Animal model for the study of methanol toxicity: Comparison of folate‐reduced rat responses with published monkey data

Abstract

We attempted to develop a rodent model that exhibits characteristics of human methanol toxicities such as acidosis and visual dysfunction, which are correlated with an accumulation of formate, a toxic metabolite of methanol. Initially three groups of Long-Evans rats with different levels of liver folate were prepared and examined for formate accumulation after methanol administration (3.5 g/kg). The folate-reduced (FR) rats prepared by feeding a folate-deficient diet with 1% succinylsulfathiazole yielded blood formate levels equivalent to those found in methanol-intoxicated humans and developed signs of the visual system toxicity (a manuscript on the latter aspect is in preparation). Responses of FR rats to a variety of methanol exposure scenarios were then investigated, and the results were compared with those reported in the literature for monkeys. Formate accumulation and/or lethality were used as toxic parameters for this comparative evaluation. In FR rats dosed orally with 3 g/kg, the blood formate concentration was 9.2 mmol/L at 24 h postadministration and increased to 15.6 mmol/L at 48 h. The same dose given to monkeys yielded a plateau of 7.4 mmol/L at 12 h after methanol administration, and stayed at this level for an additional 12 h. The area under the concentration vs. time curve for blood formate in FR rats was 2.5-fold greater than that in monkeys when 2.0 g/kg methanol was administered. After a 6-h exposure to 1200 ppm and 2000 ppm methanol, the blood formate concentrations in FR rats were increased by 370% and 636% above the endogenous level, respectively. However, blood formate did not accumulate above the endogenous level when monkeys were exposed to methanol up to 2000 ppm for 6 h. Under acute inhalation exposure conditions, FR rats exposed to 3000 ppm methanol, 20 h/d, could not survive more than 4 d. On the other hand, monkeys exposed to 3000 ppm, 21 h/d, out-lived 20 d. Moreover, monkeys survived for more than 4 d even after an exposure to 10,000 ppm. Thus, these results indicate that FR rats are more sensitive to methanol challenges than monkeys, and suggest that the FR rat could be a congruous animal model for evaluating the health effects of methanol in humans.

Absorption and Elimination of Formate Following Oral Administration of Calcium Formate in Female Human Subjects

“…In rats, folate deficiency or selective reduction of tetrahydrofolate results in formic acidemia and metabolic acidosis following methanol administration, whereas no accumulation of formate or alteration in blood pH or bicarbonate is observed in control rats (Palese and Tephly, 1975;Eells et al, 1981Eells et al, , 1982Makar and Tephly, 1982;Black et al, 1985;Johlin et al, 1987). Recent studies have also demonstrated ocular toxicity in folate-deficient monkeys (Lee et al, 1994) and tetrahydrofolate-deficient rats (Eells et al, 1996(Eells et al, , 2000Seme et al, 1999). In monkeys, folate deficiency or selective reduction of tetrahydrofolate increases formate accumulation and potentiates methanol toxicity, whereas treatment with folate derivatives decreases formate accumulation and can prevent or reverse the development of the methanol poisoning syndrome (Noker et al, 1980;Eells et al, 1983).…”

Medical toxicology and public health—Update on research and activities at the centers for disease control and prevention, and the agency for toxic substances and disease registry

“…Animal studies have shown that rodents have higher tetrahydrofolate concentrations in their liver, thus are more resistant to methanol poisoning. This protection was lost when the rodents were made to be folic acid-deficient [54][55]. On the basis of this data, folinic acid or folic acid is sometimes recommended as a supplemental treatment.…”

FASD: folic acid and formic acid — an unholy alliance in the alcohol abusing mother

“…Thus, significantly higher formate levels are achieved when the folatedeficient animals are exposed to MeOH (McMartin et al 1975;Noker et al 1980;Dorman et al 1994;Lee et al 1994). Tephly has suggested that people with inadequate folate metabolism would be prone to the MeOH toxicity, because they would have difficulty metabolizing one-carbon units (Tephly 1991).…”

“…Indeed, to prevent metabolic acidosis in MeOH poisonings, folic acid is currently part of standard of care to drive formic acid oxidation into carbon dioxide and water. It has been demonstrated that significantly higher formate levels are produced when folate-deficient animals are exposed to MeOH, as compared with folate-sufficient animals (McMartin et al 1975;Noker et al 1980;Lee et al 1994). Sokoro and colleagues determined that the half-life of formic acid was 40 min in folate-sufficient minipigs compared with 120 min in folate-deficient minipigs (Sokoro et al 2008).…”