Use of Joint Toxic Response to Define the Primary Mode of Toxic Action for Diverse Industrial Organic Chemicals

Abstract

An important aspect of understanding how multiple toxicants jointly act involves defining the primary mode of toxic action for the chemicals of interest. We have explored the use of 96-h acute toxicity tests with juvenile fathead minnows and primarily binary chemical mixtures to define the primary acute mode of toxic action for diverse industrial organic chemicals. Our investigation mainly considered the two special cases of noninteractive joint action known as concentration (simple similar) and response (independent) addition. The different forms of joint toxicity with binary mixtures were graphically illustrated by isoboie diagrams. Designated as the mode of action-specific reference toxicants were 1-octanol, phenol, and 2,4-dinitrophenol. It was observed from binary isobole diagrams that a chemical with a similar primary mode of toxic action to that of a reference toxicant would display a concentration-addition type of joint action with the reference toxicant over the entire mixture ratio range. Dissimilar chemicals with very steep concentration-response curves generally showed an interaction that was less-thanconcentration additive, but consistently demonstrated a joint toxicity that was greater than predicted by the response-addition model. The more-than-concentration additive and complex isoboles that are indicative of interactive toxicity were not commonly observed in our experiments.

Chemical Stress and Metabolic Rate in Aquatic Invertebrates: Threshold, Dose–response Relationships, and Mode of Toxic Action

“…Regardless of agreement with detailed biochemical investigations, our results do not agree with many ecotoxicologic studies, which frequently classify chlorophenols as narcotic compounds because of their high lipophilicity [17]. To some extent, this may be true, because a general shift towards narcotic action occurs as hydrophobicity increases [20]. These quantitative structure-activity relationship (QSAR)-based studies have been criticized recently by Russom et al [2], who concluded that many classification schemes and QSARs have been based on chemical classes of compounds, which can be difficult to defend from a toxicologic perspective.…”

“…Therefore, the compounds selected in this study represent aromatic molecules with different substitution patterns or different amounts of the same substituent. 2,4-Dinitrophenol (2,4-DNP) and pentachlorophenol (PCP) are known uncouplers of oxidative phosphorylation and are commonly used as reference chemicals for this mechanism [9,20]. 1,2,4-Trichlorobenzene (1,2,4-TCB) is widely used as an example of a narcotic chemical [6,8,20].…”

“…2,4-Dinitrophenol (2,4-DNP) and pentachlorophenol (PCP) are known uncouplers of oxidative phosphorylation and are commonly used as reference chemicals for this mechanism [9,20]. 1,2,4-Trichlorobenzene (1,2,4-TCB) is widely used as an example of a narcotic chemical [6,8,20]. The mode of toxic action of 2,4,5-trichlorophenol (2,4,5-TCP) was suggested to be polar narcosis and/or uncoupling of phosphorylation [3,7,11,13,16,17,21].…”

“…The mode of toxic action of 2,4,5-trichlorophenol (2,4,5-TCP) was suggested to be polar narcosis and/or uncoupling of phosphorylation [3,7,11,13,16,17,21]. The properties of the mechanisms given above are well described [20,22,23]. O.-P. Penttinen and J. Kukkonen [16].…”

“…c Hammet 1 indicates electron withdrawal from the aromatic ring by the substituent (ortho-substituents were considered to be equivalent to the para-substituents). d [20]. e [3].…”