Paul R. Graham

Evaluation of delayed neurotoxicity and dose-response relationships of phosphate esters in the adult hen.

Abstract An oral multipledose technique in hens was developed to determine the neurotoxic potential of a series of triaryl-, trialkyl-, and alkyl-aryl phosphates. This potential was estimated by observation of abnormal behavioral signs and always verified by histological examination. This procedure permits dose titration of an active material to quantify dose-response relationships. Initial evaluation of a series of phosphates for neurotoxicity yielded three active materials: tricresyl phosphate, cresyl diphenyl phosphate, and o-isopropylphenyl diphenyl phosphate. Subsequent experiments demonstrated that their neurotoxic potential differed markedly. The following conclusions regarding structure-activity relationships may be drawn from this study: (1) Phosphates prepared from o-alkyl-substituted phenols frequently are neurotoxic; however, the o-alkyl group must contain at least one hydrogen atom on the α-carbon for activation. (2) The neurotoxic potency of active o-alkyl-substituted phosphates declines with increased mass and branching of the o-substituent. (3) Neurotoxicity is reduced by further substitution in the ring already containing an o-substituent. (4) A series of unsymmetrical phosphates containing an alkyl group in the p-position of one ring are not neurotoxic even though they contain hydrogen atoms on the α-carbon. (5) p-Tertiary-butylphenyl diphenyl phosphate, with no hydrogen on the α-carbon available for activation, does not produced delayed neurotoxicity.