The Relationship Between the Chemical Structure and Neurotoxicity of Alkyl Organophosphorus Compounds

Abstract

Thirty‐six alkyl organophosphorus compounds have been tested for neurotoxicity in the chicken. The individual compounds were chosen to enable the importance of each portion of the molecule to be assessed in relation to the property of neurotoxicity. Seventeen substances were found to be neurotoxic, fifteen for the first time. All of these contained fluorine. On the basis of the results reported, certain predictions have been made about the chemical structure of compounds which would be expected to be neurotoxic. The importance of fluorine suggests that it plays a direct role in the development of the biochemical lesion, and this may occur as the result of its being carried by the molecule as a whole to specific areas in the nervous system. By the action of cholinesterase, the P‐F bond may be ruptured and ionic fluorine liberated where it blocks some metabolic cycle.

The Chemical Structure of the Lipid A Component of Lipopolysaccharides from Chromobacterium violaceum NCTC 9694

“…We have not studied the type of linkage and the site of attachment of the polysaccharide portion [25] to the lipid A component in Ch. violaceurn lipopolysaccharide.…”

COMPARISON OF THE FUNCTIONAL EFFECTS OF DYFLOS, TRI‐O‐CRESYL PHOSPHATE AND TRI‐p‐ETHYLPHENYL PHOSPHATE IN CHICKENS

“…Up to the present time all the dialkyl phosphorofluoridates (Davies et al, 1960) and all the triaryl phosphates (Hine, Dunlap, Rice, Coursey, Gross & Anderson, 1956) that produce the neurotoxic syndrome are anticholinesterases in vivo, although the converse does not hold.…”

“…Adult hens (1 to 2 years of age), pure strain white leghorns, were used in all experiments. All agents were injected into the breast muscle 10 min after an intramuscular injection of 100 mg/kg of pralidoxime (2-hydroxyiminomethyl-N-methylpyridinium) methanesulphonate and 1 mg/kg atropine sulphate (Davies, Holland & Rumens, 1960).…”

NEUROTOXIC SYNDROME PRODUCED IN CHICKENS BY A CYCLIC PHOSPHATE METABOLITE OF TRI‐o‐CRESYL PHOSPHATE—A CLINICAL AND PATHOLOGICAL STUDY

“…The nature of the biochemical lesion effected by certain organophosphate esters to produce ataxia in chickens is not known. Many organofluoro phosphorus compounds that are potent esterase inhibitors will produce this effect at intramuscular doses as low as 0.25 mg/kg (Davies et al, 1960). The tri-o-cresyl phosphate metabolite is a potent esterase inhibitor and will cause ataxia with intraperitoneal doses of 4 to 8 mg/kg, while certain anti-esterase analogues of this cyclic phosphate are effective below 1 mg/kg (Baron, Casida & Eto, unpublished observations).…”

“…The critical reaction producing ataxia probably occurs within the nerve to yield a phosphorylated esteratic site on some protein with the release of fluoride or a substituted-phenolate ion. Davies et al (1960) have proposed that the ion released produces the lesion. It appears more probable that the damage to nerve fibre results from changes in metabolism initiated by phosphorylation at a critical esteratic site of an as yet undefined protein.…”