An examination of acute environmental toxicity of pharmaceutical compounds using quantitative structure activity relationships

James Richard Hagan

doi:10.17918/00000839

With the need to satisfy the legal requirements of product review, environmental impact information for pharmaceutical compounds has been collected over the past five years. The focus of this environmental impact review was to collect acute aquatic toxicity data on Daphnia magna as well as information on the physical chemical properties of new pharmaceutical compounds so as to make inferences as to the potential environmental fate and effects of these compounds. The data resulting from this effort were collected and evaluated to determine if a screening tool could be developed that would allow for laboratory evaluations to be conducted only on those compounds that may have a potential for adverse environmental impacts. The laboratory-derived properties that were examined were the compounds' octanol-water partition coefficient and solubility. The other source of information was the molecular descriptors derived from the molecules' structural information: these included connectivity indices, molar refractivity, and the calculated octanol/water partition coefficient. While correlations between acute ecotoxicity and single parameters, either laboratory derived or calculated, were not strong, it was demonstrated that the inclusion of molecular charge as a descriptor modifier improved the correlation. The charge factors examined were the expected charge at environmental pH conditions, and the maximum charge potential of the molecule. When multiple regression analysis was carried out, the strongest correlations to acute toxicity were to three maximum charge-modified variables: the calculated octanol/water partition coefficient (CLOGP), the scaled logarithm of the molar refractivity, and the zero order connectivity index. These variables model hydrophobicity, polarizability, and molecular volume, respectively, and reflect the factors assumed to affect transport into the cell and hence the molecule's impact on the organism through non-specific polar narcosis. As a result of this study, the following model was developed and validated, with an R2 of 0.88.log(1/EC_50) = 0.16(CLOGP/(K_m + 1)) + 6.86log(0.1)(MR)/(K_m + 1) - 0.18(0[chi]/(K_m + 1)) - 1.72 where EC50 = effective concentration of 50% exotoxicity for Daphnia magna, CLOGP = Pomona College MEDCHEM calculated log of the octanol/water partition coefficient, MR = molar refractivity, 0[chi] = zero order connectivity index, and K_m = maximum potential charge on the molecule. This model may be utilized as a screening tool for predicting the ecotoxicity of pharmaceutical compounds.

An examination of acute environmental toxicity of pharmaceutical compounds using quantitative structure activity relationships

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An examination of acute environmental toxicity of pharmaceutical compounds using quantitative structure activity relationships

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