DEVELOPMENTAL PHASE ALTERS DOSIMETRY-TERATOGENICITY RELATIONSHIP FOR 2-METHOXYETHANOL IN CD-1 MICE

The industrial solvent 2-methoxyethanol (2-ME) elicits phase-specific terata in mice through its primary metabolite and proximate toxicant, 2-methoxyacetic acid (2 MAA). Recent pharmacokinetic studies indicate that the incidence and severity of digit malformations induced in CD-1 mice by 2-ME exposure on gestation day (gd) 11 (copulation plug = gd 0) correlate better with the total 2-MAA exposure over time (= area un der the curve; AUC) than with its peak concentrations (C(max)) in mate rnal plasma, embryo and extraembryonic fluid. In this study, the phase specificity of exencephaly induction by 2 ME was investigated to asce rtain whether the 2-ME/2-MAA dosimetry-teratogenicity relationship rem ains consistent throughout organogenesis. Following a single intraveno us (iv) bolus dose of 250 mg 2-ME/kg given to pregnant mice, exposure on gd 8 was decidedly the gestation day that best balanced low embryo lethality and high malformation incidence as recorded in near-term fet uses. Concentrations of 2-MAA were measured during distribution and el imination in maternal plasma and conceptuses following iv bolus doses of 175, 250, and 325 mg 2-ME/kg, as well as during and after terminati on of subcutaneous (sc) constant-rate infusions (4, 6, and 8 hr; 8 mul /hr) of 277, 392, and 606 mg 2-ME/kg total doses. For all administrati on regimens, exencephaly incidence rates were determined in fetuses on gd 18. Similar plasma 2-MAA C(max) values (approximately 5 mmol/1) an d fetal malformation frequencies (approximately 12%) were induced by s c infusion of 392 mg 2-ME/kg or a bolus dose of 250 mg 2-ME/kg. Howeve r, the AUC produced by infusion was significantly larger than that fol lowing the iv bolus dose (38 vs. 26 mmol-hr/l, respectively). In both maternal plasma and conceptuses, the correlation coefficients between C(max) and exencephaly rates, as well as developmental toxicity, were higher than they were for AUC and those end points. This outcome sugge sts that dosimetry-teratogenicity determinants may be quite specific f or a distinct developmental phase during which a particular organ diff erentiates and a specific chemical acts upon the embryo. (C) 1994 Wile y-Liss, Inc