Toxicological Information Research Articles

Repeated intratracheal instillation effects of commonly used vehicles in toxicity studies with mice

Intratracheal instillation (ITI) is considered the most pragmatic approach for investigating the potential toxicities of various respiratory exposure materials. Various respiratory exposure materials, including nanomaterials, hazardous air pollutants, fine dust, and household biocides, have raised public health concerns because of limited toxicological information and increasing consumption. Hence, toxicity studies using ITI in laboratory animals are important to accurately assess the human risks associated with these respiratory-exposed materials. However, data to adequately support the study design of ITI toxicity studies, particularly those examining the effects of commonly used vehicles following repeated exposure are insufficient. Therefore, in this study, we examined the effects of 16 types of commonly used vehicles in toxicity studies following 14-day repeated ITI in mice. General health endpoints (mortality, clinical signs, and body weight) were monitored throughout the study period, and terminal endpoints (gross observation, lung weight, bronchoalveolar lavage fluid analysis, and lung histopathological examination) were assessed after terminal sacrifice. Saline and phosphate-buffered saline elicited the least response, whereas corn oil (50 µL) showed the most severe toxicity findings. In addition, several commonly used vehicles, including distilled water, sodium carboxymethyl cellulose, dimethyl sulfoxide, ethanol, Tween 20, and Tween 80, induced mild-to-severe toxicity in the respiratory system. Based on the results of this study, some commonly used vehicles in toxicity studies should be used with caution when the ITI exposure route is considered. These results provide important background information on the effects of vehicles in ITI toxicity studies along with valuable insights for designing toxicity studies using respiratory exposure materials.

Update of a database of toxicological effects of pesticides in view of performing cumulative risk assessments. Part 1: Catalogue of toxicity endpoints and data model for the collection of toxicity endpoints.

Abstract A catalogue of toxicity endpoints was developed for a consistent collection of toxicological information. The toxicity endpoints of relevance for cumulative risk assessment were organised in a table for each target organ/tissue/system (cumulative assessment group (CAG) at level 1) including information on specific toxicological effect(s) (CAG at level 2), indicators that reflect the relevance for the CAG at level 2, and descriptions/interpretations that allow an understanding of the CAG at level 2. A data model for the collection of toxicity endpoints was developed to ensure the possibility of integration of the collected data to the EFSA OpenFoodTox database, in order to extend it to non‐critical endpoints. The collection of toxicity endpoints and grouping of active substances were performed for a total of 328 active substances and 165 of their metabolites. The data model was filled in for all the OpenFoodTox columns as far as possible and essential information which could not be entered in the OpenFoodTox columns were noted in the ‘Remark column’. In total, 29 CAGs at level 1 have been evaluated for inclusion of specific toxicological effects (CAGs at level 2), whereas four CAG1 targets (gastrointestinal tract, immune system, lungs and skin) were not evaluated as the effects observed in these CAG1 targets were not considered relevant for CAGs at level 2. A number of toxicological effects considered adverse and of relevance for human risk assessment, but generally not relevant for CAGs at level 2, include mortality, clinical signs of toxicity, changes in bodyweight and body weight gain, changes in food consumption and water consumption, changes in clinical biochemistry and urinalysis parameters and changes in organ weights without histopathological changes. © National Food Institute, Technical University of Denmark, 2024

Comprehensive Characterization of Oxidative Stress-Modulating Chemicals Using GPT-Based Text Mining.

The screening of hazardous environmental pollutants is hindered by the limited availability of toxicological databases. Large language model (LLM)-based text mining holds the potential to automatically extract complex toxicological information from the literature. Due to its relevance to diseases and the challenge of comprehensive characterization, oxidative stress serves as a suitable case for research by texting mining. In this study, a robust workflow utilizing a LLM (i.e., GPT-4) was developed to extract information on oxidative stress tests, including data collection, text preprocessing, prompt engineering, and performance evaluation procedures. A total of 17,780 relevant records were extracted from 7166 articles, covering 2558 unique compounds. A rising interest in oxidative stress was observed over the past two decades. A list of known prooxidants (n = 1416) and antioxidants (n = 1102) was established, with the leading chemical categories being pharmaceuticals, pesticides, and metals for prooxidants and pharmaceuticals and flavonoids for antioxidants. Structural alert analysis identified potential prooxidant (e.g., chlorobenzene, nitrobenzene, and tertiary amines) and antioxidant (e.g., flavonoid and thiol) substructures. These findings illustrate the feasibility of building toxicological databases through LLM-based text mining in a cost-efficient manner, and the information obtained from the technique holds significant promise for future applications in environmental and health research.

Guidance on the scientific requirements for an application for authorisation of a novel food in the context of Regulation (EU) 2015/2283.

The European Commission requested EFSA to update the scientific guidance for the preparation of applications for authorisation of novel foods, previously developed following the adoption of Regulation (EU) 2015/2283 on novel foods. This guidance document provides advice on the scientific information needed to be submitted by the applicant towards demonstrating the safety of the novel food. Requirements pertain to the description of the novel food, production process, compositional data, specifications, proposed uses and use levels and anticipated intake of the novel food. Furthermore, information needed in sections on the history of use of the novel food and/or its source, absorption, distribution, metabolism, excretion, toxicological information, nutritional information and allergenicity is also described. The applicant should integrate and interpret the data presented in the different sections to provide their overall considerations on how the information supports the safety of the novel food under the proposed conditions of use. Where potential health hazards have been identified, they are to be discussed in relation to the anticipated intake of the novel food and the proposed target populations. On the basis of the information provided, EFSA will assess the safety of the novel food under the proposed conditions of use.

TOXICOLOGICAL EVENTS ASSOCIATED WITH PARACETAMOL MANAGED BY A TOXICOLOGY INFORMATION AND ASSISTANCE CENTER

This study aimed to analyze the toxicological events associated with paracetamol managed by aToxicological Information and Assistance Center. It was a cross-sectional, retrospective study based on casesof toxicological events associated with the drug paracetamol attended by the Toxicological Information andAssistance Center of Londrina (CIATox/Londrina). The data was extracted from the Brazilian Poison DataSystem (DATATOX) from 2017 to 2021. The data was analyzed using the Statistical Package for the SocialSciences (SPSS), version 19.0. This study was approved by the Research Ethics Committee of the StateUniversity of Londrina. Between 2017 and 2021, CIATox/Londrina received 685 cases of toxicologicalevents associated with paracetamol, of which the vast majority (75.0%) were women who had attemptedsuicide (83.2%) as their main circumstance. Most cases (37.7%) occurred in the afternoon on Saturdays andSundays, the days of the week with the highest number of cases (15.7% and 16.2%, respectively).Paracetamol was combined with other substances in 156 (22.8%) cases. Almost 80.0% of the cases hadclinical manifestations, with 36.4% requiring hospitalization (minimum of one and maximum of 37 days).Most cases were categorized as mild (57.7%), and four (0.6%) deaths were identified among all the cases.The antidote N-acetylcysteine was administered to 37.1% (N=255) patients. In general, toxicological eventsassociated with paracetamol occurred predominantly in women in the afternoon and on Saturdays andSundays, and involved suicide attempts. It is, therefore, essential to develop campaigns that encourage thecorrect use of medication and other public health campaigns, especially for those individuals who are moresusceptible to suicide attempts.

Toxicity Equivalency Factors for Tetrodotoxin Analogues Determined with Automated Patch Clamp on Voltage-Gated Sodium Channels in Neuro-2a Cells.

Tetrodotoxin (TTX) is a potent marine neurotoxin, responsible for numerous poisoning incidents and some human fatalities. To date, more than 30 TTX analogues have been identified, but their individual toxicities and roles in poisoning remain largely unknown. In this work, the toxicity equivalency factors (TEFs) of five TTX analogues were determined by assessing the blockade of voltage-gated sodium channels in Neuro-2a cells using automated patch clamp (APC). All TTX analogues were less toxic than TTX. The derived TEFs were applied to the individual TTX analogues concentrations measured in pufferfish samples, using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). A comparison of these results with those obtained from APC analysis demonstrated that TEFs can be effectively used to translate LC-MS/MS analytical data into meaningful toxicological information. This is the first study to utilize APC device for the toxicological assessment of TTX analogues, highlighting its potential as a bioanalytical tool for seafood safety management and human health protection.

Combination of toxicological and epidemiological approaches for estimating the health impact of atmospheric pollutants. A proof of concept for NO2

BackgroundRegular monitoring of the air pollutant nitrogen dioxide (NO2), an indicator for traffic-related emissions, is a priority in urban environments. The health impacts associated with NO2 exposure are the result of a combination of factors, including concentration, duration of exposure, and interactions with other pollutants. WHO has established air quality guidelines based on epidemiological studies. ObjectiveThis study develops a new concept "Health Impact Pathways (HIPs)" using adversity as a probabilistic indicator of health effects. For this purpose, it integrates available toxicological and epidemiological information, using Adverse Outcome Pathways (AOPs), in order to understand chemical-biological interactions and their consequences on health. MethodsLiterature review and meta-analysis of toxicological data supported by expert judgment were performed to establish: a) adversity pathways, b) quantitative criteria for scoring the observed toxicological effects (adversity indicators), c) NO2 exposure - adversity relationship for both long-term (1–36 months) and shortterm (1–7 days). The NO2 daily concentrations from January 2001 to December 2022, were obtained from Madrid city Air Quality network monitoring database. Adversity levels were compared with relative risk levels for all-cause and respiratory mortality estimated using linear equations from WHO 2021 guidelines. ResultsNon-linear relations were obtained for all long- and short-term NO2 related adversity indicators; for long-term effects, the best fitting was obtained with a modified Haber's law model with an exponential coefficient for the exposure time of 0.25. Estimations are presented for a set of case studies for Madrid city, covering temporal and spatial variability. A clear improvement trend along the two decades was observed, as well as high inter- and intra-station variability; the adversity indicators provided integrated information on the temporal and spatial evolution of population level risk. DiscussionThe proposed HIP conceptual approach offers promising advances for integrating experimental and epidemiological data. The next step is linking the concentration-adversity relationship with population health impacts through probability estimations, the preliminary estimations confirm the need for assessing independently different population groups.

Safety of Acheta domesticus powder as a Novel food pursuant to Regulation (EU) 2015/2283.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on Acheta (A.) domesticus powder as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The main components of the NF are protein, fat and dietary fibre (chitin). The Panel notes that the concentration of contaminants in the NF depends on the occurrence levels of these substances in the insect feed. The Panel further notes that there are no safety concerns regarding the stability of the NF if the NF complies with the proposed specification limits during its entire shelf-life. The NF has a high protein content, although the true protein content is overestimated when using the nitrogen-to-protein conversion factor of 6.25 due to the presence of non-protein nitrogen from chitin. The applicant proposed to use the NF as food ingredient in a number of food products. The target population proposed by the applicant is the general population. Considering the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. The panel notes that no safety concerns arise from the toxicological information of A. domesticus. The panel considers that the consumption of the NF might trigger primary sensitisation to A. domesticus proteins and may cause allergic reactions in subjects allergic to crustaceans, mites and molluscs. Additionally, allergens from the feed may end up in the NF. The panel concludes that the NF is safe under the proposed uses and use levels.

The synthetic cathinones MDPHP and MDPV: Comparison of the acute effects in mice, in silico ADMET profiles and clinical reports

The 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (MDPHP) is a synthetic cathinone closely related to 3,4-methylenedioxypyrovalerone (MDPV), one of the most common synthetic cathinones present in the “bath salts”. MDPHP has recently gained attention due to increasing seizures and involvement in human intoxications which occurred in Europe and Italy in the last years, but currently there is a lack of information about its pharmaco-toxicological effects. With the aim at filling this gap, the present study is endeavoured to (i) evaluate the effects of acute administration of MDPHP (0.01–20 mg/kg; i.p.) on behaviour, cardiorespiratory and cardiovascular parameters in CD-1 male mice, comparing them to those observed after administration of MDPV; (ii) predict the ADMET profile of the two analogues using the Plus ADMET Predictor®; (iii) present clinical data related to MDPHP and MDPV-induced intoxications recorded between 2011 and 2023 by the Pavia Poison Control Centre (PCC) − National Toxicology Information Centre (Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Italy). Our results substantiated that MDPHP and MDPV similarly affect sensorimotor and behavioural responses in mice, importantly increased locomotion and induced aggressive behaviour, and, at higher dosage, increased heart rate and blood pressure. These findings are in line with those observed in humans, revealing severe toxidromes typically characterized by Central Nervous System (CNS) alterations (behavioural/neuropsychiatric symptoms), including psychomotor agitation and aggressiveness, cardiovascular and respiratory disorders (e.g. tachycardia, hypertension, dyspnoea), and other peripheral symptoms (e.g. hyperthermia, acidosis, rhabdomyolysis).

Risks assessment to the health of the population in the area of emissions pollutants influence of carbon graphite production enterprises

Risk assessment of the impact of the enterprise's activities on the environment includes risk assessment of the impact of the activity on the health of the population. Risk as the probability of undesirable events is an integral component of any person's life. Risk characterization integrates data on the danger of the analyzed chemical substances, the amount of exposure, parameters of "dose-response" dependence, with the aim of quantitative and qualitative assessment of risk, identification and assessment of the comparative significance of existing problems for the health of the population. In scientific terms, hazard identification is the process of establishing a causal relationship between the action of a chemical substance and the development of adverse effects on human health. The main goal of the hazard identification stage is the selection of priority, indicator chemical substances, the study of which allows to reliably characterize the sources of occurrence and the level of risk of public health impairment. Assessment of dose-response relationships is a process of quantitative characterization of toxicological information and establishment of a relationship between the likely influencing dose (concentration) of a pollutant and the incidence of adverse events in the exposed population. Characteristics of "dose-response" dependence, which are most often used to assess carcinogenic risk, have been sufficiently studied in epidemiological studies. Among them is the factor of carcinogenic potential (ICS), which reflects the probability of the development of a harmful reaction when the dose (concentration) increases by 1 mg/kg or 1 mg/m3 per exposure level, associated with a certain probability of effect (the indicators of this group are used for establishment of reference, i.e., reference doses and concentrations). The individual carcinogenic risk characterizes the upper limit of possible carcinogenic risk during the period corresponding to the average life expectancy of a person (70 years). Today, in the world, the classification and assessment of the acceptable risk to the health of the population caused by the chemical influence of chemical substances that pollute the environment is quite wide. the system of acceptance criteria recommended by WHO is used. In accordance with these criteria, the first range of risk (individual lifetime risk equal to or less than 1·10-6, which also corresponds to an additional case of serious illness or death per 1 million exposed persons) characterizes such levels of risk as are perceived by all strata population as quite small, which do not differ from ordinary everyday risks (De minimas level). Such risks do not require additional measures to reduce them and their levels are subject to periodic control. The second range (greater than 1·10-6 and less than 1·10-4) corresponds to the zone of conditionally accepted (acceptable) risk. It is at this level that most of the foreign and recommended by international organizations hygienic standards for the population as a whole are established. Levels of suitable risk belong to constant control. The third range (greater than 1·10-4 and less than 1·10-3) is suitable for professionals and unsuitable for the general population. The emergence of such a level of risk requires the development and implementation of planned health measures. The fourth range (equal to or greater than 1·10-3) is unsuitable neither for the population nor for professionals. This range is designated as De manifestis Risk, and when it is reached, it is necessary to carry out emergency health measures to reduce the risk on the part of the city authorities. During the assessment of the risk to the health of the population of Zaporizhzhia from the emissions of PJSC "Ukrgrafit", priority pollutants were identified: carbon oxides, nitrogen oxides, sulfur oxides, substances in the form of suspended solid particles of undifferentiated composition. Hazard indices were determined for individual HQ substances (non-carcinogenic risks) and in the case of combined exposure to HI, individual carcinogenic risks (ICR) and combined exposure (CRa) were calculated. Assessment of long-term effects (at the level of average annual concentration) on human health of the investigated substances. allowing to assess the chronic inhalation effect of the occurrence of negative effects in the health of the exposed population during the lifetime for the assessment and characterization of multistage risk showed that the hazard indices (HQ) do not exceed the norms.

The application of natural language processing for the extraction of mechanistic information in toxicology.

To study the ways in which compounds can induce adverse effects, toxicologists have been constructing Adverse Outcome Pathways (AOPs). An AOP can be considered as a pragmatic tool to capture and visualize mechanisms underlying different types of toxicity inflicted by any kind of stressor, and describes the interactions between key entities that lead to the adverse outcome on multiple biological levels of organization. The construction or optimization of an AOP is a labor intensive process, which currently depends on the manual search, collection, reviewing and synthesis of available scientific literature. This process could however be largely facilitated using Natural Language Processing (NLP) to extract information contained in scientific literature in a systematic, objective, and rapid manner that would lead to greater accuracy and reproducibility. This would support researchers to invest their expertise in the substantive assessment of the AOPs by replacing the time spent on evidence gathering by a critical review of the data extracted by NLP. As case examples, we selected two frequent adversities observed in the liver: namely, cholestasis and steatosis denoting accumulation of bile and lipid, respectively. We used deep learning language models to recognize entities of interest in text and establish causal relationships between them. We demonstrate how an NLP pipeline combining Named Entity Recognition and a simple rules-based relationship extraction model helps screen compounds related to liver adversities in the literature, but also extract mechanistic information for how such adversities develop, from the molecular to the organismal level. Finally, we provide some perspectives opened by the recent progress in Large Language Models and how these could be used in the future. We propose this work brings two main contributions: 1) a proof-of-concept that NLP can support the extraction of information from text for modern toxicology and 2) a template open-source model for recognition of toxicological entities and extraction of their relationships. All resources are openly accessible via GitHub (https://github.com/ontox-project/en-tox).

Novel foods, food enzymes, and food additives derived from food by-products of plant or animal origin: principles and overview of the EFSA safety assessment.

The European Union (EU) is committed to transitioning toward a circular economy model, with food waste being one of the areas to be targeted. To close the loop of food waste generated during food processing and discarded at the retail or consumption phases, research and innovation parties proposed to valorize agro-food by-products to produce novel foods and food improvement agents (food additives, food enzymes, and food flavorings). In the EU, the authorization of such novel foods and food improvement agents is governed by different regulatory frameworks. A centralized safety assessment by the European Food Safety Authority (EFSA) is the prerequisite for their authorization through the so-called Union Lists. Up to December 2023, EFSA published 45 scientific opinions on the safety of novel foods, food enzymes, and food additives derived from by-products of plant and animal origin. The current study illustrates examples of these by-products for the production of novel foods or food improvement agents and the data requirements behind their respective safety assessments conducted by EFSA. In this review, applications on novel foods, food enzymes, and food additives received by EFSA were screened and analyzed to find the common scientific requirements and differences in terms of the safety evaluation of such products. Various by-products (i.e., corncobs, coffee husks, spent grains of barley and rice, grape pomace, pumpkin peels, bovine whey, eggshells, shrimp heads, and animal organs or tissues) were described in the applications as being processed (extraction, physical treatments, and chemical and enzymatic reactions) to obtain novel foods and food improvement agents. The heterogeneity and complexity of these products emphasize the challenge of their safety assessment, depending on the characteristics of each product. However, as this study shows, the scientific requirements underpinning their safety do not differ substantially in the different regulated product areas considered, with similar information needed to assess their safety in terms of identity, production process, compositional characterization, proposed/intended uses and exposure assessment, toxicological information, and allergenicity data. Additional nutritional information and data on the history of use are required in the case of novel foods.

A review on the safety of growth factors commonly used in cultivated meat production.

Growth factors are commonly added to cell culture media in cellular agriculture to mimic the endogenous process of proliferation and differentiation of cells. Many of these growth factors are endogenous to humans and known to be present in the edible tissues and milk of food animals. However, there is little or no information on the use of growth factors intentionally added in food production before the advent of cultivated meat. Ten commonly used growth factors have been reviewed to include information on their mode of action, bioavailability, occurrence in food and food animals, endogenous levels in humans, as well as exposure and toxicological information drawn from relevant animal studies and human clinical trials with a focus on oral exposure. In addition, a comparison of homology of growth factors was done to compare the sequence homology of growth factors from humans and domestic animal species commonly consumed as food, such as bovine, porcine, and poultry. This information has been gathered as the starting point to determine the safety of use of growth factors in cultivated meat meant for human consumption. The change in levels of growth factors measured in human milk and bovine milk after pasteurization and high-temperature treatment is discussed to give an indication of how commercial food processing can affect the levels of growth factors in food. The concept of substantial equivalence is also discussed together with a conservative exposure estimation. More work on how to integrate in silico assessments into the routine safety assessment of growth factors is needed.

The surge of bromazolam-related fatalities replacing other novel designer benzodiazepines-related fatalities in San Francisco.

Bromazolam, a novel designer benzodiazepine (NBD), exhibits potent sedative, hypnotic and anxiolytic effects, raising concerns regarding its potential for misuse and fatal outcomes, particularly when combined with opioids such as fentanyl. Despite limited documented fatalities globally, its use poses a significant threat, exacerbated by under-reporting and a lack of routine testing. This study analysed NBD-related deaths in a major US city over a 4-year period. Analysis of accidental overdose deaths involving NBDs in San Francisco, CA, USA from 2020 to 2023, was performed utilizing medico-legal death investigations including comprehensive forensic toxicology, pathology and demographic information. San Francisco conducts thorough investigations into all non-natural and sudden unexpected deaths, including routine alcohol and drug testing of decedents under its jurisdiction, including etizolam, flualprazolam, flubromazolam and bromazolam analysis. There was a sudden surge in bromazolam-related deaths, with 44 fatalities documented in 2023, contrasting with relatively fewer deaths related to other NBDs. Bromazolam fatalities frequently involved co-ingestion with opioids, primarily fentanyl, and stimulants such as methamphetamine and cocaine. Demographic characteristics indicated a predominance of males, with a significant proportion lacking fixed addresses. Blood concentrations of bromazolam increased during the study period, suggesting heightened availability and/or purity in the community. There was a surge in bromazolam-related deaths during 2023 in San Francisco, CA, USA, contrasting with relatively stable numbers of deaths associated with other NBDs over the preceding years. The findings underscore the urgency for enhanced death investigation, testing and reporting to facilitate targeted harm reduction strategies for individuals at risk of bromazolam-related morbidity and mortality.

β-cyclodextrin polymer as tetrodotoxins scavenger in oyster extracts

Tetrodotoxins (TTXs) are potent marine neurotoxins involved in poisoning cases in humans after consumption of some marine organisms. A cell-based assay (CBA) providing toxicological information is a commonly used method for their detection because of its high sensitivity. However, matrix effects may interfere in the CBA. In this work, five insoluble cyclodextrin polymers, with different chemicals structures (βCDP-14-DS2, βCDP-13-DS2, βCDP-13-DS4, βCDP-14-DS4 and βCDP-N-DS5) have been investigated as novel clean-up materials for oyster extracts containing TTXs. The best recoveries have been achieved with βCDP-14-DS2 (∼100 %), which allowed exposing cells to 27-fold higher oyster matrix concentrations and decreased the LOQ down to 46 µg equiv. TTX/kg. Then, the applicability of this strategy has been demonstrated with oyster extracts from The Netherlands and comparing the results with immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS). This clean-up strategy combined with CBA could be implemented for TTXs detection in monitoring programs to ensure seafood safety.

Metabolic, neurotoxic and immunotoxic effects of PFAAs and their mixtures on the proteome of the head kidney and plasma from rainbow trout (Oncorhynchus mykiss)

PFAAs (Perfluoroalkyl acids) are a class of bioaccumulative, persistent and ubiquitous environmental contaminants which primarily occupy the hydrosphere and its sediments. Currently, a paucity of toxicological information exists for short chain PFAAs and complex mixtures. In order to address these knowledge gaps, we performed a 3-week, aqueous exposure of rainbow trout to 3 different concentrations of a PFAA mixture (50, 100 and 500 ng/L) modeled after the composition determined in Lake Ontario. We conducted an additional set of exposures to individual PFAAs (25 nM each of PFOS (12,500 ng/L), PFOA (10,300 ng/L), PFBS (7500 ng/L) or PFBA (5300 ng/L) to evaluate differences in biological response across PFAA congeners. Untargeted proteomics and phosphorylated metabolomics were conducted on the blood plasma and head kidney tissue to evaluate biological response. Plasma proteomic responses to the mixtures revealed several unexpected outcomes including Similar proteomic profiles and biological processes as the PFOS exposure regime while being orders of magnitude lower in concentration and an atypical dose response in terms of the number of significantly altered proteins (FDR < 0.1). Biological pathway analysis revealed the low mixture, medium mixture and PFOS to significantly alter (FDR < 0.05) a number of processes including those involved in lipid metabolism, oxidative stress and the nervous system. We implicate plasma increases in PPARD and PPARG as being directly related to these biological processes as they are known to be important regulators in all 3 processes. In contrast to the blood plasma, the high mixture and PFOA exposure regimes caused the greatest change to the head kidney proteome, altering many proteins being involved in lipid metabolism, oxidative stress and inflammation. Our findings support the pleiotropic effect PFAAs have on aquatic organisms at environmentally relevant doses including those on PPAR signaling, metabolic dysregulation, immunotoxicity and neurotoxicity.

Exogenous intoxication in patients treated at the Toxicological Information and Assistance Center during the COVID-19 pandemic

Poisoning is defined as an adverse event resulting from the action of chemical substances that induces a pathology in an individual. The World Health Organization (WHO) has reported three million hospital admissions occurring annually due to toxic exposure worldwide. The growth of SARS-CoV-2 infection cases in 2020 also significantly increased calls to Poison Centers due to exposure to cleaning products, hand sanitizers, and disinfectants in early March 2020 in the United States. Based on this scenario, it was hypothesized that the pattern of exogenous intoxication has changed. Therefore, the aim of this study was to analyze the epidemiological profile of exogenous intoxications recorded by CIATOX-DF from March 2020 to February 2021, during the COVID-19 pandemic. At that time, there was an increase in accidental, environmental, venomous, and non-venomous animal cases, especially in babies, pre-adolescents, adolescents (11 to 15 years old), and women, due to the greater exposure of this age group and gender who have spent more time in rural environments. Most poisonings were accidental. It was observed that there was a decrease in suicide cases, but within these cases, there was a trend increase in poisoning in pre-adolescents and adolescents (11 to 15 years old) compared to other ages, which can be related to an increase in anxiety within this age group. The main toxic agents were venomous and non-venomous animals. The pattern of high frequency in cases involving medicines, pesticides, and household cleaning products was maintained, with a significant increase in cases involving 70% alcohol. It was found that patients living in towns further away from the Pilot Plan in Brasilia suffer accidents involving venomous animals. Accidental and attempted suicide cases occurred more frequently in cities closer to the Pilot Plan region. We concluded that these changes were explained by the new pattern of social behavior during the pandemic.

Self-medication cases reported to a poison information center in Brazil from 2014 to 2020

Introduction Self-medication is the use of drugs to treat self-diagnosed illnesses or symptoms, on one’s own initiative, without the guidance of a healthcare professional. Poison centers play an important role in understanding the relationship between self-medication and poisoning. The objective of this study is to evaluate the clinical and epidemiological profile of patients exposed to and/or poisoned by different drugs through self-medication. Methods This retrospective, cross-sectional, and descriptive study analyzed data from 2014 to 2020, provided by the Toxicological Information and Assistance Center of Santa Catarina, Brazil. Data were selected, tabulated, and analyzed by using descriptive statistics and group comparison with the chi-square test or Fisher’s exact test. A P value <0.05 was considered statistically significant. Results There were 683 cases of self-medication identified. Most patients were female (62.8 percent) and between 20 and 29 years old (26.1 percent). A toxic dose of a substance was administered in only 22.8 percent of the cases, and five deaths were recorded. The most commonly used medications were anxiolytics (18 percent), followed by analgesics and antipyretics (15.4 percent). Paracetamol was the drug used in three of the five cases that resulted in deaths. Discussion This study demonstrates the prevalence of self-medication among women aged between 20 and 29 years old. Statistical analysis failed to show a relationship between a toxic dose and clinical manifestations. Anxiolytics, analgesics, and antipyretics are the most reported medications probably because healthcare professionals are mostly the ones who contact the center. Analgesics and antipyretics account for more than fifty percent of the deaths caused by self-medication in the present report. Some limitations such as secondary sources are related. Conclusion We highlight the importance of health professionals in promoting the rational use of medicines, as well as poison centers in assisting the population and raising their awareness regarding the issue.

An integrative data-centric approach to derivation and characterization of an adverse outcome pathway network for cadmium-induced toxicity

Cadmium is a prominent toxic heavy metal that contaminates both terrestrial and aquatic environments. Owing to its high biological half-life and low excretion rates, cadmium causes a variety of adverse biological outcomes. Adverse outcome pathway (AOP) networks were envisioned to systematically capture toxicological information to enable risk assessment and chemical regulation. Here, we leveraged AOP-Wiki and integrated heterogeneous data from four other exposome-relevant resources to build the first AOP network relevant for inorganic cadmium-induced toxicity. From AOP-Wiki, we filtered 309 high confidence AOPs, identified 312 key events (KEs) associated with inorganic cadmium from five exposome-relevant databases using a data-centric approach, and thereafter, curated 30 cadmium relevant AOPs (cadmium-AOPs). By constructing the undirected AOP network, we identified a large connected component of 18 cadmium-AOPs. Further, we analyzed the directed network of 59 KEs and 82 key event relationships (KERs) in the largest component using graph-theoretic approaches. Subsequently, we mined published literature using artificial intelligence-based tools to provide auxiliary evidence of cadmium association for all KEs in the largest component. Finally, we performed case studies to verify the rationality of cadmium-induced toxicity in humans and aquatic species. Overall, cadmium-AOP network constructed in this study will aid ongoing research in systems toxicology and chemical exposome.

Toxicity and Toxicokinetics of a Four-Week Repeated Gavage of Levamisole in Male Beagle Dogs: A Good Laboratory Practice Study.

Levamisole (LVM) is considered an immunomodulatory agent that has the potential to treat various cancer and inflammation diseases. However, there is still much debate surrounding the toxicokinetic and toxicological information of LVM. Therefore, it is crucial to assess its toxicity to provide useful data for future human LVM risk assessments. In this study, a barrier environment was established under the guidance of good laboratory practice (GLP) at the Fujian Center for New Drug Safety Evaluation. Male beagle dogs were orally administered with 5, 15, and 30 mg/kg of LVM daily for four weeks. Toxicity assessment was based on various factors such as mortality, clinical signs, food and water consumption, body weight, body temperature, electrocardiogram, ophthalmological examination, hematology, serum biochemistry, organ/body coefficients, histopathological study, and toxicokinetic analysis. The results of this study showed that LVM did not exhibit any significant toxicological effects on beagle dogs at the exposure levels tested. A no observed adverse effect level (NOAEL) of LVM was set at 30 mg/kg/day for male beagle dogs, which is equivalent to a 12-fold clinical dose in humans. Moreover, the repeated exposure to LVM for four weeks did not lead to any bioaccumulation. These findings provide valuable insights for future human LVM risk assessments.