Toxicological Sciences, Vol 50, 117-126, Copyright © 1999 by Society of Toxicology
EW Carney, NL Freshour, DA Dittenber and MD Dryzga
This study sought to determine the relative roles of glycolic acid (GA), a
toxicologically important metabolite of ethylene glycol (EG), and metabolic
acidosis in causing developmental toxicity in Sprague- Dawley rats. To
tease apart these two interrelated factors, we developed an experimental
approach in which high blood glycolate levels could be achieved, in either
the presence or absence of metabolic acidosis. Initially, rats previously
implanted with a carotid artery cannula were given, on gestation day (gd)
10, 40.3 mmol/kg (2500 mg/kg) of EG via gavage, 8.5 mmol/kg (650 mg/kg) of
GA via gavage, 8.5 mmol/kg (833 mg/kg) of sodium glycolate (NaG; pH 7.4)
via subcutaneous (sc) injection, or distilled water via gavage (control).
Peak serum glycolate was nearly identical (8.4-8.8 mM) in the EG, GA, and
NaG groups and, as expected, EG and GA caused a metabolic acidosis, but
acid base balance was normal with NaG. Subsequently, these treatments were
given on gd 6-15 to groups of 25 time-mated rats, followed by fetal
evaluation on gd 21. EG and GA decreased fetal body weights and caused a
similar spectrum of developmental effects, including numerous axial
skeleton malformations. NaG treatment also caused slight decreases in fetal
body weight, increases in skeletal variations, and totally malformed
fetuses. These results indicate that glycolate, in the absence of metabolic
acidosis, can cause the most sensitive of EG's developmental effects,
whereas metabolic acidosis appears to interact with glycolate at very high
doses to markedly enhance teratogenesis. These results support previous
studies, which indicated that glycolate is the proximate developmental
toxicant for EG, and that GA toxicokinetic parameters can be used to define
a quantitative, physiologically based threshold for EG-induced
developmental effects.
ARTICLES
Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis
Health and Environmental Research Laboratories, The Dow Chemical Company, Midland, Michigan 48674, USA.
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