Formate-induced alterations in retinal function in methanol-intoxicated rats.
Formic acid is the toxic metabolite in methanol poisoning. Permanent visual damage in methanol-intoxicated humans and non-human primates has been associated with prolonged exposures (> 24 hr) to blood formate concentrations in excess of 7 mM; however, little information is available on the toxicity associated with chronic low-level or repeated exposure to methanol. The present studies compared the effects on retinal function and structure of rapidly increasing formate concentrations typical of acute methanol intoxication with low-level plateau formate concentrations more likely to be generated by subacute or chronic methanol exposure. Rats that accumulated formate concentrations of 8-15 mM developed metabolic acidosis, retinal dysfunction, and retinal histopathologic changes. Retinal dysfunction was measured as reductions in the a- and b-waves of the electroretinogram that occurred coincident with blood formate accumulation. Histopathologic studies revealed vacuolation in the retinal pigment epithelium and photoreceptor inner segments. Rats exposed to formate concentrations ranging from 4 to 6 mM for 48 hr showed evidence of retinal dysfunction in the absence of metabolic acidosis and retinal histopathology. These data indicate that formic acid generated from methanol oxidation acts as a direct retinal toxin. Formate-induced retinal dysfunction in methanol-intoxicated rats can be produced by steadily increasing concentrations of formate and importantly can also be produced by prolonged exposure to lower concentrations of formate. Our findings substantiate evidence based on clinical case reports and a small number of epidemiological studies and support the hypothesis that the visual system toxicity produced by acute, subacute, or chronic methanol poisoning share a common mechanism.
Eells
J T
JT
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Salzman
M M
MM
Lewandowski
M F
MF
Murray
T G
TG
D000818:Animals; D001639:Bicarbonates / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005561:Formates / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D000432:Methanol / Q000378:metabolism / Q000506:poisoning*; D051381:Rats; D012160:Retina / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D014018:Tissue Distribution
D001639:Bicarbonates; D005561:Formates; C030544:formic acid; D000432:Methanol