No abstract

The estrogenic activity of biphenyl and 4-hydroxylated derivatives with varied levels of chloro-and/or hydroxyl substitution was measured in a Saccharomyces cerevisiae-based lac-Z (␤-galactosidase) reporter assay. ␤-Galactosidase activity was compared with competitive binding to soluble mouse uterine estrogen receptor protein. The comparison of relative potency for biphenyls hydroxylated on one ring and chlorinated on the other ring (n ϭ 5) revealed excellent correlation between the two systems (r 2 ϭ 0.995). However, estrogenicities of biphenyls hydroxylated and chlorinated on the same ring were not in agreement. Although weak ligand binding was demonstrated for these compounds, ␤-galactosidase activity was not observed. Rather, these compounds were shown to be cytotoxic to yeast. The results of this study further support the hypothesis that both an unhindered phenolic ring and molecular symmetry are structural features associated with estrogenicity.

Abstract-Acute toxicity values (5-and 30-min Vibrio fisheri 50% luminescence inhibition) of 16 organic compounds thought to elicit their response via the weak acid respiratory uncoupling mechanism of toxic action were secured from the literature. Regression analysis of toxicities revealed that a measured 5-min V. fisheri potency value can be used as a surrogate for the 30-min value. Regression analysis of toxicity (30-min for potency [log p ]) versus hydrophobicity, measured as the 1-octanol/water partition Ϫ1 T 30 coefficient (log K ow ), was used to formulate a quantitative structure-activity relationship (QSAR). The equation log p ϭ 0.489(log Ϫ1T 30 K ow ) ϩ 0.126 was found to be a highly predictive model (r 2 adj. ϭ 0.848). This V. fisheri QSAR is statistically similar to QSARs generated from weak acid uncoupler potency data for Pimephales promelas survivability and Tetrahymena pyriformis population growth impairment. This work, therefore, suggests that the weak acid respiratory uncoupling mechanism of toxic action is present in V. fisheri, and as such is not restricted to mitochondria-containing organisms.

No abstract

Quantitative structure-activity relationships (QSAR) developed and applied in the prediction of ecotoxic potencies far out number those in other areas, such as health effects. There are yet to be any formal guidelines for the development of ecotoxicological QSARs. Despite this, the depth and breadth of our knowledge of QSARs as they apply to ecotoxicology, especially short-term aquatic toxicity, allow for the formulation of characteristics that appear to be essential and/or desirable for high-quality QSARs. The three components of a QSAR are the biological activity, the property/structural descriptors, and the statistical methodology. Problems may arise from all three components and may be compounded by interactions between them. In an effort to minimize any tribulations associated with development and application of ecotoxic QSARs, a number of essential or desirable characteristics have been identified. Ecotoxicological data used in formulating the QSAR must be reliable, of high quality, and reflect a well-defined and continuous endpoint; this dataset should be diverse both in terms of potency and chemical structure (i.e., property). Descriptors used in formulating the QSAR should be of high quality, reproducible, of a number and type consistent with the endpoint being modeled, and when possible allow for a mechanistic interpretation of the QSAR. The statistical process used in formulating a QSAR should be as rigorous as possible, appropriate for the endpoint being modeled, and allow for the development of as easily interpretable (i.e., transparent) QSARs as possible. The resultant QSAR should be validated, only used within the descriptor space and chemical domain of the model, and relied on in relation to the total weight of evidence; precision of the QSAR and expectations from its application need to be related to the error in the original ecotoxicological and descriptor measurements. Finally, development of QSARs should be through the interaction of a group of multidisciplinary experts.