Frontiers in toxicology最新文献

Introduction: We previously developed a PBPK model template that consists of a single model "superstructure" with equations and logic found in many physiologically based pharmacokinetic (PBPK) models. Using the template, one can implement PBPK models with different combinations of structures and features.

Methods: To identify factors that influence computational time required for PBPK model simulations, we conducted timing experiments using various implementations of PBPK models for dichloromethane and chloroform, including template and stand-alone implementations, and simulating four different exposure scenarios. For each experiment, we measured the required computational time and evaluated the impacts of including various model features (e.g., number of output variables calculated) and incorporating various design choices (e.g., different methods for estimating blood concentrations).

Results: We observed that model implementations that treat body weight and dependent quantities as constant (fixed) parameters can result in a 30% time savings compared with options that treat body weight and dependent quantities as time-varying. We also observed that decreasing the number of state variables by 36% in our PBPK model template led to a decrease of 20-35% in computational time. Other factors, such as the number of output variables, the method for implementing conditional statements, and the method for estimating blood concentrations, did not have large impacts on simulation time. In general, simulations with PBPK model template implementations of models required more time than simulations with stand-alone implementations, but the flexibility and (human) time savings in preparing and reviewing a model implemented using the PBPK model template may justify the increases in computational time requirements.

Conclusion: Our findings concerning how PBPK model design and implementation decisions impact computational speed can benefit anyone seeking to develop, improve, or apply a PBPK model, with or without the PBPK model template.

Introduction: Data science training has the potential to propel environmental health research efforts into territories that remain untapped and holds immense promise to change our understanding of human health and the environment. Though data science training resources are expanding, they are still limited in terms of public accessibility, user friendliness, breadth of content, tangibility through real-world examples, and applicability to the field of environmental health science.

Methods: To fill this gap, we developed an environmental health data science training resource, the inTelligence And Machine lEarning (TAME) Toolkit, version 2.0 (TAME 2.0).

Results: TAME 2.0 is a publicly available website that includes training modules organized into seven chapters. Training topics were prioritized based upon ongoing engagement with trainees, professional colleague feedback, and emerging topics in the field of environmental health research (e.g., artificial intelligence and machine learning). TAME 2.0 is a significant expansion upon the original TAME training resource pilot. TAME 2.0 specifically includes training organized into the following chapters: (1) Data management to enable scientific collaborations; (2) Coding in R; (3) Basics of data analysis and visualizations; (4) Converting wet lab data into dry lab analyses; (5) Machine learning; (6) Applications in toxicology and exposure science; and (7) Environmental health database mining. Also new to TAME 2.0 are "Test Your Knowledge" activities at the end of each training module, in which participants are asked additional module-specific questions about the example datasets and apply skills introduced in the module to answer them. TAME 2.0 effectiveness was evaluated via participant surveys during graduate-level workshops and coursework, as well as undergraduate-level summer research training events, and suggested edits were incorporated while overall metrics of effectiveness were quantified.

Discussion: Collectively, TAME 2.0 now serves as a valuable resource to address the growing demand of increased data science training in environmental health research. TAME 2.0 is publicly available at: https://uncsrp.github.io/TAME2/.

There are currently no available cell lines for the ecologically relevant colonial waterbird species, the double-crested cormorant (DCCO). DCCOs are high trophic level aquatic birds that are used for routine contaminant monitoring programs in the Laurentian Great Lakes and marine coasts of Canada. Developing a DCCO cell line for in vitro toxicological screening will ideally provide improved understanding of the effects of environmental chemicals given the large differences in sensitivity between laboratory and wild avian species. In this study, an immortalized DCCO hepatic cell line, DCH22, was established from the liver of a day 22 female embryo as a potential alternative to primary DCCO embryonic hepatocytes (DCEH) for chemical screening. DCH22 cells were cultured for over a year and have hepatocyte-like morphology. Exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB-126), benzo-a-pyrene, ß-napthoflavone and phenacetin induced CYP1A activity and mRNA expression in DCH22 3D spheroids. Induction of CYP3A activity and mRNA expression was observed following exposure to hexabromocyclododecane (HBCD), tris(1,3-dichloroisopropyl)phosphate, carbamazepine, and metyrapone. The phase II metabolism gene, UGT1A1, was upregulated following HBCD exposure and DCH22 spheroids expressed vitellogenin protein after exposure to 17α-ethinylestradiol. Based on these data, the novel DCH22 cell line, cultured as 3D spheroids, has potential use as an alternative to DCEH for chemical screening and will permit the evaluation of avian species differences in sensitivity from an in vitro screening perspective.

Cannabis sativa (marijuana) is used by millions of people around the world. C. sativa produces hundreds of secondary metabolites including cannabinoids, flavones and terpenes. Terpenes are a broad class of organic compounds that give cannabis and other plants its aroma. Previous studies have demonstrated that terpenes may exert anti-inflammatory properties on immune cells. However, it is not known whether terpenes derived from cannabis alone or in combination with the cannabinoid ∆⁹-THC impacts the function of alveolar macrophages, a specialized pulmonary innate immune cell that is important in host defense against pathogens. Therefore, we investigated the immunomodulatory properties of two commercially-available cannabis terpene mixtures on the function of MH-S cells, a murine alveolar macrophage cell line. MH-S cells were exposed to terpene mixtures at sublethal doses and to the bacterial product lipopolysaccharide (LPS). We measured inflammatory cytokine levels using qRT-PCR and multiplex ELISA, as well as phagocytosis of opsonized IgG-coated beads or mCherry-expressing Escherichia coli via flow cytometry. Neither terpene mixture affected inflammatory cytokine production by MH-S cells in response to LPS. Terpenes increased MH-S cell uptake of opsonized beads but had no effect on phagocytosis of E. coli. Addition of ∆⁹-THC to terpenes did not potentiate cytotoxicity nor phagocytosis. These results suggest that terpenes from cannabis have minimal impact on the function of alveolar macrophages.

Cannabinoids are part of the most popular group of illicit substances in the Western world. The word "cannabinoid" refers to any chemical substance, regardless of structure or origin, that binds to the body's cannabinoid receptors and that has effects similar to those produced by the Cannabis plant. Regarding their origin, cannabinoids can be classified into endocannabinoids, phytocannabinoids and synthetic cannabinoids. The behavioral and physiological effects of cannabinoids have received particular attention over the last few decades, including sensations of euphoria, relaxation and loss of concentration, with their repeated use being associated with short and long-term side effects, including respiratory and cardiovascular disorders, cognitive changes, psychoses, schizophrenia and mood disorders. On the other hand, recent investigations have proposed a promising therapeutic potential of cannabinoid-based drugs for a wide range of medical situations, including neurological and psychiatric disorders, among other indications. The growing popularity in the use of cannabinoid-based compounds, both for recreational and therapeutic purposes, has been accompanied by an equally continuous and growing evolution of knowledge regarding their potential harmful and beneficial effects. However, there are several open questions and challenges to be answered, which require more and better investigations. This article's main objectives are: i) to understand the importance of the action of cannabinoids in humans; ii) identify the different types of cannabinoids that exist and understand the differences in their action; iii) distinguish the legislative framework for cannabinoid consumption; iv) identify the possible adverse effects of cannabinoid consumption, as well as their potential benefits; v) know the existing medical-scientific evidence in terms of therapeutic potential, particularly in relation to aspects of safety and efficacy; vi) encourage critical thinking about the recreational consumption and therapeutic use of cannabinoids, based both on currently available evidence and gaps in knowledge.

IAA is a by-product of the water disinfection process and has been found to be neurotoxic. However, the role and mechanism of IAA neurotoxicity remain unclear. In this review, we comprehensively discuss the neurotoxic effects and mechanisms of IAA from the molecular level, cellular level and neurological manifestations. At the molecular level, IAA causes neurotoxicity by reducing mitochondrial membrane potential, aggravating oxidative stress and DNA damage. At the cellular level, IAA causes neurotoxicity by inducing BBB disruption, neuroinflammation, and apoptosis. In neurological manifestations, IAA can lead to neurotransmitter disorders, neurodevelopment dysfunction, and even neurodegenerative diseases. Taken together, our review provides insights into the mechanisms of IAA neurotoxicity that will contribute to future studies of IAA neurotoxicity and its protective strategies.

Chlorinated paraffins (CPs) are classified as emerging persistent organic pollutants (POPs). Due to their associated environmental and health impacts, these groups of chemicals have been a subject of interest among researchers in the past decades. Here we used a scientometric approach to understand the research landscape of CPs using literature published in the Web of Science and Scopus database. RStudio and VOSviewer programs were employed as scientometric tools to analyze the publication trends in global CP-related research from 1916 to 2024. A total of 1,452 articles were published over this period, with a publication/author and co-author/publication ratio of 0.43 and 5.49, respectively. China ranked first in publication output (n = 556, 43.3%), and the highest total citations (n = 12,007), followed by Sweden (n = 90), Canada (n = 77), and Germany (n = 75). Publications from developing countries were limited, with most contributions from Africa originating from Egypt (n = 7), South Africa (n = 5), and Nigeria (n = 3), primarily through international collaborations. The average annual growth rate of 4.3% suggests a significant future article output. This scientometric analysis allowed us to infer global trends in CPs, identify tendencies and gaps, and contribute to future research. Despite having similar toxicity to short-chain chlorinated paraffin (SCCP), long-chain chlorinated paraffin (LCCP) has received less attention. Therefore, future research should prioritize studying LCCP bioaccumulation and toxicity in diverse food webs, focusing on aquatic species vulnerable to CPs and effective toxicological models. Additionally, collaborative research with developing countries should be encouraged to enhance meeting the Stockholm Convention's demand.

Objective: Carbon monoxide poisoning can cause migraine-like attacks. However, the association between carbon monoxide poisoning and the risk of migraine has not been thoroughly studied. This study aimed to investigate the long-term risk of migraine in patients with carbon monoxide poisoning.

Methods: This nationwide, population-based cohort study was conducted using the administrative database of the National Health Insurance Service of Korea from 2002 to 2021. Patients with carbon monoxide poisoning with at least one visit documented according to the International Classification of Diseases, 10th Revision code T58 were included. Patients were only included if they had the same diagnostic code at two or more outpatient clinic visits. The primary outcome of this study was the incidence of migraine after carbon monoxide poisoning.

Results: The overall risk of migraine was higher in the carbon monoxide poisoning group regardless of age, sex, or use of hyperbaric oxygen therapy (adjusted hazard ratio, 1.37; 95% confidence interval, 1.28-1.48). The carbon monoxide poisoning group had a persistently higher cumulative incidence of migraine during the observation period than the control group.

Conclusion: Carbon monoxide poisoning was associated with an increased overall risk of developing migraine during long-term follow-up.