Mycotoxins are toxic secondary metabolites produced by fungi that contaminate food worldwide and pose serious health risks to humans and livestock. According to the Food and Agriculture Organization, nearly one-fourth of global food crops are affected. India's climatic conditions, including unseasonal rains and flash floods, create a favorable environment for mold growth and mycotoxin contamination by increasing grain moisture levels. Survey data suggest that fumonisin B1 is the most prevalent mycotoxin in Indian food commodities, followed by aflatoxin B1 and combined aflatoxins. While aflatoxin B1 is frequently detected, more studies have focused on aflatoxins than fumonisin B1, with fewer studies specifically analyzing fumonisin B1 in Indian food samples. Despite this, the highly reported incidence of fumonisin B1 suggests that it may be more widespread than currently recognized. This review is the first to comprehensively compile and analyze all available survey data on mycotoxins in Indian food commodities. It examines their prevalence, toxicological impact, and associated risks for consumers. Food safety regulations concerning mycotoxins in India are less stringent than those enforced by the European Union or the United States Food and Drug Administration. This regulatory gap raises concerns about food security, especially since mycotoxin contamination in India often exceeds permissible limits. As the world's most populous country, accounting for 17.76% of the global population, India faces significant challenges due to mycotoxins in food. Given its role as a leading producer and exporter of agricultural commodities, the issue extends beyond national borders, impacting global food trade and safety. Strengthening food safety regulations, increasing surveillance, and promoting awareness are crucial steps toward mitigating mycotoxin risks. This review serves as a valuable resource for researchers, policymakers, and consumers concerned with food safety and public health.

Experimental genotoxicity data are required for pesticidal and biocidal active substances prior to regulatory approval, while for their metabolites and impurities, in silico predictions are often accepted. Nonetheless, the extent to which these compounds are represented in publicly available genotoxicity databases remains unclear. Herein, we utilize chemical space methods to define the overlap between pesticide substances (active substances, metabolites, and impurities) and activity data for six genotoxicity test types commonly employed in regulatory toxicology: the Ames test, the in vitro mammalian cell gene mutation test, the in vitro micronucleus test, the in vitro chromosomal aberration test, the in vivo micronucleus test, and the in vivo chromosomal aberration test. After merging and performing structure standardization on 18 public pesticide/biocide databases, we identified 4826 unique substances. Within 19 public genotoxicity databases, 19,897 substances had at least one data point in at least one genotoxicity test. The chemical space overlap between the pesticide substances and each genotoxicity set was evaluated by calculating physicochemical descriptors and molecular fingerprints, which were visualized by using dimensionality reduction methods. The chemical space of pesticide substances is well represented by substances with Ames test data and, to varying degrees, by substances with data from the other genotoxicity tests, with particularly low coverage for in vivo chromosomal aberration. The major scaffolds identified in pesticide substances were present in all of the genotoxicity data sets. Compared to pesticide substances, the genotoxicity data sets were enriched in functional groups characteristic of genotoxic compounds, such as annulated rings, but depleted in pesticide-typical structural motifs like halogens. Chemical space methods can assist regulatory toxicologists in understanding regions of pesticide substance chemical space that are well- or poorly characterized by genotoxicity data. This understanding is important for the accurate and targeted use of databases and data-based nontesting methods in line with regulatory requirements.

Tobacco and cannabis smoke are both complex chemical mixtures generated through combustion of biomass material. The presence of free radicals in tobacco smoke has been established for nearly seven decades. Despite similarities between cannabis and tobacco smoke and the known presence of radicals in the latter, analysis of free radicals in cannabis smoke has yet to be conducted. In this work, electron paramagnetic resonance (EPR) spectroscopy was used to detect short-lived radicals and environmentally persistent free radicals (EPFRs) in cannabis smoke. Spin-trapping techniques were employed to aid in identification of the short-lived radicals. Congruent with findings from studies conducted on tobacco smoke, short-lived free radicals were detected in the gas phase, and EPFRs were detected in the particle phase of cannabis smoke. Gas phase results indicate the presence of oxygen-centered radicals in cannabis smoke, though the shape of the resulting EPR spectra differs slightly from that of tobacco smoke. Particle phase results for cannabis match well with those from previous studies conducted on tobacco smoke, regardless of the spin trap used (or lack thereof). Quantitative findings indicate that cannabis smoke contains approximately the same radical concentration as tobacco smoke, on the order of 10 gas-phase spins and 10 particle-phase spins per cannabis preroll or tobacco cigarette. The impacts of burning method (continuous vs puffing) and cannabinoid composition on radical concentrations were also investigated here. While puffing was observed to lower radical concentrations, the cannabinoid composition of the strain of cannabis burned had no observable impact on the amount or identity of free radicals detected.

The electronic cigarette has been suggested as a safer alternative to the conventional tobacco cigarette. However, some vaping products have been shown to have cardiovascular effects, although this remains controversial. Several clinical studies have identified a possible alteration of endothelial function due to exposure to e-cigarette aerosols. However, the underlying biological mechanisms responsible for this observation in humans are still unclear. Thus, the development of preclinical mechanistic studies seems necessary. The aim of this review is, therefore, to provide a comprehensive overview of preclinical studies addressing the question of how e-cigarettes may cause endothelial dysfunction, a predictive marker of cardiovascular events. 53 papers were included in the analysis. We analyzed these papers qualitatively and quantitatively and discussed their limitations. We found that while 30% of in vitro studies showed no effect of e-cigarette aerosols on endothelial cells 26% showed variable effects, and 44% showed a significant adverse effect on endothelial function. In vivo studies were more consistent, with the vast majority (96%) reporting negative effects of e-cigarettes on endothelial function. We concluded that e-cigarettes should not be considered harmless in terms of cardiovascular effects, as they may impair endothelial function through various mechanisms such as oxidative stress and inflammation. However, more studies with standardized and optimized designs are still needed to distinguish the role of nicotine, which is known to affect the cardiovascular system, from that of other components in e-cigarette aerosol.

Trimethoprim (TMP) is an essential antibiotic used in combination with sulfamethoxazole to treat and prevent bacterial infections. Idiosyncratic adverse drug reactions (IADRs) to TMP occur in a small but significant percentage of the treatment population. TMP IADRs manifest as mild to life-threatening skin rashes, pulmonary failure, or hepatotoxicity. Currently, our incomplete knowledge of TMP metabolism is a barrier to understanding the TMP-IADR etiology. In this study, we investigated TMP phase I and II metabolism in tissues involved with IADRs including liver, lung, and skin using human s9 subcellular fractions. Triple-quadrupole and quadrupole-time-of-flight mass spectrometry were used to compare trimethoprim phase I and phase II metabolism in these organ systems and to detect identified metabolites in the urine of subjects taking and tolerating TMP. In this study, we found that phase I TMP metabolites are formed predominantly in the liver, and phase II TMP metabolites are formed differentially in extrahepatic tissues. This characterization of TMP metabolism in affected tissues is an important step toward a better understanding of the mechanisms involved in the TMP IADRs.

The Nonclinical Translation Working Group of the IQ Drug-Induced Liver Injury (DILI) Consortium conducted two surveys in 2023 and 2017 to canvas member companies on approaches and experiences in the preceding 5-year periods that inform how DILI risk assessment has evolved in the past decade. Surveys comprised 53 detailed questions to understand the current status, temporal changes, and future direction and to gain insights. Focusing on the 2023 survey for the most contemporary data, responses indicated that DILI still remains a problem during drug development, with 41% of companies in the 2023 survey (50% in 2017) filing at least one clinical expedited safety report in the last 5 years. Most companies have common nonclinical screening approaches, with the majority of companies incorporating target safety assessments, considering physicochemical properties and dose, and using multiple in vitro approaches including cytotoxicity, mitotoxicity, BSEP inhibition, and various reactive metabolite assays, with the utilization of many of these being increased in the 2023 survey compared to the 2017 survey. The impact of in vivo toxicology studies on clinical study design and compound progression is also reviewed in both the 2023 and 2017 surveys. A large majority of companies now report having new modality drugs in their portfolios, including antibody-based and oligonucleotide-based modalities, cell therapies, protein degraders, and peptide-based medicines; yet only 1 or 2 companies report having modality-specific approaches to assess DILI risk despite these modalities having very different mechanisms of causing DILI compared to small molecules. This is a key area for growth in the nonclinical assessment of hepatotoxicity to support these emerging modalities and the tremendous potential that they offer for unmet clinical needs. Collaborative partnerships will be key to driving new capabilities forward in this area, contributing to the development of safer novel therapeutics for patients.

Oxidative stress contributes to the damage of biological molecules and is linked to the development of multiple diseases, including liver disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD). In mammals, reduced glutathione (GSH) is a pivotal antioxidant that regulates cellular responses to redox imbalances caused by reactive oxygen and nitrogen species. The presence of reduced GSH within mitochondria is especially crucial for preserving the organelle's routine performance by eliminating hydrogen peroxide generated under both physiological and pathological conditions. Cumulative evidence indicates that MASLD is associated with a diminished mitochondrial GSH (mGSH) pool, attributed to alterations in mitochondrial membrane fluidity due to cholesterol accumulation. Therefore, strategies aimed at boosting mGSH may offer therapeutic benefits against MASLD-associated liver injury. This study aims to investigate whether l-cysteine-glutathione disulfide (l-CySSG), a proposed GSH donor and precursor, can effectively restore total and mGSH in vitro and in vivo in mice fed cholesterol-enriched (HC) or methionine-choline-deficient (MCD) diets. Additionally, -adenosylmethionine (SAM), a compound that serves as both a GSH precursor and a membrane fluidizer, along with -acetylcysteine (NAC), a GSH precursor by providing cysteine, was used as the control molecules in the study. Our findings show that l-CySSG has great potential as a liver protector, especially due to its good oral bioavailability. Although it does not restore GSH levels in the mitochondria as efficiently as SAM does, l-CySSG can still offer protection against liver damage, possibly through mechanisms that are not yet fully understood. Overall, l-CySSG emerges as a promising alternative for treating conditions related to oxidative stress and mitochondrial dysfunction, paving the way for future research and therapeutic development.

Apurinic/apyrimidinic (AP) sites are unavoidably generated in the DNA of living organisms by the spontaneous or catalyzed loss of coding nucleobases from the deoxyribose backbone. AP sites can lead to the generation of interstrand DNA cross-links via reactions between the ring-opened AP-aldehyde residue and exocyclic NH groups of nucleobases on the opposing strand of the double helix. Earlier works showed that dG-AP cross-links, which are generated in 2-5% equilibrium yields, can be converted via a reductive amination process to higher yields (15-50%) of a chemically stable alkylamine cross-link when NaBHCN is present in the reaction mixture. A dA-AP cross-link can be generated in equilibrium yields of 15-80%, but until now, it has been uncertain whether this cross-link could be reduced to the corresponding alkylamine cross-link by NaBHCN. The results presented here show that the dA-AP cross-link can indeed be reduced by NaBHCN to generate a chemically stable alkylamine cross-link. However, yields of the reduced dA-AP cross-link are limited by a faster, competing reduction of the AP-aldehyde to the corresponding AP-alcohol by NaBHCN. Similarly, faster reduction of the dG-AP cross-link in a 5'CXT/AAG sequence (X = AP), where both guanine and adenine residues compete for reaction with a single AP site, leads to a shift in the major site of the AP-derived cross-link attachment from adenine in the absence of NaBHCN to guanine in the presence of NaBHCN. The results show that two different nucleobase cross-links can coexist in equilibrium at a single AP site in duplex DNA. Overall, the reductive amination process may prove useful for detecting the dA-AP cross-link in cellular DNA using LC-MS/MS methods similar to those described here. In addition, these methods may be useful for the chemical synthesis of DNA duplexes containing chemically stable, site-specific cross-links.

Airborne fine particulate matter (PM) exposure has been epidemiologically linked to increased risk of cardiovascular complications, thrombosis, and hypoxia-related disorders. Quinones, prevalent constituents of PM, are suspected mediators of these health effects. Yet, the molecular mechanisms underpinning these associations remain poorly understood. Red blood cells (RBCs) have a central role in oxygen transport and vascular physiology. Thus, we investigated the effects of four environmentally relevant quinones (70 μg/mL), such as methyl-p-benzoquinone (MBQ), 1,4-naphthoquinone (NQ), 9,10-phenanthrenequinone (9,10-PQ), and 9,10-anthraquinone (9,10-AQ), on human RBCs. MBQ, NQ, and PQ significantly depleted intracellular glutathione, subsequently elevated reactive oxygen species, and triggered lipid peroxidation. Morphological analysis revealed membrane blebbing and surface protrusions of RBCs, indicative of impaired deformability and altered rheology. MBQ and NQ exposure further disrupted membrane proteins, impairing membrane fluidity and compromising membrane integrity. Tandem mass spectrometry confirmed covalent binding of MBQ and NQ to the βCys93 residue of hemoglobin via Michael addition. Native mass spectrometry revealed reduced stability of the αβ tetramer of hemoglobin. These findings were further corroborated by altered hemoglobin structure, methemoglobin formation, and hemoglobin aggregation. Mechanistically, MBQ and NQ induce RBC damage via both one-electron redox reaction and Michael addition to thiol groups, while PQ acts primarily through redox cycling without direct thiol binding. In contrast, AQ exhibited negligible effects, likely due to its low electrophilicity and steric hindrance. Our findings reveal distinct mechanistic pathways by which environmental quinones compromise RBC structure and function. This study offers a novel molecular link between airborne quinone exposure and pollution-driven health pathologies.

The 2018 U.S. Farm Bill inadvertently paved the way for a market of unregulated, hemp-derived cannabinoid vaping products, including cannabidiol (CBD) and Δ8-tetrahydrocannabinol (Δ8-THC). These products contain extremely high cannabinoid concentrations, contaminants, and potentially harmful byproducts from heating, raising concerns about respiratory toxicity. This review examines the regulatory landscape, manufacturing practices, composition, and toxicological mechanisms associated with hemp-derived cannabinoid vaping products. While vaping-related lung injuries, such as E-cigarette or Vaping, Product use-Associated Lung Injury (EVALI), have been linked to vitamin E acetate (VEA), a definitive mechanism of injury has not been established, and cases continue to be reported. Studies reveal multiple mechanisms of lung toxicity associated with cannabinoid vaping, including inflammatory responses, oxidative stress, and damage from contaminants like heavy metals and flavoring agents. Emerging evidence also highlights the formation of reactive cannabinoid quinones (e.g., CBDQ) during vaping, which form covalent adducts with protein cysteine residues, potentially altering their function, and also have the potential to drive oxidative damage through redox cycling. These electrophilic quinones may act as pleiotropic modifiers of cellular function and represent an important, yet understudied, contributor to cannabinoid vaping toxicity. This review identifies key research gaps, including the need for studies on chronic exposure models, mechanisms of lung injury, and the interplay between VEA, cannabinoid quinones, and other harmful byproducts. Additionally, given the potential for both therapeutic benefits and toxic effects, research should investigate optimal temperatures and formulations that balance efficacy and safety over potential toxicity caused by thermal oxidation. Overall, a comprehensive understanding of the toxicological mechanisms of cannabinoid vaping products is essential to guide public health decisions, inform regulatory frameworks, and support the development of safer products.

Accurate toxicity prediction is a critical component of pharmaceutical development and regulatory safety evaluation, traditionally relying on molecular descriptor-based models. This study compares the performance of descriptor-based features (Mordred, RDKit) with embeddings from ten AI language models applied to SMILES strings, chemical names, and simple descriptions, using logistic regression classifiers across the Tox21, ClinTox, and DILIst datasets. For the Tox21 dataset, Mordred achieved the highest average ROC-AUC of 0.855, outperforming language models. However, on specific endpoints, language models showed competitive performance, with MolBERT reaching an average ROC-AUC of 0.801 for SMILES-based embeddings. In contrast, language models outperformed descriptor models on the ClinTox dataset. While RDKit achieved an ROC-AUC of 0.721, GPT-3 reached 0.996 by using simple descriptions. Similarly, for the DILIst dataset, language models surpassed descriptor models, with GPT-3 achieving an ROC-AUC of 0.806 using chemical names, compared to RDKit's 0.620. These results demonstrate the promise of AI language models in predictive toxicology, particularly for specific toxicity endpoints and datasets. While molecular descriptors remain robust for multiendpoint predictions like Tox21, language models show superior performance on focused toxicity classifications such as ClinTox and DILIst. This study supports the future integration of molecular descriptors with textual embeddings to enhance overall performance and adaptability across diverse toxicity prediction tasks.

Per- and polyfluoroalkyl substances (PFAS), common environmental contaminants, can cause cardiotoxic effects particularly during fetal development. However, the effect of combined PFAS exposure, which more closely reflects real-world environmental conditions, remains poorly understood. In this study, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were exposed to three common PFAS compounds─perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), and perfluorodecanoic acid (PFDA)─individually or in combination (20-200 μM; consistent with serum levels reported in occupationally exposed populations). Compared with single compounds, combined PFAS exposure induced synergistic cytotoxicity, significantly reducing hiPSC-CM viability after 5 or 10 days. Sublethal combined exposure for 10 days altered mitochondrial membrane potential and mitochondrial content in a dose-dependent manner and shifted cysteine metabolism, potentially reflecting adaptation to oxidative challenge. After 14 days, combined PFAS increased vimentin, a fibroblast marker, and reduced NKX2.5, α-actinin, and cardiac troponin T, key markers of cardiomyocytes, as detected by immunocytochemistry. Proteomics further showed enrichment of pathways in extracellular matrix organization, cholesterol metabolism, and antioxidant defense, as well as downregulation of mitochondrial proteins. Consistent with changes in protein profiles related to oxidative stress and bioenergetic impairment, exposure of hiPSC-CMs to combined PFAS also increased the level of mitochondrial superoxide, reduced ATP content, and decreased cellular respiration. Together, these data demonstrate that PFAS mixtures drive mitochondrial dysfunction, oxidative stress, metabolic changes, and extracellular matrix remodeling in hiPSC-CMs, underscoring the importance of evaluating PFAS mixtures to better understand cardiac risks from environmental exposure.

Histones react with one of the most abundant endogenous DNA lesions, the apurinic/apyrimidinic (abasic, AP) site, to form reversible but long-lived Schiff base DNA-protein cross-links at 3'-DNA termini (3'-histone-DPCs). These DPCs need to be repaired, because 3'-hydroxyl groups are required for DNA repair synthesis and strand ligation. We previously identified three human enzymes, including tyrosyl-DNA phosphodiesterase 1, AP endonuclease 1 (APE1), and three-prime repair exonuclease 1 (TREX1), that can repair chemically synthesized adducts that closely resemble the proteolyzed Schiff base 3'-histone-DPCs. Here, we report another two human enzymes, APE2 and TREX2, that have a similar function.

Nicotine has been used in e-cigarettes for many years; however, recently, nicotine analogs have risen in popularity. E-cigarettes containing nicotine analogs such as nicotinamide and 6-methylnicotine are currently sold without regulatory oversight. They are marketed as safer alternatives to nicotine-containing products, although there is little or no scientific evidence to support this claim. This study investigated the nicotine analog, nicotinamide (NA), along with its major degradant, 3-cyanopyridine (3CP), which is produced when NA is vaped. Upon heating and aerosolization, both chemicals are present in the exposure dose. Dose-response curves are created for relative concentrations of NA and 3CP, and an isobologram is formed to investigate their mixture effects. NA is toxic at concentrations greater than 2637 ppm; however, 3CP is harmful in concentrations as low as 0.0001 ppm. The most significant finding is that the isobologram indicates that the mixture effects are synergistic, where a decrease in viability can be seen in minimal doses of 3CP (i.e., 0.000001 ppm) and 1350 ppm of NA. The interaction index was calculated for each point, and all values were less than 1, indicating a statistically synergistic biological response. The study highlights how such small levels of 3CP can play a large role in inducing toxic responses of a presumed safe chemical (i.e., nicotinamide or niacinamide, a form of vitamin B3 (niacin)). These results indicate that chemical and biochemical reactions, as well as interactions between e-cigarette aerosol components, including nicotine analogs, warrant further investigation.

Allergic diseases affect over one billion people worldwide as a common chronic condition. Conventional treatments often relieve symptoms but lack long-term efficacy or safety. Over the past decade, nanomedicine, i.e., nanoscale drugs and delivery systems, has emerged as a promising alternative that leverages the tunable physicochemical properties of nanoparticles (NPs) and enhances both diagnosis and treatment of hypersensitivity disorders. In diagnostics, nanoparticle-based biosensors have achieved detection limits as low as 42 fg/mL with specificity exceeding 90% for food and aeroallergen proteins. Therapeutic applications comprise various NPs, including gold, silver, iron oxide, carbon-based, lipid-mediated, polymeric, dendrimeric, and virus-like, as delivery vehicles and as immunomodulators. Preclinical models detect >50% reductions in pro-inflammatory cytokines (IL-4, IL-5) and two- to 3-fold reductions in eosinophil infiltration following NP-augmented allergen immunotherapy, with antigen-specific IgE titers reduced by up to 70%. Although such advancement has occurred, nanotoxicology studies highlight dose-dependent organ concentration and prolonged pulmonary half-lives that necessitate rigorous biosafety evaluation. Regulatory and manufacturability concerns remain significant hurdles for clinical translation. This article reviews up-to-date quantitative performance metrics for nanoparticle therapeutics and diagnostics in allergy control, critically examines the toxicity profiles and translational issues, and brings out directions toward individualized, safe nanotheranostic platforms.

Oxidative damage to RNA is associated with neurodegeneration, cardiovascular diseases, and cancer development. Studies that monitor RNA damage by HO often omit the physiological buffer bicarbonate in the reaction, which fails to account for the influence of the buffer on the iron-Fenton reaction. Herein, we monitored two in vitro systems to understand how bicarbonate redirects the iron-Fenton reaction from a hydroxyl radical (HO) generator in the absence of bicarbonate to one that predominantly yields carbonate radical anion (CO) in the presence of this buffer. Using the HO-selective fluorophore terephthalic acid, we found that the Fe(II)-ligand identity impacted the bicarbonate concentration required to transition the Fenton reaction to predominantly yield CO. These findings were then corroborated by following the oxidation of guanosine (rG), which reports on oxidation by both radicals, and uridine (rU) oxidation, which responds to only HO as the oxidizing species. The studies found that as the Fe(II)-ligand complex stability increased, the bicarbonate concentration inflection point to favor CO production and rG oxidation also increased. Regardless of the ligand strength, the crossover values obtained were below physiologically relevant bicarbonate concentrations (<20 mM). Next, or HEK293T cells were pre-equilibrated with bicarbonate from 0 to 20 mM before a bolus addition of HO. The bicarbonate-dependent inflection points for favoring CO over HO (or ferryl) for (7.3 mM) and HEK293T (11.3 mM) cells differed, but were below physiologically relevant concentrations, supporting the hypothesis that the cellular iron-Fenton reaction normally yields CO. The redox-cycling compound menadione was used for continuous in-cell generation of HO to find bicarbonate dependencies in oxidation reactions of RNA. The studies herein point toward the redirection of the iron-Fenton reaction in cells to predominantly yield CO that selectively damages rG sites in the transcriptome.

The mutational outcome of DNA damage as a direct result of constant chemical assault is governed by major factors, including the structure and nature of damage, replication, and repair machinery . The role of the size of the adduct, adduct-flanking bases, and the type of polymerase involved in the replication pathway is prominently seen through existing and studies. In this work, machine learning methods have been developed to predict the critical parameters for the mutational outcome of the adducts when they encounter polymerase in a particular sequence context. We carried out the analysis with three different classification models: Logistic Regression (LR), Decision Tree (DT), and Support Vector Machine (SVM). Using the literature data, mutational results of covalent DNA adducts and abasic sites were used to train the classification models. Following this, we used a generative network method with the available information on the structure of the DNA damage, polymerase, and sequence context to generate synthetic data that accurately mirrors the real data. Further, we employed an Extreme Gradient Boosting Classifier to identify the parameter that most influences the DNA mutational outcome. Metrics such as Accuracy, Sensitivity, Precision, F1 score, and AUC value have been used to evaluate the performance of classifier methods. The proposed Bootstrapped-Variational Autoencoder (BT-VAE) model enhanced the overall prediction accuracy of classifiers by 40%. The SVM model delivered the best performance across all classification metrics in predicting mutational outcomes among the three classification models evaluated. By providing the size of the carcinogen/covalent DNA adduct, polymerase, and flanking base as input, the proposed BT-VAE framework can predict the mutational outcome (match or mismatch for covalent DNA adducts and adenine or nonadenine for abasic site), an additional tool for and studies in the field of toxicology.

Despite increased recognition of the adverse impacts of PCB exposure on human health, comprehensive risk assessments, particularly regarding inhalation exposure and effects on the developing fetus, are lacking. Out of all PCB congeners, lower-chlorinated PCBs have been more prevalent in indoor and outdoor atmospheres. Thus, we investigated toxicokinetics and placental transfer of radiolabeled [C]-PCB52 (0.157 mg/kg administered intratracheally) in Sprague-Dawley rats at gestational day 11 ± 1. Following dosing, 99.4 ± 0.5% of the administered dose was distributed to the systemic circulation. Radioactivity disappeared biexponentially following lung exposure, with 41.1% of the dose retained after 96 h. PCB52 was rapidly distributed to the maternal serum, lung, heart, and liver, with subsequent accumulation in the ovaries, brain, white and brown adipose, muscle, and mammary glands. The time to reach a maximum concentration in the maternal serum was 0.21 h, with an apparent terminal elimination half-life of 40.7 h. The peak concentration of [C]-PCB52 and its metabolites in the placenta, fetus, and amniotic fluid was achieved 1.7 h after exposure, with a fetal half-life of 34.8 h. The maternal serum level was significantly correlated with levels in amniotic fluid, placenta, fetus, and the maternal brain. However, PCB52 exposure in the placenta, fetus, and amniotic fluid was limited with their respective maternal serum exposure ratio values of 0.5, 0.27, and 0.05. These results demonstrate for the first time a comprehensive whole-body disposition of PCB52 in dams and fetuses after lung exposure during gestation. PCB52 and its metabolites accumulate predominantly in the ovaries, brain, and mammary glands. The apparent half-life of PCB52 in developing fetuses and placenta is comparable to that of maternal serum. This study provides novel quantitative foundations for the development and evaluation of physiologically based toxicokinetic modeling to inform the exposure and risk assessment for public health decisions.

Olaparib, an anticancer drug, has been recently associated with major side effects (hepatotoxicity and hematotoxicity). Human CYP450 3A4/5 metabolizes olaparib and forms dehydrogenated () and hydroxylated (, metabolites. The major (dehydrogenated: ) metabolite is unreactive due to the stability of its amide bonds. Thus, the recently reported toxicities (hepato- and hemato) remain mysterious. Here, we investigate olaparib's metabolic pathways using model systems to gain insights into metabolic preferences, reactive metabolite formation, and associated toxicities. Potential energy surface (PES) analysis using activation (Δ), reaction (Δ°) free energies, and molecular docking, dynamics-based accessibility (distance of site of metabolism: SOM from heme-Fe) is utilized to explain metabolic preferences. Quantum chemical calculations showed that the formation of dehydrogenated ( and hydroxylated ( is favored relative to aromatic hydroxylated ( metabolites (reaction free energies: T = 18.5 kcal/mol as cutoff). The detailed analysis of the metabolic pathway for the major metabolite ( formation showed that hydroxylation follows the E1 mechanism, leading to dehydration and the formation of a tetrahydropyrazine derivative. The olaparib piperazine ring C approaches the heme-Fe within activating distance (6 ± 2 Å) in most docked poses and during 200 ns MD simulations. The C10 leading to hydroxylated metabolite ( remains at >10 Å, making the reactive formation less likely. Furthermore, the MM-GBSA-based per-residue calculations showed that 13 active-site residues, including Arg105, contribute significantly to the binding energy (avg: -1.24 kcal/mol). DFT-based global and local reactivity (electrophilicity: ω) analysis showed that the 4-acetylphthalazin-1(2H)-one group in the metabolite (formed from ) is highly electrophilic and might explain the idiosyncratic toxicities. These findings may offer valuable insights into the mechanisms of toxicity and for the design of novel and less toxic olaparib analogs.

Inhalation exposure to nanoplastic particles (NPPs) can lead to significant pulmonary toxicity; however, the effects of environmental processing on their toxicity remain poorly understood. This study examines the toxicity of polystyrene (PS) NPPs on lung cells following controlled atmospheric aging. Human bronchial epithelial cells (16HBE) were cultured in vitro at the air-liquid interface and acutely exposed to oxidized PS NPPs through electrostatic precipitation. Expression of proinflammatory genes interleukin-8 (-8) and tumor necrosis factor alpha (-α) was significantly elevated at 6 and 48 h postexposure to aged NPPs, with corresponding increases in interleukin-6 (IL-6) protein levels supporting an inflammatory response. The oxidative stress marker heme oxygenase-1 (HO-1) also showed significantly increased expression at 6 h postexposure, supported by protein analysis. Atomic force microscopy (AFM) and aerosol mass spectrometry (AMS) revealed increased surface roughness and oxygen to carbon ratios in the atmospherically aged NPPs. Together, these results demonstrate that atmospheric aging alters the chemical composition and surface morphology of PS NPPs, enhancing proinflammatory and oxidative stress responses in bronchial epithelial cells, highlighting the critical role of environmental processing in determining the toxicity of nanoplastics.