QSARs for aquatic toxicity: celebrating, extending and displaying the pioneering contributions of Ferguson, Konemann and Veith

Abstract

Significant advances were made in the development of quantitative structure-activity relationships (QSARs) relating molecular structure to aquatic toxicity by three studies over 30 years ago by Ferguson in 1939, Konemann in 1981, and Veith and colleagues in 1983. We revisit the original concepts and data from these studies and review these contributions from the bases of current perspectives on the hypothesized mechanism of baseline narcotic toxicity and the underlying thermodynamic and kinetic aspects. The relationships between LC50, octanol-water partition coefficient, aqueous solubility, chemical activity and chemical volume fraction in lipid phases are outlined including kinetic influences on measured toxicities. These relationships provide a compelling and plausible explanation of the success of these and other QSARs for aquatic toxicity. Suggestions are made for further advances in these QSARs to improve assessments of toxicity by baseline narcotic toxicity and selective modes of action, especially using emerging quantum chemical computational capabilities.

Application of Mass Balance Models and the Chemical Activity Concept To Facilitate the Use of in Vitro Toxicity Data for Risk Assessment

“…All chemicals are expected to exert baseline toxicity regardless of whether or not other modes of action are exhibited. For the purposes of this exercise, it is assumed that a chemical activity of 0.01 or higher indicates the potential for baseline toxicity to occur. − In an in vitro cell assay, baseline toxicity is assumed to reflect disruption of membrane integrity and functioning (e.g., loss of insular capacity) …”

“…Chemical activity, its relationship to chemical concentration, and its use to characterize baseline toxicity (narcosis) were first described by Ferguson over 70 years ago . More recently, the utility of chemical activity for distinguishing between chemicals exerting baseline toxicity and more specific modes of action and for applications in RA has been explored. − Just as with in vivo toxicity data, the ability to categorize in vitro toxicity test results in terms of mode of action would be useful. Accordingly, the main objective of this paper is to develop a generic mass balance modeling approach to estimate the distribution of neutral organic chemicals in in vitro test systems and the corresponding chemical activity.…”

Assessing the Toxicity of Individual Aromatic Compounds and Mixtures to American Lobster (Homarus americanus) Larvae Using a Passive Dosing System

“…Acute toxicity of a wide range of neutral organic compounds correlates with chemical activity, and the nonspecific or baseline toxicity of these compounds individually or in mixtures has been reported to fall within a chemical activity range of 0.01 to 1.0. (Mackay et al 2009(Mackay et al , 2014Schmidt and Mayer 2015). Also, QSAR models may be used to predict the toxicity of individual ACs or additively for compound mixtures using octanol-water partition coefficients (log K OW ; Nirmalakhandan and Speece 1988;Di Toro et al 2000).…”

Linking algal growth inhibition to chemical activity: Excess toxicity below 0.1% of saturation

“…Chemical activity (a) quantifies the energetic level, and not the mass concentration, of a HOC relative to the energetic level in its pure liquid (reference state, a=1; Reichenberg and Mayer, 2006). Several studies have linked toxicity to chemical activity, and baseline toxicity for neutral HOCs has been reported to initiate within the rather narrow range of chemical activity 0.01 to 0.1 (Reichenberg and Mayer, 2006;Mayer and Reichenberg, 2006;Mackay et al, 2009;Mackay et al, 2014). This range is fairly independent of the type of HOC and the target organism.…”