Assessment of chemical contamination by cancer drugs during use of the RIVATM compounding robot: A pilot study.

INTRODUCTION: Many hospitals are now investing in robotic compounding system for the preparation of cytotoxic agents. The objective of the present study was to describe contamination by cytotoxics inside and outside the RIVATM robot (ARxIUM, Winnipeg, Canada). MATERIAL & METHODS: We applied a risk analysis to determine which locations inside and outside the compounding robot should be monitored. Samples were collected by swabbing with a wet swab (using 0.1 mL of sterile water) before the robots was cleaned. Ten cytotoxics compounded with the robot were screened for using LC-MS/MS. We determined the percentage contamination rates inside (CRin) and outside (CRout) the robot and the amounts of each contaminant (in ng/cm²). If a sample was found to be positive, a corrective action was implemented. RESULTS: Our risk analysis highlighted 10 locations inside the robot and 7 outside. Ten sampling campaigns (10 samples per campaign) were performed. The mean CRin (40%) was significantly higher than the mean CRout (2%; p < 10-4). Gemcitabine and cyclophosphamide were the main contaminants. After the implementation of corrective measures (such as daily cleaning with SDS/isopropyl alcohol), the CRin fell from 60% to 10%. DISCUSSION/CONCLUSION: The frequency of contamination was lower for robotic compounding than for manual compounding in an isolator. However, robotic compounding tended to generated larger mean amounts of contaminant; this was related to incidents such as splashing when syringes were disposed of after the compounding. The implementation of corrective actions effectively reduced the CRs. Further longer-term studies are required to confirm these results.

Metabolomics Provides Novel Insights into the Potential Toxicity Associated with Heated Tobacco Products, Electronic Cigarettes, and Tobacco Cigarettes on Human Bronchial Epithelial BEAS-2B Cells.

Smoking is an established risk factor for various pathologies including lung cancer. Electronic cigarettes (e-cigs) and heated tobacco products (HTPs) have appeared on the market in recent years, but their safety or, conversely, their toxicity has not yet been demonstrated. This study aimed to compare the metabolome of human lung epithelial cells exposed to emissions of e-cigs, HTPs, or 3R4F cigarettes in order to highlight potential early markers of toxicity. BEAS-2B cells were cultured at the air-liquid interface and exposed to short-term emissions from e-cigs set up at low or medium power, HTPs, or 3R4F cigarettes. Untargeted metabolomic analyses were performed using liquid chromatography coupled with mass spectrometry. Compared to unexposed cells, both 3R4F cigarette and HTP emissions affected the profiles of exogenous compounds, one of which is carcinogenic, as well as those of endogenous metabolites from various pathways including oxidative stress, energy metabolism, and lipid metabolism. However, these effects were observed at lower doses for cigarettes (2 and 4 puffs) than for HTPs (60 and 120 puffs). No difference was observed after e-cig exposure, regardless of the power conditions. These results suggest a lower acute toxicity of e-cig emissions compared to cigarettes and HTPs in BEAS-2B cells. The pathways deregulated by HTP emissions are also described to be altered in respiratory diseases, emphasizing that the toxicity of HTPs should not be underestimated.

Integrating rare genetic variants into DPYD pharmacogenetic testing may help preventing fluoropyrimidine-induced toxicity.

Variability in genes involved in drug pharmacokinetics or drug response can be responsible for suboptimal treatment efficacy or predispose to adverse drug reactions. In addition to common genetic variations, large-scale sequencing studies have uncovered multiple rare genetic variants predicted to cause functional alterations in genes encoding proteins implicated in drug metabolism, transport and response. To understand the functional importance of rare genetic variants in DPYD, a pharmacogene whose alterations can cause severe toxicity in patients exposed to fluoropyrimidine-based regimens, massively parallel sequencing of the exonic regions and flanking splice junctions of the DPYD gene was performed in a series of nearly 3000 patients categorized according to pre-emptive DPD enzyme activity using the dihydrouracil/uracil ([UH2]/[U]) plasma ratio as a surrogate marker of DPD activity. Our results underscore the importance of integrating next-generation sequencing-based pharmacogenomic interpretation into clinical decision making to minimize fluoropyrimidine-based chemotherapy toxicity without altering treatment efficacy.

Extracellular vesicles derived from nasopharyngeal carcinoma induce the emergence of mature regulatory dendritic cells using a galectin-9 dependent mechanism.

Nasopharyngeal carcinoma-derived small extracellular vesicles (NPCSEVs) have an immunosuppressive impact on the tumour microenvironment. In this study, we investigated their influence on the generation of tolerogenic dendritic cells and the potential involvement of the galectin-9 (Gal9) they carry in this process. We analysed the phenotype and immunosuppressive properties of NPCSEVs and explored the ability of DCs exposed to NPCSEVs (NPCSEV-DCs) to regulate T cell proliferation. To assess their impact at the pathophysiological level, we performed real-time fluorescent chemoattraction assays. Finally, we analysed phenotype and immunosuppressive functions of NPCSEV-DCs using a proprietary anti-Gal9 neutralising antibody to assess the role of Gal9 in this effect. We described that NPCSEV-DCs were able to inhibit T cell proliferation despite their mature phenotype. These mature regulatory DCs (mregDCs) have a specific oxidative metabolism and secrete high levels of IL-4. Chemoattraction assays revealed that NPCSEVs could preferentially recruit NPCSEV-DCs. Finally, and very interestingly, the reduction of the immunosuppressive function of NPCSEV-DCs using an anti-Gal9 antibody clearly suggested an important role for vesicular Gal9 in the induction of mregDCs. These results revealed for the first time that NPCSEVs promote the emergence of mregDCs using a galectin-9 dependent mechanism and open new perspectives for antitumour immunotherapy targeting NPCSEVs.

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.).

Impact of Electronic Cigarettes, Heated Tobacco Products and Conventional Cigarettes on the Generation of Oxidative Stress and Genetic and Epigenetic Lesions in Human Bronchial Epithelial BEAS-2B Cells.

Electronic cigarettes (e-cig) and heated tobacco products (HTP) are often used as smoking cessation aids, while the harm reduction effects of these alternatives to cigarettes are still the subject of controversial debate, in particular regarding their carcinogenic potential. The objective of this study is to compare the effects of e-cig, HTP and conventional cigarette emissions on the generation of oxidative stress and genetic and epigenetic lesions in human bronchial epithelial BEAS-2B cells. Our results show that HTP were less cytotoxic than conventional cigarettes while e-cig were not substantially cytotoxic in BEAS-2B cells. E-cig had no significant effect on the Nrf2 pathway, whereas HTP and cigarettes increased the binding activity of Nrf2 to antioxidant response elements and the expression of its downstream targets HMOX1 and NQO1. Concordantly, only HTP and cigarettes induced oxidative DNA damage and significantly increased DNA strand breaks and chromosomal aberrations. Neither histone modulations nor global DNA methylation changes were found after acute exposure, regardless of the type of emissions. In conclusion, this study reveals that HTP, unlike e-cig, elicit a biological response very similar to that of cigarettes, but only after a more intensive exposure: both tobacco products induce cytotoxicity, Nrf2-dependent oxidative stress and genetic lesions in human epithelial pulmonary cells. Therefore, the health risk of HTP should not be underestimated and animal studies are required in order to determine the tumorigenic potential of these emerging products.

Lead, Mercury, and Cadmium Concentrations in Blood Products Transfused to Neonates: Elimination Not Just Mitigation.

Lead (Pb), mercury (Hg), and cadmium (Cd) are identified as potent developmental neurotoxicants. Neonates are the main group receiving multiple blood transfusions. The exposure of neonates to these heavy metals (HMs) can occur through blood transfusions. This study aimed to determine the concentrations of lead (Pb), mercury (Hg), and cadmium (Cd) in various blood products (plasma, platelets, packed red blood cells (pRBCs), and whole blood (WB)) to explore the probability of concurrent exposure of these HMs and to identify the metal load per transfusion with risk assessment. Residual bloods from blood bank bags were collected after neonatal transfusion. Pb, Hg, and Cd concentrations were determined in 120 samples of blood products by inductively coupled plasma mass spectrometry (ICP-MS). Pb and Cd levels were over the normal levels in 19.2 and 5.9% of all blood units, respectively. In 35 and 0.8% of blood units, the Pb and Cd concentrations, respectively, were higher than that recommended for transfusions in premature neonates. The anticipated safe value was surpassed by 2.5% for Cd of all transfusions, primarily because of WB. However, Hg was detected only in 5.8% of all samples and their concentrations were within the normal range. The concurrent neonatal exposure to Pb, Hg, and Cd was statistically significant. Hazard quotients of Hg and Cr were >1 and Pb cancer risk was 2.41 × 10-4. To the best of our knowledge, this study is the first report examining Pb, Hg, and Cd in blood products other than WB and pRBCs using ICP-MS. This study demonstrated the exposure of neonates to Pb, Hg, and Cd during transfusion with a considerable amount of Pb. It confirms the significant concurrent exposure to the three HMs, which maximize their potential developmental neurotoxicity with a high probability of developing non-carcinogenic and carcinogenic health effects.

Prediction of a Large-Scale Database of Collision Cross-Section and Retention Time Using Machine Learning to Reduce False Positive Annotations in Untargeted Metabolomics.

Metabolite identification in untargeted metabolomics is complex, with the risk of false positive annotations. This work aims to use machine learning to successively predict the retention time (Rt) and the collision cross-section (CCS) of an open-access database to accelerate the interpretation of metabolomic results. Standards of metabolites were tested using liquid chromatography coupled with high-resolution mass spectrometry. In CCSBase and QSRR predictor machine learning models, experimental results were used to generate predicted CCS and Rt of the Human Metabolome Database. From 542 standards, 266 and 301 compounds were detected in positive and negative electrospray ionization mode, respectively, corresponding to 380 different metabolites. CCS and Rt were then predicted using machine learning tools for almost 114,000 metabolites. R2 score of the linear regression between predicted and measured data achieved 0.938 and 0.898 for CCS and Rt, respectively, demonstrating the models' reliability. A CCS and Rt index filter of mean error ± 2 standard deviations could remove most misidentifications. Its application to data generated from a toxicology study on tobacco cigarettes reduced hits by 76%. Regarding the volume of data produced by metabolomics, the practical workflow provided allows for the implementation of valuable large-scale databases to improve the biological interpretation of metabolomics data.

Four-year follow-up of surface contamination by antineoplastic drugs in a compounding unit.

OBJECTIVES: This study aimed to monitor the contamination by antineoplastic drugs on work surfaces in a compounding unit 4 years after its implementation. METHODS: This descriptive study was done in a unit performing on average 45 000 preparations per year. Surface sampling points (N=23) were monitored monthly in the frame of routine activity from the opening of an anticancer drug compounding unit. Contamination with nine antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-fluorouracil, methotrexate, gemcitabine, cytarabine, irinotecan and doxorubicin) was assessed on wipes with a local liquid chromatography coupled with a tandem mass spectrometer analysis. The contamination rate (CR, %) was prospectively monitored every month during the entire study period. The occurrence of critical incidents was also registered. The effect of each safety measure implemented during this period was also analysed. RESULTS: Based on the 1104 samples collected between March 2016 and March 2020, the CR was 18.5%. If three different critical incidents among a vial breakage that occurred were individually considered, this CR was slightly lower than that in the literature. Eight months after opening and taking different corrective actions, the overall CR dropped from 42.39% to 11.52% (p<0.001). Contamination was limited to the area that includes the compounding room and, more precisely, the welder and the QC-Prep+ sampling points. CONCLUSIONS: From the beginning of the study and from month to month, surface contamination was limited to the nearest sampling points to the compounding unit. This 4-year monitoring study allowed us to determine the intravenous conventional antineoplastic drugs and sampling points to be focused on.

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.

Clinical Relevance of Serum Kyn/Trp Ratio and Basal and IFNγ-Upregulated IDO1 Expression in Peripheral Monocytes in Early Stage Melanoma.

Immune escape is an early phenomenon in cancer development/progression. Indoleamine 2,3-dioxygenase 1 (IDO1) is a normal endogenous mechanism of acquired peripheral immune tolerance and may therefore be tumor-promoting. This study investigated the clinical relevance of IDO1 expression by immune cells in the lymph nodes and blood and of the serum kynurenine/tryptophan (Kyn/Trp) ratio in 65 systemic treatment naïve stage I-III melanoma patients. Blood samples were collected within the first year of diagnosis. Patients had a median follow-up of 61 months. High basal IDO1 expression in peripheral monocytes and low IFNγ-induced IDO1 upregulation correlated with worse outcome independent from disease stage. Interestingly studied factors were not interrelated. During follow-up, the risk of relapse was 9% (2/22) in the subgroup with high IFNγ-induced IDO1 upregulation in monocytes. In contrast, if IDO1 upregulation was low, relapse occurred in 30% (3/10) of patients with low basal IDO1 expression in monocytes and in 61.5% (8/13) in the subgroup with high basal IDO1 expression in monocytes (Log-Rank test, p=0.008). This study reveals some immune features in the blood of early stage melanoma that may be of relevance for disease outcome. These may offer a target for sub-stratification and early intervention.

Long-Term Analgesia following a Single Application of Fentanyl Transdermal Solution in Pigs.

INTRODUCTION: In animal research, obtaining efficient and constant pain control is regulatory but challenging. The gold standard pain management consists of opioid analgesic administration, such as buprenorphine or fentanyl extended-release patches. However, as in all drugs with a short half-life time, repeated buprenorphine administrations are needed, leading to multiple injections that affect the research protocol. On the other hand, fentanyl patch efficacy is discussed in some species. These elements highlight the need of an optimal formulation of analgesic drugs for laboratory animals. In this study, we investigated how Recuvyra®, a fentanyl transdermal solution (FTS), validated in dog perioperative pain management, could provide sustained analgesia after a single topical administration in pigs in a surgical context. METHODS: A total of 11 minipigs were used in this study. As a preliminary experiment, two different doses were tested as a single application on five pigs: two pigs at full dose (2.6 mg/kg) and three pigs at half dose (1.3 mg/kg). Plasma fentanyl dosages were performed during 4 consecutive days, using liquid chromatography with tandem mass spectrometry detection. The efficacy of FTS was then evaluated in a perioperative period. Six minipigs benefited from a surgical intervention comprising a laparotomy. The FTS was blotted on the skin in a single application 20 min before the surgical incision and plasma fentanyl dosages, clinical examination (body weight, food intake, heart rate, and body temperature) and pain assessment were performed for 7 consecutive days. RESULTS: During the preliminary experiment, all fentanyl concentrations reached the minimum effective concentration (MEC) extrapolated in pigs (fentanylemia ≥0.2 ng/mL) throughout the 4 days. The half dose was chosen for the next step of the study. After the surgical intervention, all plasma fentanyl concentrations remained above the MEC up to 7 days post administration. Pig clinical examinations and pain evaluations showed efficient and constant pain control at the half dose, and few adverse events were observed. DISCUSSION AND CONCLUSION: This study confirms the pharmacological and clinical efficacy of FTS at 1.3 mg/kg in pigs throughout at least 7 postoperative days following laparotomy. The clinical analgesic effect of FTS appears more efficient and well-tolerated than the one observed with repeated injections of buprenorphine. This analgesic drug formulation could be universally used in animal research to provide optimal perioperative pain management and long-term analgesia.

Immune Monitoring in Melanoma and Urothelial Cancer Patients Treated with Anti-PD-1 Immunotherapy and SBRT Discloses Tumor Specific Immune Signatures.

(1) Background: Blockade of the PD-1/PD-L1 pathway has revolutionized the oncology field in the last decade. However, the proportion of patients experiencing a durable response is still limited. In the current study, we performed an extensive immune monitoring in patients with stage III/IV melanoma and stage IV UC who received anti-PD-1 immunotherapy with SBRT. (2) Methods: In total 145 blood samples from 38 patients, collected at fixed time points before and during treatment, were phenotyped via high-parameter flow cytometry, luminex assay and UPLC-MS/MS. (3) Results: Baseline systemic immunity in melanoma and UC patients was different with a more prominent myeloid compartment and a higher neutrophil to lymphocyte ratio in UC. Proliferation (Ki67+) of CD8+ T-cells and of the PD-1+/PD-L1+ CD8+ subset at baseline correlated with progression free survival in melanoma. In contrast a higher frequency of PD-1/PD-L1 expressing non-proliferating (Ki67-) CD8+ and CD4+ T-cells before treatment was associated with worse outcome in melanoma. In UC, the expansion of Ki67+ CD8+ T-cells and of the PD-L1+ subset relative to tumor burden correlated with clinical outcome. (4) Conclusion: This study reveals a clearly different immune landscape in melanoma and UC at baseline, which may impact immunotherapy response. Signatures of proliferation in the CD8+ T-cell compartment prior to and early after anti-PD-1 initiation were positively correlated with clinical outcome in both cohorts. PD-1/PD-L1 expression on circulating immune cell subsets seems of clinical relevance in the melanoma cohort.

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.

Comparison of the chemical composition of aerosols from heated tobacco products, electronic cigarettes and tobacco cigarettes and their toxic impacts on the human bronchial epithelial BEAS-2B cells.

The electronic cigarettes (e-cigs) and more recently the heated tobacco products (HTP) provide alternatives for smokers as they are generally perceived to be less harmful than conventional cigarettes. However, it is crucial to compare the health risks of these different emergent devices, in order to determine which product should be preferred to substitute cigarette. The present study aimed to compare the composition of emissions from HTP, e-cigs and conventional cigarettes, regarding selected harmful or potentially harmful compounds, and their toxic impacts on the human bronchial epithelial BEAS-2B cells. The HTP emitted less polycyclic aromatic hydrocarbons and carbonyls than the conventional cigarette. However, amounts of these compounds in HTP aerosols were still higher than in e-cig vapours. Concordantly, HTP aerosol showed reduced cytotoxicity compared to cigarette smoke but higher than e-cig vapours. HTP and e-cig had the potential to increase oxidative stress and inflammatory response, in a manner similar to that of cigarette smoke, but after more intensive exposures. In addition, increasing e-cig power impacted levels of certain toxic compounds and related oxidative stress. This study provides important data necessary for risk assessment by demonstrating that HTP might be less harmful than tobacco cigarette but considerably more harmful than e-cig.

Fastidious chemical decontamination after cyclophosphamide vial breakage in a compounding unit.

An important amount of cytotoxic drug may accumulate in the workplace following the breakage of a vial containing an anticancer drug. Thanks to the monthly monitoring of the surface contamination in our compounding unit, a strong increase of cyclophosphamide contamination was highlighted in the storage area following the breakage of the vial, despite application of the emergency procedure. This study presents an analysis of chemical decontamination in the context of massive contamination. Samples were taken on the floor and on the caster of a storage shelf where the vial broke. The residual contamination was measured with a liquid chromatography-mass spectrometry/mass spectrometry method. An admixture of 10-2 M sodium dodecyl sulfate and 70% isopropanol (SDS/IPA 8:2) was selected as the decontamination solution. High amounts of cyclophosphamide were retrieved. The initial contamination on the floor was over 20 ng/cm2. Three decontaminations with SDS/IPA were carried out at Day 61, Day 68, and Day 71. The amount of cyclophosphamide decreased to 0.45 ng/cm2 at D134. However, high values were still measured on the caster despite successive decontaminations, with a maximal value of 19.78 ng/cm2 observed at Day 106. Continuous monitoring in our unit led us to highlight the inefficiency of our emergency procedure to eliminate high cyclophosphamide contamination. The procedure involving the SDS/IPA admixture was more efficient on the floor compared to the caster, which is a different surface type and porosity. This work highlights the importance of improving the procedures of incident management using contamination monitoring and repeated decontamination procedures adapted to different contaminants and surfaces.

Exposure to metal fumes and circulating miRNAs in Algerian welders.

PURPOSE: A cross-sectional study was conducted in a group of Algerian welders to study the relationship between the exposure to metal particles from welding fumes and the concentration of three circulating miRNAs, miR-21, miR-146a and miR-155, as markers of renal function injury. METHODS: Characteristics of the subjects and the curriculum laboris were determined by questionnaires. We measured the concentrations of metals in blood and urine samples using ICP-MS. The three circulating miRNAs studied were measured by quantitative PCR. Associations between miRNAs and internal exposure markers were assessed by simple and multiple regression analyses. RESULTS: miR-21 was significantly lower among welders (p = 0.017), compared with controls, adjusted for age, body mass index, smoking status and seniority. Significant adjusted associations were observed between miR-21 or miR-155 and urinary chromium (p = 0.005 or p = 0.041, respectively), miR-146a and urinary nickel (p = 0.019). The results of the multivariate analysis showed that duration of employment was the main factor responsible for the variation of miRNAs among welders. CONCLUSION: In conclusion, a recent exposure to certain metals, mainly chromium and nickel, appears to be associated to a decrease in plasma expression of miR-21, miR-146a and miR-155. Further larger studies would help to determine the mechanisms of action of metal particles on miRNA expression.

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.

Risk factors associated to tobacco and alcohol use in a large French cohort of pregnant women.

Tobacco and/or alcohol use during pregnancy is a major public health concern. The aim of our study was to identify risk factors associated to maternal alcohol and tobacco use assessed by maternal self-reports combined with biological measurements in meconium samples of cotinine and ethylglucuronide which reflect fetal exposure to tobacco and alcohol, respectively, during the 3rd trimester of pregnancy. We conducted a prospective study in three maternity hospitals in a large urban area during consecutive weeks (2010 and 2011). Maternal sociodemographic and clinical characteristics were assessed after delivery, using the French version of the Addiction Severity Index. Cotinine and ethylglucuronide were measured in meconium samples. Seven hundred and twenty-four women were included, and 645 meconium samples collected. Using multivariate analyses, we found that not being married or having a smoking partner predicts maternal tobacco use. In contrast, a decreased risk was associated with higher education level and wanted pregnancy. The risk for alcohol use increased when the mother had been in conflict with any relative or her partner for a long time throughout her life, as well as in case of previous treatment for any mental or emotional disorder. Using multivariate analyses and cotinine presence in meconium samples, the risks were similar except for marital status, which was not associated to cotinine presence. Community education and prevention programs should urgently be improved for all women of childbearing age with a special focus on those with past histories of mental or emotional disorders and addictive disorders. Smoking cessation should be recommended to both parents.