Combined Toxicity Research Articles

Combined Toxicity Assessment of Deoxynivalenol and Pb2+ on HK-2 Cells Involved in Excessive ROS-Induced Ferroptosis.

The cocontamination of food by several mycotoxins and heavy metals poses significant health risks, and their combined toxic effects remain poorly understood. Particularly, specific studies exploring their combined impact on ferroptosis remain limited. In this work, we investigated the combined toxic effects of a mycotoxin, called deoxynivalenol (DON), and a heavy metal, called plumbum (Pb), and explored the potential mechanisms of DON and Pb co-occurrence via excessive ROS-induced ferroptosis in HK-2 cells. It was found that combined toxicity of DON and Pb2+ showed a synergism at low concentrations and an antagonism at high concentrations. The increase of the ROS level and iron content as well as the change expression of four ferroptosis marker proteins were observed in DON and Pb2+ individual and combined groups. Furthermore, the addition of ferroptosis inhibitor Fer-1 could mitigate the imbalance of oxidative stress and ferroptosis. Our results suggest that the co-occurrence of DON and Pb2+ might pose a slight threat to the nephrotoxicity due to the interactions related to the excessive ROS-induced ferroptosis, which would provide valuable insights into their potential combined toxic impacts to human and animal health.

Multiple physiological response analyses of Chlorella vulgaris exposed to silver nanoparticles, ciprofloxacin, and their combination.

The combination of silver nanoparticles (AgNPs) and ciprofloxacin (CIP) can be considered an alternative to combat multidrug-resistant microbial infections. However, knowledge about their combined toxicity is scarce after being released in an aquatic environment. The present study evaluated the individual toxicity of AgNPs and CIP and their combined toxicity on the unicellular green microalga Chlorella vulgaris, evaluating cellular responses and conducting metabolomic analysis. The median effective concentrations at 96 h (EC50-96h) for AgNPs, CIP, and the mixture were 132 µg L-1, 7000 µg L-1, and 452 µg L-1, respectively. CIP exhibited a synergistic effect with AgNPs. The toxic ranking for C. vulgaris was AgNPs > AgNPs + CIP > CIP. The growth rate was the most evident parameter of toxicity. Cell diameter significantly increased (p < 0.001) at 96 hours for the highest concentrations tested of AgNPs, CIP, and the mixture, with increases of 24%, 41%, and 19%, respectively, compared to the control. Photosynthetic pigment analyses revealed that C. vulgaris upregulated chlorophyll, carotenoids, and pheophytin. Cell exposure to CIP caused an SOS response involving increased protein and carbohydrate concentrations to tolerate antibiotic stress. Exposure to AgNPs and CIP increased catalase and glutathione S-transferase activity, but the mixture decreased the activity. AgNPs increased malondialdehyde content in exposed cells due to fatty acid peroxidation. These pollutants revealed their potential risks in interfering with survival and metabolism. Our findings highlight the possible hazards of co-pollutants at environmentally relevant quantities, providing insights into the individual and combined ecotoxicity of AgNPs and CIP.

Effects of Cd and Cr Stress on Physiological and Morphological Traits of Two Cultivars of Wheat (Triticum aestivum L.) under Hydroponic System

&lt;p style="line-height:150%;text-align:justify;"&gt;&lt;span style="font-family:&amp;quot;Times New Roman&amp;quot;,serif;" lang="EN-US"&gt;Hydroponic experiment was conducted to evaluate the single and combine effect of different concentration of Cd (&lt;/span&gt;&lt;span style="color:#212121;font-family:&amp;quot;Times New Roman&amp;quot;,serif;" lang="EN-US"&gt;80 µM, 100 µM&lt;/span&gt;&lt;span style="font-family:&amp;quot;Times New Roman&amp;quot;,serif;" lang="EN-US"&gt;) and Cr&lt;/span&gt;&lt;span style="color:#212121;font-family:&amp;quot;Times New Roman&amp;quot;,serif;" lang="EN-US"&gt; (120 µM, 140 µM)&amp;nbsp;&lt;/span&gt;&lt;span style="font-family:&amp;quot;Times New Roman&amp;quot;,serif;" lang="EN-US"&gt;on the seedlings of two wheat cultivars viz. FA-08 and SH-13 commonly grown in Hazara division of Khyber Pakhtunkhwa- Pakistan. High dose accumulation of Cd and Cr greatly affected the plant height and leaf number. The presence of Cd reduced the accumulation of Cr, whereas the effect of Cr on the accumulation of Cd depends on the concentrations of Cd used. Different treatments of these HMs (heavy metals) greatly fluctuate the total amount of phytochemicals in leaves of wheat seedlings. The application of Cd and Cr separately and in combination increased the total phenolics in all treatments compared to control groups which were tested on the 18&lt;sup&gt;th&lt;/sup&gt; day of treatment. Highest levels of total phenolics were recorded in FA-08 when Cd is used in a concentration of 80µM. Flavonoid content was high in FA-08 at level Cd+Cr:100+140µM. SH-13 also depicted highest antioxidant activity at level Cd:80µM against all treatments&lt;sub&gt;&amp;nbsp;&lt;/sub&gt;as compared to FA-08. Cd and Cr behaved synergistically because the combined toxicity of Cd and Cr was less than Cd or Cr alone. The current study suggests that both wheat cultivars were tolerant to stress of Cd and Cr up to certain limit and high concentration reduced the contents of phytochemicals, this might cause decrease in the wheat yield.&lt;/span&gt;&lt;/p&gt;

Combined BPA and DIBP Exposure Induced Intestinal Mucosal Barrier Impairment Through the Notch Pathway and Gut Microbiota Dysbiosis in Mice

Bisphenol A (BPA) and diisobutyl (DIBP) phthalate are widely used as typical plasticizers in food packaging. Plasticizers can be released from polymers, migrate into food, and be ingested by humans, leading to various health problems. However, little research has investigated the combined toxicity of BPA and DIBP, particularly their intestinal toxicity. Our goal is to analyse the combined toxicity of BPA (50 mg/kg) and DIBP (500 mg/kg) on the intestines of KM mice. Additionally, we tried to find natural products that can inhibit or prevent the combined toxicity of BPA and DIBP. The results indicated that the combination of BPA and DIBP exposure resulted in a reduction of beneficial flora, an increase in D-Lac levels (136 ± 14 μmol/L), an increase in intestinal permeability, activation of the notch pathway, and a decline in intestinal stem cells (ISCs) to goblet cells, compared to single-exposure sources. Nevertheless, Rubus chingii Hu phenolic extract (RHPE) (200, 400 and 600 mg/kg) ameliorated the BPA and DIBP-induced intestinal microbiota disruption and intestinal mucosal barrier impairment by inhibiting the overactivation of the notch pathway. The results of this study highlight the potential risks to human health posed by the combination of BPA and DIBP and may help explain the potential pathways of enterotoxicity caused by combined ingestion.

Detection of glyphosate, glufosinate, and their metabolites in multi-floral honey for food safety

Beehives can accumulate environmental contaminants as bees gather pollen, propolis, and water from their surroundings, contaminating hive products like honey. Moreover, in multifloral environments, bees can interact with plants treated with different pesticides, often causing higher pesticides concentrations in multi-floral honey than in mono-floral varieties. Glyphosate and glufosinate are both widely used herbicides. Glyphosate accounted for one-third of herbicide sales in Europe in 2017 and continues to raise health concerns, including its potential carcinogenicity. While the European Commission extended glyphosate’s authorisation for another 10 years in 2023, concerns remain about its impact on biodiversity and human health. This study aimed to monitor the presence of glyphosate, glufosinate, and their metabolites in 100 samples of multifloral honey representing Italian production by analysis using IC-HRMS. Results indicated that 12% of honey samples contained glyphosate residues ranging from > LOQ to 45 ng g−1, with the highest concentrations detected in the Puglia region. No sample exceeded the maximum residue levels set by EU regulations. Glufosinate and its metabolites were not detected in any samples. These findings underscore the need for continued monitoring of pesticide residues in honey, particularly given the potential ‘cocktail effect’ of multiple contaminants and their combined toxicity. This study highlights the importance of safeguarding consumer health, especially in vulnerable populations, by addressing gaps in data on pesticide residue levels.

Evaluation of the combined toxicity of compound pollutants of azole fungicides to Raphidocelis subcapitata

In order to investigate the combined toxicity of compound contaminated azole fungicides on alage. Systematic investigation of Difenoconazole, Penconazole, Metconazole, Tetraconazole, Flutriafol, Fuberidazole, Triflumizole, Terrazole, HyMexazol, 9 azole fungicides as the components of the mixture. Thirty-five binary mixture systems with 173 mixture rays were designed by direct equipartition ray method. The growth inhibition toxicity of binary mixtures to Raphidocelis subcapitata was determined by 96-well microplates. Toxic interactions were qualitatively analyzed by Concentration addition (CA) and Independent Action (IA) models. Model Deviation Ratio (MDR) was used to quantitatively evaluate the toxic interaction of binary mixtures of azole fungicides, as well as the equivalent graph method, Toxic Unit (TU) method, additivity Index method (AI), Toxicity Index (MTI) and Combination Index (CI) methods were used to analyze the combined toxicity and toxic interaction of the mixture. The results showed that the frequency of synergistic effect was higher when mixed with Difenoconazole, Penconazole and Triflumizole, and the binary mixing with Flutriafol, Fuberidazole and Metconazole could reduce the toxicity of the mixture, showing additive and antagonistic effects. The toxicity of the mixture ranged from 3.053 to 6.415. In addition, at ambient concentrations, the mixture interaction is dominated by addition.

Mechanistic insights into ferroptosis and apoptosis pathways: Synergistic effects of multi-organ toxicity and transgenerational effects induced by co-exposure of epoxiconazole and aflatoxin B1 in zebrafish.

In the environment, mycotoxins and fungicides frequently coexist, potentially causing synergistic risks to organisms. Epoxiconazole (EPO) and aflatoxin B1 (AFB1) are a common fungicide and mycotoxins, respectively, which are widely present in the environment and have toxic effects on multiple organs once entering the organism, but it is still unclear whether the co-exposure has a synergistic toxic effect. This study delves into the molecular mechanisms underlying the co-exposure to EPO and AFB1, emphasizing multi-organ toxicity in female zebrafish (F0 generation) and potential transgenerational impacts on the offspring embryos (F1 generation) through multi-omics approaches. Findings indicate that exposure to either EPO or AFB1, individually or combined, intensified intestinal pathological damage, decreased the expression of tight junction proteins, altered gut microbiota composition, and induced intestinal inflammation, with co-exposure causing more severe effects. RNA-seq analysis revealed an enrichment of ferroptosis and apoptosis pathways in the liver and ovaries of F0 zebrafish. Co-exposure markedly altered the expression of associated molecules, exacerbating pathological damage in these organs. Molecular docking studies revealed that AFB1 exhibited lower binding energies to Caspase3, GPX4 and IL-1β compared to EPO, suggesting that it may have a higher binding capacity. Furthermore, both single and combined exposures modified the expression of molecules related to apoptosis, inflammatory response, and ferroptosis in unexposed F1 embryos, with co-exposure demonstrating more significant biological effects, thereby confirming transgenerational toxicity. The present study provides preliminary evidence on the potential mechanisms of combined exposure-induced multi-organ toxicity, highlighting ferroptosis of the liver and apoptosis of the ovary as key pathways. These findings provide new perspectives and methods for risk assessment of multiple environmental pollutants.

Synergistic effects of PS-NPs and Cd on ovarian toxicity in adolescent rats: Ferroptosis by induction of mitochondrial redox imbalance via the SIRT3-SOD2/Gpx4 pathway.

Nanoplastics (NPs) are an emerging class of pollutants. They can act as a"Trojan horse" to change the bioavailability and toxicity of heavy metals in the environment. However, research on the combined toxicity of heavy metals and NPs is scarce, especially during the critical developmental period of adolescence. In this study, polystyrene nanoplastics (PS-NPs) and/or cadmium (Cd) were exposed to 4-week-old female rats for 28 days, with the aim of exploring the potential effects of combined exposure to PS-NPs and Cd on the ovaries of adolescence rats. Results showed that co-exposure to PS-NPs and Cd exacerbated ovarian toxicity in rats, primarily through increased atretic follicle numbers and endocrine disruption. Further studies revealed that PS-NPs and Cd synergistically repressed the SIRT3-SOD2/Gpx4 pathway, inducing mitochondrial oxidative stress and ferroptosis, resulting in damage to ovarian structure and function. However, the addition of the mitochondrion-targeted antioxidant SS-31 and the ferroptosis inhibitor Fer-1 reversed the harm to the ovaries from co-exposure to PS-NPs and Cd, the aberrant expression of genes related to the SIRT3-SOD2/Gpx4 pathway was also improved. Our results suggested that co-exposure to PS-NPs and Cd may trigger ferroptosis by inhibiting the SIRT3-SOD2/Gpx4 pathway, leading to mitochondrial redox imbalance, which provided novel insights into reproductive toxicity due to the interaction of PS-NPs and Cd during adolescence.

Individual and Dual Cytotoxicity of the Combination of Passiflora Caerulea Leaf Extract and Titanium Oxide Nanoparticles against A549, U937, and Hela Cells

Background: The study addresses the underexplored realm of cytotoxicity evaluation involving binary mixtures of Passiflora caerulea leaf extracts and Titanium nanoparticles (TiO2NPs). The focus lies on understanding the combined effects of these components on cancer cells (A549, U937, and HeLa). Methods: In vitro cytotoxicity assessments were employed to evaluate the toxicity of P. caerulea leaf extracts, TiO2NPs, and their combination. The study utilized MTT, NRU, and LDH assays to measure cellular viability. Additionally, reactive oxygen species (ROS) and glutathione levels were assessed alongside the aforementioned assays. Results: The toxicity percentage exhibited dose-dependent behavior for P. caerulea leaf extracts, TiO2NPs, and their combination. Interestingly, when P. caerulea leaf extract and TiO2NPs were combined, the reduction in cell viability was noticeably more than when the exposures were made separately. Moreover, the production of ROS was higher in the combined toxicity scenario, and a more pronounced decrease in glutathione levels was observed compared to individual exposures. Conclusion: The findings suggest that the combined effects of P. caerulea leaf extract and TiO2NPs induce greater cytotoxicity compared to their impacts. This underscores the potential for synergistic cytotoxicity in combined exposure scenarios, warranting further exploration of combined effects in future studies.

Evaluation of the safety and efficacy of stereotactic body radiotherapy for radio-recurrent prostate cancer: a systematic review and meta-analysis.

Stereotactic body radiotherapy (SBRT) is pivotal in managing radio-recurrent prostate cancer (PCa). This study aims to comprehensively review its efficacy and associated severe toxicities. A thorough review of PubMed and EMBASE databases up to July 2024 was conducted to assess recurrence-free survival (RFS) with salvage SBRT across various subgroups. Survival curves were reconstructed using WebPlotDigitizer and a newly developed shiny application. Thirty-six studies were analyzed, with 15 papers (682 patients) contributing to survival curve reconstruction. Median RFS was 36.2 months, with 2-, 3-, and 5-year rates of 64.8%, 50.7%, and 40.6%, respectively. Factors associated with improved RFS included whole-gland irradiation [focal vs. whole, hazard ratio (HR) 1.83 (95% CI: 1.16-2.87), p = 0.008], and higher biologically effective dose (BED) [120-138.1 Gy vs. 144-167.7 Gy, HR 1.40 (95% CI: 1.07-1.83), p = 0.015]. Severe (grade ≥ 3) acute and late genitourinary (GU) toxicities occurred in 1.4% (95% CI: 0.8-2.3) and 3.7% (95% CI: 2.6-4.9) of patients, respectively. Severe acute and late gastrointestinal (GI) toxicities were reported in 0.5% (95% CI: 0.2-1.1) and 0.4% (95% CI: 0.1-1.0) of patients, respectively. Combined severe GU and GI toxicities were observed in 5.8% (95% CI: 4.5-7.4) and 1.3% (95% CI: 0.7-2.2) of patients, respectively. This study provides a comprehensive assessment of toxicities and conducts a pooled analysis of RFS for salvage SBRT in radio-recurrent PCa. Factors such as whole-gland irradiation, and higher BED show promise as prognostic indicators for RFS. However, confirmation through randomized controlled trials is essential due to the low levels of evidence and study heterogeneity.

Antibiotic sorption onto MPs in terrestrial environment: a critical review of the transport, bioaccumulation, ecotoxicological effects and prospects.

Microplastics (MPs) and antibiotics are prevalent contaminants in terrestrial environment. MPs possess the ability to absorb antibiotics, resulting in the formation of complex pollutants. While the accumulation and fate of MPs and antibiotics in marine ecosystems have been extensively studied, their combined pollution behavior in terrestrial environments remains relatively underexplored. This paper describes the sources, migration, and compound pollution of MPs and antibiotics in soil. It reviews the mechanisms of compound toxicity associated with antibiotics and MPs, combining different biological classifications. Moreover, we highlight the factors that influence the effects of MPs as vectors and the critical elements driving the spread of antibiotic resistance genes (ARGs). These information suggests the potential mitigation measures for MPs contamination from different perspectives to reduce the impact of ARGs-carrying MPs on human health, specifically through transmission via plants, microbes, or terrestrial vertebrates. Finally, we identify gaps in scientific knowledge regarding the interaction between MPs and antibiotics in soil environments, including the need for standardized research methods, multi-dimensional studies on complex ecological effects, and more comprehensive risk assessments of other pollutants on human health. In summary, this paper provides foundational information for assessing their combined toxicity, offers insights into the distribution of these emerging pollutants in soil, and contributes to a better understanding of the environmental impact of these contaminants.

Ninety-Day Subchronic Toxicology of Individual and Combined Toxicants from the Thermal Processing of Lipid-Rich Foods.

Oxidative derivatives of triacylglycerols (ox-TGs), aldehydes, and 3-monochloropropane-1,2-diol esters (3-MCPDE) were simultaneously evaluated in a 90-day subchronic study, focusing on biological indicators, biochemical indicators, and serum metabolomics as the first part of integrated toxicity and interactions. After 90 days of feeding Kunming mice, coexposure to combined toxicants significantly inhibited the trend of liver weight gain, reduced the levels of total bilirubin (TBIL) and direct bilirubin (DBIL), and decreased uric acid (UA) compared to individual toxicant exposure. A total of 21 and 31 biomarkers in female and male mice were identified, respectively. Co-exposure to combined toxicants might mitigate the changes in cytidine, CDP, dUMP, and dUDP involved in purine and pyrimidine metabolism caused by a single exposure, but exacerbate the changes in l-tryptophan, 5-hydroxy-l-tryptophan, and 5-hydroxyindoleacetic acid, which are involved in tryptophan metabolism. These results provided new insights into a comprehensive toxicity and interaction evaluation model of multiple combined toxicants in food.

Distinct baseline toxicity of volatile organic compounds (VOCs) in gaseous and liquid phases: Mixture effects and potential molecular mechanisms.

Volatile organic compounds (VOCs) are significant pollutants found in various environments, posing health risks. Traditionally, the gaseous VOCs are adsorbed and eluted in liquid phases, and then subjected to toxicity testing, which deviates from the actual exposure scenarios of gaseous VOCs. How the physical states of VOCs (gaseous or liquid) affect their toxicity has not been well understood. This study examined the baseline toxicity of VOCs in both gaseous and liquid phases using a self-assembled passive colonization hydrogel (SAPCH) with luminous bacteria (Vibrio fischeri). The findings revealed that gaseous VOCs exhibited higher baseline toxicity than their liquid counterparts, attributed to the higher free energy and electronic activity of gaseous VOC molecules. Furthermore, the study elucidated that the differences in electronic transitions and energy gaps significantly impact the combined toxicity of VOC mixtures in different phases. Understanding these differences is crucial for assessing the real-world impact of VOCs on health and the environment.

Toxicity of Polystyrene Microplastics with Cadmium on the Digestive System of Rana zhenhaiensis Tadpoles.

Microplastics pollution in freshwater systems is attracting increasing attention. However, our knowledge of its combined toxicity with heavy metals is scarce. In this study, Rana zhenhaiensis was used as the model animal to study the combined poisoning mechanism of cadmium or microplastics on the digestive systems of tadpoles in freshwater. Results showed that the exposure to cadmium and polystyrene increased the mortality and metamorphosis rate of R. zhenhaiensis tadpoles, and delayed their growth and development. Cadmium was detected in the livers and intestines, while polystyrene mainly accumulated in the gills and intestines of tadpoles. The individual exposure of cadmium or polystyrene can cause pathological damage to liver tissue, induce oxidative stress in liver, and change gene expression. Cadmium co-exposure with polystyrene can reduce the cadmium accumulation in the liver. While polystyrene can slightly increase cadmium accumulation in the intestine. Exposure to cadmium and polystyrene altered the abundance and community structure of intestinal microbiota, and polystyrene increased the dysregulation of the gut microbiome. In this study, the combined exposure of microplastics and cadmium had a negative impact on R. zhenhaiensis tadpoles, but the introduction of microplastics on the toxicity of cadmium on the tadpoles needs further investigation, due to the different characteristics of microplastics.

Development of UHPLC‐MS/MS Method for Evaluation of the Acute Oral Toxicity and Pharmacokinetics of Ursodeoxycholic Acid and Silymarin Combination in Rats

ABSTRACTThe combination of ursodeoxycholic acid (UDCA) and silymarin has been shown to alleviate various hepatic conditions. This study aimed to evaluate the acute oral toxicity and in vivo pharmacokinetics of the combination in female Sprague Dawley rats. The acute oral toxicity and the pharmacokinetic studies were conducted using 17 rats divided into five groups and 30 rats assigned into four control groups and one treatment group, respectively. A new UHPLC/MS‐MS method was applied to determine silibinin (SIL) and UDCA in plasma, urine, and feces. This method used the BEH C8 column (1.7 µm, 100 × 2.1 mm) with a gradient elution of 0.01% formic acid in water and 0.01% formic acid in acetonitrile. The acute oral toxicity study revealed that administering the combination at 5000 mg/kg preserves a wide safety margin. In the pharmacokinetic study, the combination resulted in a significant enhancement of the absorption of both drugs and a reduction of the renal elimination of silymarin. The oral LD50 of the combination was higher than 5000 mg/kg, so according to the OECD guidelines, it was classified in Category 5 GHS. The presented data serve as scientifically defensible safety data with a defined absorption and elimination profile for the combination.

Molecular insights into acetyl triethyl citrate (ATEC) induced toxic effect in HepG2 cells based on multi‐omics integrative analysis

AbstractCitrate esters have become the main alternatives to traditional plasticizers in food packaging materials. However, there is a lack of understanding of their toxic effects, particularly the combined effects and inner mechanisms has not been well studied. Our group pioneered the study on combined toxicity of tributyl citrate (TBC) and acetyl triethyl citrate (ATEC), two commonly co‐used citrate esters in food packaging materials. The results showed that exposure to TBC and ATEC can decrease the viability of HepG2 cells in a dose dependent manner. When the mixtures of ATEC and TBC exposed to HepG2 cells, they exhibited antagonism effect. Therefore, ATEC was selected to investigate the molecular mechanisms with multi‐omics techniques at its 1/4 EC50 concentration. A total of 31 metabolites with significant changes were found as potential biomarkers. The LIPG (Lipase G, endothelial type) and GCLM (glutamate‐cysteine ligase modifier subunit) were identified as differentially expressed genes based on transcriptomic analysis. Moreover, downregulated l‐glutamate and l‐glutamine which participate in TCA cycle, resulting in the collapse of energy production and cytotoxicity. These findings on major metabolic pathways will provide insight into the mechanism of cytotoxicity of HepG2 cells after ATEC exposure.

Acute toxicity of binary and ternary mixtures of La, Ce and Dy on Daphnia magna: Toxicity patterns depend on the ratios of the components and the concentration gradient

Rare earth elements (REEs) have raised significant environmental contamination concerns, yet the combined toxicity of REE mixtures remains inadequately understood. In this study, acute toxicity of individual, binary and ternary mixtures of lanthanum (La), cerium (Ce), and dysprosium (Dy) on neonatal Daphnia magna was investigated. Dy exhibited the greatest toxicity on neonatal Daphnia magna, followed by La and Ce. The concentration addition (CA) model was superior to the independent action (IA) model for predicting the toxicity of binary mixtures. The CA model indicated additive effects for LaCe mixture and antagonistic effects for LaDy and CeDy mixtures. In contrast, IA model suggested synergistic interactions for LaCe and LaDy mixtures, with antagonistic effects for CeDy mixture when considering dissolved concentration and synergistic effects when considering free-ion concentration. The nonadditive interactions and deviation parameters from the prediction of binary mixture toxicity were assessed by using MixTox model. The ternary mixture of LaCeDy exhibited antagonistic effects on Daphnia magna, and IA model slightly outperformed CA model. Overall, the type of combined toxicity in REE mixtures is influenced by constituents in the mixture and concentration levels. These findings provide scientific basis for the toxicological assessment, risk evaluation and pollution control of REE mixtures. Environmental implicationRare earth elements (REEs) level is increasing in water environment due to wide use and exploitation. However, currently, we know little about the difference of REEs toxicity and combined toxicity of mixture to aquatic organism, which limited the assessment of toxicity and hazard risk of REEs in natural water. Here, this study demonstrates the acute toxicity of individual, binary and ternary mixtures of lanthanum, cerium, and dysprosium on neonatal Daphnia magna according to the measured data and predicted model, identifying the influence factors for combined toxicity. This discovery offers new insights for the assessment and prediction of REEs toxicity.

Importance of tailored non-clinical safety testing of novel antimalarial drugs: Industry best-practice

Malaria is an acute, debilitating parasitic illness. There were 249 million cases of malaria in 2022, resulting in 608,000 deaths globally, 76% of which were children ≤5 years. The unique nature of this disease (recurrences leading to re-treatments and numerous organ systems affected), specific clinical treatment regimens, poor compliance, and diversity of affected populations (predominantly pediatrics, women of childbearing potential, pregnant and lactating women), often makes standard testing approaches inadequate, and tailor-made safety assessments are more appropriate.We provide best practice recommendations based on company experience for the non-clinical safety assessment of antimalarial drugs, with a focus on small molecules since they represent the majority of drug candidates for this illness. We focus on specific testing considerations for repeat dose toxicity studies, including combination toxicity assessments, since new drug treatment regimens typically foresee short treatment durations to improve compliance (i.e., 1 day) with combinations of compounds to improve efficacy and limit potential resistance. Due to the target population, the timing of reproductive, developmental, and juvenile toxicity studies may be earlier than general testing roadmaps for other small molecule drugs.In conclusion, key recommendations presented should enable a more effective and efficient development path whilst protecting clinical trial participants and patients.

Evidence that cadmium aggravate the toxicity of triphenyl phosphate in aquatic sediments to Corbicula fluminea

The ubiquitous co-existence of triphenyl phosphate (TPhP) and heavy metals in sediments raises significant biotoxicity concerns. However, uncertainty still exists regarding their combined toxicity to benthic organisms. Therefore, this research was conducted to elucidate the influences of cadmium (Cd) on TPhP toxicity to Corbicula fluminea (C. fluminea) in sediments. As a result, Cd promoted the accumulation of TPhP in C. fluminea and enhanced TPhP toxicity, manifested by damaged cell membranes and pronounced histological alterations. Molecular docking revealed that TPhP-Cd complexes exhibit greater binding affinity to cytochrome P4501A1 (CYP1A1) compared to TPhP alone. With the activity of CYP1A1 increasing, the biotransformation of TPhP was promoted in low-TPhP+Cd treatments (T5C0/T5C5/T5C35). Additionally, metabolites related to antioxidant defence and repair processes were reinforced to alleviate the toxicity of TPhP and Cd. However, excessive oxidative stress impaired the CYP1A1 activity in high-TPhP+Cd treatments (T35C0/T35C5/T35C35). Furthermore, metabolic pathway analysis revealed significant perturbations in the citrate cycle, alanine, aspartate and glutamate metabolism, purine metabolism, and pyrimidine metabolism. These disruptions weakened the repair capacity and aggravated apoptosis in digestive glands, potentially contributing to the synergistic toxicity of TPhP and Cd. The results highlight the ecological risks posed by TPhP in combination with heavy metals to benthic organisms.

Microplastics from face masks: Unraveling combined toxicity with environmental hazards and their impacts on food safety.

Microplastics (MPs) refer to tiny plastic particles, typically smaller than 5mm in size. Due to increased mask usage during COVID-19, improper disposal has led to masks entering the environment and releasing MPs into the surroundings. MPs can absorb environmental hazards and transfer them to humans and animals via the food chain, yet their impacts on food safety and human health are largely neglected. This review summarizes the release process of MPs from face masks, influencing factors, and impacts on food safety. Highlights are given to the prevalence of MPs and their combined toxicities with other environmental hazards. Control strategies are also explored. The release of MPs from face masks is affected by environmental factors like pH, UV light, temperature, ionic strength, and weathering. Due to the chemical active surface and large surface area, MPs can act as vectors for heavy metals, toxins, pesticides, antibiotics and antibiotic resistance genes, and foodborne pathogens through different mechanisms, such as electrostatic interaction, precipitation, and bioaccumulation. After being adsorbed by MPs, the toxicity of these environmental hazards, such as oxidative stress, cell apoptosis, and disruption of metabolic energy levels, can be magnified. However, there is a lack of comprehensive research on both the combined toxicities of MPs and environmental hazards, as well as their corresponding control strategies. Future research should prioritize understanding the interaction of MPs with other hazards in the food chain, their combined toxicity, and integrating MPs detection and degradation methods with other hazards.