[Cannabidiol (CBD): Analytical and toxicological aspects]. / Le cannabidiol (CBD) : aspects analytiques et toxicologiques.

Cannabidiol (CBD) is a phytocannabinoid present in cannabis, obtained either by extraction from the plant or by synthesis. The latter has the advantage of being pure and contains few impurities, unlike CBD of plant origin. It is used by inhalation, ingestion or skin application. In France, the law stipulates that specialties containing CBD may contain up to 0.3% of tetrahydrocannabinol (THC), the psychoactive principle of cannabis. From an analytical point of view, it is therefore important to be able to quantify the two compounds as well as their metabolites in the various matrices that can be used clinically or forensically, in particular saliva and blood. The transformation of CBD into THC, which has long been suggested, appears to be an analytical artifact under certain conditions. CBD is not without toxicity, whether acute or chronic, as seems to attest to the serious adverse effects recorded by pharmacovigilance during the experiment currently being conducted in France by the Agence Nationale de Sécurité du Médicament et des Produits de Santé. Although CBD does not seem to modify driving abilities, driving a vehicle after consuming CBD containing up to 0.3% THC, and sometimes much more in products bought on the internet, can lead to a positive result in screening and confirmation tests by law enforcement agencies, whether salivary or blood tests, and therefore lead to a legal sanction.

[Biomononitoring of environmental exposure to inorganic arsenic]. / Surveillance biologique de l'exposition environnementale à l'arsenic inorganique.

BACKGROUND AND OBJECTIVES: The French national authority for health (Haute autorité de santé: HAS) and the French clinical toxicology society (Société de toxicologie clinique: STC) received a formal request from the French ministry for heath to elaborate recommendations for the screening of environmental overexposure to inorganic arsenic (iAs), for the medical management of overexposed patients and for the medical surveillance of exposed population. To allow these recommendations, preliminary literature retrieval and analysis were performed for identifying validated indicators of both exposure and early effects of iAs and their levels in the general population living in France. METHODS: Evaluations of inorganic arsenic toxicity conducted by national or international health agencies during the last 3 decades were all examined and analyzed. These evaluations were completed by literature retrieval through Medline and Scopus from January 2016 to December 2019. RESULTS AND CONCLUSIONS: The best biomonitoring indicator for iAs exposure is the sum of urine iAs, monmomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) concentrations (SAs). The upper limit of confidence interval of the 95th percentile of the distribution of this parameter in the general adult population living in France is 10 µg/g of creatinine, and is recommended as the limit value for the definition of overexposure. In less than 12 year-old children specific limit values are required, but not yet available. In their absence, SAs should exceed both 10 µg/g creatinine and 11 µg/L to be considered as indicating a probable overexposure to iAs. There are no useful biological indicators of iAs early effects. Non carcinogenic skin effects of inorganic arsenic (hyperpigmentation and keratosis) should be considered as the earliest deleterious effects of repeated environmental iAs exposure.

Metallic Profile of Whole Blood and Plasma in a Series of 99 Healthy Children.

In recent years, special emphasis has been put on heavy metals. Children are very sensitive to accumulation of metals. Furthermore, as regards elements, the reference values in children are scarce in the literature as it is difficult to obtain the large quantity of blood necessary to analyze many metals by the conventional atomic absorption spectrometry technique. An inductively coupled plasma mass spectrometry (ICP-MS) procedure that uses a reduced sample of 0.3 mL whole blood or plasma is adapted to multielemental determinations. We applied a previously validated technique for adults that simultaneously quantifies 25 elements by ICP-MS in whole blood and 23 in plasma in a series of 99 healthy children ranging from under 5 years to <18 years, without exposure to metal or drug-containing metals. The aims of the study were to compare metallic concentrations according to the age among children and metallic concentration differences between children and adults. The blood and plasma pediatric metallic profile is a practical useful tool for many purposes in clinical toxicology, forensic toxicology and any cases of metal environmental exposure.

Pharmacokinetic study of metopimazine by oral route in children.

Metopimazine (MPZ) is an antiemetic considered as a currently used drug. In France, it has become the leading antiemetic mediator due to its good tolerance, however, its pharmacokinetics has never previously been studied in children. MPZ was administered by oral route to 8 children with a single dose of 0.33 mg/kg during an endocrine exploration using stimuli well known for its adverse emetic effects. We used biological remnants from sera following an hGH test in order to obtain the MPZ pharmacokinetics. Plasmatic concentrations of MPZ and the active acid metabolite AMPZ, were quantified by HPLC-MS/MS during a 270 min test period. MPZ is quickly absorbed with a median C max of 17.2 ng/mL at one hour and its half-life is 2.18 h. The plasmatic concentrations of AMPZ were higher than MPZ with a median C max of 76.3 ng/mL, a T max to 150 min and its concentration was approximately maintained at 50 ng/mL from 1 to 4 h. The plasmatic concentrations in children are similar to those observed in adults. No adverse effects, nausea or vomiting occurred during the trial. Therefore, these results confirm the MPZ dosage that should be used in children under 15 kg administered as 0.33 mg/kg up to 3 times a day.

[Drug use and driving]. / Médicaments et conduite automobile.

Some drugs are known to impair driving because they can change the vision or hearing, and/or disrupt the intellectual or motor abilities: impaired vigilance, sedation, disinhibition effect, the coordination of movement disorders and the balance. The doctor during prescribing and the pharmacist during deliverance of drug treatment should inform their patients of the potential risks of drugs on driving or operating machinery. The driver has direct responsibility, who hired him and him alone, to follow the medical advice received. The pictograms on the outer packaging of medicinal products intended to classify substances according to their risk driving: The driver can whether to observe simple precautions (level one "be prudent"), or follow the advice of a health professional (level two "be very careful"), or if it is totally not drive (level three "danger caution: do not drive"). This classification only evaluates the intrinsic danger of drugs but not the individual variability. Medicines should be taken into account also the conditions for which the medication is prescribed. It is important to inform the patient on several points.

Current role of ICP-MS in clinical toxicology and forensic toxicology: a metallic profile.

As metal/metalloid exposure is inevitable owing to its omnipresence, it may exert toxicity in humans. Recent advances in metal/metalloid analysis have been made moving from flame atomic absorption spectrometry and electrothermal atomic absorption spectrometry to the multi-elemental inductively coupled plasma (ICP) techniques as ICP atomic emission spectrometry and ICP-MS. ICP-MS has now emerged as a major technique in inorganic analytical chemistry owing to its flexibility, high sensitivity and good reproducibility. This in depth review explores the ICP-MS metallic profile in human toxicology. It is now routinely used and of great importance, in clinical toxicology and forensic toxicology to explore biological matrices, specifically whole blood, plasma, urine, hair, nail, biopsy samples and tissues.

Disopyramide and mianserin intoxication: a unique fatal case--review of the literature.

Lethal occurrence is exceptional after disopyramide or mianserin poisoning. A case of intentional lethal intoxication with these drugs was reported, as well as a review of the literature. Pre- and postmortem blood concentrations of disopyramide or mianserin were assessed in a woman who died from acute cardiac failure after ingestion. The premortem blood concentration of disopyramide alone was considered lethal, and a toxic premortem concentration of mianserin was observed that may have increased cardiovascular failure induced by disopyramide because the metabolism of both drugs is mediated via cytochrome P450. Moreover, it was shown that the postmortem redistribution of disopyramide was limited, as pre- and postmortem concentrations were 48 and 65 mg/L, respectively. As regards mianserin, redistribution was observed after death with pre- and portmortem concentrations at 0.23 and 0.79 mg/L, respectively. This case illustrates that if postmortem blood concentration of disopyramide is known, the premortem concentration can be deduced.

Metallic profile of whole blood and plasma in a series of 106 healthy volunteers.

In 2003, we simultaneously quantified 27 metals by inductively coupled plasma-mass spectrometry (ICP-MS) in the whole blood, plasma and urine of 100 healthy volunteers. We again determined the metallic profile in whole blood and plasma during 2012. ICP-MS validated multielementary method was performed for metals in whole blood and plasma. Whole blood vanadium and chromium were quantified using ICP-MS collision cell technology. The aims of the study were to compare and assess any changes in this profile, particularly due to the environment. Healthy male/female staff volunteers (n = 106) with no professional exposure to metals, or medication containing lithium, strontium; or food supplements with trace elements and vitamins and with no metal prosthesis were included. Tobacco consumption and the number of dental amalgams were recorded. Our results demonstrated a blood lead level that had drastically decreased, i.e. reduced by half, during this period (12.5 versus 26.3 µg/L, P < 0.0001). Known differences were observed between males and females for copper and zinc; cadmium and lead were higher in smokers. Median plasmatic mercury, a specific test for dental amalgam exposure, did not significantly increase (0.38 versus 0.28 µg/L, P = 0.11). The ICP-MS metallic profile is a very practical concept that is useful for clinical, forensic and environmental toxicology, including industrial hygiene monitoring.

Determination of levels of current drugs in hospital and urban wastewater.

A rapid, sensitive and highly specific HPLC-MS/MS method with direct on-line preparation was applied for the determination of 20 common pharmaceuticals in hospital and urban wastewater. Median drug concentrations were quite similar in the majority of samples, cerca 1 µg L⁻¹ ranging from 0.06 to 2.67 µg L⁻¹ in both water. Pharmaceutical hospital contribution, below 1 %, was negligible, as compared to the huge amount in the municipal plant flow. Due to only partial elimination in the plant, hundreds of kilograms of harmful waste per year are discharged in the River Seine. Therefore, to reduce potential human and environmental exposure, a topic of major concern, an efficient drug treatment procedure should be used at the municipal plant stage in order to reduce urban wastewater pollution. The HPLC-MS/MS method could be a very useful tool to optimize the pharmaceutical wastewater treatment process.

Importance of anthropogenic metals in hospital and urban wastewater: its significance for the environment.

Thirty-four metals were analyzed by ICP-MS. Among these elements, anthropogenic silver, gadolinium and platinum, were representative markers of medical activities in hospital and urban wastewater. On working days, median hospital wastewater concentrations for anthropogenic silver, gadolinium, and platinum were approximately three, 13 and 27 times higher respectively than the Municipal wastewater. A drastic reduction of their emission was observed during non-working days (minus 94 % for gadolinium and 87 % for platinum). A large percentage of these metals are not trapped in the Treatment Plant, i.e. 88 % for gadolinium and 69 % for platinum. More than 4 kg and 350 g for gadolinium and platinum are respectively discharged per year in the River Seine. Therefore, it is imperative to eliminate these elements in the Plant.

Suicidal sodium azide intoxication: An analytical challenge based on a rare case.

INTRODUCTION: Intentional absorption of sodium azide is exceptional but remains extremely life-threatening because death rapidly occurs when significant doses are absorbed, either due to the direct effect of sodium azide or an indirect effect due to nitric oxide, cyanide ions or hydrazoic acid production from sodium azide. CASE REPORT: The body of a laboratory assistant, was discovered by his colleagues in the laboratory, seated on a chair located near a digital computer displaying information about sodium azide. Moreover, a half empty 99% sodium azide flask was found near the corpse. The laboratory staff confirmed that the young man was still alive 5h prior to discovery. RESULTS: Postmortem examination did not show any cutaneous signs of injury due to a defensive struggle. Bilateral ungual cyanosis was observed as well as a major cerebral edema and visceral congestion on autopsy. The elevated sodium azide concentration found in the gastric sample and the amount of gastric content allowed to conclude that sodium azide intake was more than 6g which was above the lethal dose, i.e. approximately 1g. Surprisingly, no sodium azide was found either in blood and serum, or in hepatic and renal tissue samplings. However, major concentrations were observed in the gastric contents, bile and urinary samples, as well as in cardiac and cerebral tissues samples. No other toxic element was found. Therefore, the post-mortem findings, the autopsy and the analytical results suggested that the laboratory assistant died after an intentional sodium azide ingestion. CONCLUSION: Sodium azide poisoning by ingestion has to date remained extremely rare and our case highlights the extreme lability of sodium azide as it was absent in the blood, in spite of significant concentrations in stomach content and some tissues. Therefore, the necessity of multiple tissues samples during autopsy should be underlined.

Mitochondrial myopathy caused by arsenic trioxide therapy.

Arsenic trioxide (ATO) has been successfully used as a treatment for acute promyelocytic leukemia (APL) for more than a decade. Here we report a patient with APL who developed a mitochondrial myopathy after treatment with ATO. Three months after ATO therapy withdrawal, the patient was unable to walk without assistance and skeletal muscle studies showed a myopathy with abundant cytoplasmic lipid droplets, decreased activities of the mitochondrial respiratory chain complexes, multiple mitochondrial DNA (mtDNA) deletions, and increased muscle arsenic content. Six months after ATO treatment was interrupted, the patient recovered normal strength, lipid droplets had decreased in size and number, respiratory chain complex activities were partially restored, but multiple mtDNA deletions and increased muscle arsenic content persisted. ATO therapy may provoke a delayed, severe, and partially reversible mitochondrial myopathy, and a long-term careful surveillance for muscle disease should be instituted when ATO is used in patients with APL.

Fatal poisoning due to snorting buprenorphine and alcohol consumption.

High dosage buprenorphine (Subutex(®)) has been prescribed as a replacement therapy for major opioid dependencies in France since 1996. However, several studies have underlined its lethal risk, especially when administered intravenously, or when combined with benzodiazepines, alcohol or other central nervous system depressants. We report three fatal buprenorphine-related poisonings after snorting, among outside protocol individuals, observed at the Forensic Medicine Unit of Caen University Hospital. Medico-legal autopsies and complementary examinations were performed. The results are presented and discussed. Lethal poisoning after snorting buprenorphine was considered the most probable cause of death. These observations illustrate the risk of fatal poisoning by buprenorphine per-nasal route, which has rarely been reported in the literature although snorting is particularly prized by individuals outside the substitution therapy. We also observed the combination of buprenorphine and alcohol. By evaluating the pharmacological characteristics of this substance, as well as the data previously published in the literature, we have attempted to explain the pathophysiological mechanisms of this particular mode of poisoning that can easily be fatal.

[Drug-facilitated crime: a public health problem?]. / La soumission chimique: un problème de santé publique?

Drug-facilitated crime (DFC) is well known to the public, yet general practitioners and other physicians are unfamiliar with this issue, largely because toxicology is not part of the medical curriculum. This often leads to diagnostic errors. The frequency of DFC is underestimated, often owing to late examination and analytical problems. On 24 December 2002 the French authorities issued a circular defining DFC as "the administration of a psychoactive drug without the victim's knowledge, as a means of aggression"; and listing places where victims can be managed On 19 July 2005, the French Agency for Health Product Safety (Afssaps) sent a letter to all professionals potentially concerned by this issue, offering guidelines for both medical personnel and laboratory staff conducting toxicological investigations. One difficulty in drug identification is that the doses administered are often low. Toxicology laboratories need sophisticated equipment and expertise to ensure that the perpetrator is prosecuted or, alternatively, to rule out DFC. More information is needed, not only for the public but also for physicians and toxicologists. Benzodiazepines and related compounds are identified in about 75% of DFC cases.

Plasma and urinary aluminum concentrations in severely anemic geophagous pregnant women in the Bas Maroni region of French Guiana: a case-control study.

The clays consumed by geophagous individuals contain large quantities of aluminum, a known neurological and hematological toxin. This is the first study to evaluate the risk of aluminum poisoning in geophagous individuals. Blind determinations of plasma and urinary aluminum concentrations were carried out in 98 anemic geophagous pregnant women and 85 non-anemic non-geophagous pregnant women. Aluminum concentrations were significantly higher (P < 0.0001) in the geophagous anemic women than in the controls, with odds ratios of 6.83 (95% confidence interval [CI] = 2.72-19.31) for plasma concentrations (13.92 ± 14.09 µg/L versus 4.95 ± 7.11 µg/L) and 5.44 (95% CI = 2.17-14.8) for urinary concentrations (92.83 ± 251.21 µg/L versus 12.11 ± 23 µg/L). The ingested clay is the most likely source of this overexposure to aluminum. If confirmed, the clinical consequences of this absorption for pregnant women and their offspring should be explored.

[The metallic profile: a new biological concept]. / Une nouvelle approche biologique: le profil métallique.

Considerable advances have been made in metals and metalloids analysis over the past decade. This analysis is a basic stage in deficiency or toxicity assessment. A recently introduced technique, inductively coupled plasma mass spectrometry (ICP-MS) is progressively replacing atomic absorption. This analysis permits multi-elementary determinations, many ten or so elements, among periodic classification, with an optimal gain in sensitivity in many biological matrices: i.e. whole blood, plasma, urine, hair, nail, and biopsy samples. Moreover, this method allows semi-quantitative determination with an additional thirty supplementary elements, which enables the toxicologist to sufficiently estimate the toxic levels and metal exposure. The authors demonstrate that the ICP-MS could be very useful for a wide range of clinical applications. Furthermore, this procedure offers new exploration possibilities in various fields such as clinical chemistry but also clinical toxicology, forensic toxicology as well as workplace testing or environmental exposure and permits epidemiologic studies. This analytical method in fact also provides a new biologic approach. To our knowledge we are the first to propose the metallic profile.