs and symptoms that develop following an acute exposure of humans to organophosphorus (OP) compounds, with an emphasis on nerve agents; 2) to identify animal models of the clinical manifestations of human exposure to OPs; and 3) to review the mechanisms that contribute to the immediate and delayed OP neurotoxicity. As discussed in this study, clinical manifestations of an acute exposure of humans to OP compounds can be faithfully reproduced in rodents and nonhuman primates. These manifestations include an acute cholinergic crisis in addition to signs of neurotoxicity that develop long after the OP exposure, particularly chronic neurologic deficits consisting of anxiety-related behavior and cognitive deficits, structural brain damage, and increased slow electroencephalographic frequencies. Because guinea pigs and nonhuman primates, like humans, have low levels of circulating carboxylesterases-the enzymes that metabolize and inactivate OP compounds-they stand out as appropriate animal models for studies of OP intoxication. These are critical points for the development of safe and effective therapeutic interventions against OP poisoning because approval of such therapies by the Food and Drug Administration is likely to rely on the Animal Efficacy Rule, which allows exclusive use of animal data as evidence of the effectiveness of a drug against pathologic conditions that cannot be ethically or feasibly tested in humans.
authors.affiliation: Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.).
authors.forename: Edna F R
authors.initials: EF
authors.lastname: Pereira
authors.affiliation: Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.).
authors.forename: Yasco
authors.initials: Y
authors.lastname: Aracava
authors.affiliation: Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.).
authors.forename: Louis J
authors.initials: LJ
authors.lastname: DeTolla
authors.affiliation: Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.).
authors.forename: E Jeffrey
authors.initials: EJ
authors.lastname: Beecham
authors.affiliation: Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.).
authors.forename: G William
authors.initials: GW
authors.lastname: Basinger
authors.affiliation: Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.).
authors.forename: Edgar J
authors.initials: EJ
authors.lastname: Wakayama
authors.affiliation: Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.) ealbuquerque@som.umaryland.edu.
authors.forename: Edson X
authors.initials: EX
authors.lastname: Albuquerque
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced; D004569:Electroencephalography / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D007928:Lethal Dose 50; D018782:Maze Learning / Q000187:drug effects; D023421:Models, Animal; D062025:Organophosphate Poisoning / Q000150:complications*; D009943:Organophosphorus Compounds / Q000633:toxicity
chemical_list: D009943:Organophosphorus Compounds