Structure-activity relationships in the acute and delayed neurotoxicity of methyl- and ethylphosphonothionates

Robert L. Metcalf, B. Magnus Francis, Robert A. Metcalf, Miranda Farage-Elawar, Larry G. Hansen

Research output: Contribution to journalArticlepeer-review

Abstract

Data on acute toxicity to house flies and mice, and delayed neurotoxicity to hens, are presented for 24 O-alkyl O-halogenated phenyl alkyl and aryl phosphonothionates, providing comparisons of the three sets of major structural parameters involved in the toxic action of these compounds. In the house fly, topical LD50 values showed consistent similarities between phenyl- and methylphosphonothionates with comparable O-alkyl and O-phenyl substitution. The phenyl compounds were consistently less toxic than the methyl compounds and the ratio of LD50 values averaged 3.8. In both series of compounds the LD50 values decreased with increasing halogenation as predicted by summed σ values for the substituents. The degree of steric hinderance on reactivity of the central phosphorus atom was particularly significant in comparisons of phenyl- and methylphosphonothionates. Thus in the methyl series there was only a 4-fold decrease in the LD50 with increase in the size of the O-alkyl group from Me to Et to Pr but with the more bulky phenyl series, this range of increase in the size of the O-alkyl group resulted in a greater than 10-fold decrease in LD50. Similarly, in comparing the effects of 2,6-dichloro with 2,5-dichloro substitution of the O-phenyl group, the two ortho-substituents decreased the LD50 value 3-fold with the methylphosphonothionates and 12-fold with the phenylphosphonothionates. The acute mammalian toxicity of organophosphorus esters is less closely linked to structural parameters, and several compounds were less toxic (respectively more toxic) to mice than structural considerations predict. In hens, organophosphorus ester-induced delayed neurotoxicity (OPIDN) was induced by all methylphosphonothionates tested; the 2,5-Cl2 and 2,6-Cl2 compounds were the most effective delayed neurotoxicants. For p-halogenated analogs, the identity of the halogen was less important for methyl- than for phenylphosphonothionates. And, in marked contrast to the phenylphosphonothionates, there was no appreciable difference between the OPIDN potential of O-methyl and O-ethyl methylphosphonothionates. For leptophos and its methylphosphonothionate analog, inhibition of neurotoxic target enzyme (NTE) corresponded with observed symtomatology. When hens were treated with equimolar doses of the two compounds, NTE inhibition reached 80% at 24 hr, but recovery was more rapid in the leptophos-treated hens, which did not become paralyzed, than in the O-2,5-dichloro-4-bromophenyl O-methyl methylphosphonothionate, which progressed to paraplegia.

Original languageEnglish (US)
Pages (from-to)46-56
Number of pages11
JournalPesticide Biochemistry and Physiology
Volume30
Issue number1
DOIs
StatePublished - Jan 1988

ASJC Scopus subject areas

  • Agronomy and Crop Science
  • Health, Toxicology and Mutagenesis

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