The Ratios of Individual Chemicals in a Mixture Determine the Degree of Joint Effect: The Climax Hypothesis

Abstract

Abstract.A new hypothesis, the Climax Hypothesis, is proposed to describe how the ratios of individual chemicals influence the joint effects of chemical mixtures. This hypothesis is derived from a generalized approach using ''isobolograms.'' With this hypothesis, one can predict that for a given mixture, a curvilinear correlation exists between the joint effects and the ratios of individual chemicals and that this curve has a climax at the equitoxic ratio. This prediction is supported by the observed toxicity to Vibrio fischeri of 18 mixtures (12 binary mixtures, 4 ternary mixtures, and 2 quaternary mixtures). With this prediction, the Climax Hypothesis has some promising applications such as controlling the discharge of effluents in environmental science, maximizing detoxifying effects in medicine, and optimizing combined pesticides in agriculture.Increasing concern over the usual exposure to multiple rather than to single chemicals has promoted investigations into the joint effects of chemical mixtures. Because of the flood of chemical pollutants, it is not feasible to test the toxicity of all mixtures at all ratios. Understanding of the rules for joint toxic effects is therefore necessary.As is well known, the joint effects of chemical mixtures can be qualitatively described as simple addition, synergism, antagonism, or independent action (Placket and Hewlett 1967; Xu and Nirmalakhandan 1998) as follows: (1) simple addition: ideal additive effects are observed when the joint toxic response is equal to the sum of the individual chemical toxicities; (2) synergism: more than addition, the combined effect is greater than the sum of the toxicities of the individual chemicals; (3) antagonism: less than addition, the overall toxic effect is less than the sum of the toxicities of the individual chemicals; and (4) independent action: the joint toxic effect is equal to that caused by the individual chemical with the greatest toxicity. To further quantitatively assess the degree of joint effect, three indicators have been proposed by toxicologists: toxic units (TU); the additive index (AI); and the mixture toxicity index (MTI) (Sprague and Ramsay 1965;Marking 1977;Kçnemann 1981). Definitions and uses of these concepts are listed in Table 1 As pointed out by toxicologists (Chen and Huang 1996), the joint effect depends on both the slopes and the ratios of the individual toxicants. The influence of the slopes for the individual toxicants on the joint effect was demonstrated by Chen and Huang (1996). Based on the slope, they successfully derived some criteria to qualitatively predict the likelihood of occurrence of joint effects in mixture toxicity. However, these criteria cannot provide quantitative predictions of the degree of joint effect (Chen and Huang 1996). As for the ratio of individual chemicals, many studies have found that this did influence the joint effect of a chemical mixture (Dong and Feng 1994). However, it remains unclear how the ratio influences the joint effect and whether its influence is quantitative....

New Insight Regarding the Relationship Between Enantioselective Toxicity Difference and Enantiomeric Toxicity Interaction from Chiral Ionic Liquids

“…There were two pairs of inverted U-shaped relationships between the P i of components and the toxicities (pEC 30 , pEC 50 , pEC 80 ) of mixtures of EL and ED, and OD and OL. This phenomenon basically conformed to the climax hypothesis proposed by Lin et al [50]. The climax hypothesis concluded that there was a climax at the equitoxic ratio when plotting the toxic ratios of individual chemicals in mixtures versus their joint effects [51].…”

“…The variability of the blank control in the test was controlled within ±20%. The indicators of effect concentration EC 80 , EC 50 , and EC 30 are shown in Table 1. According to these indicators, the toxicity order of single enantiomers was OL ≥ OD > HL > HD > BD > BL > EL ≥ ED.…”

Joint toxic effects of the type-2 alkene electrophiles

“…5B) for the selected chemicals showed that different binary permutations produced synergistic joint effects except at very low values of k 1 which showed additive effects. Although the underlying reason for this ratio-dependent conversion is not known, it has been noted in previous mixture studies (e.g., see Lin et al, 2005; Tian et al, 2013a). …”

The mixture toxicity of environmental contaminants containing sulfonamides and other antibiotics in Escherichia coli: Differences in both the special target proteins of individual chemicals and their effective combined concentration

“…More details regarding the difference between EC 50mix and TU can be found the research of Tian et al (Tian et al, 2013a). In addition, the toxic ratio for most of the binary mixtures was set to 1:1 based on the Climax Hypothesis that we proposed in our previous research (Lin et al, 2005), which indicated that the joint effect was closely associated with the toxic ratio of each component and that the most obvious effect would appear at the equitoxic ratio.…”