DEVELOPMENTAL TOXICITY OF CARBOXYLIC-ACIDS TO XENOPUS EMBRYOS - A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP AND COMPUTER-AUTOMATED STRUCTURE EVALUATION

The developmental toxicity for each of 45 carboxylic acids was determi ned for Xenopus embryos. Acids tested included 12 unbranched, saturate d aliphatics, 12 branched, saturated aliphatics, 12 unsaturated alipha tics, and 9 aromatics. Embryos were collected following hormone-induce d breeding and exposed to at least eight concentrations of the acid, a long with a control. For each concentration, 25 properly developing em bryos were exposed to the acid solution for 96 h. Each acid was tested on at least three separate occasions and the data were pooled to calc ulate 96-h LC50 (lethality), 96-h EC50 (malformation), and DHI (develo pmental hazard index = 96-h LC50/96-h EC50) values. The endpoint data were subjected to quantitative structure-activity relationship (QSAR) analyses and computer-automated structure evaluation (CASE). Variation in acid-induced lethality was effectively explained by partitioning a nd ionizability of the acids, while partitioning alone was somewhat ef fective in explaining variation for acid-induced malformation. The res ults indicated that developmental hazard of the acids to Xenopus embry os is primarily dependent on carbon-chain length, with acids containin g five carbon atoms in the chain tending to be the most potent. Unsatu ration reduced the hazard in comparison with the corresponding unbranc hed saturated acid. Developmental hazard was highest for 2-position br anched compounds with a 5- or 6-C chain, but was reduced for 2-positio n branched acids with a 3- or 4-C chain. Hazard of the non-2-position branched acids was variable. Valproic (2-propylpentanoic) acid showed the highest developmental hazard with Xenopus, twice that of any other acid tested. (C) 1996 Wiley-Liss, Inc.