Biomedical Engineering Reference
In-Depth Information
maternal metabolism to elicit developmental toxicity and suggest that
the greater sensitivity of the mouse to the developmental toxicity of
methanol is at least in part due to an intrinsic difference in embryonal
sensitivity. However, they do not address the question of whether the
embryo itself might metabolize sufficient amounts of methanol to toxic
metabolites.
Adult human acute toxicity of methanol has been ascribed to
accumulation of the metabolite formate. The study of formate devel-
opmental toxicity in intact rodents is precluded because of rapid
metabolic elimination, but it has been tested in rodent embryos in
culture. Andrews et al. (1993b) cultured presomite rat embryos for
48 hours in serum containing concentrations of Na
þ
-formate ranging
from 0 to 1.6mg/ml. The starting pH of the culture medium was 8.13
and was not affected by the addition of Na
þ
-formate. Since metabolism
of methanol to formate in vivo would produce a metabolic acidosis, the
effects of lowering pH in addition to formate exposure were tested. At
pH 8.13, embryo development and growth was affected by Na
þ
-formate
only at the highest concentration, 1.6mg/ml (23.5mM formate). How-
ever, decreasing media pH by the addition of HCl exacerbated the effect
of formate, such that at pH 6.5 most developmental parameters were
affected at 0.8mg Na
þ
-formate/ml culture medium (11.8mM formate).
Confirming the results of Andrews et al. (1993b), Brown-Woodman
et al. (1995) reported that concentrations at or above 18.66mM formic
acid or Na
þ
-formate were developmentally toxic to rat embryos in vitro,
but that Na
þ
-formate was less toxic due to the exacerbating effect of low
pH in formic acid-treated cultures. The developmental toxicities of
Na
þ
-formate and formic acid were subsequently compared in mouse
and rat embryos (Andrews et al., 1995). Rat and mouse embryos
exposed to either agent for 24 hours exhibited concentration-dependent
reductions in growth and development and increased incidences of
malformed embryos. In contrast to results of previous studies with
methanol, no difference in species sensitivity to Na
þ
-formate or formic
acid was observed. Various developmental parameters were adversely
affected at concentrations of 11.8mM and above for both forms of this
metabolite. The concentrations of formate found to be toxic to rat or
mouse embryos growing in vitro are relevant to human risk assessment,
