2-Methoxyacetic acid dosimetry-teratogenicity relationships in CD-1 mice exposed to 2-methoxyethanol.
The teratogen 2-methoxyethanol (2-ME), an industrial solvent, was administered to pregnant CD-1 mice either as a single subcutaneous (sc) bolus dose (100-250 mg/kg) or via constant-rate infusion from sc implanted osmotic minipumps (34.7 or 69.4 mg/kg/hr for up to 12 hr) on gestation Day 11, when embryonic paw development is maximally sensitive to perturbation by this agent. The sc entry route most closely reflects likely human exposures via dermal penetration, while bolus and constant-rate infusion administrations were contrasted to mimic potential occupational exposure scenarios. The pharmacokinetic profiles of 2-methoxyacetic acid (2-MAA), the proximate toxic metabolite of 2-ME, were quantitated, generating peak concentration (Cmax) and total 2-MAA exposure values (24-hr area under the concentration-time curve; AUC) in the maternal plasma, extraembryonic fluid, and embryo. The total 2-ME dose (mg/kg) required to achieve similar 2-MAA levels (Cmax or AUC) in these compartments was 2- to 3-fold higher by constant-rate infusion than by bolus injection; therefore, no simple association existed between 2-MAA levels and the total 2-ME dose, when the dose rate was not considered. Similarly, there was no good correlation between the combined total 2-ME doses and the fetal malformation rate, although clear dose-response patterns for paw malformations were observed in litters and fetuses for each individual dosing regimen. However, the combined 2-MAA pharmacokinetic data from each of the dosing regimens demonstrated that during the phase of maximum susceptibility of paw morphogenesis to disruption by 2-MAA (from gd 11 to gd 11.5), a strong linear correlation existed between fetal malformation incidence and 2-MAA AUC levels in either maternal plasma or embryonic compartments (linear correlation coefficient, r2 0.91-0.92). The correlation with Cmax was less favorable (r2 0.74-0.81) over the dose range studied. In a further experiment designed to investigate the importance of AUC vs Cmax regarding 2-ME teratogenicity, infusion of 2-ME (34.7 mg/kg/hr for 8 hr) beginning 2.5 hr after bolus loading (175 mg/kg) provided an increased 24-hr 2-MAA AUC without increased Cmax. This resulted in greater than 70% of the fetuses having various digit malformations (micro-, syn-, ectro-, and polydactyly), compared to only 32-35% of fetuses with mostly stunted digits when either dose was applied singularly. These data support total 2-MAA exposure (AUC levels), rather than peak 2-MAA concentrations, as the principle determinant of teratogenesis following exposure to 2-ME.(ABSTRACT TRUNCATED AT 400 WORDS)
Clarke
D O
DO
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Duignan
J M
JM
Welsch
F
F
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000015:Abnormalities, Multiple / Q000139:chemically induced*; D000085:Acetates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains
D000085:Acetates; D005026:Ethylene Glycols; C005219:methyl cellosolve; C013598:methoxyacetic acid