Novel Segmented Concentration Addition Method to Predict Mixture Hormesis of Chlortetracycline Hydrochloride and Oxytetracycline Hydrochloride to Aliivibrio fischeri

Abstract

Hormesis is a concentration-response phenomenon characterized by low-concentration stimulation and high-concentration inhibition, which typically has a nonmonotonic J-shaped concentration-response curve (J-CRC). The concentration addition (CA) model is the gold standard for studying mixture toxicity. However, the CA model had the predictive blind zone (PBZ) for mixture J-CRC. To solve the PBZ problem, we proposed a segmented concentration addition (SCA) method to predict mixture J-CRC, which was achieved through fitting the left and right segments of component J-CRC and performing CA prediction subsequently. We selected two model compounds including chlortetracycline hydrochloride (CTCC) and oxytetracycline hydrochloride (OTCC), both of which presented J-CRC to Aliivibrio fischeri (AVF). The seven binary mixtures (M1–M7) of CTCC and OTCC were designed according to their molar ratios of 12:1, 10:3, 8:5, 1:1, 5:8, 3:10, and 1:12 referring to the direct equipartition ray design. These seven mixtures all presented J-CRC to AVF. Based on the SCA method, we obtained mixture maximum stimulatory effect concentration (ECm) and maximum stimulatory effect (Em) predicted by SCA, both of which were not available for the CA model. The toxicity interactions of these mixtures were systematically evaluated by using a comprehensive approach, including the co-toxicity coefficient integrated with confidence interval method (CTCICI), CRC, and isobole analysis. The results showed that the interaction types were additive and antagonistic action, without synergistic action. In addition, we proposed the cross point (CP) hypothesis for toxic interactive mixtures presenting J-CRC, that there was generally a CP between mixture observed J-CRC and CA predicted J-CRC; the relative positions of observed and predicted CRCs on either side of the CP would exchange, but the toxic interaction type of mixtures remained unchanged. The CP hypothesis needs to be verified by more mixtures, especially those with synergism. In conclusion, the SCA method is expected to have important theoretical and practical significance for mixture hormesis.

Humic Substances Mitigate the Impact of Tritium on Luminous Marine Bacteria. Involvement of Reactive Oxygen Species

“…According to the hormesis toxicological model [ 32 , 33 , 34 , 35 ], Figure 1 , the stages of the dose–response model demonstrate either activation or inhibition of organismal physiological functions; the absence of the effect can occur as well. It should noted that our previous studies revealed variations in the bacterial luminescence response to tritium in the frames of hormesis model: bi-phasic time dependence (activation + inhibition) was found in [ 30 , 31 ], and the mono-phasic time dependence (only activation) was found in [ 22 , 28 , 29 ].…”

“…In addition, variations of the effect types were observed under the conditions of low-dose alpha and gamma irradiation [ 25 , 26 , 27 , 31 ]. All these variations are explained in terms of the “hormesis” approach [ 32 , 33 , 34 , 35 ]: the organismal response is not unified; it depends on the type of organism, its state, and external conditions; all the response specificities are the particular cases of the generalized hormesis model. Additionally, it is known that a dose–response dependence can be absent at all, the low-dose radiobiological responses can be “noisy”.…”

“…Our previous works revealed the peculiarities of the response of luminous marine bacteria to the low-dose radiation of alpha-, beta-, and gamma-types [ 15 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Bacterial responses to alpha- and beta- radionuclides corresponded to the conventional “hormesis” dose–response model [ 32 , 33 , 34 , 35 ]. The scheme of this model is presented in Figure 1 ; it includes three stages: stress recognition, stimulation (activation), and inhibition of an organismal function.…”

Enzymatic Responses to Low-Intensity Radiation of Tritium

“…Hormesis is considered as a basis for the most general toxicological model, which involves opposite response types: the activation of physiological functions under low-dose exposures and their inhibition by higher doses. Two other toxicological models, linear and threshold, might be considered as particular cases of hormesis [ 8 , 15 , 16 , 17 ]. It is supposed that hormesis is a highly general phenomenon that is independent from the biological model and the level of organization of a biological system (e.g., cell, organ, or organism) [ 9 ].…”

Development of Cellular and Enzymatic Bioluminescent Assay Systems to Study Low-Dose Effects of Thorium

“…Our previous works showed that the responses of luminous marine bacteria to the low-dose radiation of alpha and beta types [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 27 , 28 ] correspond to the conventional “hormesis” model [ 29 , 30 , 31 , 32 ]. This model includes, in the broadest case, three stages of the biological dose-dependent response—stress recognition, activation, and inhibition of organismal functions.…”