A current overview of the pharmacological composition of "La Chimique" consumed in Mayotte: Preliminary results of the CHASSE-MAREE protocol.

Mayotte Island, a French department located in the Mozambique Channel, has for several years been faced with the consumption of "La Chimique" (LC), reputed (but extremely poorly documented) to be a mixture of tobacco and synthetic cannabinoid receptor agonists (SCRAs). One of the objectives of the CHASSE-MAREE protocol is to assess the composition and heterogeneity of LC products through successive LC sample collection campaigns among users. Currently underway, we present here the first analytical results (samples collected in 2022). Between September and December 2022, 80 samples were collected throughout the island over three periods: 70 in the usual form of LC (small folded papers containing a plant-like sample, mostly tobacco), 6 powders, and 4 cigarettes. Analysis was performed using liquid chromatography with high-resolution mass spectrometry. The detected substances (number of detections) included SCRAs (MDMB-4en-PINACA [35], ADB-FUBIATA [25], MDMB-INACA [16], ADB-BUTINACA [15], AFUBIATA [11], 4F-MDMD-BICA [7], CH-PIATA [14], 5C-APINACA [3], BZO-HEXOXIZID [2], and 4F-ABINACA [1]), nicotine (68), tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) (2), medications (amantadine [11], cyamemazine [6], and acetaminophen [3]), and a designer benzodiazepine (bromazolam [4]). The SCRAs currently in use are varied, and the market for "cooks" (those who prepare LC) is dispersed according to where and when samples are collected. These preliminary results will be supplemented by analysis of samples collected in the first half of 2023 and by an improved description of the current panorama of consumption of LC in Mayotte (mapping, effects felt and dependence, etc.).

Metabolite elucidation of 2-fluoro-deschloroketamine (2F-DCK) using molecular networking across three complementary in vitro and in vivo models.

This work first aims to investigate metabolites of 2-fluoro-deschloroketamine (2F-DCK), a new arylcyclohexylamine derivatives (a group of dissociative ketamine-based substances) using two in vitro experimental approaches, and to compare obtained results by means of molecular networking. Metabolites of 2F-DCK were investigated using both human liver microsomes (HLMs) and hepatic (HepaRG) cell line incubates using molecular networking approach: 2F-DCK pure substance was incubated with HLMs for up to 1 h at two concentrations (100 and 500 µM) and with HepaRG cells for two time periods (8 and 24 h) at one concentration (20 µM). In vitro obtained results were subsequently applied to a 2F-DCK-related fatality case. In vitro-produced metabolites were investigated using high-resolution accurate mass spectrometry using Orbitrap mass analyzer technology. Thirteen metabolites were in vitro produced and several metabolic pathways can be postulated. Seven additional metabolites were found in post-mortem samples (bile and urine) of the case, comprising three Phase II metabolites, which appear to be minor in vivo metabolites. HLMs and HepaRG cell models appear to be complementary and obtained data allowed the identification of several specific 2F-DCK metabolites in biological samples. In practical terms, observed metabolic ratios suggested that nor-2F-DCK (208.1137 m/z) and a hydrogenated metabolite (224.1443 m/z) could be proposed as reliable metabolites to be recorded in HRMS libraries in order to improve detection of 2F-DCK use.

At the Origins of Tobacco-Smoking and Tea Consumption in a Virgin Population (Yakutia, 1650-1900 A.D.): Comparison of Pharmacological, Histological, Economic and Cultural Data.

(1) Background: The way tobacco and tea spread among virgin populations is of major interest our understanding of how ancient economic and cultural practices could have influenced current habits. (2) Methods: hair concentrations of theobromine, theophylline, caffeine, nicotine, and cotinine were measured in hair samples from 47 frozen bodies of people from eastern Siberia, dated from the contact with Europeans to the assimilation of people into Russian society. (3) Results: hair concentration of theobromine, theophylline, and caffeine vary with the type of beverage consumed: green, black, or local herbal teas. Shortly after the first contacts, a few heavy consumers of tobacco were found among light or passive consumers. Tobacco-related co-morbidities began to be recorded one century after and heavy tea users were only found from the 19th century (4) Conclusions: Economic factors and social and family contacts seem to have played a decisive role in tobacco consumption very early on. Behavioral evolution governed the process of substance integration into Siberian culture and was a determinant for the continuity of its use across long periods of time. Analyzing the respective contributions of social and economic processes in the use of these substances opens avenues of investigation for today's public health.

Involuntary 5F-ADB-related intoxication following e-cigarette use.

The detection of synthetic cannabinoid (SC) intoxication cases is challenging, even more when the involved SC identification is requested in a forensic context. This situation can be complicated by new modes of SC consumption, non-specific symptomatology, and analytical pitfalls. To illustrate these issues, we report the case of a 16-year-old man who presented symptoms evocating of a seizure disorder in the minutes following the use of a friend's e-cigarette. At admission in the emergency department, his electroencephalogram was interpreted as coherent with a recent seizure episode. 5F-ADB, a third generation SC, was detected in the e-liquid and in an early collected (H2 after the e-cigarette use) serum sample (0.50 µg/L), but not in urine samples (H18 and H38). One 5F-ADB metabolite, O-desmethyl-5F-ADB (M5), was detectable in urine up to at least 38 h after intoxication. Neither 5F-ADB nor its metabolites could be detected in victim's hair sampled 3 months after the intoxication. Although leading to a non-specific symptomatology, acute SC intoxication should be considered when the case history is related to e-cigarette or e-liquid use. Early biological samples are recommended, even if analytical screening can be positive for SC metabolites in urine sampled until 2 days after exposure. Accordingly, data from the literature and the present case underscore the relevance of adding both main 5F-ADB metabolites (M5 and 5-OH-pentyl-ADB) to mass spectrum databases used for toxicological screening in order to reduce the risk of false-negative results in intoxication cases involving 5F-ADB.

The association between blood cadmium and glycated haemoglobin among never-, former, and current smokers: A cross-sectional study in France.

INTRODUCTION: The association between cadmium levels in the body and diabetes has been extensively studied, with sometimes contrasting results. Smoking is the primary non-occupational source of cadmium, and constitutes a risk factor for diabetes. One can therefore hypothesize that the putative association with cadmium is actually explained by tobacco. To fully control for this confounding factor, we studied the relationship between blood cadmium and glycated haemoglobin (HbA1c) levels separately in never-, former and current smokers. METHODS: We studied a sample of 2749 middle-aged adults from the cross-sectional ELISABET survey in and around the cities of Lille and Dunkirk; none had chronic kidney disease or a history of haematological disorders, and none were taking antidiabetic medication. The blood cadmium level-HbA1c associations in never-, former and current smokers were studied in separate multivariate models. The covariables included age, sex, city, educational level, tobacco consumption (or passive smoking, for the never-smokers), body mass index, estimated glomerular filtration rate, and (to take account of the within-batch effect) the cadmium batch number. RESULTS: In the multivariate analysis, a significant association between cadmium and HbA1c levels was found in all three smoking status subgroups. A 0.1 µg/L increment in blood cadmium was associated with an HbA1c increase [95% confidence interval] of 0.016% [0.003; 0.029] among never-smokers, 0.024% [0.010; 0.037] among former smokers, and 0.020% [0.012; 0.029] among current smokers. CONCLUSIONS: The observation of a significant association between the blood cadmium concentration and HbA1c levels in a group of never-smokers strengthens the hypothesis whereby diabetes is associated with cadmium per se and not solely with tobacco use. The small effect size observed in our population of never smokers with low levels of exposure to cadmium suggested that the risk attributable to this metal is not high. However, the impact of exposure to high cadmium levels (such as occupational exposure) on the risk of diabetes might be of concern.

A decontamination process adding a tensioactive agent and isopropanol to a closed-system drug transfer device for better control of isolator contamination. A prospective, parallel study.

BACKGROUND: Despite the use of closed system drug transfer devices (CSTD), residual contamination from antineoplastic drugs is still detected inside isolators. The aim of this study was to compare the decontamination level obtained using a CSTD + standard cleaning procedure with a CSTD + standard cleaning procedure + specific decontamination procedure. METHODS AND FINDINGS: A comparative and prospective study was carried out in a newly opened compounding unit. Compounding was performed with a CSTD (BD-Phaseal, Becton-Dickinson). In the Control isolator (C), the cleaning process was completed daily with a standard biocide solution (AnioxysprayTM, Anios, France). In the Intervention isolator (I), weekly decontamination with a homemade admixture of sodium dodecyl sulfate 10(-2) M/70% isopropanol (80/20, v/v) was added. Monitoring was performed via a validated LC-MS/MS method. Eight drugs (cyclophosphamide, cytarabine, dacarbazine, fluorouracile, gemcitabine, ifosfamide, irinotecan and methotrexate) were monitored daily over 14 consecutive weeks on three sites inside the isolators: gloves, workbench and window. Results are presented as the odds-ratio (OR) of contamination and as overall decontamination efficiency (EffQ, %). The proportion of EffQ ≥ 90% was assessed by a Fisher's exact test (p<0.05). Overall contamination rates (CR, %) were significantly different from one isolator to the other (CRC = 25.3% vs. CRI = 10.4%; OR = 0.341; p<0.0001). Overall EffQ values (median; 1st and 3rd quartiles) were higher in the intervention isolator (I: 78.3% [34.6%;92.6%] vs. C: 59.5% [-5.5%;72.6%]; p = 0.0015) as well as the proportion of days with an EffQ ≥ 90% (I: 42.9% vs. C: 7.1%; p = 0.077) but very variable depending on drugs. CONCLUSION: Adding a decontamination protocol with a tensioactive agent to a CSTD leads to better control of chemical contamination inside isolators. Improving decontamination by increasing decontamination frequency or modifying the protocol will be further studied.

In vitro Characterization of NPS Metabolites Produced by Human Liver Microsomes and the HepaRG Cell Line Using Liquid Chromatographyhigh Resolution Mass Spectrometry (LC-HRMS) Analysis: Application to Furanyl Fentanyl.

BACKGROUND: Identification of metabolites is of importance in the challenge of new psychoactive substances (NPS) as it could improve the detection window in biological matrices in clinical and forensic cases of intoxication. Considering the numerous and diverse NPS reported each year, producers increasingly appear today to be targeting non-controlled synthetic opioids, involving fentanyl derivatives such as furanyl fentanyl (Fu-F). OBJECTIVE: This work aims to investigate and compare metabolites of Fu-F using two in vitro experimental approaches. METHODS: CYP- and UGT-dependent metabolites of Fu-F were investigated by means of analyses of both human liver microsome (HLM) and hepatic (HepaRG) cell line incubates using liquid chromatography with high-resolution mass detection and, subsequently, compared and confronted to recently published data. RESULTS: Seventeen Fu-F metabolites were produced and several metabolic pathways can be postulated. HLMs and HepaRG cultures appear to be complementary: HepaRG cells produced 9 additional metabolites, but which appear to be minor in vivo metabolites. Specific* and/or abundant Fu-F metabolites are dihydrodiol-Fu-F*, norFu-F* and despropionylfentanyl. However, norFu-F seems to be inconstantly observed in in vivo cases. Furthermore, a sulfate metabolite presents at significant rate in urine obtained from FU-F users was not identified here, as in another in vitro study. CONCLUSION: HLMs represent an acceptable first choice tool for a single NPS metabolism study in forensic laboratories. Dihydrodiol-Fu-F and despropionylfentanyl could be proposed as reliable metabolites to be recorded in HRMS libraries in order to improve detection of Fu-F users. Nevertheless, additional verifications of in vivo data remain necessary to confirm relevant blood and urinary metabolites of Fu-F.

Blood and urinary levels of metals and metalloids in the general adult population of Northern France: The IMEPOGE study, 2008-2010.

BACKGROUND: The assessment of human chemical risks related to occupational or environmental exposure to pollutants requires the use of both accurate exposure indicators and reference values. The objective of this study was to evaluate the blood and urinary levels of various metals and metalloids in a sample of adults aged 20-59 years of the general population of Northern France, a formerly heavily industrialised area that retains some industrial activity. METHODS: A cross-sectional study was conducted between 2008 and 2010, enrolling 2000 residents of Northern France. The quota method was used to guarantee the representativeness of the participants on a sex, age, social category and smoking status basis, according to the census done by the French National Institute of Statistics and Economic Studies. The levels of 14 metals: aluminium (Al), antimony (Sb), total arsenic (As), beryllium (Be), cadmium (Cd), cobalt (Co), chromium (Cr), mercury (Hg), manganese (Mn), nickel (Ni), lead (Pb), thallium (Tl), vanadium (V) and zinc (Zn) were quantified by ICP-MS in urine and blood samples. RESULTS: A total of 982 men and 1018 women participated, allowing the analysis of 1992 blood and 1910 urine samples. Some metal(loid)s were detected in over 99% of the blood (Cd, Co, Mn, Ni, Pb) and urine (As, Co, Pb, Zn) samples and the remaining metals in 84-99% of the samples, with the exception of blood V (19%), blood Be (57%) and urine Be (58%). Mean blood levels of Pb and Zn were significantly higher in men, and Mn, Co and Cr in women. In urine, mean Pb, Tl and Sb concentrations were significantly higher in men, and Al and Co in women. Current smokers had significantly higher mean levels of blood Cd and Pb and lower blood Co, Mn and Hg. In urine (adjusted on urinary creatinine), the smokers had higher mean levels of Cd, Pb, V and Zn and lower mean levels of As, Co, and Hg. Overall, the mean urinary levels of most metal(loid)s found in the general population of Northern France were higher than those found in the French national survey for the same period except for urinary V. Mean blood lead level was markedly less than that of the French national population. CONCLUSION: This first biomonitoring survey of a large number of metal(loid)s in the general population of Northern France provides useful information on exposure levels to toxic elements and highlights the specificity of the regional environment. These data could be used, in complement to the national human biomonitoring reference values, for the interpretation of biomonitoring results.

Detection of the designer benzodiazepine metizolam in urine and preliminary data on its metabolism.

Designer benzodiazepines provide an attractive alternative to prescribed benzodiazepines for abuse purposes as they are readily available via the Internet without control. Metizolam was ordered via the Internet and a 2 mg blue tablet was orally administered to a 54-year-old man. Urine samples were collected over 6 days in polypropylene tubes. After liquid/liquid extraction at pH 9.5, metizolam was analyzed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) using a standard method devoted to benzodiazepines, and ions transitions, at m/z 328.9 > 275.0 and 328.9 > 300.0. Metizolam was detectable in hydrolyzed urine during the 46-h period, with concentrations always lower than 11 ng/mL. About 0.3% of the initial dose was excreted in urines as total unchanged metizolam during the first 24 h. The most relevant potential CYP- and UGT-dependent metabolites of metizolam were investigated in vitro using human liver microsome incubation and, subsequently, liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF-MS) analysis. Three mono-hydroxylated metabolites were produced including a hydroxylation compound at the 2-ethyl moiety of metizolam (M1) as quantitatively main metabolite, and a N-hydroxymetiazolam (M2). The structure of the third metabolite (M3) could not be elucidated because of a too low experimental production rate. Two authentic urine samples were analyzed using the same analytical method to search for metabolites of metizolam. M1, together with its glucuronide (M1-Glu), and M2 were observed in urine at the 8 h mark, whereas only M1 and M1-Glu were still detected in urine at 30 h post administration. Copyright © 2016 John Wiley & Sons, Ltd.

Effectiveness of a Closed-System Transfer Device in Reducing Surface Contamination in a New Antineoplastic Drug-Compounding Unit: A Prospective, Controlled, Parallel Study.

BACKGROUND: The objective of this randomized, prospective and controlled study was to investigate the ability of a closed-system transfer device (CSTD; BD-Phaseal) to reduce the occupational exposure of two isolators to 10 cytotoxic drugs and compare to standard compounding devices. METHODS AND FINDINGS: The 6-month study started with the opening of a new compounding unit. Two isolators were set up with 2 workstations each, one to compound with standard devices (needles and spikes) and the other using the Phaseal system. Drugs were alternatively compounded in each isolator. Sampling involved wiping three surfaces (gloves, window, worktop), before and after a cleaning process. Exposure to ten antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-FU, methotrexate, gemcitabine, cytarabine, irinotecan, doxorubicine and ganciclovir) was assessed on wipes by LC-MS/MS analysis. Contamination rates were compared using a Chi2 test and drug amounts by a Mann-Whitney test. Significance was defined for p<0.05. Overall contamination was lower in the "Phaseal" isolator than in the "Standard" isolator (12.24% vs. 26.39%; p < 0.0001) although it differed according to drug. Indeed, the contamination rates of gemcitabine were 49.3 and 43.4% (NS) for the Standard and Phaseal isolators, respectively, whereas for ganciclovir, they were 54.2 and 2.8% (p<0.0001). Gemcitabine amounts were 220.6 and 283.6 ng for the Standard and Phaseal isolators (NS), and ganciclovir amounts were 179.9 and 2.4 ng (p<0.0001). CONCLUSION: This study confirms that using a CSTD may significantly decrease the chemical contamination of barrier isolators compared to standard devices for some drugs, although it does not eliminate contamination totally.

Current sources of lead exposure and their relative contributions to the blood lead levels in the general adult population of Northern France: The IMEPOGE Study, 2008-2010.

There is justification for limiting lead (Pb) exposure as much as possible, given its impact on health at low concentrations. Consequently, the aim of this study was to measure blood lead levels (BLL) and examine exposure factors related to BLL variations in the general adult population of northern France, a current and past industrial area. Two thousand inhabitants of northern France, aged between 20 and 59 years, were recruited using the quota method with caution. Blood lead levels were quantified by inductively coupled plasma-mass spectroscopy (ICP-MS), and variation factors were studied separately in men and women using multivariate stepwise linear and logistic regression models. The geometric mean of the BLL was 18.8 µg/L (95% confidence interval [CI]: 18.3-19.3). Occupational factors affected BLL only in men and represented 14% of total explained variance of BLL. External occupational factors significantly increasing mean levels of BLL were tobacco, consumption of some beverages (wine, coffee, tea, and/or tap water), raw vegetables, housing characteristics (built prior to 1948, Pb piping in the home) and do-it-yourself or leisure activities (paint stripping or rifle shooting). Consumption habits accounted together for 25% and 18% of the total explained variance, respectively, in men and women. Industrial environment did not significantly contribute to BLL variations. Blood lead levels observed in the general population of this industrial part of France did not appear to be excessively elevated compared to values found internationally. Nonetheless, these BLL remain a public health issue in regard to nonthreshold toxicity attributed to Pb.