Animal models that best reproduce the clinical manifestations of human intoxication with organophosphorus compounds.

The Journal of pharmacology and experimental therapeutics

PubMedID: 24907067

Pereira EF, Aracava Y, DeTolla LJ, Beecham EJ, Basinger GW, Wakayama EJ, Albuquerque E. Animal models that best reproduce the clinical manifestations of human intoxication with organophosphorus compounds. J Pharmacol Exp Ther. 2014;.
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: (i) 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, (ii) to identify animal models of the clinical manifestations of human exposure to OPs, and (iii) to review the mechanisms that contribute to the immediate and delayed OP neurotoxicity. As discussed here, clinical manifestations of an acute exposure of humans to OP compounds can be faithfully reproduced in rodents and non-human primates. These manifestations include an acute cholinergic crisis in addition to signs of neurotoxicity that develop long after the OP exposure, particularly chronic neurological deficits consisting of anxiety-related behavior and cognitive deficits, structural brain damage, and increased slow electroencephalographic frequencies. Because guinea pigs and non-human 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 pathological conditions that cannot be ethically or feasibly tested in humans.