The delayed neurotoxicity of phosphorodiamidic fluorides

Davies, D. R.; Holland, P.; Rumens, M. J.

doi:10.1016/0006-2952(66)90085-2

Cited by 21 publications

(3 citation statements)

References 2 publications

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“…This correlates well with the ratio of the reported neurotoxic doses for these two compounds (0.10 and 25mg./kg. respectively; ratio 250; Davies, Holland & Rumens, 1966) and strengthens the association between the value of (B) -(C) and neurotoxicity. Table 4 shows that (B) -(C) measured for normal brain increased continuously as the Butafox concentration was increased from 0-8,UM (equivalent to 128 ItM-Mipafox as used in the standard test) to 51-2UM.…”

Section: Resultsmentioning

confidence: 64%

A phosphorylation site in brain and the delayed neurotoxic effect of some organophosphorus compounds

Johnson

1969

Biochemical Journal

152

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1. It is proposed that part of a neurotoxic dose of di-isopropyl phosphorofluoridate will be covalently bound in vivo to a specific component in the brain and spinal cord as the initial biochemical event in the genesis of the lesion. 2. A test system in vitro was devised that removes many di-isopropyl phosphorofluoridate-binding sites and indicates that the specific component may be a protein present in brain at a concentration comparable with that of the cholinesterases. 3. The site was found to be present and capable of binding di-isopropyl phosphorofluoridate in vitro in brain samples taken from either normal hens or those dosed with organophosphorus esterase inhibitors that are not neurotoxic. 4. Very little of the specific binding activity was found in brain samples from hens pre-dosed with a variety of neurotoxic organophosphorus compounds. 5. A solubilized preparation of the active brain component was obtained, suitable for further purification and study.

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Section: Resultsmentioning

confidence: 64%

A phosphorylation site in brain and the delayed neurotoxic effect of some organophosphorus compounds

Johnson

1969

Biochemical Journal

152

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“…This is an isolated instance. and other compounds, the phosphorofluoridates (Davies et al, 1960(Davies et al, , 1966 or the di-2-chloroethylphosphates (Malone, 1964); Aldridge & Barnes, 1966 a ) do not fit into such a structure-activity relationship. An illustration from recent work of the effect of minor changes in structure is given in FIGURE 2.…”

Section: Specles Affectedmentioning

confidence: 99%

“…1. There is no evidence that a freely soluble ion such as fluoride would have the required activity to account for the high toxicity of N,N'-di-n-butylphosphoroamidic fluoride (0.1 mg/ kg: Davies et al, 1966).…”

Section: Specles Affectedmentioning

confidence: 99%

Studies on Delayed Neurotoxicity Produced by Some Organophosphorus Compounds

Aldridge

Barnes

Johnson

1969

Annals of the New York Academy of Sciences

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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...

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Di‐(N‐Butylamino)Fluorophosphine Oxide 590‐69‐2

2004

Sax's Dangerous Properties of Industrial Materials

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The delayed neurotoxicity of phosphorodiamidic fluorides

Cited by 21 publications

References 2 publications

A phosphorylation site in brain and the delayed neurotoxic effect of some organophosphorus compounds

A phosphorylation site in brain and the delayed neurotoxic effect of some organophosphorus compounds

Studies on Delayed Neurotoxicity Produced by Some Organophosphorus Compounds

Di‐(N‐Butylamino)Fluorophosphine Oxide 590‐69‐2

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