Structure-toxicity relationships for selected halogenated aliphatic chemicals

Toxicity to the ciliate Tetrahymena pyriformis (log (IGC(50)(-1))) for 39 halogen-substituted alkanes, alkanols, and alkanitriles were obtained experimentally. Log(IGC(50)(-1)) along with the hydrophobic term, log K-ow (1-octanol/water partition coefficient) and the electrophilic parameter, E-lumo (the energy of the lowest unoccupied molecular orbital) were used to develop quantitative structure-activity relationships (QSARs). Two strong hydrophobic dependent relationships were obtained: one for the haloalkanes and a second for the haloalcohoIs. The relationship for the haloalkanes [log(IGC(50)(-1))=0.92 (logK(ow))-2.58; n=4, r(2) = 0.993, s = 0.063, f= 276, Pr >f= 0.0036] was not different from baseline toxicity. With the rejection of 1,3-dibromo-2-propanol as a statistical outlier, the relationship [log (IGC(50)(-1))= 0.63(log K-ow)- 1.18; n = 19, r(2) = 0.860, s = 0.274, f= 104, Pr>f=0.0001] was observed for the haloalcohoIs. No hydrophobicity-dependent model (r(2) =0.165) was observed for the halonitriles. However, an electrophilicity-dependent model [log(IGC(50)(-1)) = - 1.245(E-lumo)+ 0.73; n = 15, r(2) = 0.588, s = 0.764, F= 18.6, Pr >f= 0.0009] was developed for the halonitriles. Additional analysis designed to examine surface-response modeling of all three chemical classes met with some success. Following rejection of statistical outliers, the plane [log(IGC(50)(-1))= 0.60(log K-ow) - 0.747(E-lumo) - 0.37; n = 34, r(2) = 0.915, s = 0.297, F= 162, Pr > F= 0.0001] was developed. The halogenated alcohols and nitriles tested all had observed toxicity in excess of non-reactive baseline toxicity (non-polar narcosis). This observation along with the complexity of the structure-toxicity relationships developed in this study suggests that the toxicity of haloalcohols and halonitriles is by multiple and/or mixed mechanisms of action which are electro(nucleo)philic in character. (C) 1999 Published by Elsevier Science B.V. All rights reserved.