QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE DEVELOPMENTAL TOXICITY OF HALOACETIC ACIDS IN MAMMALIAN WHOLE-EMBRYO CULTURE

Developmental toxicity in mouse whole embryo culture assay has been re ported for acetic acid (AA) and a series of ten haloacetic acids, incl uding mono-, di-, tri-fluoro (MFA, DFA, TFA), chloro (MCA, DCA, TCA), bromo [MBA, DBA, TEA), and monoiodo (MIA) acetic acids. Benchmark conc entrations (BCm), calculated as the lower 95% confidence limit of mola r acid concentration producing a 5% increase in embryos with neural tu be defects, provided potency estimates for development of quantitative structure-activity relationships (QSARs). The best overall regression was obtained for the ten halo-acids (excluding AA] and related log(1/ BCm) to the energy of the lowest unoccupied molecular orbital (E(Iumo) ) and acid dissociation constant (pKa) with a correlation coefficient of r = 0.97, and a sample size-adjusted r(2) = 0.92. This QSAR suggest ed a common basis for the mechanism of HA activity, which would imply additivity for mixtures of these acids. Examination of QSARs for subse ts of the total data set (e.g., monohaloacids) highlighted parameter r elationships embedded in the total QSAR, helping to unravel the separa te contributions of E(Iumo) and pKa to the overall potency. The releva nce of these parameters is discussed in terms of postulated mechanisms of developmental toxicity involving changes in intercellular pH and r edox metabolism. The whole embryo assay results pertain to direct embr yo exposure and toxicity without the confounding influence of maternal factors. The resulting QSAR model offers possible insight into the me chanism of embryo toxicity that will hopefully contribute to understan ding of the more complex, in vivo teratogenicity problem. (C) 1996 Wil ey-Liss, Inc.