US EPA

31005 

Journal Article 

Abstract 

A pilot developmental toxicity study of methanol in folate-deficient Long-Evans rats 

Ryan, BM; Hatoum, NS; Mallett, EJ; Yermakoff, JK 

1994 

1 

Teratology
ISSN: 0040-3709
EISSN: 1096-9926 

49 

5 

399 

English 

BCI:BCI199497385776 

Methanol (MeOH) burns cleaner than gasoline and is being considered as an alternative fuel. While the acute toxicity of MeOH is well known, its potential developmental toxicity is not. Previously reported developmental toxicity studies have been conducted in traditional rodents models; in these studies the dams have been relatively resistant to MeOH toxicity. Other biologically relevant models have yet to be evaluated. Therefore, a pilot study was conducted to assess the utility of the folic acid-deficient rat model, a model which would be sensitive to MeOH and potentially reflective of human risk/response. Long-Evans female rats were rendered folate-deficient by supplying a folate-deficient diet augmented with 1% succinylsulfathiazole for a period of 16 weeks prior to mating. MeOH was administered in drinking water on gestation days 6 through 15 at concentrations of 0.5, 1.0 and 2.0% to three groups of 7 to 9 sperm-positive Long-Evans rats. Resulting MeOH blood levels averaged 0.21, 0.26 and 0.67 mg/mL, respectively. Equal sized folate-deficient sham and basal diet control groups were concurrently evaluated. MeOH administration induced a dose-dependent increase in the incidence of maternal and developmental effects over a consistent background of a folate deficiency-induced fetal growth retardation. Frank maternal and developmental toxicity was observed in the 1 and 2% MeOH-treated groups. Minimal body weight change in the 0.5% group was also suggestive of maternal toxicity. The number of live fetuses was significantly reduced in the 2% group, and fetal resorptions/deaths were significantly increased in both the 1 and 2% groups. Visceral anomalies were similar for all groups. Except for single observations of unilateral anophthalmia in the 0.5 and 1% groups, cephalic exams were unremarkable. Skeletal malformations and anomalies were increased in fetuses of the 1 and 2% MeOH-treated dams, and the incidence in the 0.5% group was also suggestive of developmental toxicity. These findings suggest a maternal and developmental NOEL of less than 0.5% or 0.21 mg/mL MeOH blood level compared to that of 2 mg/mL or greater reported in a non-folate-deficient model. Finally, these data demonstrate the utility of the folate-deficient rat model in the evaluation of MeOH developmental toxicity.