Trends in fentanyl and fentanyl analogue-related overdose deaths - Montgomery County, Ohio, 2015-2017.

INTRODUCTION: There is a lack of information on illicitly manufactured fentanyl and fentanyl analogue-related (IMF) unintentional overdose death trends over time. The study analyzes IMF-related unintentional overdose fatalities that occurred between July 2015 and June 2017 in Montgomery County, Ohio, an area with the highest rates of unintentional overdose mortality in Ohio. METHODS: LC-MS/MS-based method was used to identify fentanyl analogs and metabolites in 724 unintentional overdose death cases. The Chi-square statistic was used to assess differences over time in demographic and drug-related characteristics. RESULTS: The number of unintentional overdose death cases testing positive for IMFs increased by 377% between second half of 2015 and first half of 2017. The majority of decedents were white (82.5%) and male (67.8%). The proportion of fentanyl-only (no other analogs) cases declined from 89.2%-24.6% (p < 0.001), while proportion of fentanyl analogue-containing cases increased from 9.8%-70.3% (p < 0.001) between the second half of 2015 and first half of 2017. The most commonly identified fentanyl analogs were carfentanil (29.7%), furanyl fentanyl (14.1%) and acryl fentanyl (10.2%). Proportion of IMF cases also testing positive for heroin declined from 21.6% to 5.4% (p < 0.001), while methamphetamine positive cases increased from 1.4%-17.8% (p < 0.001) over the same time period. DISCUSSION: Emergence of fentanyl analogs contributed to substantial increases in unintentional overdose deaths. The data indicate a growing overlap between the IMF and methamphetamine outbreaks. Continuous monitoring of local IMF trends and rapid information dissemination to active users are needed to reduce the risks associated with IMF use.

Fatality Following Ingestion of Tetrahydrofuranylfentanyl, U-49900 and Methoxy-Phencyclidine.

Novel psychoactive substances (NPS), and specifically novel opioids, continue to cause adverse events, including death, within drug-using populations. As the number of opioid-related overdoses continues to increase, laboratories have identified the emergence of new fentanyl analogues and other synthetic opioid-related drugs. Tetrahydrofuranylfentanyl (THFF) has been identified in Europe and the United States as an emerging novel opioid, causing death in at least 15 drug-using individuals to date. THFF is structurally similar to furanylfentanyl, a previously characterized novel opioid responsible for numerous adverse events, including death. In this case report, THFF, U-49900 and methoxy-phencyclidine were identified in postmortem blood and urine specimens collected after a suspected overdose. As part of the death investigation, an unknown substance was collected from the scene and analytically confirmed as THFF and U-49900. To further assist laboratories in identifying THFF ingestion, metabolic profiling was conducted using pooled human liver microsomes. Characterized metabolites were then confirmed in the specimens collected during this investigation. In total, seven metabolites were identified for THFF, most notably THF-norfentanyl and hydroxyl-THFF. THF-norfentanyl provides utility as a biomarker because it is a unique metabolite of THFF. 4-Anilino-N-phenethylpiperidine (4-ANPP) and its metabolite, hydroxyl-4-ANPP, were identified in microsomal incubations and collected specimens, but usefulness as biomarkers is limited due to commonality between other fentanyl analogues and co-ingestion as a synthesis precursor. To our knowledge, this case report is the first to document a fatality after ingestion of THFF and U-49900 in the United States.

Postmortem and Toxicological Findings in a Series of Furanylfentanyl-Related Deaths.

Over the course of 4 months in 2015 and 2016, a cluster of seven fatal intoxications involving the opioid-analogue furanylfentanyl occurred in Sweden; toxicological analysis showed presence of furanylfentanyl either as the only drug or in combination with other illicit substances. Previous publications have only reported non-lethal furanylfentanyl intoxications. In the cases presented here, furanylfentanyl intoxication-alone or in combination with other drugs-was determined to be the cause of death by the responsible pathologist. All victims were young (24-37 years old) males, five of which had a well-documented history of drug abuse. Femoral blood concentration of furanylfentanyl ranged from 0.41 ng/g to 2.47 ng/g blood. Five cases presented a complex panel of drugs of abuse and prescription drugs. Moreover, in five cases the concurrent presence of pregabalin corroborates previous observations indicating pregabalin as a possible contributing factor in polydrug intoxications. We conclude that it is difficult to establish a specific lethal concentration of furanylfentanyl, due to incompletely known effects of possible pharmacokinetic and pharmacodynamic interactions with other drugs, as well as to the unknown degree of tolerance to opioids. We suggest that a full toxicological screening-to assess the possibility of drug interactions-together with segmental hair analysis regarding opioids-to estimate the level of opioid tolerance-be carried out to assist in the interpretation of cases involving synthetic opioids such as furanylfentanyl.

Ecological risk assessment for mink and short-tailed shrew exposed to PCBs, dioxins, and furans in the Housatonic River area.

A probabilistic risk assessment was conducted to characterize risks to a representative piscivorous mammal (mink, Mustela vison) and a representative carnivorous mammal (short-tailed shrew, Blarina brevicauda) exposed to PCBs, dioxins, and furans in the Housatonic River area downstream of the General Electric (GE) facility in Pittsfield, Massachusetts. Contaminant exposure was estimated using a probabilistic total daily intake model and parameterized using life history information of each species and concentrations of PCBs, dioxins, and furans in prey collected in the Housatonic River study area. The effects assessment preferentially relied on dose-response curves but defaulted to benchmarks or other estimates of effect when there were insufficient toxicity data. The risk characterization used a weight of evidence approach. Up to 3 lines of evidence were used to estimate risks to the selected mammal species: 1) probabilistic exposure and effects modeling, 2) field surveys, and 3) species-specific feeding or field studies. The weight of evidence assessment indicated a high risk for mink and an intermediate risk for short-tailed shrew.

Marine toxins and the cytoskeleton: azaspiracids.

The azaspiracids (AZAs) are a group of marine phycotoxins discovered during the second half of the 1990s. Several cases of human intoxication due to the presence of AZAs in shellfish have been reported, with gastrointestinal symptoms. Toxicological studies in vivo and in vitro have revealed that various cell types are sensitive to AZA toxicity; however, the biological target of the toxin is still unknown. One of the in vitro signs of AZA toxicity is the alteration of the actin cytoskeleton arrangement, which is accompanied by changes in cell shape and loss of cell adherence to the substrate. Moreover, the cytoskeletal damage is irreversible after toxin withdrawal. Several other in vitro effects of AZAs have been described that could be related to cytoskeletal changes, such as E-cadherin degradation, caspase activation/apoptosis, membrane cholesterol reduction, or gene expression alterations, although evidence for a direct relationship between any of these effects and AZA-induced cytoskeletal damage is still nonexistent.

Detection of diarrheic shellfish poisoning and azaspiracid toxins in Moroccan mussels: comparison of the LC-MS method with the commercial immunoassay kit.

Diarrheic shellfish poisoning (DSP) is a recurrent gastrointestinal illness in Morocco, resulting from consumption of contaminated shellfish. In order to develop a rapid and reliable technique for toxins detection, we have compared the results obtained by a commercial immunoassay-"DSP-Check" kit" with those obtained by LC-MS. Both techniques are capable of detecting the toxins in the whole flesh extract which was subjected to prior alkaline hydrolysis in order to detect simultaneously the esterified and non esterified toxin forms. The LC-MS method was found to be able to detect a high level of okadaic acid (OA), low level of dinophysistoxin-2 (DTX2), and surprisingly, traces of azaspiracids 2 (AZA2) in mussels. This is the first report of a survey carried out for azaspiracid (AZP) contamination of shellfish harvested in the coastal areas of Morocco. The "DSP-Check" kit was found to detect quantitatively DSP toxins in all contaminated samples containing only OA, provided that the parent toxins were within the range of detection and was not in an ester form. A good correlation was observed between the two methods when appropriate dilutions were performed. The immunoassay kit appeared to be more sensitive, specific and faster than LC-MS for determination of DSP in total shellfish extract.

Persistent organochlorine chemicals in plasma and risk of non-Hodgkin's lymphoma.

Polychlorinated biphenyls (PCB) have been suspected as possible contributors to increasing non-Hodgkin's lymphoma incidence during the latter half of the 20th century based on their toxicologic properties and provocative epidemiologic reports. We investigated PCBs and other organochlorines and risk of non-Hodgkin's lymphoma in a population-based case-control study in the United States. Congeners of PCBs (including coplanar congeners), dioxins, furans and pesticides or pesticide metabolites were measured in plasma of 100 untreated cases and 100 control subjects. We used a multiple imputation procedure to fill in missing values of levels determined to be below the detection limits. Risks of non-Hodgkin's lymphoma associated with each analyte were estimated using conditional logistic regression for the continuous measure, exposure quartiles, trend across quartile categories, and exposures above the 95th percentile. Certain PCB congeners were associated with increased risk of non-Hodgkin's lymphoma, including coplanar PCBs 156, 180, and 194, with odds ratios for the highest versus lowest quartile ranging from 2.7 to 3.5, and significant trends. Each of the furan congeners was associated with risk of non-Hodgkin's lymphoma, as were total furans, with 3.5-fold increased risk for the highest versus lowest quartile and a significant trend across quartiles (P = 0.006). The toxic equivalency quotient (TEQ), a summed metric that weights congeners by their dioxin-like potency, was associated with non-Hodgkin's lymphoma, with 35% increased risk per 10 TEQ pg/g lipid (95% confidence interval, 1.02-1.79). Our results add to existing literature, which suggests that exposure to organochlorines contributes to non-Hodgkin's lymphoma risk; these risks were most apparent for certain PCBs and furans.

Incineración de residuos hospitalarios, farmacéuticos y peligrosos: riesgos para la salud / Incineration of hospital, pharmaceutical and dangerous wastes: health risks

La incineración industrial de residuos hospitalarios, farmacéuticos y peligrosos, contribuye a la emisión de diversos contaminantes ambientales. Varios de estos contaminantes son especialmente relevantes: dioxinas, otros compuestos orgánicos persistentes policlorados, hidrocarburos policíclicos aromáticos, metales pesados. Estos producen efectos adversos sobre la salud de tipo inmediato o tempranos por exposición aguda, efectos progresivos causados por exposición crónica, y efectos diferidos, como cáncer (que se puede manifestar a los 30 años después de iniciada la exposición), malformaciones fetales y mutaciones; además causa efectos irreversibles inducidos por exposición prenatal, neonatal o infantil por el mecanismo del imprinting (programación celular), y que determinan el desarrollo de enfermedades más tarde en la vida.

The effect of disinfection by-products and mutagenic activity on birth weight and gestational duration.

Epidemiologic studies of disinfection by-products have traditionally focused on total trihalomethane (TTHM) concentration as a surrogate for maternal exposure during pregnancy. We used birth certificate data on 196,000 infants to examine the effect of third-trimester exposures on various indices of fetal development. We examined the effect of town-average concentrations of TTHM and additional exposure metrics in relation to mean birth weight, mean gestational age, small for gestational age (SGA) infancy, and preterm delivery. Trihalomethane data (TTHM, chloroform, and bromodichloromethane) from 1995-1998 were available for 109 towns in Massachusetts. Data from 1997-1998 on haloacetic acid (total haloacetic acids, dichloroacetic acid, and trichloroacetic acid), 3-chloro-4-(dichloromethyl)-5- hydroxy-2(5H)-furanone (MX), and mutagenicity were available for a limited number of towns. We observed reductions in mean birth weight (12-18 g) for maternal trihalomethane exposures > the 90th percentile compared with those < the 50th percentile. Birth weight reductions were detected for chloroform exposures > 20 microg/L and TTHM exposures > 40 microg/L. Elevated trihalomethanes were associated with increases in gestational duration and a reduced risk of preterm delivery. We found evidence of an exposure-response effect of trihalomethanes on risk of SGA, with odds ratios (ORs) ranging from 1.09 to 1.23 for bromodichloromethane exposures > 5 microg/L. Elevated mutagenic activity was associated with SGA [OR = 1.25; 95% confidence interval (CI), 1.04 to 1.51] and mean birth weight (-27 g; 95% CI, -54 to -1). Although smaller in magnitude, our findings are consistent with previous studies reporting associations between trihalomethanes and SGA. These data also suggest a relationship between fetal development indices and mutagenic activity independent of exposure to trihalomethanes, haloacetic acids, and MX.

Exposure and effects of chemical contaminants on tree swallows nesting along the Housatonic River, Berkshire County, Massachusetts, USA, 1998-2000.

Hatching success of tree swallows (Tachycineta bicolor) was assessed for three years in relation to chemical contamination along the Housatonic River, Berkshire County (MA, USA), in 1998, 1999, and 2000. Nest boxes were erected at five sites along the Housatonic River and its tributaries and at one reference location. Concentrations of total polychlorinated biphenyls (PCBs) were some of the highest ever reported in bird eggs. Mean concentrations at sites along the Housatonic River ranged between 32 and 101 microg/g wet weight. A significant negative relationship was observed between concentrations of total PCBs in clutches and hatching success. A significant negative relationship was also observed between hatching success and the sum of the total dioxins and furans and the associated toxic equivalents (TEQs) for dioxins and furans. In a combined model with PCB TEQs and dioxin/furan TEQs, PCB TEQs were not significantly correlated to hatching success, whereas dioxin/furan TEQs were. Contamination of tree swallows was from local food sources. Accumulation rates of total PCBs in 12-d-old nestlings averaged between 34 and 76 microg/d at the sites along the main stem of the Housatonic River compared to <1 microg/d at the reference location.

Identification and quantitation of xenobiotics by 1H NMR spectroscopy in poisoning cases.

In order to analyse a wide range of xenobiotics and their metabolites present in biological fluids, NMR spectroscopy can be used. A large variety of xenobiotics (therapeutic agents, pesticides, solvents, alcohols) can be characterized and quantitated directly, without sample preparation. NMR investigations were applied to acute poisoning cases, involving drugs such as salicylates and valproic acid (VPA). In a salicylate poisoning case, the three major metabolites of acetylsalicylic acid have been detected in crude urine, and rapid identification of lysine revealed the origin of the intoxication, namely lysine acetylsalicylate (Aspegic). Valproic acid as its glucuronide was identified in urine samples from two poisoned patients. 1H NMR was also used to identify and quantitate paraquat (Gramoxone) in urine owing to its two aromatic signals at 8.49 and 9.02 ppm, in two acutely poisoned patients (183 and 93 mg/l). An intentional poisoning case with tetrahydrofuran (THF) was also investigated. Serum and urine samples were collected. THF was characterized by its resonances at 1.90 and 3.76 ppm, and quantified at 813 and 850 mg/l in the two biological fluids, respectively. Moreover, two other compounds were detected: lactate and gamma-hydroxybutyric acid (GHB). 1H NMR spectroscopic analysis of serum samples from three poisoned patients revealed methanol in one case and ethylene glycol in the two others. Moreover, in the same spectrum, the corresponding metabolites formate and glycolate were found. Compared with the reference chromatographic or spectrophotometric methods, requiring time-consuming extraction and/or derivatization steps, NMR spectroscopy allows the determination of many exogenous and endogenous compounds, without any pre-selection of the analytes.

1H NMR spectroscopic investigation of serum and urine in a case of acute tetrahydrofuran poisoning.

This article reports the investigation by 1H nuclear magnetic resonance (1H NMR) spectroscopy of biological fluids in a case of intentional poisoning with tetrahydrofuran (THF). Occupational exposures to this solvent are well documented, but acute poisoning cases are extremely rare, and the one presented here is the second known case of this kind. Urine and serum samples were collected. Without any pretreatment, the presence of THF was confirmed by characteristic resonances at 1.90 and 3.76 ppm; high lactate levels were also observed. The presence of gamma-hydroxybutyric acid (GHB) was noted. Quantitative analysis was performed by relative integration of peak areas. THF concentrations were 813 and 850 mg/L (11.3 and 11.8 mmol/L), and GHB concentrations 239 and 2,977 mg/L (2.3 and 28.6 mmol/L) in serum and urine, respectively. A gas chromatographic-mass spectrometric method confirmed 1H NMR observations. The origin of GHB detected in serum and urine is also discussed.

The possible involvement of 3-methoxy-2(5H)-furanone in the etiology of Narthecium asiaticum maxim. associated nephrotoxicity in cattle.

Two samples of Narthecium asiaticum Maxim leaves collected in Japan were found to contain 103 microg(-1) and 160 microg g(-1) dry matter of 3-methoxy-2(5H)-furanone respectively. 3-Methoxy-2(5h)-furanone was suggested to be the toxic principle of N. asiaticum causing nephrotoxicity in cattle in Japan. Two other furanones, which are thought to be non-toxic, were also isolated from the two samples. These were 4-methoxy-2(5H)-furanone and 5-hydroxy-4-methoxy-2(5H)-furanone.

First report of pectenotoxin-2 (PTX-2) in algae (Dinophysis fortii) related to seafood poisoning in Europe.

Pectenotoxin-2 (PTX-2), a polyether-lactone included in the neutral class of diarrhoetic shellfish poisoning (DSP) toxins, has been unambiguously detected in Dinophysis fortii collected in the northern Adriatic Sea (Emilia Romagna coasts). This is the first report of such a toxin in Europe. This lipid soluble toxin was identified both in crude methanolic phytoplankton extract and in the neutral fraction obtained by extract chromatography on a basic alumina column. The techniques used were reversed phase high-performance liquid chromatography followed either by UV diode-array detection (LC-UV-DAD) or by mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS-MS) using an atmospheric-pressure ionization source and an ionspray interface. Okadaic acid (OA) was also found in the D. fortii specimens and quantified as 15 pg/cell. Although quantitation of PTX-2 was not possible due to the lack of pure toxin, the high PTX-2:OA ratio suggested PTX-2 was significant in the D. fortii specimens. The presence of PTX-2 in a region with no previous report of DSP neutral toxic compounds may indicate a risk of human poisoning. Serious efforts should therefore be made to develop suitable routine methods capable of detecting the presence of PTXs in biological materials of marine origin, in order to assure the wholesomeness of seafood products.

A review of the significance of animal food products as potential pathways of human exposures to dioxins.

The polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins) are groups of compounds with similar chemical and toxicological properties. Carcinogenicity was considered the most serious toxic end point when setting previous regulatory policies, but recent concerns have focused on the possible endocrine-disrupting activities of the dioxins. Toxicity is related to the 2,3,7,8 pattern of chlorine substitution, a pattern that also leads to chemical and metabolic stability. Dioxins are practically insoluble in water and concentrate in lipids of biological systems, leading to low background concentrations in fat of the general human population. Major environmental sources of dioxins are emissions from industrial chlorination processes and combustion of materials containing chlorine. Inhalation and water have been ruled out as significant exposure pathways, which suggests that food is the primary source. Pathways of entry into food chains are atmospheric transport of emissions and their subsequent deposition on plants, soils, and water. The major food sources seem to be fat-containing animal products and some seafoods. This conclusion is based on evaluations of potential environmental pathways involving dioxins and related compounds. Generally, dioxins and other lipophilic compounds are not taken up and translocated by plants, so residues in foods and feeds derived from seeds should be negligible. Animals on high-roughage diets, or those that ingest contaminated soil, are the most likely to accumulate dioxin residues from the environment. The conclusion that animal products are a major source of human exposure requires verification by appropriate food sampling programs and animal metabolism studies. If it is desirable to reduce human exposure to dioxins via the food supply, reduction of sources would be a more effective strategy than changing agricultural practices and food consumption patterns.

Ductular hepatocytes. Evidence for a bile ductular cell origin in furan-treated rats.

Cholangiolar-like structures composed of biliary epithelial cells and typically a single ductular hepatocytic cell in various stages of maturation appeared in association with an extensive bile ductular reaction within the atrophied right liver lobe of young adult Fischer 344 rats that had been subjected to a severely hepatotoxic treatment with furan. In contrast to normal cholangioles, these cholangiolar-like structures were completely surrounded by a basement membrane, which gave strong immunohistochemical staining reactions for both laminin and type IV collagen. All of the biliary epithelial cells and ductular hepatocytic cells exhibited a strongly positive immunohistochemical staining for gamma-glutamyl transpeptidase and for cytokeratin 8. Cytokeratin 19 was also strongly expressed in all of the biliary epithelial cells, but in just some of the ductular hepatocytic cells, whereas only the latter cells were immunohistochemically positive for albumin and contained peroxisomes in their cytoplasm. Cell junctions were formed between individual ductular hepatocytic cells and adjacent biliary epithelial cells of the same cholangiolar-like structures. In this novel model of severe hepatic injury, the range of cell and nuclear diameters characterizing the ductular hepatocytic cells, together with their phenotypic features, are consistent with a differentiation of rare bile ductular-like cells to transitional ductular cells to more mature ductular hepatocytes.

Placental transport of dioxins from mother to fetus. II. PCBs, dioxins and furans and vitamin K metabolism.

Placental transport of dioxins and furans from mother to fetus takes place. It is probably related to the fatty acid transport. Between 10 and 20% of fatty acids in a full-term baby are of maternal origin. In adipose tissue of children that died in the early neonatal period concentrations of +/- 25% were found of three dioxin and furan congeners 12378 P5CDD, 123678 H6CDD, and 23478 P5CDF in relation to a mean concentration of these congeners in the fat of 14 breastmilk samples. Data of concentrations are given as measured in liver and adipose tissue. In the placenta of a Dutch woman an accumulation of dioxins and furans is found in relation to blood. Animal studies support the hypothesis that polychlorobifenyls play a role in the cause of the late hemorrhagic disease in the newborn, in particular the 2, 4, 5, 2, 4, 5-hexachlorobifenyl that is present in relatively high concentrations in breastmilk.

[Massive poisoning by naftidrofuryl with severe disorders of rhythm and conduction]. / Intoxication massive par le naftidrofuryl avec troubles sévères du rythme et de la conduction.

The authors report the case of a 35-year old woman with normal heart who voluntarily poisoned herself by swallowing 6 grams of naftidrofuryl. She developed disorders of atrioventricular conduction and a ventricular-like arrhythmia with collapse which resolves after mechanical ventilation. Data from the literature indicate that naftidrofuryl possesses class I electrophysiological properties which must not be ignored and which account for the cardiac effects observed in this particular case and in cases of parenteral overdosage already reported. By analogy with class I antiarrhythmic agents, treatment of naftidrofuryl poisoning with disorders of conduction could include the administration of molar sodium lactate.