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.

Repeated exposure to chlorpyrifos leads to prolonged impairments of axonal transport in the living rodent brain

“…The toxic ''cholinergic crisis'' associated with acute poisoning with OPs and the associated variety of long term neurologic and neurobehavioral consequences have been studied extensively and are primarily attributed to the inhibition of acetylcholinesterase (AChE) (Ecobichon, 2001, for review see also Pereira et al, 2014), However, there is also significant evidence in the human epidemiological literature (e.g., Ross et al, 2013) that OP exposures not associated with acute toxicity may also result in prolonged neurological and neurobehavioral deficits including impairments of cognition. Moreover, as an etiological mechanism, AChE A B S T R A C T The toxicity of the class of chemicals known as the organophosphates (OP) is most commonly attributed to the inhibition of the enzyme acetylcholinesterase.…”

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

“…A variety of longterm neurologic consequences of acute poisonings with OPs have also been documented and include electroencephalogram abnormalities, mood disorders (e.g., anxiety and depression), deficits in psychomotor speed and coordination, and a variety of cognitive deficits (Brown and Brix, 1998;Miyaki et al, 2005;Pereira et al, 2014). A number of epidemiologic studies also suggest that exposures to OPs at levels not associated with acute symptoms of toxicity can result in long-term neurobehavioral abnormalities, especially cognitive abnormalities (e.g., deficits in attention, working memory, executive function, visuospatial ability and visual memory [Pope et al, 2005;Ross et al, 2013]).…”

“…The mechanism of the acute toxicity of OPs is well established and attributed to the irreversible inhibition of acetylcholinesterase (AChE), which leads to elevations of synaptic acetylcholine and a variety of peripheral, autonomic, and central nervous system symptoms such as muscle weakness and fasciculations, vomiting, and seizures, collectively described as the "cholinergic crisis," which can be life threatening (Ecobichon, 2001;Pereira et al, 2014). A variety of longterm neurologic consequences of acute poisonings with OPs have also been documented and include electroencephalogram abnormalities, mood disorders (e.g., anxiety and depression), deficits in psychomotor speed and coordination, and a variety of cognitive deficits (Brown and Brix, 1998;Miyaki et al, 2005;Pereira et al, 2014).…”

Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population

“…Death may ensue due to the peripheral cholinergic crisis that follows acetylcholinesterase inhibition, and/or the prolonged seizures and status epilepticus (SE) which are initiated by excessive accumulation of acetylcholine in neuronal synapses in the brain, and overstimulation of cholinergic receptors. If death is prevented by pharmacological intervention, brain damage may still occur, primarily caused by the SE (Shih et al, 2003;Prager et al, 2013), but also via mechanisms independent of seizures (Yokoyama, 2007;Pereira et al, 2014). The neurological, cognitive, and/or emotional deficits that follow nerve agent-induced brain damage are longlasting, as we know from animal studies (Aroniadou-Anderjaska et al, 2016), but also from studies in humans, after the terrorist attacks in Matsumoto, in 1994, and Tokyo, in 1995(Murata et al, 1997Sekijima et al, 1997;Ohtani et al, 2004;Yanagisawa et al, 2006).…”