Absence of neurovisual effects due to tissue and blood cholinesterase depression in a chronic disulfoton feeding study in dogs.
Technical grade disulfoton (DiSyston) was fed to Beagle dogs (four animals per sex and treatment level) at nominal concentrations of 0, 0.5, 4 and 12 ppm for 1 year. The purpose of this study was to characterize the potential general and neurovisual toxicity according to routine Environmental Protection Agency (EPA) guideline requirements, and by use of ancillary ocular and neurologic tests established in this Laboratory. Ophthalmological tests included: ocular tissue cholinesterase and histopathology, electroretinography (ERG), tracking, refractivity, intraocular pressure and pachymetry (corneal thickness) measurements. Neurological examinations included; peripheral and cranial reflex tests, task performance tests, gait and behavioral observations, and rectal temperature measurements. Plasma, erythrocyte and corneal cholinesterase were significantly depressed at 4 and 12 ppm in both sexes. Brain cholinesterase was depressed at 4 and 12 ppm in females. Retinal cholinesterase was depressed at 4 ppm in females and at 12 ppm in males. Ciliary body cholinesterase was depressed at 12 ppm in both sexes. Despite these cholinergic effects, there were no ophthalmologic findings in measurements of ERG, tracking, refractivity, intraocular pressure or pachymetry. There were no clinical neurology findings related to compound administration. We conclude that 0.5 ppm was a no-observable effect level (NOEL), and effects were limited to cholinesterase changes that had no detectable physiologic impact. This study demonstrates that special mechanistic investigations incorporated within guideline studies, enhances scientific integrity and can minimize the need for dedicated organ system studies.
Jones
R D
RD
Toxicology Department, Bayer Corporation, Stilwell, KS 66085, USA. randy.jones.b@bayer.com
Hastings
T F
TF
Landes
A M
AM
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004222:Disulfoton / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D005123:Eye / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D008297:Male
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D004222:Disulfoton