FORMATE-INDUCED ALTERATIONS IN RETINAL FUNCTION IN METHANOL-INTOXICATED RATS

Formic acid is the toxic metabolite in methanol poisoning. Permanent v isual damage in methanol-intoxicated humans and non-human primates has been associated with prolonged exposures (>24 hr) to blood formate co ncentrations in excess of 7 mM; however, little information is availab le on the toxicity associated with chronic low-level or repeated expos ure to methanol. The present studies compared the effects on retinal f unction and structure of rapidly increasing formate concentrations typ ical of acute methanol intoxication with low-level plateau formate con centrations more likely to be generated by subacute or chronic methano l exposure. Rats that accumulated formate concentrations of 8-15 mM de veloped metabolic acidosis, retinal dysfunction, and retinal histopath ologic 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 vacuolati on 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 a cid generated from methanol oxidation acts as a direct retinal toxin. Formate-induced retinal dysfunction in methanol-intoxicated rats can b e produced by steadily increasing concentrations of formate and import antly can also be produced by prolonged exposure to lower concentratio ns of formate. Our findings substantiate evidence based on clinical ca se reports and a small number of epidemiological studies and support t he hypothesis that the visual system toxicity produced by acute, subac ute, or chronic methanol poisoning share a common mechanism. (C) 1996 Academic Press, Inc.