Identifying and designing chemicals with minimal acute aquatic toxicity

Abstract

Industrial ecology has revolutionized our understanding of material stocks and flows in our economy and society. For this important discipline to have even deeper impact, we must understand the inherent nature of these materials in terms of human health and the environment. This paper focuses on methods to design synthetic chemicals to reduce their intrinsic ability to cause adverse consequence to the biosphere. Advances in the fields of computational chemistry and molecular toxicology in recent decades allow the development of predictive models that inform the design of molecules with reduced potential to be toxic to humans or the environment. The approach presented herein builds on the important work in quantitative structure-activity relationships by linking toxicological and chemical mechanistic insights to the identification of critical physical-chemical properties needed to be modified. This in silico approach yields design guidelines using boundary values for physiochemical properties. Acute aquatic toxicity serves as a model endpoint in this study. Defining value ranges for properties related to bioavailability and reactivity eliminates 99% of the chemicals in the highest concern for acute aquatic toxicity category. This approach and its future implementations are expected to yield very powerful tools for life cycle assessment practitioners and molecular designers that allow rapid assessment of multiple environmental and human health endpoints and inform modifications to minimize hazard.

Keywords: green chemistry; rational design; safer chemicals; toxicity prediction.

Fig. 1.

Scatter plots of (A) the octanol-water partition coefficient (logP_o/w) vs. energy difference between the highest occupied and the lowest unoccupied frontier orbitals (ΔE) and (B) the octanol-water distribution coefficient (logD_o/w) vs. ΔE. The 555 compounds represented are colored by category of concern for acute aquatic toxicity as described in Table 1 (red, high concern; orange, medium concern; yellow, low concern; green, no concern) based on a 96-h toxicity assay of the fathead minnow (44).

Fig. 2.

Box plot showing distribution of molecular volume (V) by concern category for acute aquatic toxicity for compounds (Table 1) that have logD_o/w < 1.7 and ΔE > 6 eV.

Fig. 3.

Bar graphs showing distribution of the four toxicity concern categories (Table 1) as each property filter is applied for (A) narcotics, (B) electrophiles or proelectrophiles, (C) polar narcotics, and (D) compounds with undetermined toxic MOAs. logD, octanol-water distribution coefficient at pH 7.4; dE (eV), energy difference between the highest occupied and lowest unoccupied frontier orbitals; V, molecular volume (ų).

Fig. 4.

Scatter plot of octanol-water distribution coefficient at pH 7.4 (logD_o/w) vs. the energy difference between the highest occupied and lowest unoccupied frontier orbitals. ΔE (eV) for 345 compounds, colored by category of concern for acute aquatic toxicity based on a 48-h toxicity assay of Daphnia magna (48). (red, high concern; orange, medium concern; yellow, low concern; green, no concern).