Studies on Delayed Neurotoxicity Produced by Some Organophosphorus Compounds

Abstract

It has been known for over 30 years (Smith & Elvove, 1930) that tri 2-methylphenylphosphate produces in man and the hen a delayed neurotoxicity characterized by ataxia and weakness of the limbs. For the purposes of this p ' ! y r , we will discuss the clinical condition in hens that appears 8 to I 4 days after dosing and from which there is little or no recovery within 2 months in birds cver 9 months of age. We exclude from this discussion the acute cholinergic response to some compounds and also the condition produced by treatment with dimethyl S-( 1,2-dicarbethoxyethyI) dithiophosphate (malathion: Durham et al., 1956) or tetramethylthio-di-4-phenylene phosphorothioate (abate: Gaines et al., 1966). In contrast to delayed neurotoxicity, this condition is characterized by the appearance of leg weakness immediately after dosing, and there is usually complete recovery within a month. Our intention is to present our view of the present status of the problem and to describe recent experiments to try to elucidate the mechanism of the processes involved. It is not our intention to review the literature describing all the compounds producing this condition in hens: this has been adequatcly dealt with elsewhere (Davies, 1963: Casida et al., 1963: Aldridge & Barnes, I96 I , 1966a, 1967.Large doses (0.5-0.75 g/ kg) of tri-2-methylphenylphosphate are required to produce the condition in all hens. However, in 1953 Barnes and Denz established the fact that di-;so-propylphosphorofluoridate ( D F P ) and bis mono-iso-propylphosphorodiamidic fluoride (Mipafox) produce the same clinical condition and pathology: 1 mg/kg DFP was effective. Since then, there has been a considerable extension in the number of organophosphorus compounds effective in low doses (Davics et al., 1960(Davics et al., , 1966: Aldridge RL Barnes, 1966 a;Malone, 1964). Although it was suspected that tri-2-niethylphenylphosphate must be metabolized in vivo to be active (Aldridge, 1954), this was not conclusively proved until 1961 (Casida ct a ] . , 1961). Various saligenin phosphates are produced; such compounds may be neurotoxic in doses of 1 nig/ kg. For this conversion to take place, an alkyl substituent in the 2-position on one of the aryl rings is required. Tri-4ethylphenylphosphate produces at high doses a similar condition (Bondy ef al., 1960): it is di8icult to envisage a mctabolic conversion similar to that of tri 2methylphenylphosphnte. In fact. we have somc information suggesting that different samples of tri-4-ethylphenylphosphate have different activities. In order to determine whether this difference is catised by an active impurity, we hope shortly to test a specimen prepared from highly purified p-ethylphenol. Lt is clear, therefore, that many organophosphorus compounds can produce delayed neurotoxicity in low doses. It is also clear that many conipocnds are inert ( Bondy rr ul., 1960; Aldridge & Barnes, 196 1 ; Henschler & Bayer, 1958) : for example, 2.5 g/ kg daily for 20 days of tri-2:3-dimethylphenylphosphates is ineffectivc. Tetraethylpyr...

Effect of Acute and Chronic Cholinesterase Inhibition with Diisopropylfluorophosphate on Muscarinic, Dopamine, and GABA Receptors of the Rat Striatum

“…Organophosphates exhibit behavioral, neurological, and biochemical effects in both animals and humans (Holmstedt, 1959; Davis and Richardson, 1980). On long‐term exposure, these compounds are known to induce neurotoxic effects (Aldridge et al, 1969; Johnson, 1975; 1977). Tolerance develops to the behavioral effects of these agents and evidence suggests that this may result from subsensitivity to acetylcholine (ACh) (Russell et al, 1969; 1981).…”

Organophosphorus Chemical Warfare Agents

“…It has also been shown that only that a negligible proportion of soman-inhibited NTE from hen brain and spinal cord undergoes the ageing reaction believed to be an essential preliminary to the development of OPIDP. Additionally, structure-activity considerations would not lead one to expect nerve agents to be neuropathic (Aldridge et al, 1969). Thus, soman demonstrably lacks neuropathic potential.…”

Organophosphates, Affective Disorders and Suicide

“…The phosphate group of the OPs is highly reactive [22] and Schulman has recently reviewed the importance of phosphorylation in neuronal plasticity and gene expression [23]. Active phosphate group donors, therefore, would seem highly likely to have profound deranging influences on these important processes.…”