The physicochemical basis of QSARs for baseline toxicity

Abstract

The physico-chemical properties relevant to the equilibrium partitioning (bioconcentration) of chemicals between organisms and their respired media of water and air are reviewed and illustrated for chemicals that range in hydrophobicity. Relationships are then explored between freely dissolved external concentrations such as LC50s and chemical properties for one important toxicity mechanism, namely baseline toxicity or narcosis. The 'activity hypothesis' proposed by Ferguson in 1939 provides a coherent and compelling explanation for baseline toxicity of chemicals in both water- and air-respiring organisms, as well as a reference point for identifying more specific toxicity pathways. From inhalation studies with fish and rodents, narcosis is shown to occur at a chemical activity exceeding approximately 0.01 and there is no evidence of narcosis at activities less than 0.001. The activity hypothesis provides a framework for directly comparing the toxic potency of chemicals in both air- and water-breathing animals. The activity hypothesis is shown to be consistent with the critical body residue concept, but it has the advantage of avoiding the confounding effect of lipid content of the test organism. It also provides a theoretically sound basis for assessing the baseline toxicity of mixtures. It is suggested that since activity is readily calculated from fugacity, observed or predicted environmental abiotic and biotic fugacities can be used to evaluate the potential for baseline toxicity. Further, models employing fugacity or activity can be used to improve the experimental design of bioassays, thus possibly reducing unnecessary animal testing.

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment

“…The understanding of baseline toxicity serves as a useful reference point for identifying specific toxicity, that is, AOPs initiated by biological-chemical interactions more specific than hydrophobicity alone [10]. This aspect of the AOP also supports the use of additive joint toxicity models, which provides a foundation for predicting toxicity from critical body burdens of narcotic chemicals [22,23] and for proposed water and sediment quality criteria for both single compounds and mixtures of narcosis chemicals [24,25].…”

“…Although narcosis is the least detailed of the AOPs that we will discuss, it is particularly important in ecotoxicology because approximately 60% of all industrial organic chemicals are thought to act via this AOP [8]. Narcosis is described by Overton [9] as nonspecific toxicity resulting from weak and reversible hydrophobic interactions and is referred to in ecotoxicology as baseline toxicity, meaning that, if a chemical does not produce toxicity by some more specific mechanism, it will act by narcosis, providing it is sufficiently soluble in water at high enough concentrations to achieve the required chemical activity [10]. In fish, narcosis is characterized by decreased respiratory rate, slowed metabolic rate, low blood oxygen, loss of equilibrium, and eventual plasma ion imbalance prior to death [11].…”

“…To date, most applications of models based on the narcosis AOP relate toxicity to chemical concentrations in the water, but this baseline toxicity is better explained by a common chemical activity independent (at least to useful approximation) of the chemical identity [10]. The understanding of baseline toxicity serves as a useful reference point for identifying specific toxicity, that is, AOPs initiated by biological-chemical interactions more specific than hydrophobicity alone [10].…”

Uptake and toxicity of polycyclic aromatic hydrocarbons in terrestrial springtails—studying bioconcentration kinetics and linking toxicity to chemical activity

“…Naphthalene, phenanthrene, and pyrene are believed to be baseline toxicants and, thus, to have the same mode of action, that is, perturbation of the cell membrane integrity [17]. Baseline toxicity is expected to initiate in the chemical activity range 0.01 to 0.1 [2,11,34], and springtail lethality values of all three PAHs were within this range (Fig. 3C), which is also in good agreement with the results of a pilot experiment (Supplemental Data, Fig.…”

Prediction of Acute Rodent Toxicity on the Basis of Chemical Structure and Physicochemical Similarity

“…[3] Most of the studies in the literature correlate acute mammalian toxicity values with hydrophobicity [4,5] although it is widely recognized that a description of this complex endpoint by only transport-related parameters alone is insufficient. [6][7][8] Recently we demonstrated the application of the Arithmetic Mean Toxicity (AMT) Modelling Approach in the prediction of acute intravenous chemical toxicity to mice. [9] This report develops te AMT approach and includes the results of its application in the evaluation of 906 chemicals of known toxicity taken from the REACH Pre-Registration Substance (PRS) list (http://apps.echa.europa.eu/registered/registered-sub.aspx#phasein).…”