Experts In Toxicology Research Articles

From historical drugs to present perils: UHPLC-QqQ-MS/MS determination of methaqualone and its designer analogs (NPS) with comprehensive fragmentation pathways study (QTOF)

Methaqualone, introduced in the 1960s as a sedative-hypnotic alternative to barbiturates, was withdrawn from the market due to its side effects and growing recreational use. Despite this, interest in methaqualone and its analogs remains high, raising concerns about potential abuse in the future. An ultra-high-performance liquid chromatography method coupled with triple quadrupole tandem mass spectrometry (UHPLC-QqQ-MS/MS) was developed to determine nine methaqualone-related compounds simultaneously. Biological samples were prepared using liquid-liquid extraction with ethyl acetate at pH 9, quantification was performed in blood using multiple reaction monitoring (MRM) mode. Methaqualone-d7 served as an internal standard. The limit of quantification (LOQ) ranged from 0.1 to 0.2 ng/mL, with precision and accuracy within 20%. Recovery ranged from 84.2% to 113.7%. The developed method allowed chromatographic separation of all compounds tested, including two structural isomers: methtylmethaqualone and etaqualone. The mass spectra aquired from quadrupole time-of-flight mass spectrometer allowed for the elucidation of comprehensive fragmentation study of methaqualone derivatives. The described situation poses a significant problem from the analytical point of view, as well as interpretation and forensic toxicological expertise. The developed method will contribute to increased analytical capabilities and enhanced detection of compounds from the methaqualone group that may appear on the illicit market.

Comparing answers of artificial intelligence systems and clinical toxicologists to questions about poisoning: Can their answers be distinguished?

To present questions about poisoning to 4 artificial intelligence (AI) systems and 4 clinical toxicologists and determine whether readers can identify the source of the answers. To evaluate and compare text quality and level of knowledge found in the AI and toxicologists' responses. Ten questions about toxicology were presented to the following AI systems: Copilot, Bard, Luzia, and ChatGPT. Four clinical toxicologists were asked to answer the same questions. Twenty-four recruited experts in toxicology were sent a pair of answers (1 from an AI system and one from a toxicologist) for each of the 10 questions. For each answer, the experts had to identify the source, evaluate text quality, and assess level of knowledge reflected. Quantitative variables were described as mean (SD) and qualitative ones as absolute frequency and proportion. A value of P .05 was considered significant in all comparisons. Of the 240 evaluated AI answers, the expert evaluators thought that 21 (8.8%) and 38 (15.8%), respectively, were certainly or probably written by a toxicologist. The experts were unable to guess the source of 13 (5.4%) AI answers. Luzia and ChatGPT were better able to mislead the experts than Bard (P = .036 and P = .041, respectively). Text quality was judged excellent in 38.8% of the AI answers. ChatGPT text quality was rated highest (61.3% excellent) vs Bard (34.4%), Luzia (31.7%), and Copilot (26.3%) (P .001, all comparisons). The average score for the level of knowledge perceived in the AI answers was 7.23 (1.57) out of 10. The highest average score was achieved by ChatGPT at 8.03 (1.26) vs Luzia (7.02 [1,63]), Bard (6.91 [1.64]), and Copilot (6.91 [1.46]) (P .001, all comparisons). Luzia and ChatGPT answers to the toxicology questions were often thought to resemble those of clinical toxicologists. ChatGPT answers were judged to be very well-written and reflect a very high level of knowledge.

Establishment of the First Institution-Based Poison Information Center in Nepal Through a Multilateral International Partnership.

Toxicological emergencies present a significant health challenge in Nepal. Despite the high burden, the country has inadequate formal toxicology training, medical toxicology expertise, and adequate poison control infrastructure. In recognition of this need, the Nepal Poison Information Center (PIC) was established as a collaborative effort involving local and international partners. Through a comprehensive partnership framework, the Nepal PIC provides 24 hours a day, 7 days a week expert guidance to health care workers, conducts educational webinars, and engages in research. Initial data from the pilot phase indicate successful consultation delivery. Challenges include bureaucratic hurdles and the need for sustainable funding. Despite these challenges, the Nepal PIC demonstrates early feasibility and potential for expansion into a comprehensive toxicology center, contributing to the advancement of clinical toxicology in Nepal. Long-term sustainability relies on governmental support and continued advocacy efforts.

Novel Technique for Simultaneous Ethylene Glycol and Its Metabolites Determination in Human Whole Blood and Urine Samples Using GC-QqQ-MS/MS.

Toxicological analyses often necessitate the identification of compounds belonging to diverse functional groups. For GC-MS analyses, derivatization of compounds belonging to different functional groups can pose a challenge and requires the development of comprehensive methods of analysis. One example could be ethylene glycol, whose widespread use is related to possible unintentional or suicidal intoxications. This fact clearly indicates the need to develop sensitive methods for the determination of ethylene glycol and its metabolites in biological material, as only such complex analysis allows for proper toxicological expertise. A simultaneous GC-QqQ-MS/MS method for the determination of ethylene glycol together with its metabolites, glyoxal and glycolic acid, as well as the detection of glyoxylic acid and oxalic acid, was developed and fully validated. A novel approach for simultaneous derivatization of substances from different groups (alcohols, aldehydes, and carboxylic acids) was established. Sample preparation included the addition of three internal standards (BHB-d4, ethylene glycol-d4 and methylglyoxal), precipitation with acetonitrile and subsequent derivatization with N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA), as well as pentafluorophenylhydrazine (PFPH). Detection was carried out with the use of triple quadrupole mass spectrometer. The ionization method was electron impact, and quantitative analysis was carried out in multiple reaction monitoring mode. The lower limit of quantification was 1 μg/mL, 0.1 μg/mL, and 500 μg/mL for ethylene glycol, glyoxal, and glycolic acid, respectively. The presented method was applied in three authentic postmortem cases of ethylene glycol intoxication.

A strategy to detect metabolic changes induced by exposure to chemicals from large sets of condition-specific metabolic models computed with enumeration techniques

BackgroundThe growing abundance of in vitro omics data, coupled with the necessity to reduce animal testing in the safety assessment of chemical compounds and even eliminate it in the evaluation of cosmetics, highlights the need for adequate computational methodologies. Data from omics technologies allow the exploration of a wide range of biological processes, therefore providing a better understanding of mechanisms of action (MoA) related to chemical exposure in biological systems. However, the analysis of these large datasets remains difficult due to the complexity of modulations spanning multiple biological processes.ResultsTo address this, we propose a strategy to reduce information overload by computing, based on transcriptomics data, a comprehensive metabolic sub-network reflecting the metabolic impact of a chemical. The proposed strategy integrates transcriptomic data to a genome scale metabolic network through enumeration of condition-specific metabolic models hence translating transcriptomics data into reaction activity probabilities. Based on these results, a graph algorithm is applied to retrieve user readable sub-networks reflecting the possible metabolic MoA (mMoA) of chemicals. This strategy has been implemented as a three-step workflow. The first step consists in building cell condition-specific models reflecting the metabolic impact of each exposure condition while taking into account the diversity of possible optimal solutions with a partial enumeration algorithm. In a second step, we address the challenge of analyzing thousands of enumerated condition-specific networks by computing differentially activated reactions (DARs) between the two sets of enumerated possible condition-specific models. Finally, in the third step, DARs are grouped into clusters of functionally interconnected metabolic reactions, representing possible mMoA, using the distance-based clustering and subnetwork extraction method. The first part of the workflow was exemplified on eight molecules selected for their known human hepatotoxic outcomes associated with specific MoAs well described in the literature and for which we retrieved primary human hepatocytes transcriptomic data in Open TG-GATEs. Then, we further applied this strategy to more precisely model and visualize associated mMoA for two of these eight molecules (amiodarone and valproic acid). The approach proved to go beyond gene-based analysis by identifying mMoA when few genes are significantly differentially expressed (2 differentially expressed genes (DEGs) for amiodarone), bringing additional information from the network topology, or when very large number of genes were differentially expressed (5709 DEGs for valproic acid). In both cases, the results of our strategy well fitted evidence from the literature regarding known MoA. Beyond these confirmations, the workflow highlighted potential other unexplored mMoA.ConclusionThe proposed strategy allows toxicology experts to decipher which part of cellular metabolism is expected to be affected by the exposition to a given chemical. The approach originality resides in the combination of different metabolic modelling approaches (constraint based and graph modelling). The application to two model molecules shows the strong potential of the approach for interpretation and visual mining of complex omics in vitro data. The presented strategy is freely available as a python module (https://pypi.org/project/manamodeller/) and jupyter notebooks (https://github.com/LouisonF/MANA).

123 Utilizing Project ECHO to mitigate environmental impacts on health through collaborative provider education

OBJECTIVES/GOALS: Launch a case-based learning collaborative on best practices that meet social, emotional and physical health needs of underserved communities as they relate to environmental toxins—specifically those related to the train derailment in OH. Topics discussed could also include disasters and spills, air quality, extreme heat, and water. METHODS/STUDY POPULATION: In response to a call for action delivered by PA’s Acting Secretary of Health, we established a partnership between Penn State CTSI, Project ECHO at Penn State, and Primary Health Network (PHN). PHN is the largest Federally Qualified Health Center in PA, making it uniquely qualified to reach rural providers diagnosing and treating patients impacted by environmental events. Utilizing the ECHO model, we are hosting monthly, 1-hour sessions on environmental determinants of health starting October 2023. Experts in pulmonology, toxicology, atmospheric science, and rural medicine (whom many participants would have limited access to outside of the ECHO platform) and participants have the opportunity to share and learn from their varied experiences exemplifying a culture of ‘all teach, all learn’. RESULTS/ANTICIPATED RESULTS: Project ECHO is an ideal model for upscaling workforce quickly, allowing participants to be responsive in the care of their community, regardless of location and access to specialty clinics. 74 participants across 26 PA counties registered for the series, ranging from PCPs, medical directors, and state officials. Upon registration, nearly half of our direct patient-care participants do not routinely conduct an environmental exposure history and almost 70% report receiving questions from their patients related to how the environment might impact their health. More than half of those providers reported feeling unprepared to answer patients’ questions related to the environment’s impact on their health. Evaluation data will be collected at enrollment, after each session, and post-series. DISCUSSION/SIGNIFICANCE: This series could result in: * Reduction of health disparities caused by environmental events (no cost, virtual learning) * Increased preparedness to quickly address health questions/symptoms related to environmental exposures * Increased awareness of the environmental impacts on health. * Improved testing/treatment for patients

Accuracy and replicability of identifying eyelid tremor as an indicator of recent cannabis smoking

Introduction Cannabis intoxication may increase the risk of motor vehicle crashes. However, reliable methods of assessing cannabis intoxication are limited. The presence of eyelid tremors is among the signs of cannabis use identified under the Drug Evaluation and Classification Program of the International Association of Chiefs of Police. Our objectives were to assess the accuracy and replicability of identifying eyelid tremor as an indicator of recent cannabis smoking using a blinded, controlled study design. Methods Adult subjects (N = 103) were recruited into three groups based on their cannabis use history: daily, occasional, and no current cannabis use. Participants’ closed eyelids were video recorded for 30 seconds by infrared videography goggles before and at a mean ± standard deviation time of 71.4 ± 4.6 minutes after the onset of a 15-minute interval of ad libitum cannabis flower smoking or vaping. Three observers with expertise in neuro-ophthalmology and medical toxicology were trained on exemplar videos of eyelids to reach a consensus on how to grade eyelid tremor. Without knowledge of subjects’ cannabis use history or time point (pre- or post-smoking), observers reviewed each video for eyelid tremor graded as absent, slight, moderate, or severe. During subsequent data analysis, this score was further dichotomized as a consensus score of absent (absent/slight) or present (moderate/severe). Results Kappa and intraclass correlation coefficient statistics demonstrated moderate agreement among the coders, which ranged from 0.44–0.45 and 0.58–0.61, respectively. There was no significant association between recent cannabis use and the observers’ consensus assessment that eyelid tremor was present, and cannabis users were less likely to have tremors (odds ratio: 0.75; 95 percent confidence interval: 0.25, 2.40). The assessment of eyelid tremor as an indicator of recent cannabis smoking had a sensitivity of 0.86, specificity of 0.18, and accuracy of 0.64. Discussion Eyelid tremor has fair sensitivity but poor specificity and accuracy for identification of recent cannabis use. Inter-rater reliability for assessment of eyelid tremor was moderate for the presence and degree of tremor. The weak association between recent cannabis use and eyelid tremor does not support its utility in identifying recent cannabis use. Limitations Videos were recorded at only one time point after cannabis use. Adherence to abstinence could not be strictly supervised. Due to regulatory restrictions, we were unable to control the cannabis product used or administer a fixed Δ9-tetrahydrocannabinol dose. Participants were predominately non-Hispanic and White. Conclusions In a cohort of participants with a range of cannabis use histories, acute cannabis smoking was not associated with the presence of eyelid tremor, regardless of cannabis use history, at 70 minutes post-smoking. Additional research is needed to identify the presence of eyelid tremor accurately, determine the relationship between cannabis dose and timeline in relation to last cannabis use to eyelid tremor, and determine how it should be, if at all, utilized for cannabis Drug Recognition Evaluator examinations.

How can outdoor sports protect themselves against climate change-related health risks? – A prevention model based on an expert Delphi study

ObjectivesTo systematically develop an adaptation model to reduce climate change-related health risks for outdoor athletes. DesignDelphi Method study. MethodsA classic asynchronous Delphi study was conducted with a total of three survey rounds. 24 experts from the eight largest outdoor sport associations by membership in the German Olympic Sports Confederation were included as well as 24 medical experts with expertise in sport medicine, internal medicine, allergology, dermatology, infectiology, or toxicology. Based on open-ended questions, panelists were asked to consider prevention measures for sport organizations and clubs. Free text responses were analyzed by qualitative content analysis according to Mayring. ResultsExperts recommended establishing the following eight fields of prevention measures: technical and structural measures; organizational measures; personalized measures; basic, advanced, and continuing education; concepts of action, warning concepts, and financial concepts; cooperation and coordination; campaigns; and evaluation measures. ConclusionsThe pyramid model presented in this study systematizes possible sport-specific adaptation measures on climate change by empirical aggregation of knowledge from scientists, sport organizations, clubs, trainers, and professional athletes. To assess the effectiveness of these prevention measures, sport organizations may incorporate them not only into broader operations but also everyday training routines.

Trends in Fatal Poisoning Among Drug Users in France From 2011 to 2021

The DRAMES (Décès en Relation avec l'Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses. To describe drug-related deaths in France and report trends over an 11-year period. This case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022. Demographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports. Among the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin-44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%). This case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored.

Focusing on the 5F-MDMB-PICA, 4F-MDMB-BICA synthetic cannabinoids and their primary metabolites in analytical and pharmacological aspects

Nowadays, more and more new synthetic cannabinoids (SCs) appearing on the illicit market present challenges to analytical, forensic, and toxicology experts. For a better understanding of the physiological effect of SCs, the key issue is studying their metabolomic and psychoactive properties.In this study, our validated targeted reversed phase UHPLC-MS/MS method was used for determination of urinary concentration of 5F-MDMB-PICA, 4F-MDMB-BICA, and their primary metabolites. The liquid-liquid extraction procedure was applied for the enrichment of SCs. The pharmacological characterization of investigated SCs were studied by radioligand competition binding and ligand stimulated [35S]GTPγS binding assays.For 5F-MDMB-PICA and 4F-MDMB-BICA, the median urinary concentrations were 0.076 and 0.312 ng/mL. For primary metabolites, the concentration range was 0.029–881.02* ng/mL for 5F-MDMB-PICA-COOH, and 0.396–4579* ng/mL for 4F-MDMB-BICA-COOH. In the polydrug aspect, the 22 urine samples were verified to be abused with 6 illicit drugs. The affinity of the metabolites to CB1R significantly decreased compared to the parent ligands. In the GTPγS functional assay, both 5F-MDMB-PICA and 4F-MDMB-BICA were acting as full agonists, while the metabolites were found as weak inverse agonists. Additionally, the G-protein stimulatory effects of the full agonist 5F-MDMB-PICA and 4F-MDMB-BICA were reduced by metabolites. These results strongly indicate the dose-dependent CB1R-mediated weak inverse agonist effects of the two butanoic acid metabolites.The obtained high concentration of main urinary metabolites of 5F-MDMB-PICA and 4F-MDMB-BICA confirmed the relevance of their routine analysis in forensic and toxicological practices. Based on in vitro binding assays, the metabolites presumably might cause a lower psychoactive effect than parent compounds.

A First-Tier Framework for Assessing Toxicological Risk from Vaporized Cannabis Concentrates.

Vaporization is an increasingly prevalent means to consume cannabis, but there is little guidance for manufacturers or regulators to evaluate additive safety. This paper presents a first-tier framework for regulators and cannabis manufacturers without significant toxicological expertise to conduct risk assessments and prioritize additives in cannabis concentrates for acceptance, elimination, or further evaluation. Cannabinoids and contaminants (e.g., solvents, pesticides, etc.) are excluded from this framework because of the complexity involved in their assessment; theirs would not be a first-tier toxicological assessment. Further, several U.S. state regulators have provided guidance for major cannabinoids and contaminants. Toxicological risk assessment of cannabis concentrate additives, like other types of risk assessment, includes hazard assessment, dose-response, exposure assessment, and risk characterization steps. Scarce consumption data has made exposure assessment of cannabis concentrates difficult and variable. Previously unpublished consumption data collected from over 54,000 smart vaporization devices show that 50th and 95th percentile users consume 5 and 57 mg per day on average, respectively. Based on these and published data, we propose assuming 100 mg per day cannabis concentrate consumption for first-tier risk assessment purposes. Herein, we provide regulators, cannabis manufacturers, and consumers a preliminary methodology to evaluate the health risks of cannabis concentrate additives.

Considerations towards the better integration of epidemiology into quantitative risk assessment.

Environmental epidemiology has proven critical to study various associations between environmental exposures and adverse human health effects. However, there is a perception that it often does not sufficiently inform quantitative risk assessment. To help address this concern, in 2017, the Health and Environmental Sciences Institute initiated a project engaging the epidemiology, exposure science, and risk assessment communities with tripartite representation from government agencies, industry, and academia, in a dialogue on the use of environmental epidemiology for quantitative risk assessment and public health decision making. As part of this project, four meetings attended by experts in epidemiology, exposure science, toxicology, statistics, and risk assessment, as well as one additional meeting engaging funding agencies, were organized to explore incentives and barriers to realizing the full potential of epidemiological data in quantitative risk assessment. A set of questions was shared with workshop participants prior to the meetings, and two case studies were used to support the discussion. Five key ideas emerged from these meetings as areas of desired improvement to ensure that human data can more consistently become an integral part of quantitative risk assessment: 1) reducing confirmation and publication bias, 2) increasing communication with funding agencies to raise awareness of research needs, 3) developing alternative funding channels targeted to support quantitative risk assessment, 4) making data available for reuse and analysis, and 5) developing cross-disciplinary and cross-sectoral interactions, collaborations, and training. We explored and integrated these themes into a roadmap illustrating the need for a multi-stakeholder effort to ensure that epidemiological data can fully contribute to the quantitative evaluation of human health risks, and to build confidence in a reliable decision-making process that leverages the totality of scientific evidence.

Ethyl acetate from nail polish remover inhalation in a case of fatal voluntary intoxication

To describe a case of fatal voluntary intoxication involving ethyl acetate (EA) inhalation. A 57-year-old woman was found dead on her bed with a plastic bag over her head filled with cotton balls soaked with nail polish remover. Several empty nail polish remover bottles corresponding to a total volume of approximatly one liter of EA, were found near the body. Among her medical history, gastric banding, an orphan disease that required numerous orthopedic surgeries, depression and suicide attempts were notified. Medications were found at home such as venlafaxine, lorazepam, acetaminophen and zopiclone. At the autopsy, no traumatic injuries were observed. A non-specific asphyxia syndrome with organ congestion was notified with macroscopic lesions in favor of an acute or subacute pathological condition with obstruction of the upper airways by gastric contents up to the main bronchi resulting in pulmonary edema. Anoxia was confirmed by the findings of the microscopic examination. The following samples were available for toxicological analysis: peripheral and cardiac blood, urine, stomach content and bile. A comprehensive forensic toxicological expertise was carried out including investigation of illegal drugs, prescribed drugs, alcohol, volatile substances and other poisons like carbon monoxide with several screenings (immunoassay, gas chromatography-mass spectrometry and liquid chromatography-mass tandem) of various postmortem samples. Each substance detected was quantified by a validated method. Lorazepam, zopiclone and venlafaxine and metabolite were quantified by high-performance liquid chromatography with photodiode-array detection. EA, ethanol and methanol were quantified by gas chromatography and static headspace gas chromatography with flame ionization detector. Peripheral blood concentrations of lorazepam, zopiclone and venlafaxine and O-desmethyl-Venlafaxine were respectively at 55, 49, 414 and < 20 μg/L. EA and ethanol concentrations were at 0.033 and 2.58 g/L in peripheral blood, at 0.034 and 2.76 g/L in cardiac blood, at 0.069 and 2.33 g/L in urine, at 0.155 and 2.27 g/L in stomach content and at 0.014 and 2.87 g/L in bile. EA is commonly used as component in nail polish remover. After exposure to EA vapor, absorption is mainly respiratory and percutaneous. Distribution involves all organs but predominates in fatty tissues. EA is rapidly metabolized by plasma esterases resulting in ethanol and acetic acid synthesis. EA may cause drowsiness, sleepiness, unconsciousness, narcosis, stupor and central nervous system depression. These symptoms are potentiated with ethanol. In this case, the low ratio of EA to ethanol concentrations in all postmortem samples confirmed this rapid biotransformation. This was already mentioned in a case of accidental workplace exposure (Coopman. Forensic Sci Int 2005;154:92–95). Blood concentrations of prescribed drugs were here within the therapeutic range. An EA blood concentration of 0.033 g/L can therefore be considered lethal associated with an ethanol concentration around 2.6 g/L. To our knowledge, this is the first fatal case of voluntary intoxication with EA inhalation. The measured concentrations in all usual autopsy samples can be added to toxicological databases.

Increase of high-risk tramadol use and harmful consequences in France from 2013 to 2018: Evidence from the triangulation of addictovigilance data.

AimsThe aim of this paper is to assess recent developments in non‐medical tramadol use, tramadol use disorder, illegal procurement and deaths.MethodsThis study used repeated cross‐sectional analysis of data collected nationwide from 2013 to 2018. Analysis was conducted through multisource monitoring of the French Addictovigilance Network of: (1) validated reports of high‐risk tramadol use, (2) record systems collecting information from toxicology experts investigating analgesic‐related deaths (DTA) and deaths related to substance abuse (DRAMES), and pharmacists for forged prescriptions (OSIAP), and (3) survey of drug users, with investigation of patterns of use while visiting addiction‐specialised institutions (OPPIDUM).ResultsDespite a plateauing level of tramadol exposure in the French population, the proportion of tramadol reports increased 1.7‐fold (187 cases in 2018, 3.2% (95% confidence interval [CI]: 2.74–3.63%), versus 1.9% (95% CI: 1.49–2.42% in 2013). Trends were similar in OSIAP: 11.9% of forged prescriptions in 2018 (95% CI: 10.56–13.45%); 1.7‐fold increase; in OPPIDUM: 0.76% (95% CI: 0.55–1.02); 2.2‐fold increase; and DRAMES: 3.2% of drug abuse‐related deaths in 2018 (95% CI: 1.89–5.16) versus 1.7% in 2013 (95% CI: 0.65–3.84). Tramadol was the primary opioid in analgesic‐related deaths in DTA (45% in 2018). Two profiles of high‐risk tramadol users were identified: (1) patients treated for pain or with tramadol persistence when pain disappeared (mainly women; mean age 44 years), and (2) individuals with non‐medical use for psychoactive effects (mainly men; mean age 36 years).ConclusionThe triangulation of the data obtained through addictovigilance monitoring evidenced a recent increase in high‐risk tramadol use. These findings have a practical impact on the limitation of the maximal duration of tramadol prescriptions.

Guidance on the need for contraception related to use of pharmaceuticals: the Japan Agency for Medical Research and Development Study Group for providing information on the proper use of pharmaceuticals in patients with reproductive potential

BackgroundThe U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have published guidelines on the use of cancer treatments in young people of reproductive potential. However, no such guideline is available in Japan. Therefore, this project aimed to gather relevant data and draft a respective guidance paper.MethodsFrom April 2019 to March 2021, the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential at the Japan Agency for Medical Research and Development gathered opinions from experts in reproductive medicine, toxicology, and drug safety measures. The group considered these opinions, the FDA and EMA guidelines, and relevant Japanese guidelines and prepared a guidance paper, which they sent to 19 related organizations for comment.ResultsBy November 2020, the draft guidance paper was completed and sent to the related organizations, 17 of which provided a total of 156 comments. The study group finalized the guidance paper in March 2021.ConclusionsThe “Guidance on the Need for Contraception Related to Use of Pharmaceuticals” (The report of the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential, Research on Regulatory Science of Pharmaceuticals and Medical Devices, Japan Agency for Medical Research and Development: JP20mk0101139) is expected to help Japanese healthcare professionals provide fertility-related care and advice to adolescents, and young adults with cancer and their families.

The importance of the quality of toxicological expertise for the need of the judiciary in the historical and contemporary aspect

The history of humanity is closely related to the use of various poisons, different in each epoch. They served different purposes for centuries. In addition to being a remedy for various ailments and diseases, they also helped to bear the hard life of a person thanks to the possibility of causing mental elation, making it more bearable. They were also used to kill other people, most often for very low motives. The number of poisons existing in particular stages of civilization has been systematically increasing, reaching the number of 100,000 - 500,000 toxicologically active compounds in modern times, with the generally estimated number of known chemical compounds at the level of about 240 million. The research work of thinkers and people of progress is a counterbalance to the evil deeds of poisoners in antiquity and the Middle Ages. These works appeared in the late Middle Ages and are continued in various forms until the present day. As a result of these works, modern toxicological forensic expertise has been developed. However, before it appeared in its modern shape, it had to go through a very difficult development path, which lasted continuously for several centuries. Modern toxicological expertise, based on a highly specialized instrumental methodology, operating with high methodological standards, is the achievement of many generations. These standards have now become a requirement for expert works of our times, and failure to comply with them is treated as a malpractice. This work is a review of the types of poisons and reports in terms of the development and application of toxicological forensic expertise for the purposes of the judiciary.

Reddit discussions about buprenorphine associated precipitated withdrawal in the era of fentanyl

Background Induction of buprenorphine, an evidence-based treatment for opioid use disorder (OUD), has been reported to be difficult for people with heavy use of fentanyl, the most prevalent opioid in many areas of the country. In this population, precipitated opioid withdrawal (POW) may occur even after individuals have completed a period of opioid abstinence prior to induction. Our objective was to study potential associations between fentanyl, buprenorphine induction, and POW, using social media data. Methods This is a mixed methods study of data from seven opioid-related forums (subreddits) on Reddit. We retrieved publicly available data from the subreddits via an application programming interface, and applied natural language processing to identify subsets of posts relevant to buprenorphine induction, POW, and fentanyl and analogs (F&A). We computed mention frequencies for keywords/phrases of interest specified by our medical toxicology experts. We further conducted manual, qualitative, and thematic analyses of automatically identified posts to characterize the information presented. Results: In 267,136 retrieved posts, substantial increases in mentions of F&A (3 in 2013 to 3870 in 2020) and POW (2 in 2012 to 332 in 2020) were observed. F&A mentions from 2013 to 2021 were strongly correlated with mentions of POW (Spearman’s ρ: 0.882; p = .0016), and mentions of the Bernese method (BM), a microdosing induction strategy (Spearman’s ρ: 0.917; p = .0005). Manual review of 384 POW- and 106 BM-mentioning posts revealed that common discussion themes included “specific triggers of POW” (55.1%), “buprenorphine dosing strategies” (38.2%) and “experiences of OUD” (36.1%). Many reported experiencing POW despite prolonged opioid abstinence periods, and recommended induction via microdosing, including specifically via the BM. Conclusions Reddit subscribers often associate POW with F&A use and describe self-managed buprenorphine induction strategies involving microdosing to avoid POW. Further objective studies in patients with fentanyl use and OUD initiating buprenorphine are needed to corroborate these findings. HIGHLIGHTS Increase in mentions of precipitated opioid withdrawal (POW) on Reddit from 2012 to 2021 was associated with the increase in fentanyl and analog mentions. Experiences of precipitated opioid withdrawal (POW) were described by individuals despite reporting prolonged periods of abstinence compared to standard buprenorphine induction protocols. People with Opioid Use Disorder (OUD) on Reddit are using and recommending microdosing strategies with buprenorphine to avoid POW. People who used fentanyl report experiencing POW following statistically longer periods of abstinence than people who use heroin.

The EXIMIOUS project-Mapping exposure-induced immune effects: connecting the exposome and the immunome.

Immune-mediated, noncommunicable diseases—such as autoimmune and inflammatory diseases—are chronic disorders, in which the interaction between environmental exposures and the immune system plays an important role. The prevalence and societal costs of these diseases are rising in the European Union. The EXIMIOUS consortium—gathering experts in immunology, toxicology, occupational health, clinical medicine, exposure science, epidemiology, bioinformatics, and sensor development—will study eleven European study populations, covering the entire lifespan, including prenatal life. Innovative ways of characterizing and quantifying the exposome will be combined with high-dimensional immunophenotyping and -profiling platforms to map the immune effects (immunome) induced by the exposome. We will use two main approaches that “meet in the middle”—one starting from the exposome, the other starting from health effects. Novel bioinformatics tools, based on systems immunology and machine learning, will be used to integrate and analyze these large datasets to identify immune fingerprints that reflect a person’s lifetime exposome or that are early predictors of disease. This will allow researchers, policymakers, and clinicians to grasp the impact of the exposome on the immune system at the level of individuals and populations.

Consensus Development of a Core Content for a Standardized Medical Toxicology Curriculum for Medical Students.

BackgroundCurrently, no standardized core content in medical toxicology exists for medical students. The goals of this study were to (1) assess the current state and needs of medical toxicology clerkships and (2) develop a consensus-derived list of core topics that should be covered during a medical toxicology clerkship.MethodsWe assembled a task force established by the American College of Medical Toxicology (ACMT) of nine experts in medical toxicology or emergency medicine. We developed a needs assessment survey that was sent to all medical student clerkship directors in medical toxicology. Based on their responses, we used a modified Delphi process to develop a consensus of core topics that should be covered during a medical student clerkship.ResultsNineteen out of 42 (45%) clerkship directors completed the survey; 18 met inclusion criteria. The majority of clerkships were 4 weeks in duration with an average of 15 students/year. The three most common teaching methods used were bedside teaching (n = 17/18), classroom teaching (n = 17/18), and journal club (n = 14/18). All the clerkship directors (n = 18/18) reported they would use a standardized curriculum as well as educational content developed by ACMT. There was overwhelming consensus on the core topics which included, but were not limited to, pharmacology/toxicology; drugs; drugs of abuse; natural products; pharmacological basis of antidote use; toxicologic syndromes; vital sign abnormalities; initial management; supportive and other care; withdrawal syndrome management; industrial, household, and environmental toxins; differential diagnosis by clinical findings; and ABCs-resuscitation.ConclusionThe ACMT task force developed a medical toxicology clerkship core content. The task force also identified a need for shared resources among clerkships.

A brief history of toxicology in France during the last two centuries (1789–1989)

The history of toxicology in France over the last two centuries has been marked by numerous authors who have progressively broadened the fields of investigation: initially concerned with criminal or accidental poisonings, they have also taken an interest in the environment, workers' health, doping and illicit products, the dangers of radioactivity or combat gases, the risks associated with drugs, etc. Often pharmacists, these toxicology experts were specialists in analytical chemistry and developed numerous methods to refine the detection and characterization of potentially toxic products, and to better understand the mechanisms of toxicity produced by these substances.