The Toxicity of Soman in the African Green Monkey (Chlorocebus aethiops)

Abstract

This study determines soman toxicity in African green monkeys (Chlorocebus aethiops) and is the first step in exploring the suitability of this species as a model for nerve agent studies. Male African green monkeys were surgically implanted with telemetry devices to monitor electroencephalographic (EEG) and electrocardiographic (ECG) activity. Blood was taken at various times to measure whole blood acetylcholinesterase (AChE) activity and cardiac troponin I (cTnI). Blood AChE activity relative to baseline was 0.0% to 2.5% 6 h after soman exposure and recovered to 31.9% to 72.0% by 30 days after exposure. The 6 h postexposure cTnI levels varied from 0.64 to 6.55 ng/mL, suggesting cardiac damage. Soman was prepared in saline to a concentration of 100 mug/mL. Using an up-down design for small samples, subjects were exposed to 5.01, 6.31, or 7.94 mug/kg soman IM. The first subject was given 5.01 mug/kg soman IM and survived. Three subjects received 6.31 mug/kg soman IM and survived. Three subjects received 7.94 mug/kg soman IM and died within 25 min, 26 min, or 6 h. In all subjects, toxic signs of muscle fasciculation, tremors, chewing, and profuse salivation developed within 2 to 7 min. Tonic-clonic motor convulsions and EEG seizure began between 2 and 18 min after tremor onset. The 48 h IM LD50 of soman in saline in the African green monkey was calculated to be 7.15 mug/kg. The signs and speed of soman intoxication in African green monkeys were consistent with those described in rhesus, cynomolguscynomolgus, and baboons.

Hematological, biochemical, respiratory, cardiovascular and electroneurophysiological parameters in African green monkeys (Cercopithecus aethiops sabaeus). Its use in non‐clinical toxicological studies

“…They are considerably less aggressive than rhesus, and well‐trained personnel can perform repeated blood sampling from superficial veins. Wild‐caught, Caribbean origin, African green monkeys are available from a variety of sources for around 30% of the cost of a rhesus monkey and, most important, they do not carry Cercopithecine herpesvirus 1 [14]. As the number of biotechnology very species‐specific proteins for treating, mainly, immune and cancer diseases is increasing every year and the number of classical non‐human primates as experimental models for pharmacodynamic, pharmacokinetic and toxicological tests is limited, the dilemma related with their use should be also increasing.…”

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

“…Following exposure of different animal species to high doses of nerve agents, a cholinergic crisis develops and is characterized by chewing and gnawing, profuse secretions, diarrhea, muscle fasciculation, restlessness, tremors, motor convulsions, and respiratory distress that can lead to death (Deshpande et al, 1986;Kawabuchi et al, 1989;Albuquerque et al, 2006;Maxwell et al, 2006;Despain et al, 2007). The rank order of lethal potencies (LD 50 ) of the nerve agents is invariably the same among the different species, with the LD 50 increasing from VX to soman to sarin (Bajgar, 1992;Koplovitz and Stewart, 1994;Lenz et al, 2005;Maxwell et al, 2006;Fawcett et al, 2009).…”

“…However, spontaneous recurrent motor convulsions and electrical seizures in addition to neurodegeneration have been observed in rats long after acute seizures following an exposure to nerve agents were terminated by benzodiazepines (de Araujo Furtado et al, 2010). Spontaneous recurrent motor convulsions and/or electrical seizures have also been reported in soman-exposed rats and nonhuman primates long after the acute toxicity of the nerve agent subsided Despain et al, 2007). Therefore, treatment with anticonvulsants, although essential to control the acute tonic-clonic convulsions and improve survivability among animals exposed to high levels of nerve agents, is not sufficient to counter the development of delayed neurologic deficits.…”

An anesthetized rat assay for evaluating the effects of organophosphate-based compounds and countermeasures on intracranial EEG and respiratory rate

“…Acute toxicity from OPs in diverse animal species, including rodents and large mammals, closely mirrors human exposure symptoms. High doses of OPs induce a cholinergic crisis in conscious animals, marked by manifestations such as chewing, gnawing, profuse secretions, diarrhea, muscle fasciculation, restlessness, tremors, convulsions, and fatal respiratory distress [3,[7][8][9][10]. The correlation between LD50s and in vitro acetylcholinesterase (AChE) inhibition in brain extracts underscore AChE inhibition as a critical factor in OP-induced toxicity in animal models [3,8,[11][12][13][14].…”