Quantitative structure-activity relationships for the prediction of relative in vitro potencies (REPs) for chloronaphthalenes.

Chloronaphthalenes (CNs), due to their structural similarities to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the other "dioxin-like" compounds, can bind to the aryl hydrocarbon receptor (AhR) and induce a wide range of pleotrophic effects. Relative potency of individual dioxin analogues can be measured relative to that of TCDD. Relative effects potencies (REP) can be based on many responses, including in vivo and in vitro responses. Both in vivo and in vitro tests, based on either indigenous responses such as the induction of ethoxyresorufin O-deethylase (EROD) or exogenous reporter genes under the control of the AhR such as luciferase can be used to determine REP values. Here we used measured REP values determined for CNs in two assays. Both assays are based on H4IIE rat hepatoma cells. The H4IIE assay is based on expression of the endogenous reporter gene (CYP-1 A) that codes for the expression of EROD and the H4IIE-luc assay which is based on the exogenous reporter gene (luciferase) transfected into the H4IIE cell line. Experimentally determined REP were available for only 17 and 18 of the 75 possible choronaphthalene congeners, for the H4IIE and H4IIE-luc assays, respectively. For this reason computational models were developed to allow prediction of the relative potencies of the other CN congeners. Predictive relationships were based on quantum chemical descriptors obtained from Density Functional Theory (DFT) calculations (B3LYP/6-311++G**). The final models were found by means of a hybrid method combining a genetic algorithm and artificial neural networks. REP values estimated for individual CNs based on the H4IIE assay ranged from 4.3 x 10(- 9) to 3.2 x 10(- 2) while those based on the H4IIE-luc assay ranged from 4.0 x 10(- 8) to 1.8 x 10(- 3). CN congeners nos. 66, 67, 70 and 73 were exhibited the greatest REP values in both assays. The 1,2,3,5,6,8-hexaCN congener (no. 68) had a REP value that was 10-fold less. The remaining congeners had REP values that were less or did not cause sufficient up-regulation of the monitored genes to allow for the calculation of a REP. Interactions of CNs with the AhR could be affected by three possible factors: molecular size, steric interactions and electrostatic interactions. These findings are discussed relative to the use of consensus TCDD equivalency factors' (TEFs) for use in risk assessments of CNs for regulatory purposes.