DEVELOPMENTAL TOXICITY OF CARBOXYLIC-ACIDS TO XENOPUS EMBRYOS - A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP AND COMPUTER-AUTOMATED STRUCTURE EVALUATION
Da. Dawson et al., DEVELOPMENTAL TOXICITY OF CARBOXYLIC-ACIDS TO XENOPUS EMBRYOS - A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP AND COMPUTER-AUTOMATED STRUCTURE EVALUATION, Teratogenesis, carcinogenesis, and mutagenesis, 16(2), 1996, pp. 109-124
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.