Toxic Responses Research Articles

The anti-PD-L1/CTLA-4 bispecific antibody KN046 plus lenvatinib in advanced unresectable or metastatic hepatocellular carcinoma: a phase II trial

This open-label phase II trial (NCT04542837) aimed to evaluate the efficacy and safety of KN046 combined with lenvatinib in patients with advanced hepatocellular carcinoma (HCC), and explore the potential response biomarkers. Participants received KN046 5 mg/kg every 3 weeks and lenvatinib 12 or 8 mg once daily. The primary endpoints were safety, tolerability, dose-limiting toxicity (DLT), and objective response rate (ORR) according to RECIST v1.1. A total of fifty-five participants were enrolled. The results meet the pre-specified primary endpoints. No DLT was observed in the safety run-in period. The incidence of serious adverse events and grade ≥3 treatment-related adverse events (TRAEs) was 30.9% and 47.3%, respectively. Grade ≥3 immunotherapy-related adverse events occurred in 3 (5.5%) participants. Five (9.1%) participants discontinued treatment due to TRAEs, all of which were grade 1-2. The ORR was 45.5% (95% CI, 31.97-59.45). The median progression-free survival was 11.0 (95% CI, 8.21-15.24) months. The median overall survival (OS) was 16.4 (95% CI, 11.20-not estimable) months, and 12-month OS rate was 60.0% (95% CI, 45.87-71.55). Circulating tumor DNA status before the third cycle of treatment was associated with prognosis. In conclusion, First-line KN046 plus lenvatinib shows promising efficacy for advanced unresectable or metastatic HCC.

Toxicological interactions of cosmetic and personal care additives mixtures: An update based on measurement and simulation.

The toxicity of chemical mixtures may be misestimated, as the assessment of individual chemicals may not adequately reflect their combined toxic effects. However, numerous combinations of chemicals and various interactions make it impossible to measure all possible mixtures. Computational toxicology can help to mitigate this issue, particularly with new methodologies that rely upon alternatives to animal testing. For cosmetic and personal care additives (CPCAs), the ever-increasing of consumption has triggered their complex co-existence in the aquatic environment. To assess their ecological risks, CPCAs experimentally mix at realistic low concentrations with multi-components and different combinations needs to be examined firstly. In this study, toxicity and interactions of multi-component CPCAs mixtures were analyzed taking Daphnia magna as model organism. Also, the contributions of components to the mixture toxicity at different effect levels were discussed. Apparently, the mixture toxicity is closely related to components proportion and impacted by dilution effect. Different forms of combined toxic effects occur in different effect levels. The more components, the less interactions, and the combined toxic effect tends to be additive. Then, Quantitative Structure-Activity Relationship (QSAR) models were developed and evaluated to predict the aquatic toxicity of CPCAs mixtures at various effect levels. The model performance at the median effect level is the best. The descriptors associated most to the toxicity response of CPCA multi-component mixtures are autocorrelation and radial distribution function (RDF), which provide structural information about the spatial distribution of electronic properties and atomic mass.

Occupational Health Risk Assessment of Microbiological Air Quality in Buhemba Small Scale Gold Mines, Tanzania

A large part of bio-aerosols is composed of biological particles such as bacteria, fungi, viruses, pollens, and their by-products such as endotoxins, metabolites, toxins, and other microbial fragments. These micro-organisms may affect human health with a wide range of adverse health effects including respiratory infections, allergies or toxic response in some individuals, especially susceptible ones. A cross-sectional study was conducted among purposely selected mining pits of Buhemba gold mine in Mara, Tanzania. To determine the microbial count, an agar strip loaded RCS® Microbial Air Sampler was used. Samples were collected at different microenvironments of the mining pit at a flow rate of 100 L min–1 for 5 minutes to yield a sample volume of 500 liters. Morphological characterization of both bacterial and fungal colonies was carried out followed by microscopic examination of fungal and gram-stained bacterial colonies. Regression analysis between mean bacterial and fungal spore counts with environmental factors like temperature and relative humidity was performed. The total aerobic bacteria concentration varied significantly (p value<0.05) between sampled pits (n=15), with the highest and lowest values of 3859 CFU/m3 and 1309 CFU/m3, respectively. However, there was no significant difference in total anaerobic bacteria concentration between sampled pits. The highest and lowest values of anaerobic bacteria were respectively 4284 CFU/m3 and 1190 CFU/m3. The highest and lowest values of total fungi concentration were 3314 CFU/m3 and 646 CFU/m3, respectively. High bacteria load that exceeds 1000 CFU/m3 as recommended by WHO was found in Buhemba gold mine.

Nivolumab and rituximab in treatment naive follicular lymphoma: the phase II '1st FLOR' study.

Follicular lymphoma (FL) outcomes are heavily influenced by host immune activity with immune anti-tumor activity mitigated by PD-1/PD-L1 pathway engagement. Combination CD20-directed therapy plus PD-1 inhibition (PD-1i) increases T-cell tumor killing and NK-cell antibody-dependent cell cytotoxicity (ADCC). Mounting evidence supports immune-priming using PD-1i before cancer-directed agents. Our multicentre, open-label, phase II 1st FLOR study (NCT03245021) enrolled 39 previously-untreated advanced-stage FL patients to receive 4 cycles of nivolumab (240mg) then 4 cycles of 2-weekly nivolumab plus rituximab 375mg/m2 (induction) then 1 year of monthly nivolumab (480mg) plus 2 years of 2-monthly rituximab maintenance. Participants with complete response (CR) after nivolumab priming continued nivolumab monotherapy. The primary endpoint was toxicity during induction. Adverse events (AEs) ≥ grade 3 during induction occurred in 33% (n=13); most commonly elevated amylase/lipase (15%), liver enzyme derangement (11%) and infection (10%). Three patients discontinued nivolumab secondary to toxicity; two pancreatitis, one acute kidney injury. Overall response rate (ORR) was 92% (CR 59%). Median follow-up was 51 months. Median and 4-year progression-free survival (PFS) were 61 months (95%CI 2-72) and 58% (95%CI 34-97); 70% of responders remained in CR. 4-year overall survival was 95%. High baseline total metabolic tumor volume and total lesion glycolysis conferred inferior PFS (p=0.04 and p=0.02). Additionally, high baseline tumor CD8A gene expression was associated with improved PFS (p=0.03). Nivolumab priming followed by nivolumab-rituximab in treatment-naive FL is associated with favorable toxicity and high response rates potentially providing an alternative to chemotherapy. TMTV and high tumor CD8A expression are promising immunotherapy biomarkers for FL.

Toxicity responses of different bee species to flupyradifurone and sulfoxaflor insecticides reveal species and sex-based variations.

Mason bees (Osmia spp.) are solitary, tunnel-nesting bees. Several species, including the horn-faced bee (Osmia cornifrons) and the blue orchard bee (Osmia lignaria), are commercially managed, primarily for the pollination of fruit trees and tree nuts. They are efficient pollinators and have high pollen fidelity, and so can greatly benefit orchard yields compared to honey bees (Apis mellifera) alone. Apis mellifera are often used as surrogates for other pollinators during pesticide risk assessment. Non-Apis bee species, however, can be more sensitive to certain pesticides, so it is also important to research the impact of novel pesticides on other bee species. This study investigated the effect of two formulated pesticide products containing recently approved active ingredients, sulfoxaflor and flupyradifurone, on the survival of A. mellifera and three species of mason bees (O. lignaria, O. cornifrons, and Osmia californica). Bees were orally exposed to sulfoxaflor or flupyradifurone and their survival was measured over four days following exposure. Bee sensitivity to the insecticides varied by species and sex of bee. Apis mellifera was the least sensitive, followed by O. cornifrons, with O. lignaria and O. californica as the most sensitive. Male Osmia spp. bees were less sensitive than females. These insecticides may pose a higher risk to the health of Osmia spp. compared to A. mellifera.

Comparative study of the toxicity responses of Vallisneria natans and Pistia stratiotes to sulfadiazine under different planting methods.

Sulfonamides are receiving increased attention due to their persistence in the environment and potential ecological risks. However, there are currently relatively few studies on the toxicity response of aquatic plants grown under the single and mixed planting methods to sulfadiazine (SD). This study investigated the response of the Vallisneria natans (Lour.) Hara (V. natans) and the Pistia stratiotes L. (P. stratiotes) to SD toxicity under single and mixed planting methods. The findings demonstrated that under the mixed planting method, 0.3 μg/L SD significantly reduced the biomass of V. natans (p < 0.05) while increasing the biomass of P. stratiotes. Under the single planting method, the chlorophyll a content of V. natans and P. stratiotes showed the highest value when exposed to 0.3 μg/L SD. The chlorophyll b content of V. natans and P. stratiotes was higher in the single planting method compared to mixed planting method. In single planting, V. natans exhibited the highest superoxide dismutase (SOD) activity when exposed to high concentrations of SD (3.0 μg/L). However, under the mixed planting method, the SOD activity of V. natans and P. stratiotes reduced at 0.3 μg/L SD. P. stratiotes showed increased malondialdehyde (MDA) and glutathione S-transferase (GST) activities at 3.0 μg/L SD under the single planting method. The comprehensive stress resistance ranking was as follows: single planting (V. natans) > mixed planting (P. stratiotes) > mixed planting (V. natans) > single planting (P. stratiotes). Moreover, exposure to SD downregulated the cell motility metabolic pathway of V. natans and P. stratiotes, particularly under the mixed planting method, to increase the resistance of V. natans and P. stratiotes to SD exposure. Proteobacteria, Actinobacteria and Bacteroidetes were the dominant phyla. This study provides basic data and scientific support for the selection of plants for remediation of higher SD polluted waters using ecological remediation.

Combined exposure to microplastics and copper elicited size-dependent uptake and toxicity responses in red swamp crayfish (Procambarus clarkia).

In recent years, the toxicity of microplastics (MPs) in combination with heavy metals, particularly the influence of varying microplastic sizes on their toxic effects, has attracted widespread attention. In this study, red swamp crayfish (Procambarus clarkia) were exposed to MPs of two particle sizes (S-MPs: 5 μm, 1 mg/L; and L-MPs: 100 μm, 1 mg/L) and Cu (5 mg/L) individually or in combination for 96 h. The accumulation patterns of MPs were as follows: gills > intestines > hepatopancreas > muscles. Moreover, the accumulation pattern of Cu was as follows: intestines > gills > hepatopancreas > muscle. Additionally, S-MPs and L-MPs enhanced Cu accumulation, with the highest levels observed in the S-MPs+Cu-treated group. Histopathological analysis showed that the combined exposure led to greater hepatopancreatic damage. Assessment of antioxidant enzymes showed decreased activities of superoxide dismutase, catalase, and glutathione among the different treatments, except for malondialdehyde, which was elevated compared to the control group. In the S-MPs+Cu-treated group, the expression levels of Cu homeostasis genes (MTF-1, ATP2, Atox1, MT) were significantly lower than those in the Cu treated group. This study provides a valuable reference for studying the combined toxic effects of MPs with varying particle sizes on heavy metals.

Using the TOPSIS method to select the best low-toxicity organic cosolvent for rice-based toxicity tests.

The application of low-toxicity cosolvents in phytotoxicity tests is a common technique to enhance the distribution of non-water-soluble organic pollutants in the aqueous phase. In this study, the physiological and biochemical responses of rice seedlings to four commonly used organic solvents i.e., dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), pyridine, and Tween-80 were investigated using 16 parameters to assess their impacts on rice plants. Results from phytotoxicity tests indicated that these organic solvents caused varying toxic responses in rice plants and significantly affected the uptake and distribution of mineral nutrients within rice tissues. In order to select the best organic solvent for rice-based toxicity tests among the four solvents with optimal concentrations, the technique for order preference by similarity to ideal solution (TOPSIS) was employed to minimize the variations across different treatment groups. Three different weighting coefficients, namely entropy weight coefficients (EWCs), contribution factor coefficients (CFCs), and combination effective coefficients (CECs) were adopted to calibrate the initially created evaluation matrices. All estimations were judged by the relative closeness coefficients, in which the higher relative closeness value means the better solution to the optimal result. Among the four organic solvents evaluated by TOPSIS, pyridine at 1.24 mmol/L emerged as the most effective solution for rice-based phytotoxicity tests. Overall, this study represents the first attempt to comprehensively evaluate the toxic responses of cosolvents to rice plants using the TOPSIS method. It also offers valuable insights into a number of ecotoxicological applications like the analysis of solvent-generated extracts of environmental matrices from soils and sediments, or the detection of organic compounds induced toxicity with cosolvents.

A phase II study of ramucirumab and somatostatin analog therapy in patients with advanced neuroendocrine tumors.

Well-differentiated neuroendocrine tumors (NET) are highly vascular tumors characterized by their expression of vascular endothelial growth factor (VEGF). This trial investigated the activity of ramucirumab, a monoclonal antibody that targets VEGF receptor-2 (VEGFR-2) and inhibits activity of VEGF, in combination with somatostatin analog therapy in patients (pts) with advanced extra-pancreatic NET. We conducted a single-arm phase II trial enrolling pts with advanced, progressive extra-pancreatic NET. Patients were treated with ramucirumab 8mg/kg intravenously on days 1 and 15 of each 28-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints toxicity, radiographic and biochemical tumor response rate, and overall survival (OS). The trial enrolled 43 patients. Primary tumor sites included small intestine 20 (46%), lung 10 (23%), thymus 3 (7%), rectum 1(2%), kidney 1(2%), and unknown primary 8(18%). Median PFS was 14.2 months (95% CI, 9.0-25.6 months), and median OS was 24.9 months (95% CI, 20.7-43.1 months). Best response by RECIST 1.1: partial response 5% (95% CI, 0.6%-15.8%). Chromogranin A levels dropped by at least 50% in 10% of the 37 patients who had elevated levels at baseline. Most common all-grade adverse events included fatigue (84%) and hypertension (84%). Ramucirumab demonstrated efficacy and safety in this single-arm phase II trial. These findings support the continued evaluation of angiogenesis inhibitors in the treatment of NET. NCT02795858.

Quantifying liver-toxic responses from dose-dependent chemical exposures using a rat genome-scale metabolic model.

Because the liver plays a vital role in the clearance of exogenous chemical compounds, it is susceptible to chemical-induced toxicity. Animal-based testing is routinely used to assess the hepatotoxic potential of chemicals. While large-scale high-throughput sequencing data can indicate the genes affected by chemical exposures, we need system-level approaches to interpret these changes. To this end, we developed an updated rat genome-scale metabolic model to integrate large-scale transcriptomics data and utilized a chemical structure similarity-based ToxProfiler tool to identify chemicals that bind to specific toxicity targets to understand the mechanisms of toxicity. We used high-throughput transcriptomics data from a 5-day in vivo study where rats were exposed to different non-toxic and hepatotoxic chemicals at increasing concentrations and investigated how liver metabolism was differentially altered between the non-toxic and hepatotoxic chemical exposures. Our analysis indicated that the genes identified via toxicity target analysis and those mapped to the metabolic model showed a distinct gene expression pattern, with the majority showing upregulation for hepatotoxicants compared to non-toxic chemicals. Similarly, when we mapped the metabolic genes at the pathway level, we identified several pathways in carbohydrate, amino acid, and lipid metabolism that were significantly upregulated for hepatotoxic chemicals. Furthermore, using our system-level integration of gene expression data with the rat metabolic model, we could differentiate metabolites in these pathways that were systematically elevated or suppressed due to hepatotoxic versus non-toxic chemicals. Thus, using our combined approach, we were able to identify a set of potential gene signatures that clearly differentiated liver toxic responses from non-toxic chemicals, which helped us identify potential metabolic pathways and metabolites that are systematically associated with the toxicant exposure.

Two- and Three-Dimensional Culture Systems: Respiratory In Vitro Tissue Models for Chemical Screening and Risk-Based Decision Making.

Risk of lung damage from inhaled chemicals or substances has long been assessed using animal models. However, New Approach Methodologies (NAMs) that replace, reduce, and/or refine the use of animals in safety testing such as 2D and 3D cultures are increasingly being used to understand human-relevant toxicity responses and for the assessment of hazard identification. Here we review 2D and 3D lung models in terms of their application for inhalation toxicity assessment. We highlight a key case study for the Organization for Economic Cooperation and Development (OECD), in which a 3D model was used to assess human toxicity and replace the requirement for a 90-day inhalation toxicity study in rats. Finally, we consider the regulatory guidelines for the application of NAMs and potential use of different lung models for aerosol toxicity studies depending on the regulatory requirement/context of use.

Multiple myeloma and anti-BCMA CAR-T therapy: a literature review

Significant progress has been made in the treatment of multiple myeloma (MM), leading to improved clinical outcomes. However, despite the success of traditional methods such as surgery, radiotherapy, and chemotherapy, the challenge of fully curing patients with relapsed and refractory MM remains pressing. A promising therapeutic approach is the use of chimeric antigen receptor T-cells (CAR-T), which has demonstrated efficacy in patients with resistant B-cell malignancies and is actively being studied for the treatment of MM. Special attention is being given to B-cell maturation antigen (BCMA) as a potential target for CAR-T therapy in MM.The objective is to analyze the current state of anti-BCMA CAR-T therapy in ММ, covering aspects of production, preclinical and clinical trials, as well as examining therapy-related toxicity and relapses.Data analysis was conducted using specialized medical databases such as PubMed, Scopus, Web of Science, Frontiers, and Google Scholar from 1974 to 2024. The article reviews latest achievements in CAR-T therapy for MM, current advances in the production and application of BCMA CAR T-cells, along with key challenges faced by this technology. The data obtained confirm significant progress in optimizing CAR T-cell structures and improving manufacturing processes, making the therapy more accessible for clinical use.Although early-phase trials of anti-BCMA CAR-T therapy show promising results, challenges remain, such as toxicity and insufficient response in some patients. Optimization of CAR structure and manufacturing technologies may improve the efficacy and accessibility of CAR T-cell therapy, making it a key direction for future research.

Fish early-life stage toxicity and environmental relevance: What does high-dose toxicity testing tell us?

Abstract The early-life stage (ELS) toxicity syndrome for fish is well described and has been reported in hundreds of toxicity studies. It is generally characterized by a reduced heart rate, yolk sac and pericardial edemas, and various morphological abnormalities, the most common being spinal curvature. For many of those studies it appears that the ELS toxicity syndrome is the result of non-specific (baseline) toxicity that occurs at aqueous and whole-body concentrations that are just below lethal concentrations. Baseline toxicity is essentially a non-specific response that results from chemicals accumulating in and disturbing the function of biological membranes that leads to lethality and sublethal effects at relatively high doses. The commonality of this acute ELS toxicity syndrome among highly diverse organic and inorganic chemicals is remarkable. It is important to identify baseline toxicity because it is considered minimal toxicity that acts in all tissues and cells, and it has the potential to impair all cellular functions. This means if an effect is observed around baseline-toxic concentrations, it is likely that other cellular functions are also affected, ie, the effect is not specific. The fish ELS toxicity syndrome can also be the result of specific effects involving receptor interactions; therefore, we emphasize the importance of distinguishing between specific and non-specific toxicity responses to provide the most relevant data for environmental risk assessment.

Influence of physicochemical factors on the interaction of metallic nanoparticles with immune system cells

Different physicochemical factors, such as size, concentration, shape, exposure time, area, and surface chemistry, influence the interaction between metallic nanoparticles (MNPs) and immune system cells. Particle size is particularly significant, as smaller particles facilitate easier cell internalization, while larger particles exhibit lower immunogenicity. Concentration also plays a critical role; high concentrations may trigger toxic responses, while low concentrations may act beneficially. Additionally, the morphology of nanoparticles affects their affinity for different cell types. It modulates the intensity of immune responses, while exposure time determines whether the immune response manifests as acute or chronic. The material composition of nanoparticles influences the initial interaction with cells, including protein adsorption and recognition by cell receptors. Understanding and controlling physicochemical factors is essential for developing therapeutic applications based on MNPs and minimizing potential adverse effects on the immune system. This paper reviews the reported biological effects of MNPs on various immune cell types, including B and T lymphocytes, neutrophils, monocytes, macrophages, dendritic cells, natural killer cells, mast cells, basophils, and eosinophils.

Toxicity assessment and i-QSTTR analysis of ionic liquids on D. magna, D. rerio, and R. subcapitata.

The study aimed to assess the impacts of ionic liquids (ILs) as innovative alternatives to traditional organic solvents on aquatic environments and human health. Five machine learning methods, including multiple linear regression (MLR), partial least squares regression (PLS), random forest regression (RF), support vector regression (SVR), and extreme gradient boosting (XGBoost), were used to construct the prediction models of the toxicity of ILs to D. magna, D. rerio, and R. subcapitata. Rigorous validation criteria were implemented to evaluate the robustness and predictive accuracy of these models. The results indicated SVR and XGBoost models demonstrated superior predictive performance. In addition, for these three species of D. magna, D. rerio, and R. subcapitata. The six interspecies quantitative structure-toxicity-toxicity (i-QSTTR) models were developed to analyze the cross-species toxicity responses of ILs. The results revealed a strong interspecies correlation in the toxicity of ILs to D. magna and D. rerio, as well as between D. rerio and R. subcapitata. However, the correlation between D. magna and R. subcapitata was weaker, indicating significant differences in the responses of ILs toxicity between these two aquatic species. This study not only filled the data gap in the biotoxicity of ILs but also provided an important theoretical basis for their safe application.

An investigation of the effect of the protein corona on the cellular uptake of nanoliposomes under flow conditions using quartz crystal microgravimetry with dissipation.

When nanoparticle delivery systems are immersed in biological fluids, a complex assembly of proteins forms on their surface, creating a protein corona. The protein corona alters the physicochemical properties, toxicity, biodistribution, cellular uptake, and immune response of the nanoparticles, and consequently, their therapeutic efficacy. Currently, there is a lack of in vitro methods to assess the effects of the protein corona on nanoparticle uptake under dynamic flow and assess their binding kinetics in real-time. Here, we introduce quartz crystal microbalance with dissipation (QCM-D) as an in vitro technique, capable of incorporating dynamic flow, to study the effect of the protein corona on the binding of nanoliposome (NLP) formulations to cell surfaces as a first step in their cellular uptake. The interactions of four NLP formulations (low PEGylated, high PEGylated, negatively charged and positively charged NLPs) with A375 melanoma and THP1 cell lines were assessed by QCM-D, before and after the formation of a protein corona. Through real-time recording of the frequency and dissipation shifts (Δf and ΔD, respectively), the QCM-D results provided strong evidence of the role of the protein corona in the cellular interaction of these NLP formulations, with a variation in their adsorption kinetics depending on their initial composition. NLP's attachment to the cell surface was the lowest for PEGylated NLPs (<5%), while the positively charged NLPs showed the highest cellular attachment (≈100%), regardless of the presence of the protein corona or cell type. The effect of the protein corona was more pronounced for the negatively charged NLPs, where a significant reduction in the NLP attachment was observed. To complement the QCM-D data on the NLP attachment and to determine whether the NLP attachment leads to cellular uptake, confocal microscopy and flow cytometry were used to confirm NLP uptake by A375 and THP1 cells. Proteomic analysis revealed a differential composition of the protein corona on the various NLPs with possible implications for their sequestration and cellular uptake. Collectively, the findings suggest that QCM-D can be an important tool to study the binding of NLP formulations or other nanoparticles with cell membranes under dynamic flow, which very often differs from nanoparticle uptake under static conditions.

Advanced 3D bioprinted liver models with human-induced hepatocytes for personalized toxicity screening

The development of advanced in vitro models for assessing liver toxicity and drug responses is crucial for personalized medicine and preclinical drug development. 3D bioprinting technology provides opportunities to create human liver models that are suitable for conducting high-throughput screening for liver toxicity. In this study, we fabricated a humanized liver model using human-induced hepatocytes (hiHeps) derived from human fibroblasts via a rapid and efficient reprogramming process. These hiHeps were then employed in 3D bioprinted liver models with bioink materials that closely mimic the natural extracellular matrix. The constructed humanized 3D bioprinted livers (h3DPLs) exhibited mature hepatocyte functions, including albumin expression, glycogen storage, and uptake/release of indocyanine green and acetylated low-density lipoprotein. Notably, h3DPLs demonstrated increased sensitivity to hepatotoxic agents such as acetaminophen (APAP), making them a promising platform for studying drug-induced liver injury. Furthermore, our model accurately reflected the impact of rifampin, a cytochrome P450 inducer, on CYP2E1 levels and APAP hepatotoxicity. These results highlight the potential of hiHep-based h3DPLs as a cost-effective and high-performance alternative for personalized liver toxicity screening and preclinical drug testing, paving the way for improved drug development strategies and personalized therapeutic interventions.

Real-world outdoor air exposure effects in a model of the human airway epithelium - A comparison of healthy and asthmatic individuals using a mobile laboratory setting.

We developed a mobile laboratory allowing field exposure of lung tissue models to ambient air at localities with various pollution sources (Background, Industrial, Traffic, Urban) in different seasons (summer/fall/winter). In samples originating from healthy and asthmatic individuals, we assessed the parameters of toxicity, lipid peroxidation and immune response; we further performed comprehensive monitoring of air pollutants at sampling sites. We measured lactate dehydrogenase (LDH) and adenylate kinase (AK) production and transepithelial electrical resistance (TEER), analyzed 15-F2t-isopostane (IsoP) and a panel of 20 cytokines/chemokines/growth factors. In the ambient air, we detected particulate matter (PM), and other relevant chemicals (benzene, benzo[a]pyrene (BaP), NOx). In the Traffic locality, we found very high concentrations of ultrafine particles and NOx and observed low TEER values in the exposed samples, indicating significant traffic-related toxicity of the ambient air. In the Urban locality, sampled in winter, we observed high PM and BaP levels. We found lower AK levels in samples from healthy individuals exposed in this locality than in the asthmatic samples. In the samples from the Industrial locality, sampled in summer, we detected higher concentrations of TNFα, MIP-1α, Eotaxin, GROα, GM-CSF, IL-6 and IL-7 than in the Urban locality samples. We hypothesize that pollen or other plant-related components of the ambient air were responsible for this response. In conclusion, our data proved the feasibility of our mobile laboratory for field measurements of the biological response of lung tissue models exposed to ambient air, reflecting not only the levels of toxic compounds, but also season-specific parameters.

The differentiation state of small intestinal organoid models influences prediction of drug-induced toxicity.

Drug-induced intestinal toxicity (GIT) is a frequent dose-limiting adverse event that can impact patient compliance and treatment outcomes. In vivo, there are proliferative and differentiated cell types critical to maintaining intestinal homeostasis. Traditional in vitro models using transformed cell lines do not capture this cellular complexity, and often fail to predict intestinal toxicity. Primary tissue-derived intestinal organoids, on the other hand, are a scalable Complex in vitro Model (CIVM) that recapitulates major intestinal cell lineages and function. Intestinal organoid toxicity assays have been shown to correlate with clinical incidence of drug-induced diarrhea, however existing studies do not consider how differentiation state of the organoids impacts assay readouts and predictivity. We employed distinct proliferative and differentiated organoid models of the small intestine to assess whether differentiation state alone can alter toxicity responses to small molecule compounds in cell viability assays. In doing so, we identified several examples of small molecules which elicit differential toxicity in proliferative and differentiated organoid models. This proof of concept highlights the need to consider which cell types are present in CIVMs, their differentiation state, and how this alters interpretation of toxicity assays.

28-Day Repeated Dose Toxicity and Toxicokinetics Study on Dihydroartemisinin (DHA) in SD Rats.

Dihydroartemisinin (DHA) is an effective antimalarial drug with potential antitumor efficacy, yet toxicological information is limited. The present study was designed to evaluate the potential toxicity of oral DHA. DHA was administered orally by gavage to SD rats at doses of 0, 25, 50, and 75/60 mg/kg b.w./day for 28 days, followed by a 4-week recovery period. Concomitant toxicokinetics was also evaluated. Due to potential toxicity affecting survival, only the female top dose was adjusted from 75 to 60 mg/kg on study day 14 (D14). Female rats in the low-dose group and male rats in the low- and medium-dose groups did not show any signs of toxicity. In contrast, male rats in the high-dose group and female rats in the medium- and high-dose groups showed significant toxic effects, including weight loss, hair loss, and gastrointestinal reactions (soft stools, perianal dirt, and fecal abnormalities). At the end of administration, female rats in the 75/60 (dose-adjusted) mg/kg dose group had significantly higher reticulocytes (Ret% and RETIC) and alanine aminotransferase (ALT), increased liver weights, and significantly lower hemoglobin (HGB). In addition, histopathology showed mild vacuolation of hepatocytes. These findings suggest that female rats have a greater toxic response than males, and toxicokinetics further demonstrate this sex difference. However, the toxic effects of DHA were reversed at the end of the 4-week recovery period. Therefore, the liver was identified as the primary target organ. The no-observed-adverse-effect-level (NOAEL) was 25 and 50 mg/kg b.w./day in female and male rats, respectively.