Regulatory Toxicology and Pharmacology最新文献

Methoxyflurane, a self-administered fluorinated hydrocarbon, provides rapid, relief for traumatic pain. While low-dose methoxyflurane poses minimal risk, paramedics may experience intermittent exposure. This study assesses occupational risks to enhance paramedic safety, health standards, and patient care directives. Active air sampling was conducted in a Ministry of Health-approved ambulance, in the driver and patient compartment, under controlled conditions, both with and without ventilation. Twelve healthy participants inhaled for 15 minutes, with samples collected per EPA and ISO standards. Results were adjusted for time weighted average (TWA) exposure. Twenty-four air samples were collected (median age 30.5 years, 50% female). Exposure concentrations remained below 8-hour TWA occupational limits and NIOSH 60-minute ceiling limits. With ventilation, 8-hour TWA levels were 0.001 ppm (driver) and 0.033 ppm (patient compartment), rising to 0.017 ppm and 0.057 ppm without ventilation. Maximum TWA levels for 22 transports (30-minute duration) reached 0.019 ppm (driver) and 0.736 ppm (patient) with ventilation, increasing to 0.377 ppm and 1.254 ppm without. These were based upon worst-case assumptions of 22 treatment and transport events, each lasting 30 minutes, over a 12 hour work shift. Ventilation significantly reduced exposure, with 99.1% protocol adherence and no adverse events. This controlled study confirms methoxyflurane's safe use in ambulances with exposure well below safety thresholds. Ventilation minimizes potential risk(s), ensuring paramedic safety and uninterrupted pain management.

Pesticides are suspected to cause health effects in humans health, but human-based data on their toxicity are often insufficient to establish associations and quantify risks. We reviewed literature on trichlorfon and investigated methodological aspects of risk assessment for pesticides based on human data. We provided an overview of epidemiology of pesticide toxicity, with focus on methodological features of the available studies, combined with a systematic review of the health effects of the pesticide, trichlorfon in humans, focusing on studies published after 1990. Studies on dichlorvos, the metabolite of trichlorfon, as well as metrifonate, a medication with the identical formula as trichlorfon, were included. A total of 60 publications were identified on health effects of trichlorfon, dichlorvos and metrifonate. Studies on acute effects (N=23 publications) comprised mainly case-reports related to accidents and suicidal attempts, and were connoted by cholinergic syndrome, gastrointestinal and general symptoms. Evidence on chronic effects derived from analyses of the Agricultural Health Study (28 publications), as well as case-control and cross-sectional studies (9 publications). Evidence of possible associations between trichlorfon or dichlorvos exposure and various outcomes was heterogeneous and insufficient to establish causality. Critical features of epidemiology studies used for pesticide risk assessment include study design, exposure misclassification, lack of quantitative exposure data, and lack of consideration to potential confounders. Few high-quality epidemiology studies are available on potential health effects of trichlorfon. Future studies conducted according to established guidelines and supported by artificial intelligence might help to fill the gap on human health risks from pesticides.

Aurantii Fructus Immaturus (AFI) water extract has been utilized in traditional medicine; however, its toxicity data are still lacking. In this study, we evaluated the general and genetic toxicity of the AFI water extract as a project of the Korea National Toxicology Program (KNTP). Naringin and neohesperidin, marker compounds of AFI, contained in the AFI water extract were 7.63% and 4.51%, respectively. These levels were higher than AFI powders, which contain about 4% naringin and 3% neohesperidin. The acute oral toxicity study in rats, conducted at doses of 2500-10000 mg/kg, demonstrated that the median lethal dose (LD₅₀) of AFI water extract exceeds 10000 mg/kg. Subacute oral toxicity tests at doses up to 5000 mg/kg/day and subchronic toxicity studies conducted over 13 weeks at similar dose ranges showed no treatment-related adverse effects. Thus, the no-observed-adverse-effect level (NOAEL) of AFI water extract in rats was 5000 mg/kg bw/day. Additionally, three genotoxicity assays (bacterial reverse mutation, in vitro chromosomal aberration, and in vivo micronucleus tests) confirmed that the AFI water extract is not genotoxic. These results will provide the toxicity data for the risk assessment of AFI water extract for human consumption.

This study analyzes the landscape of studies using New Approach Methodologies (NAMs) and submitted to the FDA over the past 15 years. The study utilized a custom-developed Center for Drug Evaluation and Research (CDER) search tool to examine keywords in Module 4 of the Electronic Common Technical Document (eCTD) across various drug applications. The investigation focused on five NAM categories, including some of those identified in the 2022 Food and Drug Omnibus Reform Act (FDORA): in vitro, in silico, in chemico, nonhuman in vivo, and other NAMs. Results indicated that 93% of NAM submissions were concentrated in two categories: in silico (49%) and in vitro (44%), with other categories (including in chemico, nonhuman in vivo from phylogenetically lower species and other combined methods) demonstrating significantly lower representation. In vitro NAMs, including stem cell-derived and sandwich culture models, showed higher prevalence compared to 3D models and organ chip or MPS models. The relatively high prevalence of in silico NAMs, was due to the submission of multiple study reports per application, attributed to various metabolites and the use of different in silico platforms. In chemico and nonhuman in vivo NAMs demonstrated limited submissions, with zebrafish studies predominating in the latter category. This study highlights one of CDER's activities aimed at better understanding the current usage of NAMs in drug development, while providing evidence to support areas of focus and prioritization of resources towards the validation of NAMs with significant regulatory impact potential. Despite technical limitations in the datamining work presented here, the findings confirm that CDER has been receiving NAMs data in drug applications for a long time. Nevertheless, we acknowledge that industry submits only a fraction of their NAM data to FDA, therefore we encourage increased NAM submissions which would contribute to building scientific confidence in these methods. It is only through the availability of sufficient case studies, that CDER can move towards reaching the goals of NAMs Roadmap issued in April 2025, and ultimately phasing out animal studies when possible and feasible.

We developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the isobutyl metabolic series, which includes isobutyl acetate, isobutanol, isobutyraldehyde, and isobutyric acid. Given chemical similarities, we used a previously developed PBPK model for the propyl metabolic series as a framework to create the isobutyl PBPK model. To support model development, we measured in vitro metabolism of isobutyl acetate in rat and human blood and liver S9 fractions. Our findings indicated that humans exhibited faster isobutyl acetate hydrolysis in liver S9 fractions compared to rats, while hydrolysis rates in blood were similar between the two species. Experiments involving closed chamber exposures of rats to isobutyl acetate or isobutanol revealed higher isobutanol concentrations in blood compared to other isobutyl compounds. Using these data to parameterize the model, the PBPK model accurately simulated available time-course concentrations of isobutyl compounds in blood of rats and humans. The isobutyl PBPK model enables comparisons of internal dose metrics across various isobutyl compound exposures and species and allows for calculation of equivalent external exposures that result in the same dose metric. Regulators can employ this PBPK model to predict and align internal dose metrics of isobutyl compounds for risk assessment purposes.