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EXPOSURE-DISEASE CONTINUUM FOR 2-CHLORO-2'-DEOXYADENOSINE (2CDA), A PROTOTYPE OCULAR TERATOGEN. 1. DOSE-RESPONSE ANALYSIS
Citation:
Wubah, J., R W. Setzer, AND P. knudsen. EXPOSURE-DISEASE CONTINUUM FOR 2-CHLORO-2'-DEOXYADENOSINE (2CDA), A PROTOTYPE OCULAR TERATOGEN. 1. DOSE-RESPONSE ANALYSIS. TERATOLOGY 64:154-169, (2001).
Description:
Treatment of pregnant mice with 2-chloro-2'-deoxyadenosine (2CdA) on day 8 of gestation induces coloboma, microphthalmia and anophthalmia through a mechanism coupled to the effects of the p53 tumor suppressor gene (Wubah et al.'96). The present study defines the dosimetry for 2CdA with respect to exposure (pharmacokinetics) and disease (micro-/anophthalmia). Pregnant CD-1 mice dosed with 0.5- to 10.0 mg/kg 2CdA on day 8 of gestation provided fetuses for teratological evaluation. Microphthalmia appeared first in the dose response curve and the lowest 2CdA dosage having no observable adverse effect on the quantal (litter) and continuous (individual) parameters was 1.5 mg/kg. The upper asymptote, 11.8 mg/kg 2CdA, modeled for complete penetrance of micro-/anophthalmia, was fully embryolethal. The benchmark dose that produced an extra 5% risk for microphthalmia (BMD5), 2.5 mg/kg, was well below the embryolethal range. Pharmacokinetic analysis revealed Cmax within 15 min of intraperitoneal injection and clearance of 2CdA below the detection limits within 180 min post-injection. The Cmax and total integrated exposure (AUC) for the antimesometrium was modeled at 2.0 ?M and 68.8 ?M-min, respectively, for the developmental NOAEL (1.5 mg/kg), and 4.5 ?M and 154.8 ?M-min, respectively for the BMD5 (2.5 mg/kg). Because p53 is an important biological factor in 2CdA-induced microphthalmia, the systematic analysis of this exposure-disease relationship provides a framework to build an embryo-based modeling core for low dose extrapolation of the adverse developmental effects of environmental agents.