A new parameter for quantitatively characterizing antibiotic hormesis: QSAR construction and joint toxic action judgment.

Antibiotics usually induce the hormetic effects on bacteria, featured by low-dose stimulation and high-dose inhibition, which challenges the central belief in toxicity assessment and environmental risk assessment of antibiotics. However, there are currently no ideal parameters to quantitatively characterize hormesis. In this study, an effective area in hormesis (AH) was developed to quantify the biphasic dose-responses of single antibiotics (sulfonamides (SAs), sulfonamides potentiators (SAPs), and tetracyclines (TCs)) and binary mixtures (SAs-SAPs, SAs-TCs, and SAs-SAs) to the bioluminescence of Aliivibrio fischeri. Using Ebind (the lowest interaction energy between antibiotic and target protein) and Kow (octanol-water partition coefficient) as the structural descriptors, the reliable quantitative structure-activity relationship (QSAR) models were constructed for the AH values of test antibiotics and mixtures. Furthermore, a novel method based on AH was established to judge the joint toxic actions of binary antibiotics, which mainly exhibited synergism. The results also indicated that SAPs (or TCs) contributed more than SAs in the hormetic effects of antibiotic mixtures. This study proposes a new quantitative parameter for characterizing and predicting antibiotic hormesis, and considers hormesis as an integrated whole to reveal the combined effects of antibiotics, which will promote the development of risk evaluation for antibiotics and their mixtures.

Ecological risk of synthetic phenolic antioxidants: A study based on their spatial distribution in water, sediment, and soil from the Yangtze River Delta, China.

Environmental occurrence and risks of novel synthetic phenolic antioxidants (SPAs) remain largely unclear. By using a typical algae (Chlorella pyrenoidosa) as model organism, we evaluated the ecological risks of both traditional and novel SPAs, based on their concentrations in water, sediment, and soil collected from the Yangtze River Delta, China. Detection frequencies (DFs) of 10 novel SPAs were 25-100% in water, 3-100% in sediment, and 0-100% in soil, with geometric means (GMs) of 2700 ng/L, 1270 ng/g, and 2440 ng/g, respectively. For 8 traditional SPAs, DFs were 50-100% (GM: 680 ng/L), 3-100% (534 ng/g), and 47-100% (2240 ng/g) in water, sediment, and soil, respectively. AO3114 was the main pollutant in water, while AO1010 dominated in sediment and soil. Notably, low-molecular-weight SPAs showed migration behavior from sediment to water. Four SPAs (AO626, AO1035, AO1098, and AO1076) showed dose- and time-dependent toxicity on Chlorella pyrenoidosa. As time progressed, sediment-released SPAs became more toxic than those in water. Two SPAs (AO1135 and BHT-Q) posed high risks (RQW > 1) to green algae, daphnia, and fish. The SPA mixture exhibited high risks (RQmix > 1) to these organisms, increasing with the trophic level. This research holds valuable guidance for further SPA risk assessments.

An innovative mixture sampling strategy with uniform design: Application to global sensitivity analysis of mixture toxicity.

Global sensitivity analysis combined with quantitative high-throughput screening (GSA-qHTS) uses random starting points of the trajectories in mixture design, which may lead to potential contingency and a lack of representativeness. Moreover, a scenario in which all factor levels were at stimulatory effects was not considered, thereby hindering a comprehensive understanding of GSA-qHTS. Accordingly, this study innovatively introduced an optimised experimental design, uniform design (UD), to generate non-random and representative sample points with smaller uniformity deviation as starting points of multiple trajectories. By combining UD with the previously optimised one-factor-at-a-time (OAT) method, a novel mixture design method was developed (UD-OAT). The single toxicity tests showed that three pyridinium and five imidazolium ionic liquids (ILs) exerted stimulatory effects on Vibrio qinghaiensis sp.-Q67; thus, four stimulatory effective concentrations of each IL were selected as factor levels. The UD-OAT generated 108 mixture samples with equal frequency and without repetition. High-throughput microplate toxicity analysis revealed that all 108 mixtures exhibited inhibitory effects. Among these, type B mixtures exhibited increasing toxicities that subsequently decreased, unlike type C mixtures, which consistently increased over time. GSA successfully identified three of the eight ILs as important factors influencing the toxicities of the mixtures. When individual ILs produced stimulatory effects, mixtures containing two to three ILs exhibited either stimulatory effects or none. In contrast, mixtures containing five to eight ILs exhibited inhibitory effects, while those containing four ILs showed a transition from stimulatory to inhibitory effects. This study provides a novel mixture design method for studying mixture toxicity and fills the application gap of GSA-qHTS. The phenomenon of individuals being beneficial while mixtures can be harmful challenges traditional mixture risk assessments.

Derivation of water quality criteria for paraquat, bisphenol A and carbamazepine using quantitative structure-activity relationship and species sensitivity distribution (QSAR-SSD).

The risk assessment of an expanding array of emerging contaminants in aquatic ecosystems and the establishment of water quality criteria rely on species sensitivity distribution (SSD), necessitating ample multi-trophic toxicity data. Computational methods, such as quantitative structure-activity relationship (QSAR), enable the prediction of specific toxicity data, thus mitigating the need for costly experimental testing and exposure risk assessment. In this study, robust QSAR models for four aquatic species (Rana pipiens, Crassostrea virginica, Asellus aquaticus, and Lepomis macrochirus) were developed using leave-one-out (LOO) screening variables and the partial least squares algorithm to predict toxicity data for paraquat, bisphenol A, and carbamazepine. These predicted data can be integrated with experimental data to construct SSD models and derive hazardous concentration for 5 % of species (HC5) for the criterion maximum concentration. The chronic water quality criterion for paraquat, bisphenol A, and carbamazepine were determined at 6.7, 11.1, and 3.5 µg/L, respectively. The QSAR-SSD approach presents a viable and cost-effective method for deriving water quality criteria for other emerging contaminants.

Screening for frequently detected quaternary ammonium mixture systems in waters based on frequent itemset mining and prediction of their toxicity.

Screening and prioritizing research on frequently detected mixture systems in the environment is of great significance, as conducting toxicity testing on all mixtures is impractical. Therefore, the frequent itemset mining (FIM) was introduced and applied in this paper to identify variables that commonly co-occur in a dataset. Based on the dataset of the quaternary ammonium compounds (QACs) in the water environment, the four frequent QAC mixture systems with detection rate ≥ 35 % were found, including [BDMM]+Cl--[BTMM]+Cl- (M1), [BDMM]+Cl--[BHMM]+Cl- (M2), [BTMM]+Cl- -[BHMM]+Cl- (M3), and [BDMM]+Cl--[BTMM]+Cl--[BHMM]+Cl- (M4). [BDMM]+Cl-, [BTMM]+Cl-, and [BHMM]+Cl- are benzyl dodecyl dimethyl ammonium chloride, benzyl tetradecyl dimethyl ammonium chloride, and benzyl hexadecyl dimethyl ammonium chloride, respectively. Then, the toxicity of the representative mixture rays and components for the four frequently detected mixture systems was tested using Vibrio qinghaiensis sp.-Q67 (Q67) as a luminescent indicator organism at 0.25 and 12 h. The toxicity of the mixtures was predicted using concentration addition (CA) and independent action (IA) models. It was shown that both the components and the representative mixture rays for the four frequently detected mixture systems exhibited obvious acute and chronic toxicity to Q67, and their median effective concentrations (EC50) were below 7 mg/L. Both CA and IA models predicted the toxicity of the four mixture systems well. However, the CA model had a better predictive ability for the toxicity of the M3 and M4 mixtures than IA at 12 h.

Acute toxicity of binary mixtures for quorum sensing inhibitors and sulfonamides against Aliivibrio fischeri: QSAR investigations and joint toxic actions.

Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and aquaculture fields. Due to the co-existence of QSIs and antibiotics in environmental media, it is necessary to evaluate their joint risk. However, there is little information about the acute toxicity of mixtures for QSIs and antibiotics. In this study, 10 QSIs and 3 sulfonamides (SAs, as the representatives for traditional antibiotics) were selected as the test chemicals, and their acute toxic effects were determined using the bioluminescence of Aliivibrio fischeri (A. fischeri) as the endpoint. The results indicated that SAs and QSIs all induced S-shaped dose-responses in A. fischeri bioluminescence. Furthermore, SAs possessed greater acute toxicity than QSIs, and luciferase (Luc) might be the target protein of test chemicals. Based on the median effective concentration (EC50) for each test chemical, QSI-SA mixtures were designed according to equitoxic (EC50(QSI):EC50(SA) = 1:1) and non-equitoxic ratios (EC50(QSI):EC50(SA) = 1:10, 1:5, 1:0.2, and 1:0.1). It could be observed that with the increase of QSI proportion, the acute toxicity of QSI-SA mixtures enhanced while the corresponding TU values decreased. Furthermore, QSIs contributed more to the acute toxicity of test binary mixtures. The joint toxic actions of QSIs and SAs were synergism for 23 mixtures, antagonism for 12 mixtures, and addition for 1 mixture. Quantitative structure-activity relationship (QSAR) models for the acute toxicity QSIs, SAs, and their binary mixtures were then constructed based on the lowest CDOCKER interaction energy (Ebind-Luc) between Luc and each chemical and the component proportion in the mixture. These models exhibited good robustness and predictive ability in evaluating the toxicity data and joint toxic actions of QSIs and SAs. This study provides reference data and applicable QSAR models for the environmental risk assessment of QSIs, and gives a new perspective for exploring the joint effects of QSI-antibiotic mixtures.

Time-dependent nonmonotonic concentration-response and synergism of alkyl glycosides with different alkyl side chain to Vibrio qinghaiensis sp. -Q67.

Alkyl glycosides (AGs), commonly used nonionic surfactants, may have toxic effects on the environmental organisms. However, the complex concentration-response patterns of AGs with varying alkyl side chains and their mixtures have not been thoroughly studied. Therefore, the luminescence inhibition toxicities of six AGs with different alkyl side chains, namely, ethyl (AG02), butyl (AG04), hexyl (AG06), octyl (AG08), decyl (AG10), and dodecyl (AG12) glucosides, were determined in Vibrio qinghaiensis sp. -Q67 (Q67) at 0.25, 3, 6, 9, and 12 h. The six AGs exhibited time- and side-chain-dependent nonmonotonic concentration- responses toward Q67. AG02, with a short side chain, presented a concentration-response curve (CRC) with two peaks after 6 h and stimulated the luminescence of Q67 at both 6 and 9 h. AG04, AG06, and AG08 showed S-shaped CRCs at five exposure time points, and their toxicities increased with the side-chain length. AG10 and AG12, with long side chains, exhibited hormesis at 9 and 12 h. Molecular docking was performed to explore the mechanism governing the possible influence of AGs on the luminescence response. The effects of AGs on Q67 could be attributed to multiple luminescence-regulatory proteins, including LuxA, LuxC, LuxD, LuxG, LuxI, and LuxR. Notably, LuxR was identified as the primary binding protein among the six AGs. Given that they may co-exist, binary mixtures of AG10 and AG12 were designed to explore their concentration-response patterns and interactions. The results revealed that all AG10-AG12 binary mixture rays showed time-dependent hormesis on Q67, similar to that shown by their individual components. The interactions of these binary mixtures were mainly characterized by low-concentration additive action and high-concentration synergism at different times.

Time-dependent hormesis transfer from five high-frequency personal care product components to mixtures.

There is potential for personal care products (PCPs) components and mixtures to induce hormesis. How hormesis is related to time and transmitted from components to mixtures are not clear. In this paper, we conducted determination of components in 16 PCP products and then ran frequent itemset mining on the component data. Five high-frequency components (HFCs), betaine (BET), 1,3-butanediol (BUT), ethylenediaminetetraacetic acid disodium salt (EDTA), glycerol (GLO), and phenoxyethanol (POE), and 14 mixtures were identified. For each mixture system, one mixture ray with the actual mixture ratios in the products was selected. Time-dependent microplate toxicity analysis was used to test the luminescence inhibition toxicity of five HFCs and 14 mixture rays to Vibrio qinghaiensis sp.-Q67 at 12 concentration gradients and eight exposure times. It is showed that BET, EDTA, POE, and 13 mixture rays containing at least one J-type component showed time-dependent hormesis. Characteristic parameters used to describe hormesis revealed that the absolute value of the maximum stimulatory effect (|Emin|) generally increased with time. Notably, mixtures composed of POE and S-type components showed greater |Emin| than POE alone at the same time. Importantly, the maximum stimulatory effective concentration, NOEC/the zero effective concentration point, and EC50 remained relatively stable. Nine hormesis transmission phenomena were observed in different mixture rays. While all mixtures primarily exhibited additive action, varying degrees of synergism and antagonism were noted in binary mixtures, with no strong synergism or antagonism observed in ternary and quaternary mixtures. These findings offer valuable insights for the screening of HFCs and their mixtures, as well as the study of hormesis transmission in personal care products.

Beneficial or harmful: Time-dependent hormesis induced by typical disinfectants and their mixtures with toxicological interaction.

Disinfectants and their mixtures can induce hormesis. However, how the mixture hormesis is related to those of components and the interactions in disinfectant mixtures remain unclear. In this paper, the luminescence inhibition toxicities of chlorinated sodium phosphate (CSP), dodecyl dimethyl benzyl ammonium bromide (DOB), dodecyl dimethyl benzyl ammonium chloride (DOC), ethanol (EtOH), glutaraldehyde (GLA), hydrogen peroxide (H2O2), isopropyl alcohol (IPA), n-propanol (NPA), and 20 mixture rays in four mixture systems (EtOH-H2O2, DOB-H2O2, DOC-EtOH, and EtOH-IPA-NPA) containing at least one component showing hormesis to Vibrio qinghaiensis sp.-Q67 (Q67) were determined at 0.25, 3, 6, 9, and 12 h. The synergism-antagonism heatmap based on independent action model (noted as SAHmapIA) was developed to systematically evaluate the interactions in various mixtures. It was shown that five disinfectants (CSP, EtOH, H2O2, NPA, and IPA) and 17 mixture rays exhibited time-dependent hormesis. The hormetic component was responsible for the hormesis of the mixture rays. Most mixture rays showed low- concentration/dose additive action and high-concentration/dose synergism at different time. This study further exemplified the interrelationship between the hormesis in the mixtures and their components and implied the need to pay attention to the time-dependent hormesis and interactions induced by the disinfectants.

Time-dependent hormetic dose responses of skin care product mixtures to Vibrio qinghaiensis sp.-Q67: Appearance and quantification.

Hormesis is a widely recognized and extensively studied phenomenon. However, few studies have described the quantitative characteristics of hormesis required for appropriate risk assessment. Although skin care product (SCP) mixtures and their active ingredients can induce the hormesis of Vibrio qinghaiensis sp.-Q67 (Q67), the quantitative characteristics of time-dependent hormetic dose responses in SCPs have not yet been investigated. In this study, 28 SCP mixtures were tested for luminescence toxicity against Q67 after five exposure durations (0.25, 3, 6, 9, and 12 h). With increasing exposure duration, the concentration response curves (CRCs) were classified as constant monotonic nonlinear (S-shaped) for four SCPs, S- to hormetic (J-shaped) for 13 SCPs, and constant J-shaped for 11 SCPs. Of 140 CRCs, 98 were J-shaped. An increased frequency of SCPs inducing hormesis was observed. The toxicity (pEC50) of the SCPs was independent of the exposure duration and product type. The maximum stimulatory effect (Emin) of the 12 SCPs increased with exposure duration. We proposed a modified parameter, the width of inhibition dose zone (WIDZ; EC50/EC10), to depict the width of inhibition dose zone. The WIDZ of S-shaped CRCs were significantly larger than that of J-shaped CRCs. In addition, the characteristic parameters reported in the general literature were analyzed. The good linear relationship between EC50 and the maximum stimulatory effective concentration (ECmin) indicated that toxicity may be transformed into stimulatory effects over exposure durations. The width of stimulation dose zone (WSDZ) and Emin of the seven SCPs had the same increasing trends with increasing exposure duration. The combination of WIDZ with other characteristic parameters (e.g., zero effective concentration point, ECmin, etc.) could better depict hormesis with low-dose stimulation and high-dose inhibition. The quantitative characteristics of the dose-responses of hormesis-inducing SCPs could provide reference basis for the risk assessment of SCP mixtures.

Optimized Derivation of Predicted No-Effect Concentrations (PNECs) for Eight Polycyclic Aromatic Hydrocarbons (PAHs) Using HC10 Based on Acute Toxicity Data.

For persistent organic pollutants, a concern of environmental supervision, predicted no-effect concentrations (PNECs) are often used in ecological risk assessment, which is commonly derived from the hazardous concentration of 5% (HC5) of the species sensitivity distribution (SSD). To address the problem of a lack of toxicity data, the objectives of this study are to propose and apply two improvement ideas for SSD application, taking polycyclic aromatic hydrocarbons (PAHs) as an example: whether the chronic PNEC can be derived from the acute SSD curve; whether the PNEC may be calculated by HC10 to avoid solely statistical extrapolation. In this study, the acute SSD curves for eight PAHs and the chronic SSD curves for three PAHs were constructed. The quantity relationship of HC5s between the acute and chronic SSD curves was explored, and the value of the assessment factor when using HC10 to calculate PNEC was derived. The results showed that, for PAHs, the chronic PNEC can be estimated by multiplying the acute PNEC by 0.1, and the value of the assessment factor corresponding to HC10 is 10. For acenaphthene, anthracene, benzo[a]pyrene, fluoranthene, fluorene, naphthalene, phenanthrene, and pyrene, the chronic PNECs based on the acute HC10s were 0.8120, 0.008925, 0.005202, 0.07602, 2.328, 12.75, 0.5731, and 0.05360 µg/L, respectively.

Novel macromolecular synthetic phenolic antioxidants in sludge on a national scale in China: Their distribution, potential transformation products, and ecological risk.

To fulfill the growing demand for retarding the oxidation of polymers and minimizing their migration from various products, new macromolecular synthetic phenolic antioxidants (SPAs) have emerged in the market. There is a concern that these SPAs may be released into wastewater streams during their manufacturing and use, eventually ending up in wastewater treatment plants (WWTPs). Nevertheless, information regarding the occurrence of these SPAs in sludge, particularly on a national scale, is scarce. In this study, several macromolecular SPAs and their transformation products (TPs) were investigated in sludge samples from 45 Chinese municipal WWTPs. All 14 analytes were detected in the sludge samples, among which, 12 analytes were first reported in sludge. 2,4,6-tri-tert-butylphenol (AO246) and 2 macromolecular SPAs, pentaerythritol tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate] (AO1010) and octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (AO1076), were the most dominant SPAs, with geometric mean (GM) concentrations of 547, 212, and 35.2 ng/g dw, respectively. Two TPs, 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoic acid (fenozan) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH), were found in some sludge samples (48.9-71.1 %) with GM of 45.5 and 12.8 ng/g dw, respectively. By using LC-Q-TOF-MS/MS analysis, we tentatively identified previously unknown TPs of 10 macromolecular SPAs in sludge. This suggests that there are still unclear mechanisms modulating the transformation of these SPAs, which underscores the complexity of their fate. Additionally, using the freshwater photobacteria Vibrio qinghaiensis sp.-Q67 (Q67) as model organism, the acute and chronic EC50 of the 14 analytes were assessed for ecological risk assessment. By considering toxicity data obtained from algae, daphnia, and fish collected or predicted from various databases, we found that these analytes, including their mixture at low detected concentrations, pose risks to aquatic systems that should not be disregarded. Overall, the current study provides a comprehensive overview of novel SPAs and their TPs in sludge, offering valuable insights for investigating their environmental behavior, fate, and risks.

Study on the characterization of pesticide modes of action similarity and the multi-endpoint combined toxicity of pesticide mixtures to Caenorhabditis elegans.

With the widespread use of pesticides, the coexistence of multiple low-residue pesticides in environmental media has increased significantly, and the "cocktail" effect caused by this phenomenon has garnered increasing attention. However, owing to the scarcity of information regarding the modes of action (MOAs) of chemicals, the application of concentration addition (CA) models for evaluating and predicting the toxicity of mixture with similar MOAs is limited. Additionally, the joint toxicity laws of complex mixture systems to different toxicity endpoints in organisms remain unclear, and effective methods to test the mixture toxicity on lifespan and reproductive inhibition are lacking. Therefore, in this study, the similarity of pesticide MOAs was characterized using molecular electronegativity-distance vector (MEDV-13) descriptors based on eight pesticides (aldicarb, methomyl, imidacloprid, thiamethoxam, dichlorvos, dimethoate, methamidophos and triazophos). Additionally, the methods of lifespan and reproduction inhibition microplate toxicity analysis of elegans (EL-MTA and ER-MTA) were established to test the lifespan and reproduction inhibition toxicity of Caenorhabditis elegans. Finally, a unified scale synergistic-antagonistic heatmap (SAHscale) method was proposed to explore the combined toxicity of the mixtures on the lifespan, reproduction, and mortality of nematodes. The results showed that the MEDV-13 descriptors could effectively characterize the similarity in MOAs. The lifespan and reproductive ability of Caenorhabditis elegans were significantly inhibited when the pesticide exposure concentration was one order of magnitude lower than the lethal dose. The sensitivity of lifespan and reproductive endpoints to mixtures was dependent on the concentration ratio. The same rays in the mixture had consistent toxicity interactions on the lifespan and reproductive endpoints of Caenorhabditis elegans. In conclusion, we demonstrated the feasibility of MEDV-13 in characterizing the similarity of MOAs, and provided a theoretical basis for exploring the mechanism of chemical mixtures by studying their apparent toxicity of mixtures on nematode lifespan and reproduction endpoints.

A novel equal frequency sampling of factor levels (EFSFL) method is applied to identify the dominant factor inducing the combined toxicities of 13 factors.

The research framework combining global sensitivity analysis (GSA) with quantitative high-throughput screening (qHTS), called GSA-qHTS, provides a potentially feasible way to screen for important factors that induce toxicities of complex mixtures. Despite its value, the mixture samples designed using the GSA-qHTS technique still have a shortage of unequal factor levels, which leads to an asymmetry in the importance of elementary effects (EEs). In this study, we developed a novel method for mixture design that enables equal frequency sampling of factor levels (called EFSFL) by optimizing both the trajectory number and the design and expansion of the starting points for the trajectory. The EFSFL has been successfully employed to design 168 mixtures of 13 factors (12 chemicals and time) that each have three levels. By means of high-throughput microplate toxicity analysis, the toxicity change rules of the mixtures are revealed. Based on EE analysis, the important factors affecting the toxicities of the mixtures are screened. It was found that erythromycin is the dominant factor and time is an important non-chemical factor in mixture toxicities. The mixtures can be classified into types A, B, and C mixtures according to their toxicities at 12 h, and all the types B and C mixtures contain erythromycin at the maximum concentration. The toxicities of the type B mixtures increase firstly over time (0.25 âˆ¼ 9 h) and then decrease (12 h), while those of the type C mixtures consistently increase over time. Some type A mixtures produce stimulation that increases with time. With the present new approach to mixture design, the frequency of factor levels in mixture samples is equal. Consequently, the accuracy of screening important factors is improved based on the EE method, providing a new method for the study of mixture toxicity.

Transfer pattern of hormesis into personal care product mixtures from typical hormesis-inducing compounds.

Some personal care products (PCPs) and their chemical components showed a hormetic effect in the freshwater photobacterium Vibrio qinghaiensis sp. -Q67 (Q67) after long-term exposure. However, how hormesis transfers between chemical components and PCP mixture, and which chemical component plays a major role remain unknown. To this end, according to the seven compounds detected in one skin lotion (SK5) and their concentration ratios, many mixture rays were constructed to simulate the SK5. Of these seven compounds, three presented monotonic concentration-response curves (CRC) to Q67 at 0.25 and 12 h (called a S-shaped compound). The other four compounds showed hormetic CRCs after 12 h and monotonic CRCs at 0.25 h (called a J-shaped compound). Based on their mixture ratios, we designed one ternary mixture ray of all S-shaped compounds, one quaternary mixture ray of all J-shaped compounds, and four quaternary mixture rays of one J-shaped and three S-shaped compounds. It was shown that SK5 could be approximately simulated by the mixture ray of the seven compounds detected in SK5 and only the mixture rays containing at least one hormesis-inducing compound produced hormesis to Q67 at 12 h. Based on the concentration ratios of various compounds and comparison of four hormetic characteristic parameters to those of various mixture rays, it was found that the compound betaine (BET) is a key compound affecting the hormesis of mixtures. Additionally, we studied the hormesis mechanism of BET on Q67 via quorum sensing (QS). This preliminarily indicated that the autoinducer-2 triggered the QS pathway. This study elucidated the transfer pattern of hormesis into mixtures, which would be an efficient method to identifying the potential components that affect hormesis transfer in mixtures. We expect that this study will provide new insights into hormesis and its mixtures.

SAHmap: Synergistic-antagonistic heatmap to evaluate the combined synergistic effect of mixtures of three pesticides on multiple endpoints of Caenorhabditis elegans.

The environmental pollution caused by toxic chemicals such as pesticides has become a global problem. The mixture of dichlorvos (DIC), dimethoate (DIM), aldicarb (ALD) poses potential risks to the environment and human health. To fully explore the interaction of complex mixtures on Caenorhabditis elegans behavioral toxicity endpoint. This study created a synergistic-antagonistic heatmap (SAHmap) based on the combination index to systematically describe the toxicological interaction prospect of the mixture system. It was shown that the three pesticides and their binary as well as ternary mixture rays have significant concentration-response relationship on three behavioral endpoints of nematodes, From the perspective of synergistic-antagonistic heatmaps, all the mixture rays in the DIC-DIM mixture system showed strong synergism on the three behavioral and lethal endpoints. In the ternary mixture system, the five mixture rays showed different interaction between the behavioral endpoint and the lethal endpoint, and showed slight synergism to two behavioral endpoints as a whole. The emergence of synergism should arouse our attention to these hazardous chemicals. In addition, the use of SAHmap and the significant linear correlation among three behavioral endpoints further improved the efficiency of the study on the behavioral toxicity of pesticide mixtures to Caenorhabditis elegans.

Introduction of Flavor Chemical Eugenol Attenuating the Synergistic Toxicological Interactions of Flavor Mixtures.

The flavor chemicals benzyl alcohol (BEA), phenylethanol (PHA), and cinnamaldehyde (CID) and their binary mixtures have high toxicity sensitivity to the lethal endpoint of Caenorhabditis elegans. Some binary flavor mixtures even have synergistic toxicological interactions. Eugenol (EUG) is closely related to human life and has many special nonlethal effects on organisms. The effect of its introduction on the combined toxicities of flavor mixtures is worth studying. We introduced EUG into three binary (BEA-PHA, BEA-CID, and PHA-CID) and one ternary (BEA-PHA-CID) flavor mixture systems. Five representative mixture rays were selected from each of the four mixture systems using the uniform design ray (UD-Ray) method. The lethal toxicity of each mixture ray to C. elegans was measured at three different exposure volumes (100, 200, and 400 µL), and a dose-effect model was established. The new parameter iSPAN was used to quantitatively characterize the toxicity sensitivity of each chemical and mixture ray. The toxicological interaction of each mixture was evaluated by the toxicological interaction heatmap based on the combination index (CI). It can be seen that all flavor chemicals and their ternary and quaternary mixture rays have high iSPANs, and the highest value is 16.160 (BEA-PHA-CID-EUG-R1 at 400 µL). According to the heatmap and CI, the introduction of EUG attenuates the synergistic toxicological interactions of flavor mixtures, leading to the transformation ofsynergistic interactions in flavor mixtures into additive action and even antagonistic interaction, and the CI value of the antagonistic interaction is up to 1.8494 (BEA-CID-EUG-R4 at 400 µL).

Hormetic dose-response of halogenated organic pollutants on Microcystis aeruginosa: Joint toxic action and mechanism.

Quinolones (QNs), dechloranes (DECs), and chlorinated paraffins (CPs) are three kinds of new halogenated organic pollutants (HOPs), which originate from the use of flame retardants, lubricants and pesticides. Since QNs, DECs, and CPs are frequently detected in waters and sediments, it is necessary to investigate the toxic effects of these HOPs with dwelling phytoplankton, especially for cyanobacteria, to explore their potential hormetic effects and contributions to algal blooms. In the present study, we investigate single and joint toxicity of QNs, DECs and CPs on Microcystis aeruginosa (M. aeruginosa), a cyanobacterium that is frequently implicated with algal blooms. The results indicate single QNs and DECs induce marked hormetic effects on the proliferation of M. aeruginosa but CPs do not. The stimulatory effect of hormesis is linked with accelerated replication of DNA, which is considered to stem from the moderate rise in intracellular reactive oxygen species (ROS). Joint toxicity tests reveal that both QNs & CPs mixtures and DECs & CPs mixtures show hormetic effects on M. aeruginosa, but QNs & DECs mixtures show no hormetic effect. QNs & DECs mixtures exhibit synergistic toxic actions, which may be caused by a sharp rise in intracellular ROS simultaneously produced by the agents. Joint toxic actions of both QNs & CPs, and DECs & CPs shift from addition to antagonism as concentration increases, and this shift may mainly depend on the influence of CPs on cell membrane hydrophobicity of M. aeruginosa. This study provides data and toxic mechanisms for the hormetic phenomenon of single and joint HOPs on M. aeruginosa. The hormetic effects of HOPs may benefit the proliferation of M. aeruginosa in the aquatic environment, aggravating the formation of algal blooms. This study also reflects the important role of hormesis in environmental risk assessment of pollutants.

Deriving the predicted no effect concentrations of 35 pesticides by the QSAR-SSD method.

The widespread use of pesticides results in their frequent detection in water bodies and other environmental media. Pesticide residues may cause certain risks to the environment and human health, and reliable predicted no effect concentrations (PNEC) must be obtained when assessing environmental risks. Species sensitivity distribution (SSD) is an important method for the derivation of chemical PNECs. Construction of the SSD model requires sufficient toxicity data to various species including at least eight families in three phyla, suitable nonlinear fitting functions and assessment factors (AFs) with certain uncertainty. However, most chemicals could not collect sufficient species toxicity data, while some chemicals had sufficient species toxicity data but could not find suitable fitting functions, thus hindering the construction of effective SSD models. To this end, the established QSAR models were applied to predict toxicity of chemicals to specific species to fill in the toxicity data gaps required for SSD and selecting multiple nonlinear functions to optimize the SSD model. Combined with QSAR and SSD methods, a new method of PNEC derivation was developed and successfully applied to the derivation of PNEC for 35 pesticides. Three QSAR models were used to predict the toxicities of six pesticides with few toxicity data. Nine two-parameter nonlinear functions were used to fit the toxicity-cumulative probability data one by one to determine the optimal SSD models. The hazardous concentrations at the cumulative probability of 5% and 10%, i. e, HC5 and HC10, respectively, were calculated by the optimal SSD model. The assessment factor used to determine the PNEC of the chemical based on the HC10 was derived from the quantitative correlation between HC10 and HC5 of pesticides found in this study. When the toxicity data are insufficient, it may be more appropriate to calculate the PNECs of chemicals using HC10 than using HC5.

New methods of top-to-down mixture toxicity prediction: A case study of eliminating of the effects of cosolvent from binary mixtures.

At present, the toxicity prediction of mixtures mainly focuses on the concentration addition (CA) and independent action (IA) based on individual toxicants to predict the toxicity of multicomponent mixtures. This process of predicting the toxicity of multicomponent mixtures based on single substances or low component mixtures is called down-to-top method in this study. However, due to the particularity of some toxicants, we have to use the top-to-down idea to obtain or eliminate the toxicity of some components from mixtures. For example, the toxicity of toxicants is obtained from the toxicity of a mixture with, especially toxic, cosolvent added. In the study, two top-to-down methods, the inverse CA (ICA) and inverse IA (IIA) models, were proposed to eliminate the effects of a certain component from multicomponent mixtures. Furthermore, taking the eight binary mixtures consisting of different shapes of cosolvents (isopropyl alcohol (IPA) having hormesis and dimethyl sulfoxide (DMSO)) and toxicants (two ionic liquids and two pesticides) as an example, combined with the interaction evaluated by CA and IA model, the influence of different shapes of components on top-to-down toxicity prediction was explored. The results showed that cosolvent IPA having hormesis may cause unpredictable effects, even at low concentrations, and should be used with caution. For DMSO, most of the toxicant's toxicity obtained by ICA and IIA models were almost in accordance with those observed experimentally, which showed that ICA and IIA could effectively eliminate the effects of cosolvent, even if toxic cosolvent, from the mixture. Ultimately, a frame of cosolvent use and toxicity correction for the hydrophobic toxicant were suggested based on the top-to-down toxicity prediction method. The proposed methods improve the existing framework of mixture toxicity prediction and provide a new idea for mixture toxicity evaluation and risk assessment.