Toxicity of 2-methyl-4-chlorophenoxy acetic acid alone and in combination with cyhalofop-butyl to Cyprinus carpio embryos.

Herbicides may pose considerable danger to non-target aquatic organisms and further threaten human health. The present investigation was aimed to assess the effects of 2-methyl-4-chlorophenoxy acetic acid (MCPA-Na) on Cyprinus carpio embryos. Embryos were exposed to six concentrations of MCPA-Na (0, 52, 54, 56, 58 and 60 mg/L) for 96 h. A series of symptoms were observed in developmental embryos during MCPA-Na exposure, including increased death, hatching inhibited and morphological deformities. Further, MCPA-Na exposure leading to a series of morphological changes (pericardial edema, tail deformation, and spine deformation) in embryos, which were consistent with modifications in the associated genes. In this work, we also investigated the joint toxicity of herbicides (MCPA-Na and cyhalofop-butyl) commonly used in paddy fields on carp embryos, using the 96 h-LC50 of herbicides (59.784 mg/L MCPA-Na and 1.472 mg/L cyhalofop-butyl) and confirmed that a synergistic effect existing in the binary mixtures.

A preliminary investigation of lung availability of cannabinoids by smoking marijuana or dabbing BHO and decarboxylation rate of THC- and CBD-acids.

Highly potent cannabis concentrates obtained by butane or by supercritical carbon dioxide-extraction are gaining popularity. These extracts called butane hash oil (BHO) with Δ9-tetrahydrocannabinolic acid A (THCA) contents above 60% are consumed by flash vaporization on a glowing titanium nail, followed by inhalation of the resulting vapor through a water pipe in a single puff - a technique referred to as "dabbing". We herein investigated the decarboxylation rate of THCA during artificial smoking of cannabis plant material and simulated dabbing, and the lung availability of Δ9-tetrahydrocannabinol (THC) which we define as the recovery of THC in the smoke and vapor condensates. Preliminary smoking and dabbing experiments were performed using an apparatus built in-house. Due to availability of cannabidiol (CBD)-rich hemp in Switzerland, we included a sample of CBD flowers in our experiments and investigated the decarboxylation and recovery of cannabidiolic acid (CBDA) and CBD, respectively. Decarboxylation of THCA and CBDA during combustion of the plant material and vaporization of the BHO, respectively, was complete. The high recovery of total THC (75.5%) by dabbing cannot be achieved by smoking marijuana. Lung availability ranged from 12% for mixed cannabis material with a rather low THC content, to approximately 19-27% for marijuana flowers, similar for THC in marijuana as for CBD in CBD-rich marijuana. In reality, when smoking a joint, further losses in recovery must be assumed by additional sidestream smoke. The rather high lung availability of THC via dabbing can explain the increased psychoactive and adverse effects associated with this new trend of cannabis consumption.

Para-tertiary butyl catechol (PTBC), an industrial antioxidant induces human platelet apoptosis.

The catecholic derivative para-tertiary butyl catechol (PTBC) is a conventional antioxidant and polymerization inhibitor, which exhibits melanocytotoxic effects and contact dermatitis often leading to occupational leucoderma or vitiligo. Although numerous industrial workers will be in constant exposure to PTBC and its chances of getting entry into blood are most expected, its effect on blood components is still undisclosed. As platelets play a prominent role in dermatitis, inflammation, and immunity, in this study we have evaluated the effect of PTBC on human platelets in vitro. Exposure of platelets to PTBC showed increased reactive oxygen species (ROS), intracellular calcium, cardiolipin oxidation, mitochondrial permeability transition pore (MPTP) formation, activation of caspases, phosphatidylserine (PS) externalization and decreased mitochondrial membrane potential. In addition, there was a significant decrease in cellular glutathione level, increased γ-glutamyltransferase (GGT) activity and cell death. These findings demonstrate that PTBC could induce toxic effects on blood components, which is often ignored field of research. Since dermal exposure of humans to toxic chemicals covers an important issue in various industries, there is a need of such work to understand and update the long-term toxicities induced by PTBC usage in industrial sectors and public domain.

Cardiac arrest by inhalation of deodorant spray.

Drug abuse by inhalation of volatile household product substances is uncommon, however, it can have devastating consequences. This case report describes the fatal outcome of deodorant inhalation by a 19-year-old patient in a detoxification clinic who developed a cardiac arrest after inhaling butane from a deodorant spray. Despite initial successful resuscitation, he developed a postanoxic encephalopathy with a status epilepticus resistant to extensive treatment. Inhalant abuse can be a cause of death in young patients.

BCPA {N,N'-1,4-Butanediylbis[3-(2-chlorophenyl)acrylamide]} Inhibits Osteoclast Differentiation through Increased Retention of Peptidyl-Prolyl cis-trans Isomerase Never in Mitosis A-Interacting 1.

Osteoporosis is caused by an imbalance of osteoclast and osteoblast activities and it is characterized by enhanced osteoclast formation and function. Peptidyl-prolyl cis-trans isomerase never in mitosis A (NIMA)-interacting 1 (Pin1) is a key mediator of osteoclast cell-cell fusion via suppression of the dendritic cell-specific transmembrane protein (DC-STAMP). We found that N,N'-1,4-butanediylbis[3-(2-chlorophenyl)acrylamide] (BCPA) inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in a dose-dependent manner without cytotoxicity. In addition, BCPA attenuated the reduction of Pin1 protein during osteoclast differentiation without changing Pin1 mRNA levels. BCPA repressed the expression of osteoclast-related genes, such as DC-STAMP and osteoclast-associated receptor (OSCAR), without altering the mRNA expression of nuclear factor of activated T cells (NFATc1) and cellular oncogene fos (c-Fos). Furthermore, Tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells were significantly decreased by BCPA treatment compared to treatment with the Pin1 inhibitor juglone. These data suggest that BCPA can inhibit osteoclastogenesis by regulating the expression of the DC-STAMP osteoclast fusion protein by attenuating Pin1 reduction. Therefore, BCPA may be used to treat osteoporosis.

Toxic effects of cyhalofop-butyl on embryos of the Yellow River carp (Cyprinus carpio var.): alters embryos hatching, development failure, mortality of embryos, and apoptosis.

As a universal environmental contaminant, the herbicide cyhalofop-butyl is considered to have infested effects on the embryonic development of aquatic species. The present study focused on an assessment of the impacts of cyhalofop-butyl on Yellow River carp embryos. It was found that cyhalofop-butyl inhibited the hatching of the embryos, and the hatching rate decreased with higher concentrations of the herbicide. The mortality rate was increased on exposure to cyhalofop-butyl and was significantly higher in the 1.6 and 2 mg/L treatment groups over 48 h. All of the embryos of the 2 mg/L treatment group died within the 48 h post-hatching stage. And the transcription of several embryos related to apoptosis was also influenced by cyhalofop-butyl exposure. Further, cyhalofop-butyl exposure leads to a series of morphological changes (pericardial edema, tail deformation, and spine deformation) in embryos, which were consistent with significant modifications in the associated genes. These results provided a scientific basis for further studies into the effects of cyhalofop-butyl on aquatic organisms.

Mechanism of resistance to cyhalofop-butyl in Chinese sprangletop (Leptochloa chinensis (L.) Nees).

Chinese sprangletop (Leptochloa chinensis (L.) Nees) is a serious grass weed in rice paddies. In some areas, L. chinensis has become resistant to the herbicide cyhalofop-butyl because of its frequent and extensive use over the past five years. In this study, whole-plant dose-response assays were conducted, and a L. chinensis population (ZHYH) had a 75.8-fold resistance index to cyhalofop-butyl. Molecular analyses revealed that this resistance was attributed to a tryptophan (Trp)-2027-to-cysteine (Cys) substitution in the CT domain of the ACCase gene. To our knowledge, this is the first report revealing the mechanism underlying cyhalofop-butyl resistance in L. chinensis. Furthermore, a derived cleaved amplified polymorphic (dCAPS) assay was developed to rapidly detect the Trp-2027-Cys mutation. Of the 100 ZHYH plants analyzed, 52 were heterozygous mutants and 48 were susceptible homozygous plants. In addition, the cyhalofop-butyl-resistant L. chinensis was cross-resistant to aryloxyphenoxypropionate and phenylpyrazoline herbicides, but not to cyclohexanedione, acetolactate synthase-inhibiting, protoporphyrinogen oxidase, and urea herbicides, and had only slight resistance to the hormonal herbicide quinclorac.

Associations between butane hash oil use and cannabis-related problems.

BACKGROUND: High-potency cannabis concentrates are increasingly popular in the United States, and there is concern that use of high-potency cannabis might increase risk for cannabis-related problems. However, little is known about the potential negative consequences of concentrate use. This study reports on associations between past-year use of a high-potency cannabis concentrate, known as butane hash oil (BHO), and cannabis-related problems. METHODS: A sample of 821 college students were recruited to complete a survey about their health and behavior. Participants who had used cannabis in the past year (33%, n=273) completed questions about their cannabis use, including their use of BHO and cannabis-related problems in eight domains: physical dependence, impaired control, academic-occupational problems, social-interpersonal problems, self-care problems, self-perception, risk behavior, and blackouts. RESULTS: Approximately 44% (n=121) of past-year cannabis users had used BHO in the past year. More frequent BHO use was associated with higher levels of physical dependence (RR=1.8, p<0.001), impaired control (RR=1.3, p<0.001), cannabis-related academic/occupational problems (RR=1.5, p=0.004), poor self-care (RR=1.3, p=0.002), and cannabis-related risk behavior (RR=1.2, p=0.001). After accounting for sociodemographic factors, age of onset of cannabis use, sensation seeking, overall frequency of cannabis use, and frequency of other substance use, BHO use was still associated with higher levels of physical dependence (RR=1.2, p=0.014). CONCLUSIONS: BHO use is associated with greater physiological dependence on cannabis, even after accounting for potential confounders. Longitudinal research is needed to determine if cannabis users with higher levels of physiological dependence seek out BHO and/or if BHO use increases risk for physiological dependence.

Synthesis and evaluation of halogenated 12N-sulfonyl matrinic butanes as potential anti-coxsackievirus agents.

Twenty-eight new 12N-benzenesulfonyl matrinic butane and halogenated 12N-sulfonyl matrinic butane/ethane derivatives were designed, synthesized and evaluated for their anti-coxsakievirus activities against CVB3 taking compound 1 as the lead. SAR analysis indicated the introduction of a fluoro atom on the 1'-position might be helpful for keeping potency. Among them, compound 8a exhibited potential activities against all CVBs with IC50 ranging from 0.69 to 5.14 µM, suggesting a broad-spectrum anti-coxsackievirus B feature. In addition, it also displayed an excellent PK and a good safety profile, indicating a highly druggable nature. Thus, we consider compound 8a to be a promising drug candidate in the treatment of not only viral myocarditis caused by CVB3 but also various diseases infected with coxsackieviruses B.

Resistance to aryloxyphenoxypropionate herbicides in Amazon sprangletop: Confirmation, control, and molecular basis of resistance.

Amazon sprangletop is problematic weed of rice in the midsouthern USA. Two biotypes of this species from rice fields approximately 100km apart in Louisiana were unaffected when sprayed with the labeled field rate of cyhalofop-butyl (314g ai ha-1) in 2008. Dose response studies were conducted to confirm the level of resistance to cyhalofop-butyl over a range of doses. Cross-resistance to acetyl-CoA carboxylase (ACCase)-inhibiting herbicides from two different chemical families and multiple herbicide resistance to other mechanisms of action were evaluated. Sequencing using the Illumina Hiseq platform and ACCase gene sequencing revealed two different amino acid substitutions, Trp2027-to-Cys in the first resistant biotype and Asp2078-to-Gly in the second resistant biotype, within the CT domain of the ACCase gene. Two known amino acid substitutions confirmed resistance to cyhalofop-butyl and fenoxaprop-P-ethyl in resistant Amazon sprangletop biotypes. Asp2078-to-Gly amino acid substitution that was detected in one of the resistant biotypes did not result in cross-resistance to clethodim, an ACCase-inhibiting cyclohexandione herbicide which has endowed clethodim resistance in other weed species. Based on this research, both resistant Amazon sprangletop biotypes have evolved target-site resistance to the APP herbicides; yet, alternative herbicides are still active on these plants.

Acute and short-term developmental toxicity of cyhalofop-butyl to zebrafish (Danio rerio).

Cyhalofop-butyl is an aryloxyphenoxypropionate post-emergence herbicide widely used around the world in agriculture. The acute toxicity of cyhalofop-butyl to embryos, larvae (12 and 72 h post-hatching), and adult zebrafish, as well as the short-term developmental toxicity of cyhalofop-butyl to embryo and sac-fry stages, was tested. The results showed that the 96-h LC50 values of cyhalofop-butyl to embryos, 12 h post-hatching larvae, 72 h post-hatching larvae, and adult fish were 2.03, 0.58, 1.42, and 3.49 mg/L, respectively, suggesting zebrafish early life stages were more sensitive to cyhalofop-butyl than adult stage. Cyhalofop-butyl would inhibit the spontaneous movement, heartbeat, hatching rate of embryos, and the body length of surviving larvae of zebrafish at 1.00 mg/L or higher concentrations. Morphological abnormalities, including pericardial edema, yolk sac edema, deformation of tail, and deformation of spine, were induced by cyhalofop-butyl. The results indicated that cyhalofop-butyl had significant negative impacts on zebrafish at different life stages, and spontaneous movement and hatching rate were sensitive endpoints for assessing short-term developmental toxicity of cyhalofop-butyl.

Butane Hash Oil Burns Associated with Marijuana Liberalization in Colorado.

Butane hash oil (BHO), also known as "amber," "dab," "glass," "honey," "shatter," or "wax," is a potent marijuana concentrate, containing up to 90 % tetrahydrocannabinol (THC). BHO is easily manufactured using highly volatile butane as a solvent. Our objective was to characterize hydrocarbon burns associated with BHO manufacture in Colorado. This was a cross-sectional study utilizing the National Burn Repository to capture all hydrocarbon burns reported to the local burn center from January 1st, 2008, through August 31st, 2014. We abstracted demographic and clinical variables from medical records for patients admitted for hydrocarbon burns associated with butane hash oil extraction. Twenty-nine cases of BHO burns were admitted to the local burn center during the study period. Zero cases presented prior to medical liberalization, 19 (61.3 %) during medical liberalization (Oct 2009-Dec 2013), and 12 (38.7 %) in 2014 since legalization. The majority of cases were Caucasian (72.4 %) males (89.7 %). Median age was 26 (range 15-58). The median total-body-surface-area (TBSA) burn size was 10 % (TBSA range 1-90 %). Median length of hospital admission was 10 days. Six required intubation for airway protection (21 %). Nineteen required skin grafting, eight wound care only, one required surgical fracture repair, and one required surgical debridement. Hydrocarbon burns associated with hash oil production have increased since the liberalization of marijuana policy in Colorado. A combination of public health messaging, standardization of manufacturing processes, and worker safety regulations are needed to decrease the risks associated with BHO production.

Cyhalofop-butyl has the potential to induce developmental toxicity, oxidative stress and apoptosis in early life stage of zebrafish (Danio rerio).

Cyhalofop-butyl is a selective herbicide widely employed in paddy field, which can transfer into aquatic environments. However, details of the environmental risk and aquatic toxicity of cyhalofop-butyl have not been fully investigated. In this study, zebrafish (Danio rerio) embryos were exposed to a range of cyhalofop-butyl until 120 hour post-fertilization (hpf) to assess embryonic toxicity of the chemical. Our results demonstrated that cyhalofop-butyl was highly toxic to zebrafish embryos, with concentration-dependent negative effects in embryonic development. In addition, exposure to cyhalofop-butyl resulted in significant increases in reactive oxygen species (ROS) production and cell apoptosis in heart area. The mRNA levels of the genes related to oxidative stress and apoptosis were also altered significantly after cyhalofop-butyl exposure. Moreover, the activity of capspase-9 and caspase-3 were significantly increased. Therefore, we speculated that oxidative stress-induced apoptosis should be responsible for abnormal development during embryogenesis after cyhalofop-butyl exposure.

Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae.

BACKGROUND: Resistance to fluconazole, a commonly used azole antifungal, is a challenge for the treatment of fungal infections. Resistance can be mediated by overexpression of ABC transporters, which promote drug efflux that requires ATP hydrolysis. The Pdr5p ABC transporter of Saccharomyces cerevisiae is a well-known model used to study this mechanism of antifungal resistance. The present study investigated the effects of 13 synthetic compounds on Pdr5p. RESULTS: Among the tested compounds, four contained a tellurium-butane group and shared structural similarities that were absent in the other tested compounds: a lateral hydrocarbon chain and an amide group. These four compounds were capable of inhibiting Pdr5p ATPase activity by more than 90%, they demonstrated IC50 values less than 2 µM and had an uncompetitive pattern of Pdr5p ATPase activity inhibition. These organotellurides did not demonstrate cytotoxicity against human erythrocytes or S. cerevisiae mutant strains (a strain that overexpress Pdr5p and a null mutant strain) even in concentrations above 100 µM. When tested at 100 µM, they could reverse the fluconazole resistance expressed by both the S. cerevisiae mutant strain that overexpress Pdr5p and a clinical isolate of Candida albicans. CONCLUSIONS: We have identified four organotellurides that are promising candidates for the reversal of drug resistance mediated by drug efflux pumps. These molecules will act as scaffolds for the development of more efficient and effective efflux pump inhibitors that can be used in combination therapy with available antifungals.

Volatile substance misuse: an updated review of toxicity and treatment.

Educational campaigns and legislative actions may have led to an overall decrease in the prevalence of volatile substance misuse (VSM) in many countries; however, it is still a common practice throughout the world. Studies currently suggest that girls are misusing volatile substances more than before and at a prevalence rate equal to or exceeding that of boys in several countries. Products that may be misused are ubiquitous and relatively easy to acquire. The most commonly misused substances in recent studies are fuels such as butane or petrol and compressed gas dusters and deodorants that may contain fluorocarbons and/or butane. Detection of VSM is challenging, therefore physicians must maintain a high level of suspicion based on history and clinical presentation. Clues to misuse are often subtle and may include the patient's proximity to a volatile substance or paraphernalia when found intoxicated, dermal burns, blisters, pigments, or rashes, and chemical odors. The primary targets of toxicity are the brain and the heart. The leading cause of death from VSM is from ventricular dysrhythmias. Treatment of toxicity begins with support of airway, breathing, and circulation. Exogenous catecholamines should be avoided if possible due to the theoretical "sensitized" and irritable myocardium. In the case of ventricular dysrhythmias, direct current defibrillation and/or beta-adrenergic receptor antagonism should be used. New evidence demonstrates the addictive potential of VSM yet effective therapy remains uncertain. Further research is needed in developing methods for preventing, detecting, and treating the harmful effects of VSM.

The novel proteasome inhibitor BSc2118 protects against cerebral ischaemia through HIF1A accumulation and enhanced angioneurogenesis.

Only a minority of stroke patients receive thrombolytic therapy. Therefore, new therapeutic strategies focusing on neuroprotection are under review, among which, inhibition of the proteasome is attractive, as it affects multiple cellular pathways. As proteasome inhibitors like bortezomib have severe side effects, we applied the novel proteasome inhibitor BSc2118, which is putatively better tolerated, and analysed its therapeutic potential in a mouse model of cerebral ischaemia. Stroke was induced in male C57BL/6 mice using the intraluminal middle cerebral artery occlusion model. BSc2118 was intrastriatally injected 12 h post-stroke in mice that had received normal saline or recombinant tissue-plasminogen activator injections during early reperfusion. Brain injury, behavioural tests, western blotting, MMP9 zymography and analysis of angioneurogenesis were performed for up to 3 months post-stroke. Single injections of BSc2118 induced long-term neuroprotection, reduced functional impairment, stabilized blood-brain barrier through decreased MMP9 activity and enhanced angioneurogenesis when given no later than 12 h post-stroke. On the contrary, recombinant tissue-plasminogen activator enhanced brain injury, which was reversed by BSc2118. Protein expression of the transcription factor HIF1A was significantly increased in saline-treated and recombinant tissue-plasminogen activator-treated mice after BSc2118 application. In contrast, knock-down of HIF1A using small interfering RNA constructs or application of the HIF1A inhibitor YC1 (now known as RNA-binding motif, single-stranded-interacting protein 1 (RBMS1)) reversed BSc2118-induced neuroprotection. Noteworthy, loss of neuroprotection after combined treatment with BSc2118 and YC1 in recombinant tissue-plasminogen activator-treated animals was in the same order as in saline-treated mice, i.e. reduction of recombinant tissue-plasminogen activator toxicity through BSc2118 did not solely depend on HIF1A. Thus, the proteasome inhibitor BSc2118 is a promising new candidate for stroke therapy, which may in addition alleviate recombinant tissue-plasminogen activator-induced brain toxicity.

Fragrance material review on 1,3-dimethyl-3-phenylbutyl acetate.

A toxicologic and dermatologic review of 1,3-dimethyl-3-phenylbutyl acetate when used as a fragrance ingredient is presented. 1,3-Dimethyl-3-phenylbutyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1 to 4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1,3-dimethyl-3-phenylbutyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, elicitation, phototoxicity, and photoallergy data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.