5-HT2A receptors are involved in the pharmaco-toxicological effects of the synthetic cannabinoids JWH-018 and 5F-PB22: In vivo studies in mice.

Over the last years, Synthetic Cannabinoids (SCs) have been among the largest and most frequently seized groups of Novel Psychoactive Substances (NPS). These substances have been frequently detected in biological samples from patients involved in several intoxication and death cases. Their serious adverse effects have been related to their action as potent agonist of cannabinoid CB1 receptors. However, evidence concerning the potential interaction between SCs and serotoninergic mechanisms has emerged. Therefore, this study aims to evaluate the involvement of 5-HT2A receptors in the effects induced by acute systemic administration of 1-pentyl-3-(1-naphthoyl)indole (JWH-018; 1 mg/kg) and quinolin-8-yl 1-pentyfluoro-1H-indole-3-8-carboxylate (5F-PB22; 1 mg/kg). Sensorimotor (visual, acoustic, and tactile) responses, pain threshold (acute mechanical and thermal nociception), core temperature, breath rate and motor performance (stepping activity) have been assessed in CD-1 male mice. The present results pointed out that both substances deeply alter sensorimotor responses, nociceptive threshold, core temperature, breath rate and motor activity in mice. Noteworthy, pretreatment with the selective 5-HT2A receptors antagonist MDL100907 (0.1 mg/kg) at least partially prevented sensorimotor disruption, antinociception and hypothermic effects. Conversely, the respiratory and motor impairment was not prevented. Thus, it states the relevance of serotoninergic 5-HT2A mechanisms on pharmaco-toxicological effects induced by SCs.

A cytotoxicity and mechanistic investigation of mono- and di-chloro naphthalenes.

Polychlorinated naphthalenes (PCNs) were characterized as persistent organic pollutants (POPs) that were widely distributed in the environment. Although the striking in vivo toxicity of these pollutants towards both animals and humans was well documented, their cytotoxicity and mechanism of action have not been extensively investigated. In this study, the in vitro antiproliferative activity of mono- and di-chloronaphthalenes as representative PCNs were evaluated and the results indicated strong growth inhibitory effects against mammalian cells, especially the human breast MCF-10A cell and human hepatic HL-7702 cells. 2-Chloronaphthalene with the most potent antiproliferative effects within the tested PCNs, which showed IC50 values ranging from 0.3 mM to 1.5 mM against selected human cell lines, was investigated for its working mechanisms. It promoted cellular apoptosis of MCF-10A cells upon the concentration of 200 µM. It also induced the autophagy of MCF-10A cells in a dose-dependent manner, resulting in cell death via the interaction of autophagy and apoptosis. Thus, these findings supported the theoretical foundation for interventional treatment of PCNs toxicity and also provided implications for the use of chemopreventive agents against the toxic chlorinated naphthalenes in the environments.

Genotoxicity assessment in HepaRG™ cells as a new approach methodology follow up to a positive response in the human TK6 cell micronucleus assay: Naphthalene case study.

We are evaluating the use of metabolically competent HepaRG™ cells combined with CometChip® for DNA damage and the micronucleus (MN) assay as a New Approach Methodology (NAM) alternative to animals for follow up genotoxicity assessment to in vitro positive genotoxic response. Naphthalene is genotoxic in human TK6 cells inducing a nonlinear dose-response for the induction of micronuclei in the presence of rat liver S9. of naphthalene. In HepaRG™ cells, naphthalene genotoxicity was assessed using either 6 (CometChip™) or 12 concentrations of naphthalene (MN assay) with the top dose used for assessment of genotoxicity for the Comet and MN assay was 1.25 and 1.74 mM respectively, corresponding to approximately 45% cell survival. In contrast to human TK6 cell with S9, naphthalene was not genotoxic in either the HepaRG™ MN assay or the Comet assay using CometChip®. The lack of genotoxicity in both the MN and comet assays in HepaRG™ cells is likely due to Phase II enzymes removing phenols preventing further bioactivation to quinones and efficient detoxication of naphthalene quinones or epoxides by glutathione conjugation. In contrast to CYP450 mediated metabolism, these Phase II enzymes are inactive in rat liver S9 due to lack of appropriate cofactors causing a positive genotoxic response. Rat liver S9-derived BMD10 over-predicts naphthalene genotoxicity when compared to the negative genotoxic response observed in HepaRG™ cells. Metabolically competent hepatocyte models like HepaRG™ cells should be considered as human-relevant NAMs for use genotoxicity assessments to reduce reliance on rodents.

Sensitivity of the Indo-Pacific coral Acropora millepora to aromatic hydrocarbons.

The risks posed by petroleum spills to coral reefs are poorly understood and quantifying acute toxicity thresholds for aromatic hydrocarbons to reef-building corals is required to assess their sensitivity relative to other taxa. In this study, we exposed Acropora millepora to toluene, naphthalene and 1-methylnaphthalene (1-MN) in a flow-through system and assessed survivorship and sublethal responses including growth, colour and the photosynthetic performance of symbionts. Median 50% lethal concentrations (LC50s) decreased over the 7-d exposure period, reaching asymptotic values of 22,921, 5,268, 1167 µg L-1 for toluene, naphthalene and 1-MN, respectively. Corresponding toxicokinetic parameters (εLC50) defining the time progression of toxicity were 0.830, 0.692, and 0.256 d-1, respectively. Latent effects after an additional 7-d recovery in uncontaminated seawater were not observed. Effect concentrations (EC50s) for 50% growth inhibition were 1.9- to 3.6-fold lower than the LC50s for each aromatic hydrocarbon. There were no observed effects of aromatic hydrocarbon exposure on colour score (a proxy for bleaching) or photosynthetic efficiency. Acute and chronic critical target lipid body burdens (CTLBBs) of 70.3 ± 16.3 and 13.6 ± 18.4 µmol g-1 octanol (± standard error) were calculated for survival and growth inhibition based on 7-d LC50 and EC10 values, respectively. These species-specific constants indicate adult A. millepora is more sensitive than other corals reported so far but is of average sensitivity in comparison with other aquatic taxa in the target lipid model database. These results advance our understanding of acute hazards of petroleum contaminants to key habitat-building tropical coral reef species.

Polychlorinated naphthalene concentrations and temporal trends in serum from the general Chinese adult population and effects of polychlorinated naphthalenes on thyroid function.

Polychlorinated naphthalenes (PCNs) have stopped being produced and used but have been detected in human serum around the world. Investigating temporal trends in PCN concentrations in human serum will improve our understanding of human exposure to PCNs and the risks posed. We determined the PCN concentrations in serum collected from 32 adults in five consecutive years (2012-2016). The total PCN concentrations in the serum samples were 0.00-5443 pg/g lipid weight. We found no significant decreases in the total PCN concentrations in human serum and even found that the concentrations of some PCN congeners (e.g., CN20) increased over time. We found differences in the PCN concentrations in serum from males and females, the CN75 concentration being significantly higher in serum from females than males, meaning CN75 poses more serious risks to females than males. We found, using molecular docking techniques, that CN75 interferes with thyroid hormone transport in vivo and that CN20 affects thyroid hormone binding to receptors. These two effects are synergistic and can cause hypothyroidism-like symptoms.

Combined toxicity of 3,5,6-trichloro-2-pyridinol and 2-(bromomethyl)naphthalene in the early stages of zebrafish (Danio rerio) embryos: Abnormal heart development at lower concentrations via differential expression of heart forming-related genes.

Combined toxicity can occur in the environment according to the combination of single substances, and the combination works additively or in a synergistic or antagonistic mode. In our study, 3,5,6-trichloro-2-pyridinol (TCP) and 2-(bromomethyl)naphthalene (2-BMN) were used to measure combined toxicity in zebrafish (Danio rerio) embryos. As the lethal concentration (LC) values were obtained through single toxicity, the lethal effects at all combinational concentrations were considered synergistic by the Independent Action model. At 96 hpf, the combined toxicity of TCP LC10 + 2-BMN LC10, the lowest combinational concentration, resulted in high mortality, strong inhibition of hatching, and various morphological changes in zebrafish embryos. Combined treatment resulted in the downregulation of cyp1a, leading to reduced detoxification of the treated chemicals in embryos. These combinations may enhance endocrine-disrupting properties via upregulation of vtg1 in embryos, and inflammatory responses and endoplasmic reticulum stress were found to upregulate il-ß, atf4, and atf6. These combinations might induce severe abnormal cardiac development in embryos via downregulation of myl7, cacna1c, edn1, and vmhc expression, and upregulation of the nppa gene. Therefore, the combined toxicity of these two chemicals was observed in zebrafish embryos, which proves that similar substances can exhibit stronger combined toxicity than single toxicity.

Computational modeling of aquatic toxicity of polychlorinated naphthalenes (PCNs) employing 2D-QSAR and chemical read-across.

Polychlorinated naphthalenes (PCNs) are produced from a variety of industrial sources, and they reach the aquatic ecosystems by the dry-wet deposition from the atmosphere and also by the drainage from the land surfaces. Then the PCNs can be transmitted through the food chain to humans and show toxic effects on different aquatic animals as well as humans. Considering this scenario, it is an obligatory task to explore the toxicity data of PCNs more deeply for the species of an aquatic ecosystem (green algae-Daphnia magna-fish), and to extrapolate those data for humans. But the toxicity data for different aquatic species are quite limited. The laboratory experimentations are complicated and ethically troublesome to fill toxicity data gaps; therefore, different in silico methods (e.g., QSAR, quantitative read-across predictions) are emerging as crucial ways to fill the data gaps and hazard assessments. In the present study, we developed individual toxicity models as well as interspecies models from the 75 PCN toxicity data against three aquatic species (green algae-Daphnia magna-fish) by employing easily interpretable 2D descriptors; these models were validated rigorously employing different globally accepted internal and external validation metrics. Then we interpreted the modelled descriptors mechanistically with the endpoint values for better understanding. And finally, we endeavored to improve the prediction quality in terms of external validation metrics by employing a novel quantitative read-across approach by pooling the descriptors from the developed individual QSAR models.

Toxicokinetic analyses of naphthalene, fluorene, phenanthrene, and pyrene in humans after single oral administration.

Polycyclic aromatic hydrocarbons (PAHs) are generated by incomplete combustion of organic matter. They have health effects in multiple organs and can cause lung, skin, and bladder cancers in humans. Although data regarding their toxicity is available, information on the absorption, distribution, metabolism, and excretion of PAHs in humans is very limited. In the present study, deuterium-labeled naphthalene (Nap), fluorene (Flu), phenanthrene (Phe), and pyrene (Pyr) were orally administered as a single dose (0.02-0.04 mg/kg) to eight healthy adults. Both serum and urine samples were monitored for 72 h after the exposure. Parent compounds and PAH metabolites (monohydroxy-PAHs; OH-PAHs) were measured by headspace-solid phase microextraction coupled with gas chromatography-mass spectrometry and high-performance liquid chromatography-tandem mass spectrometry, respectively. Based on the time-concentration profiles in serum and urine, non-compartmental analysis was performed, and two-compartment models were constructed and validated for each PAH. Subsequently, all of the parent compounds were rapidly absorbed (Tmax: 0.25 to 1.50 h) after oral administration and excreted in urine with a biological half-life (T1/2) of 1.01 to 2.99 h. The fractional urinary excretion (Fue) of OH-PAHs ranged from 0.07 % to 11.3 %; their T1/2 values ranged from 3.4 to 11.0 h. The two-compartment models successfully described the toxicokinetic characteristics of each PAH and its metabolites. Fue and the two-compartment models could be useful tools for exposure simulation or dose-reconstruction of PAHs. The results of this study will provide useful information for interpreting biomonitoring data of PAHs.

Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS.

There is growing concern about the consumption of synthetic cannabinoids (SCs), one of the largest groups of new psychoactive substances, its consequence on human health (general population and workers), and the continuous placing of new SCs on the market. Although drug-induced alterations in neuronal function remain an essential component for theories of drug addiction, accumulating evidence indicates the important role of activated astrocytes, whose essential and pleiotropic role in brain physiology and pathology is well recognized. The study aims to clarify the mechanisms of neurotoxicity induced by one of the most potent SCs, named MAM-2201 (a naphthoyl-indole derivative), by applying a novel three-dimensional (3D) cell culture model, mimicking the physiological and biochemical properties of brain tissues better than traditional two-dimensional in vitro systems. Specifically, human astrocyte spheroids, generated from the D384 astrocyte cell line, were treated with different MAM-2201 concentrations (1-30 µM) and exposure times (24-48 h). MAM-2201 affected, in a concentration- and time-dependent manner, the cell growth and viability, size and morphological structure, E-cadherin and extracellular matrix, CB1-receptors, glial fibrillary acidic protein, and caspase-3/7 activity. The findings demonstrate MAM-2201-induced cytotoxicity to astrocyte spheroids, and support the use of this human 3D cell-based model as species-specific in vitro tool suitable for the evaluation of neurotoxicity induced by other SCs.

Proteomic response of Pseudomonas aeruginosa IIPIS-8 during rapid and efficient degradation of naphthalene.

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed in the ecosystem and are of significant concern due to their toxicity and mutagenicity. Bioremediation of PAHs is a popular and benign approach that ameliorates the environment. This study investigated the biodegradation and proteome response of Pseudomonas aeruginosa IIPIS-8 for two-ringed PAH: naphthalene (NAP) to understand proteome alteration during its bioremediation. Rapid biodegradation was observed up to 98 ± 1.26% and 84 ± 1.03%, respectively, for initial concentrations of 100 mg L-1 and 500 mg L-1 of NAP. Degradation followed first-order kinetics with rate constants of 0.12 h-1 and 0.06 h-1 and half-life (t1/2) of 5.7 h and 11.3 h, respectively. Additionally, the occurrence of key ring cleavage and linear chain intermediates, 2,3,4,5,6, -pentamethyl acetophenone, 1-octanol 2-butyl, and hexadecanoic acid supported complete NAP degradation. Proteomics study of IIPIS-8 throws light on the impact of protein expression, in which 415 proteins were quantified in sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) analysis, of which 97 were found to be significantly up-regulated and 75 were significantly down-regulated by ≥ 2-fold change (p values ≤ 0.05), during the NAP degradation. The study also listed the up-regulation of several enzymes, including oxido-reductases, hydrolases, and catalases, potentially involved in NAP degradation. Overall, differential protein expression, through proteomics study, demonstrated IIPIS-8's capability to efficiently assimilate NAP in their metabolic pathways even in a high concentration of NAP.

Histopathological and Biochemical Changes in the Gills of Anabas testudineus on Exposure to Polycyclic Aromatic Hydrocarbon Naphthalene.

Naphthalene, a polycyclic aromatic hydrocarbon, is generated by various distillation, petroleum, and coal-tar production units and is used worldwide as mothballs, soil fumigants, and toilet deodorants. Considering the susceptibility of aquatic animals to different types of stressors in several water bodies, this study was carried out to evaluate the impact of naphthalene on the architecture of gill tissue including response of various enzymes like cholinesterase (ChE) activity, lactate dehydrogenase (LDH) activity, and lipid peroxidation (LPX) level of the freshwater fish Anabas testudineus. Activities of antioxidants like catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) were also evaluated. Constant loss of gill structure and secondary lamellar fusion was observed in fishes exposed to various concentrations of naphthalene. ChE, LDH, LPx, CAT, Gpx and GSH activities indicated significant variation (p < 0.05) between the control and experimental groups. ChE activity was lowered in experimental fishes; however, LDH activity, LPx levels, and CAT activity were elevated in response to various concentrations of naphthalene as compared to control group. Both GPx and GSH activities decreased in the gill tissue of the experimental fishes. Thus, a conclusion was drawn that naphthalene is a potent toxicant capable of inflicting tissue damage leading to physiological changes in the exposed fishes.

In vitro airway models from mice, rhesus macaques, and humans maintain species differences in xenobiotic metabolism and cellular responses to naphthalene.

The translational value of high-throughput toxicity testing will depend on pharmacokinetic validation. Yet, popular in vitro airway epithelia models were optimized for structure and mucociliary function without considering the bioactivation or detoxification capabilities of lung-specific enzymes. This study evaluated xenobiotic metabolism maintenance within differentiated air-liquid interface (ALI) airway epithelial cell cultures (human bronchial; human, rhesus, and mouse tracheal), isolated airway epithelial cells (human, rhesus, and mouse tracheal; rhesus bronchial), and ex vivo microdissected airways (rhesus and mouse) by measuring gene expression, glutathione content, and naphthalene metabolism. Glutathione levels and detoxification gene transcripts were measured after 1-h exposure to 80 µM naphthalene (a bioactivated toxicant) or reactive naphthoquinone metabolites. Glutathione and glutathione-related enzyme transcript levels were maintained in ALI cultures from all species relative to source tissues, while cytochrome P450 monooxygenase gene expression declined. Notable species differences among the models included a 40-fold lower total glutathione content for mouse ALI trachea cells relative to human and rhesus; a higher rate of naphthalene metabolism in mouse ALI cultures for naphthalene-glutathione formation (100-fold over rhesus) and naphthalene-dihydrodiol production (10-fold over human); and opposite effects of 1,2-naphthoquinone exposure in some models-glutathione was depleted in rhesus tissue but rose in mouse ALI samples. The responses of an immortalized bronchial cell line to naphthalene and naphthoquinones were inconsistent with those of human ALI cultures. These findings of preserved species differences and the altered balance of phase I and phase II xenobiotic metabolism among the characterized in vitro models should be considered for future pulmonary toxicity testing.

The toxicological profile of polychlorinated naphthalenes (PCNs).

The legacy of polychlorinated naphthalenes (PCNs) manufactured during the last century continues to persist in the environment, food and humans. Metrological advances have improved characterisation of these occurrences, enabling studies on the effects of exposure to focus on congener groups and individual PCNs. Liver and adipose tissue show the highest retention but significant levels of PCNs are also retained by the brain and nervous system. Molecular configuration appears to influence tissue disposition as well as retention, favouring the higher chlorinated (≥ four chlorines) PCNs while most lower chlorinated molecules readily undergo hydroxylation and excretion through the renal system. Exposure to PCNs reportedly provokes a wide spectrum of adverse effects that range from hepatotoxicity, neurotoxicity and immune response suppression along with endocrine disruption leading to reproductive disorders and embryotoxicity. A number of PCNs, particularly hexachloronaphthalene congeners, elicit AhR mediated responses that are similar to, and occur within similar potency ranges as most dioxin-like polychlorinated biphenyls (PCBs) and some chlorinated dibenzo-p-dioxins and furans (PCDD/Fs), suggesting a relationship based on molecular size and configuration between these contaminants. Most toxicological responses generally appear to be associated with higher chlorinated PCNs. The most profound effects such as serious and sometimes fatal liver disease, chloracne, and wasting syndrome resulted either from earlier episodes of occupational exposure in humans or from acute experimental dosing of animals at levels that reflected these exposures. However, since the restriction of manufacture and controls on inadvertent production (during combustion processes), the principal route of human and animal exposure is likely to be dietary intake. Therefore, further investigations should include the effects of chronic lower level intake of higher chlorinated PCN congeners that persist in the human diet and subsequently in human and animal tissues. PCNs in the diet should be evaluated cumulatively with other similarly occurring dioxin-like contaminants.

Insights into toxicity of polychlorinated naphthalenes to multiple human endocrine receptors: Mechanism and health risk analysis.

This study explored the combined disruption mechanism of polychlorinated naphthalenes (PCNs) on the three key receptors (estrogen receptor, thyroid receptor, and adrenoceptor) of the human endocrine system. The intensity of PCN endocrine disruption on these receptors was first determined using a molecular docking method. A comprehensive index of PCN endocrine disruption to human was quantified by analytic hierarchy process and fuzzy analysis. The mode of action between PCNs and the receptors was further identified to screen the molecular characteristics influencing PCN endocrine disruption through molecular docking and fractional factorial design. Quantitative structure-activity relationship (QSAR) models were established to investigate the toxic mechanism due to PCN endocrine disruption. The results showed that the lowest occupied orbital energy (ELUMO) was the most important factor contributing to the toxicity of PCNs on the endocrine receptors, followed by the orbital energy difference (ΔE) and positive Millikan charge (q+). Furthermore, the strategies were formulated through adjusting the nutritious diet to reduce health risk for the workers in PCN contaminated sites and the effectiveness and feasibility were assessed by molecular dynamic simulation. The simulation results indicated that the human health risk caused by PCN endocrine disruption could be effectively decreased by nutritional supplementation. The binding ability between PCNs and endocrine receptors significantly declined (up to -16.45%) with the supplementation of vitamins (A, B2, B12, C, and E) and carotene. This study provided the new insights to reveal the toxic mechanism of PCNs on human endocrine systems and the recommendations on nutritional supplements for health risk reduction. The methodology and findings could serve as valuable references for screening of potential endocrine disruptors and developing appropriate strategies for PCN or other persistent organic pollution control and health risk management.

Comprehensive Evaluation of Dietary Exposure and Health Risk of Polychlorinated Naphthalenes.

Intake from food is considered an important route of human exposure to polychlorinated naphthalenes. To our knowledge, several studies have quantified dietary exposure but only in European countries and measuring only a few of the 75 congeners. In addition, the influence of source diversity on human exposure has seldom been assessed. We analyzed 192 composite food samples composed of 17,280 subsamples from 24 provinces in China to measure the concentrations of polychlorinated naphthalenes and estimate their daily intake and potential health risks on a national scale. The estimated cancer risk was in the range of 6.8 × 10-8 to 4.6 × 10-7. We compared our findings for 75 congeners with reports in the literature that quantified only 12 congeners. We estimate that these 12 congeners contribute only approximately 4% to the total mass daily intake of polychlorinated naphthalenes and 70% to the total toxic equivalent quantity, indicating underestimation of dietary exposure. The contributions of combustion-associated congeners to the total concentrations of polychlorinated naphthalenes were in the range of 31-52%, suggesting that the ongoing unintentional release of these compounds from industrial thermal processes is an important factor in polychlorinated naphthalene contamination and human exposure in China.

Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia.

Verinurad (RDEA3170) is a selective URAT1 inhibitor under investigation for the treatment of gout and hyperuricemia. In an effort to further improve the pharmacodynamics/pharmacokinetics of verinurad and to increase the structural diversity, we designed novel verinurad analogs by introducing a linker (e.g. aminomethyl, amino or oxygen) between the naphthalene and the pyridine ring to increase the flexibility. These compounds were synthesized and tested for their in vitro URAT1-inhibitory activity. Most compounds exhibited potent inhibitory activities against URAT1 with IC50 values ranging from 0.24 µM to 16.35 µM. Among them, compound KPH2f exhibited the highest URAT1-inhibitory activity with IC50 of 0.24 µM, comparable to that of verinurad (IC50 = 0.17 µM). KPH2f also inhibited GLUT9 with an IC50 value of 9.37 ± 7.10 µM, indicating the dual URAT1/GLUT9 targeting capability. In addition, KPH2f showed little effects on OAT1 and ABCG2, and thus was unlikely to cause OAT1/ABCG2-mediated drug-drug interactions and/or to neutralize the uricosuric effects of URAT1/GLUT9 inhibitors. Importantly, KPH2f (10 mg/kg) was equally effective in reducing serum uric acid levels and exhibited higher uricosuric effects in a mice hyperuricemia model, as compared to verinurad (10 mg/kg). Furthermore, KPH2f demonstrated favorable pharmacokinetic properties with an oral bioavailability of 30.13%, clearly better than that of verinurad (21.47%). Moreover, KPH2f presented benign safety profiles without causing hERG toxicity, cytotoxicity in vitro (lower than verinurad), and renal damage in vivo. Collectively, these results suggest that KPH2f represents a novel, safe and effective dual URAT1/GLUT9 inhibitor with improved druggabilities and is worthy of further investigation as an anti-hyperuricemic drug candidate.

Acute and developmental toxic effects of mono-halogenated and halomethyl naphthalenes on zebrafish (Danio rerio) embryos: Cardiac malformation after 2-bromomethyl naphthalene exposure.

Polyhalogenated polycyclic aromatic hydrocarbons (HPAHs) represent a major environmental concern due to their persistency and toxicity. Among them, mono-halogenated (HNs) and halomethyl naphthalenes (HMNs) are not well-studied, and the toxicity of many HNs to fishes has not been reported. In this study, we exposed zebrafish (Danio rerio) embryos to naphthalene and five HNs at concentrations ranging from 0.25 to 2.0 mg L-1 to assess acute toxicities and developmental effects. Among them, 2-bromomethyl naphthalene (2-BMN) produced moderate lethal effects (96-h LC50 = 1.4 mg L-1) and significantly reduced hatchability. Abnormal phenotypes, including pericardial edema, spine curvature, and shortened body length, were also induced by 2-BMN (96-h EC50 = 0.45 mg L-1). Treatments of 0.5-2.0 mg L-1 2-BMN evoked cardiac malformations via significant down-regulation of the cacna1c gene, which codes the voltage-dependent calcium channel, at 72 hpf and up-regulation of the nppa gene, responsible for the expression of natriuretic peptides, at 96 hpf in zebrafish. One presumable toxic photo-dissociated metabolite of 2-BMN, the 2-naphthylmethyl radical, may be responsible for the toxic effect on zebrafish embryos. HPAHs must be monitored and managed due to their adverse effects on living organisms at low concentrations.

Psychotomimetic symptoms after a moderate dose of a synthetic cannabinoid (JWH-018): implications for psychosis.

BACKGROUND: Synthetic cannabinoids (SCs) are the largest class of novel psychoactive substances (NPS) and are associated with an increased risk of overdosing and adverse events such as psychosis. JWH-018 is one of the earliest SCs and still widely available in large parts of the world. Controlled studies to assess the safety and behavioural profiles of SCs are extremely scarce. AIM: The current study was designed to assess the psychotomimetic effects of a moderate dose of JWH-018. METHODS: Twenty-four healthy participants (10 males, 14 females) entered a placebo-controlled, double blind, within-subjects trial and inhaled vapour of placebo or 75µg/kg bodyweight JWH-018. To ascertain a minimum level of intoxication, a booster dose of JWH-018 was administered on an as-needed basis. The average dose of JWH-018 administered was 5.52 mg. Subjective high, dissociative states (CADSS), psychedelic symptoms (Bowdle), mood (POMS) and cannabis reinforcement (SCRQ) were assessed within a 4.5-h time window after drug administration. RESULTS: JWH-018 caused psychedelic effects, such as altered internal and external perception, and dissociative effects, such as amnesia, derealisation and depersonalisation and induced feelings of confusion. CONCLUSION: Overall, these findings suggest that a moderate dose of JWH-018 induces pronounced psychotomimetic symptoms in healthy participants with no history of mental illness, which confirms that SCs pose a serious risk for public health.