International Journal of Toxicology最新文献

In a 4-week rat study, a nucleotide prodrug antiviral agent containing a synthetic non-natural amino acid (C-331) induced a dose-related vacuolation in the brain's white matter tracts without concurrent neuronal loss, gliosis, or neurological deficits. Routine safety pharmacology studies showed no effects. Penetration of the drug through the blood-brain barrier was negligible. Rat-specific metabolites were not evident. A follow-up 13-week rat study with a 4-week interim assessment was performed using oral doses of 0, 100, 300, or 1000 mg/kg/day for 4 or 13 weeks. Intermittent, transient clonic convulsions (<1 min) occurred in 1 male rat at 100 mg/kg/day (3 observations) and 5 animals at 1000 mg/kg/day during the dosing phase but were not observed during recovery; their relationship to brain vacuolation remains uncertain. No test article-related neurobehavioral or open-field changes, or ophthalmic abnormalities were noted. In all treated groups, widespread vacuolation predominantly affecting white matter was observed in the cerebellum, thalamus, and striatum. The severity of vacuolation increased over time and persisted after the 4-week recovery period. Based on ultrastructural evaluation, the vacuolation resulted from myelin sheath splitting (intramyelinic edema) without axonal degeneration. The vacuolation was considered to be an adverse effect based on the severity and extent of the changes and the potential for causing oligodendrocyte dysfunction. An NOAEL in the rat was not identified. Because of multiple unknowns, including the lack of consistent neurobehavioral signs, species specificity, low exposure multiples, and the potential human significance, further development of C-331 was terminated. The study describes the unusual presentation of species-specific, drug-induced splitting of myelin sheaths/intramyelinic edema without clear correlative neurofunctional effects.

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a serotonin receptor agonist, in clinical development for the treatment of major depression and other psychiatric disorders. A critical safety concern for serotonergic compounds is their potential to induce seizures, as a severe manifestation of serotonin toxicity. The objective of this study was to evaluate the seizure liability of 5-MeO-DMT in a canine model. Beagle dogs (n = 8) were surgically instrumented for continuous telemetric recording of electroencephalography (EEG) and electromyography (EMG), coupled with behavioral video monitoring. Following a baseline period, animals were intranasally administered with control vehicle or escalating doses of 5-MeO-DMT (0.5, 1.0, and 1.5 mg/kg/day), once daily for nine consecutive days. Plasma samples for determination of pharmacokinetic parameters were collected from a satellite group (n = 3). Intranasal administration of 5-MeO-DMT resulted in centrally mediated and dose-dependent behavioral signs, such as head shaking, salivation, repetitive movements, dilated pupils, increased muscle tone, and tremors. A majority of these signs had a rapid onset and offset, which correlated with the peak plasma levels and resolved within 1 hour post-dose, and they were consistent with serotonergic agonism of 5-MeO-DMT. The continuous EEG recording revealed no evidence of seizures or epileptiform discharges at any dose levels throughout the study. In a canine model, considered sensitive to serotonergic drug-induced seizures, daily intranasal administration of escalating doses of 5-MeO-DMT did not induce seizures or epileptiform activity, even at doses causing significant physiological signs of serotonergic stimulation. These results provide robust critical safety information for a low seizure liability of 5-MeO-DMT.

Exposure to diesel exhaust air pollutants is a key environmental threat for pulmonary and cardiovascular diseases. Oxidative stress and Transient Receptor Potential Vanilloid-1 (TRPV1) receptors exhibit pivotal contributions in mediating lung injury induced by environmental pollutants. This study investigates the histological changes in lung tissue induced by short-term particulate-free filtered diesel exhaust (FDE) exposure, with a focus on TRPV1 receptor expression and oxidative stress pathways. Male rats were allocated to four groups randomly: Non-exposed (NE), clean air exposed (CAE), FDE-exposed, and NAC pre-treated FDE-exposed groups. FDE exposure lasted 5 hours per day for five days, with histological examination and TRPV1 expression analysis conducted on day six. The NAC pre-treated group received NAC (200 mg/kg) for five days prior to each exposure. Lung tissue samples were analyzed using hematoxylin and eosin staining, and immunofluorescence for TRPV1 expression. FDE exposure caused significant histological alterations, including alveolar septal thickening, interstitial inflammation, capillary congestion, perivascular inflammation, bronchial epithelial necrosis, endothelial discontinuity, and interstitial fibrosis, as classified by a semi-quantitative INHAND (International Harmonization of Nomenclature and Diagnostic) scoring criteria for rats, visualized on a heat map. TRPV1 expression was upregulated in FDE-exposed lung tissues, particularly around congested vessels and thickened septa. NAC pre-treatment significantly reduced both histological damage and TRPV1 expression. Our study highlights a potential mechanistic relationship between TRPV1 receptor expression and oxidative stress pathways in the lung damage induced by FDE exposure, underscoring the therapeutic potential of NAC in countering these effects.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Diatomaceous Earth as used in cosmetic formulations. It is reported to function as an abrasive, absorbent, anticaking agent, bulking agent, and opacifying agent in cosmetic products. The Panel reviewed all relevant data, and concluded that Diatomaceous Earth is safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Many antiviral agents are known to induce off-target mitochondrial toxicity due to the prokaryotic origin of mitochondria. Mitochondrial dysfunction is frequently linked to cardiotoxicity. We aimed to elucidate the mitochondrial toxicity profile of molnupiravir via focusing on mitochondrial dynamics, biogenesis, and oxidative stress in cardiac cells. Mitochondrial function was evaluated by luminometric measurement of ATP (adenosine triphosphate) content, and flow cytometric analysis of mitochondrial membrane potential, and mitochondrial mass. The expression levels of genes involved in mitochondrial fusion-fission were assessed by RT-PCR. In addition, molecular docking analysis was performed to evaluate the interaction between molnupiravir and the dynamin related-protein DRP1. Protein carbonylation was determined as an oxidative stress parameter. Toxicity evaluation was further investigated in Caenorhabditis elegans to support the in vitro findings at the organismal level. Molnupiravir exposure led to a significant dose-dependent reduction in intracellular ATP level and mitochondrial mass, accompanied by increased protein carbonylation. Mitochondrial membrane potential remained slightly increased. Alterations in the expression of genes regulating mitochondrial dynamics suggested an imbalance between fusion and fission processes, while mitochondrial biogenesis-related signaling was progressively suppressed. C. elegans exposed to higher concentrations of the drug (20-500 µM) exhibited significant lifespan reduction at all doses. Molecular docking analysis demonstrated a moderate binding affinity of molnupiravir to DRP1, supporting a potential direct interaction with mitochondrial fission machinery. In conclusion, our results demonstrate that molnupiravir induces mitochondrial stress through oxidative damage, impaired biogenesis, and altered dynamics, emphasizing the need for careful evaluation of mitochondrial safety of molnupiravir in cardiac tissue.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 5 glycolactone ingredients. Glucoheptonolactone and Gluconolactone are reported to function in cosmetics as skin-conditioning agents-miscellaneous, and Gluconolactone is also reported to function as a chelating agent. No functions are reported for the other 3 ingredients. The Panel considered the available data and concluded that Gluconolactone is safe in cosmetics in the present practices of use and concentration described in this safety assessment; however, the Panel concluded the available data are insufficient to make a determination that Galactonolactone, Glucarolactone, Glucoheptonolactone, and Ribonolactone are safe under the intended conditions of use in cosmetic formulations.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of brown algae-derived ingredients; 82 brown algae-derived ingredients were found in the in the International Cosmetic Ingredient Dictionary (Dictionary), however, several of these ingredients may be equivalent according to accepted scientific names. The Panel reviewed the available data to determine the safety of these ingredients, which are frequently reported to function in cosmetics as skin-conditioning agents. Impurities, particularly arsenic, may be present in these ingredients. Industry should continue to use good manufacturing practices to monitor and limit these possible impurities. The Panel concluded that 68 brown algae-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment. The Panel also concluded that the data are insufficient to determine the safety of the remaining ingredients under the intended conditions of use in cosmetic formulations.

Probiotics are living microorganisms that, when given in sufficient quantities, boost the host's health. Probiotics have been used more often in recent years as dietary supplement to prevent illnesses, including diarrhea, obesity, and constipation. The probiotic strain Bacillus subtilis BSP110 is being developed as a dietary supplement. In this work, we assessed the in vivo safety of the probiotic strain Bacillus subtilis BSP110 in rats as per OECD-423 and 407 guidelines. Female rats were given a single oral (gavage) dosage of 2000 mg/kg (4 × 10¹¹ CFU/g) to assess the maximum tolerated dose (MTD). This was followed by a 28-day sub-acute toxicity study in which Bacillus subtilis BSP110 was given orally (gavage) once daily to male and female rats at dose levels of 250, 500, and 1000 mg/kg/day. No effects of Bacillus subtilis BSP110 were noted at any of the dosage levels given over the course of 28 days. Between the control and test groups, there was no discernible difference in body weight, clinical symptoms, urinalysis, hematological tests, clinical biochemistry, gross pathology, or histopathological evaluation. Additionally, in vitro cytotoxicity was evaluated using the MTT assay with the VERO cell line, and Bacillus subtilis BSP110 was found to be non-cytotoxic at 4 × 10¹¹ CFU/kg. The single dose MTD was ≥2000 mg/kg, and the NOAEL was 1000 mg/kg/day.