A double-blind placebo-controlled randomized trial on the effect of hyosine n-butyl bromide for improving duration of labor in term pregnancies.

AIM: To compare the effectiveness of intramuscular hyocine n-butyl bromide (HBB) with placebo for shortening the duration of the first stage of labor in term pregnancies. METHODS: A double blind placebo-controlled randomized trial of parturients who presented at term in the active phase of labor was conducted. They were randomly (1:1 ratio) given intramuscular injection of either 40 mg (2 mL) of HBB or 2 mL of water for injection as a placebo. The primary outcome measures were the duration of first and second stages of labor. Subgroup analysis of primigravid and multigravid women were also performed for various outcomes. We did intention-to-treat analysis. RESULTS: Sixty-two women were randomized to each group and none were lost to follow-up. Baseline characteristics were similar between the HBB and placebo groups. The mean duration of first stage of labor was noted to be significantly shorter in the HBB group for both the primigravidas (246.6 ± 21.9 vs 391.8 ± 56.6 min for control; P < 0.001) and for multigravidas (205.9 ± 17.8 vs 323.8 ± 16.0 min for control;P < 0.001).There was also significantly shorter duration of second stage of labor in the HBB group (primigravida: P = 0.013; multigravida: P = 0.016). The duration of third stage of labor, mode of delivery and maternal and/or neonatal outcomes for both classes of parturients were not significantly different. CONCLUSION: HBB is effective in reducing the first and second stages of labor without adverse maternal or neonatal outcome. HBB does not significantly influence the duration of third stage of labor including mode of delivery. More evidence is needed to further explore the potential useful role of HBB in the active phase of labor.

Hexabromocyclododecane (HBCD): A case study applying tiered testing for human health risk assessment.

Current global efforts are aiming to increase use of mechanistic information in regulatory testing. In tiered testing paradigms, in vitro, in silico, and in vivo studies are employed progressively to identify and classify health hazards, which are then compared against human equivalent doses. We used data from three companion papers on the brominated flame retardant hexabromocyclododecane (HBCD) to conduct a case study on tiered testing. We included ToxCast™ and in vitro-in vivo extrapolation (Tier 1), rat liver transcriptomic (Tier 2), and conventional rat (Tier 3) data. Bioactivity-exposure ratios (BERs) were derived by comparing human administered dose equivalents of the measured effects to Canadian exposure levels. Biological perturbations were highly aligned between Tiers 1/2, and consistent with apical effects in Tier 3. Tier 1 had the smallest BERs, and Tiers 2/3 were similar. The study demonstrates the promise of using physiologically-based pharmacokinetic modeling and mechanistic analyses in a tiered framework to identify pathways through which chemicals exert toxicological effects; however, they also point to some shortcomings associated with in vitro and in silico approaches. Additional case studies of chemicals from multiple classes are required to define optimal tiered screening procedures to reduce future in vivo requirements in health hazard assessments.

URC102, a potent and selective inhibitor of hURAT1, reduced serum uric acid in healthy volunteers.

OBJECTIVE: URC102, a novel and potent inhibitor of human uric acid transporter 1 (hURAT1), is currently under clinical development to treat patients with gout. We performed a randomized, double-blind, placebo-controlled, phase I study to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of URC102 after single and multiple oral administration in healthy male subjects. METHODS: Thirty-one Koreans and 23 Caucasians received a single dose of URC102 at 1-30 mg and 1-10 mg, respectively, while 44 Koreans received URC102 once-daily for 7 days at 1-20 mg. We evaluated safety and tolerability throughout the study, and serially determined serum uric acid, the fractional excretion of uric acid and URC102 concentrations. RESULTS: URC102 was well tolerated over the dose range of 1-10 mg after single and multiple administration. URC102 rapidly reduced serum uric acid, which was maintained over the entire treatment period. Furthermore, URC102 increased the area-under-the-effect curve over 168 h for fractional excretion of uric acid in a dose-dependent manner. The maximum plasma concentration and the area under the plasma concentration-time curve of URC102 increased dose-proportionally. The pharmacokinetic and pharmacodynamics characteristics of URC102 were similar in Koreans and Caucasians. CONCLUSION: URC102 was safe and effectively lowered serum uric acid, which should be tested and confirmed in patients with hyperuricaemia and/or gout through further studies. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01953497 and NCT02524678.

Acute Administration of Desformylflustrabromine Relieves Chemically Induced Pain in CD-1 Mice.

Neuronal nicotinic acetylcholine receptors are cell membrane-bound ion channels that are widely distributed in the central nervous system. The α4ß2 subtype of neuronal nicotinic acetylcholine receptor plays an important role in modulating the signaling pathways for pain. Previous studies have shown that agonists, partial agonists, and positive allosteric modulators for the α4ß2 receptors are effective in relieving pain. Desformylflustrabromine is a compound that acts as an allosteric modulator of α4ß2 receptors. The aim of this study was to assess the effects of desformylflustrabromine on chemically induced pain. For this purpose, the formalin-induced pain test and the acetic acid-induced writhing response test were carried out in CD-1 mice. Both tests represent chemical assays for nociception. The results show that desformylflustrabromine is effective in producing an analgesic effect in both tests used for assessing nociception. These results suggest that desformylflustrabromine has the potential to become a clinically used drug for pain relief.

28-Day somatic gene mutation study of 1-bromopropane in female Big Blue® B6C3F1 mice via whole-body inhalation: Support for a carcinogenic threshold.

A 2-year inhalation rat and mouse cancer study by the National Toxicology Program (NTP) on 1-bromopropane, a brominated solvent most commonly used as a vapor degreaser, showed significant increase in tumors in the lung of female mice and in the large intestine of male and female rats. The most sensitive endpoint was lung tumors in female mice. Mice of both sexes had hyperplasia and inflammation of the nose and showed regeneration of lung tissue. The NTP assumed that these tumors were due to genotoxic effects and that a linear dose-response relationship was appropriate. It is plausible that, similar to chloroform, hyperplasia and inflammation are required as initial events for tumor development. If true, then a threshold-based model may be more appropriate for 1-bromopropane. To test this hypothesis, a 28-day repeat dose inhalation Big Blue® Assay was conducted using female transgenic B6C3F1 mice. The target exposure concentrations and the exposure regimen were identical to those used by the NTP. Results demonstrated no elevation in mutant frequency of the cII transgene in lung, colon, or liver. Positive controls produced statistically significant increases in mutant frequencies across all tested tissues. These results demonstrate that 1-bromopropane does not induce cII mutants in lungs, colon, or liver under the testing conditions. These data have important ramifications in the quantitative evaluation of tumor results for this chemical and support a mechanism of action where a threshold for carcinogenicity is plausible.

Effect of Premedication Hyoscine-N-Butylbromide before Hysterosalpingography for Diagnosis of Proximal Tubal Obstruction in Infertile Women: A Randomized Double-Blind Controlled Trial.

STUDY OBJECTIVE: To assess the effect of hyoscine-N-butylbromide (HBB) as premedication on the rate of proximal tubal obstruction during hysterosalpingography (HSG). DESIGN: A randomized, double-blind controlled trial (Canadian Task Force classification I). SETTING: The Infertility Clinic of Songklanagarind Hospital. PATIENTS: One hundred and forty-six infertile women indicated for HSG investigation. INTERVENTIONS: Between May 1, 2016, and March 31, 2017, patients were assigned at random to receive either oral HBB 20 mg or placebo 30 minutes before the HSG procedure. If proximal tubal obstruction was found, participants were be assigned to undergo a second confirming HSG or laparoscopy with chromopertubation within 6 months. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the rate of proximal tubal obstruction. The secondary outcome was the false-positive result of proximal tubal occlusion from HSG. Proximal tubal obstruction was found in 6 of 70 patients in the HBB group and in 16 of 71 in the placebo group. The rate of proximal tubal obstruction was significantly lower in the HBB group than in the placebo group (8.6% vs 22.5%; p = .04; absolute difference, 13.9%; 95% confidence interval [CI], 0.02-0.26; relative risk, 0.38; 95% CI, 0.16-0.92). After the second HSG or laparoscopy was performed (n = 22), the rate of false occlusion was 20% (1 of 6 patients) in the HBB group, compared with 69.2% (9 of 16 patients) in the placebo group. CONCLUSION: Premedication with HBB before HSG can reduce the rate of diagnosis of proximal tubal obstruction and false occlusion.

Evaluation of the postoperative cognitive dysfunction in elderly patients with general anesthesia.

OBJECTIVE: The present study is aimed to study the neuron-specific enolase (NSE) and S100b proteins in the evaluation of postoperative cognitive dysfunction in elderly patients with general anesthesia. PATIENTS AND METHODS: A total of 142 aged patients, who were treated with transurethral resection of the prostate (TURP) surgery under general anesthesia with propofol from June 2014 to December 2015, were randomly divided into two groups. The experiment group was given scopolamine butylbromide by intramuscular injection before the operation, while the control group had no preoperative intramuscular injection. The propofol was used for maintenance during the operation. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scales were adopted for testing the patients on preoperative day 1, postoperative day 2 and postoperative day 9. After the surgery, there were 4 cases of postoperative cognitive dysfunction (POCD) patients in experiment group, while 21 cases of POCD patients in control group. While the 142 healthy adult volunteers, who were admitted to physical examination center of our hospital in the corresponding period, were selected as healthy controls. The expression levels of S100b and NSE of patients, as well as healthy controls, were detected by ELISA. RESULTS: In POCD patients, serum S100b and NSE levels were evidently higher than those of patients without POCD and healthy control group (p < 0.05). S100b and NSE levels of POCD patients in experiment group were significantly lower than those of control group (p < 0.05). Serum S100b and NSE levels are higher, the longer duration of POCD is, as the correlation coefficient rs = -0.1342, -1.6644, p < 0.05. CONCLUSIONS: The expression levels of S100b protein and plasma NSE in the serum of POCD patients increased, which indicated the severity of the disease. The preoperative intramuscular injection of scopolamine butylbromide has important clinical significance for the prevention of POCD.

Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450.

Neurotoxicity of 1-bromopropane (1-BP) has been reported in both human cases and animal studies. To date, neurotoxicity of 1-BP has been induced in rats but not in mice due to the lethal hepatotoxicity of 1-BP. Oxidization by cytochromes P450 and conjugation with glutathione (GSH) are two critical metabolism pathways of 1-BP and play important roles in toxicity of 1-BP. The aim of the present study was to establish a murine model of 1-BP neurotoxicity, by reducing the hepatotoxicity of 1-BP with 1-aminobenzotriazole (1-ABT); a commonly used nonspecific P450s inhibitor. The results showed that subcutaneous or intraperitoneal injection of 1-ABT at 50mg/kg body weight BID (100mg/kg BW/day) for 3days, inhibited about 92-96% of hepatic microsomal CYP2E1 activity, but only inhibited about 62-64% of CYP2E1 activity in brain microsomes. Mice treated with 1-ABT survived even after exposure to 1200ppm 1-BP for 4 weeks and histopathological studies showed that treatment with 1-ABT protected mice from 1-BP-induced hepatic necrosis, hepatocyte degeneration, and hemorrhage. After 4-week exposure to 1-BP, the brain weight of 1-ABT(+)/1200ppm 1-BP group was decreased significantly. In 1-ABT-treated groups, expression of hippocampal Ran protein and cerebral cortical GRP78 was dose-dependently increased by exposure to 1-BP. We conclude that the control of hepatic P450 activity allows the observation of effects of 1-BP on the murine brain at a higher concentration by reduction of hepatotoxicity. The study suggests that further experiments with liver-specific control of P450 activity using gene technology might provide better murine models for 1-bromopropane-induced neurotoxicity.

Single and 14-day repeated dose inhalation toxicity studies of hexabromocyclododecane in rats.

Limited toxicological information is available for hexabromocyclododecane (HBCD),a widely used additive brominated flame retardant. Inhalation is a major route of human exposure to HBCD. The aim of this study was to determine the acute inhalation toxicity and potential subchronic inhalation toxicity of HBCD in Sprague-Dawley rats exposed to HBCD only through inhalation. The acute inhalation toxicity of HBCD was determined using the limit test method on five male and five female Sprague-Dawley rats at a HBCD concentration of 5000 mg/m(3). Repeated-dose toxicity tests were also performed, with 20 males and 20 females randomly assigned to four experimental groups (five rats of each sex in each group). There were three treatment groups (exposed to HBCD concentrations of 125,500, and 2000 mg/m(3)) and a blank control group (exposed to fresh air). In the acute inhalation toxicity study, no significant clinical signs were observed either immediately after exposure or during the recovery period. Gross pathology examination revealed no evidence of organ-specific toxicity in any rat. The inhalation LC50(4 h) for HBCD was higher than 5312 ± 278 mg/m3 for both males and females. In the repeated dose inhalation study, daily head/nose-only exposure to HBCD at 132 ± 8.8, 545.8 ± 35.3, and 2166.0 ± 235.9 mg/m(3) for 14 days caused no adverse effects. No treatment-related clinical signs were observed at any of the test doses. The NOAEL for 14-day repeated dose inhalation toxicity study of HBCD is 2000 mg/m(3).

Brominated flame retardants - Exposure and risk assessment for the general population.

Brominated flame retardants (BFRs) are a large group of different substances used in numerous products to prevent fire hazards. Some of them are persistent in the environment, accumulate in the food chain and are of toxicological concern, while for others current data are limited. Meanwhile, BFRs have been found in many environmental media, foods, and biota including humans. This review presents recent findings obtained from monitoring data in environmental media relevant for human exposure, as well as dietary exposure. In this context, concentrations in indoor and ambient air and in house dust are outlined. Furthermore, we summarize human biomonitoring data on BFR levels in blood and breast milk. Current estimates of the overall exposure of the general population using different relevant subsets are also addressed. All of these data are discussed in relation to currently available toxicological reference values used for risk assessment purposes. Obviously, the exposure of the general population varies considerably in different parts of the world and even within countries. Polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) show the highest intake during infancy. While the highest intake for BDE 47 for all groups was observed in the US, the total BDE 209 and HBCD intake was highest in the UK. For HBCD and all PBDEs except BDE 209, diet accounts for a large proportion of the total intake during infancy in all countries. With regard to toddlers and adults, the contribution of diet to total intake is high in Germany and the UK, while in the US, the high concentrations of PBDE in dust resulted in a notably smaller proportion of the intake being attributed to diet.

Comparative Metabolism Studies of Hexabromocyclododecane (HBCD) Diastereomers in Male Rats Following a Single Oral Dose.

Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively accounting for 42% of dose for α-HBCD, 59% for ß-HBCD, and 53% for γ-HBCD. Urine was also an important route of HBCD excretion, accounting for 13% of dose for α-HBCD, 30% for ß-HBCD, and 21% for γ-HBCD. Total metabolism of HBCD diastereomers followed the rank order ß > γ > α, and was >65% of that administered. The metabolites formed were distinct in male rats: α-HBCD did not debrominate or stereoisomerize, but formed two hydroxylated metabolites; ß- and γ-HBCD were both extensively metabolized via pathways of stereoisomerization, oxidation, dehydrogenation, reductive debromination, and ring opening. ß-HBCD was biotransformed to two mercapturic acid pathway metabolites. The metabolites of ß- and γ-HBCD were largely distinct, and could possibly be used as markers of exposure. These isomer-specific data suggest that α-HBCD would be the most dominant HBCD diastereomer in biological tissues because it was metabolized to the lowest degree and also accumulated from the stereoisomerization of the ß- and γ- diastereomers.

Transcriptomic and metabolomic approaches to investigate the molecular responses of human cell lines exposed to the flame retardant hexabromocyclododecane (HBCD).

The potential for human exposure to the brominated flame retardant, hexabromocyclododecane (HBCD) has given rise to health concerns, yet there is relatively limited knowledge about its possible toxic effects and the underlying molecular mechanisms that may mediate any impacts on health. In this study, unbiased transcriptomic and metabolomic approaches were employed to investigate the potential molecular changes that could lead to the toxicity of HBCD under concentrations relevant to human exposure conditions using in vitro models. A concentration-dependent cytotoxic effect of HBCD to A549 and HepG2/C3A cells was observed based on MTT assays or CCK-8 assays with EC50 values of 27.4 µM and 63.0 µM, respectively. Microarray-based transcriptomics and mass spectrometry-based metabolomics revealed few molecular changes in A549 cells or HepG2/C3A cells following a 24-hour exposure to several sub-lethal concentrations (2 to 4000 nM) of HBCD. Quantification of the level of HBCD in the HepG2/C3A exposed cells suggested that the flame retardant was present at concentrations several orders of magnitude higher than those reported to occur in human tissues. We conclude that at the concentrations known to be achievable following exposure in humans, HBCD exhibits no detectable acute toxicity in A549 cells, representative of the lung, or in HepG2/C3A cells, that are hepatocytes with some xenobiotic metabolic capacity.

Involvement of decreased neuroglobin protein level in cognitive dysfunction induced by 1-bromopropane in rats.

1-Bromopropane (1-BP) is used as a substitute for ozone-depleting solvents (ODS) in industrial applications. 1-BP could display central nervous system (CNS) neurotoxicity manifested by cognitive dysfunction. Neuroglobin (Ngb) is an endogenous neuroprotectant and is predominantly expressed in the nervous system. The present study aimed to investigate Ngb involvement in CNS neurotoxicity induced by 1-BP in rats. Male Wistar rats were randomly divided into 5 groups (n=14) and treated with 0, 100, 200, 400 and 800 mg/kg bw 1-BP, respectively, by gavage for consecutive 12 days. Rats displayed cognitive dysfunction dose-dependently through Morris water maze (MWM) test. Significant neuron loss in layer 5 of the prelimbic cortex (PL) was observed. Moreover, 1-BP decreased Ngb protein level in cerebral cortex and Ngb decrease was significantly positively correlated with cognitive dysfunction. Glutathione (GSH) content, GSH/oxidized glutathione (GSSG) ratio and glutamate cysteine ligase (GCL) activity decreased in cerebral cortex, coupled with the increase in GSSG content. GSH and GSH/GSSG ratio decrease were significantly positively correlated with cortical Ngb decrease. Additionally, levels of N-epsilon-hexanoyl-lysine (HEL) and 4-hydroxy-2-nonenal (4-HNE) modified proteins in cerebral cortex of 1-BP-treated rats increased significantly. In conclusion, it was suggested that 1-BP resulted in decreased endogenous neuroprotectant Ngb in cerebral cortex, which might play an important role in CNS neurotoxicity induced by 1-BP and that 1-BP-induced oxidative stress in cerebral cortex might partly be responsible for Ngb decrease.

Physiologically based pharmacokinetic modeling for 1-bromopropane in F344 rats using gas uptake inhalation experiments.

1-Bromopropane (1-BP) was introduced into the workplace as an alternative to ozone-depleting solvents and increasingly used in manufacturing industry. The potential exposure to 1-BP and the current reports of adverse effects associated with occupational exposure to high levels of 1-BP have increased the need to understand the mechanism of 1-BP toxicity in animal models as a mean of understanding risk in workers. Physiologically based pharmacokinetic (PBPK) model for 1-BP has been developed to examine 2 metabolic pathway assumptions for gas-uptake inhalation study. Based on previous gas-uptake experiments in the Fischer 344 rat, the PBPK model was developed by simulating the 1-BP concentration in a closed chamber. In the model, we tested the hypothesis that metabolism responsibilities were shared by the p450 CYP2E1 and glutathione (GSH) conjugation. The results showed that 2 metabolic pathways adequately simulated 1-BP closed chamber concentration. Furthermore, the above model was tested by simulating the gas-uptake data of the female rats pretreated with 1-aminobenzotrizole, a general P450 suicide inhibitor, or d,l-buthionine (S,R)-sulfoximine, an inhibitor of GSH synthesis, prior to exposure to 800 ppm 1-BP. The comparative investigation on the metabolic pathway of 1-BP through the PBPK modeling in both sexes provides critical information for understanding the role of p450 and GSH in the metabolism of 1-BP and eventually helps to quantitatively extrapolate current animal studies to human.

The regeneration of P2 olfactory sensory neurons is selectively impaired following methyl bromide lesion.

The capacity of the peripheral olfactory system to recover after injury has not been thoroughly explored. P2-IRES-tauLacZ mice were exposed to methyl bromide, which causes epithelial damage and kills 90% of the P2 neurons. With subsequent neuronal regeneration, P2 neurons recover within their usual territory to equal control numbers by 1 month but then decline sharply to roughly 40% of control by 3 months. At this time, the P2 projection onto the olfactory bulb is erroneous in several respects. Instead of converging onto 1 or 2 glomeruli per surface, small collections of P2 axons innervate multiple glomeruli at roughly the same position in the bulb as in controls. Within these glomeruli, the P2 axons are aggregated near the edge, whereas the remainder of the glomerulus contains olfactory marker protein (+), non-P2 axons, violating the one receptor-one glomerulus rule normally observed. The aggregates are denser than found in control P2-innervated glomeruli, suggesting that the P2 axons may not be synaptically connected. Based on published literature and other data, we hypothesize that P2 neurons lose out in an activity-based competition for synaptic territory within the glomeruli and are not maintained at control numbers due to a lack of trophic support from the bulb.

Exposure to an environmentally relevant mixture of brominated flame retardants affects fetal development in Sprague-Dawley rats.

Brominated flame retardants are incorporated into a wide variety of consumer products and are known to enter into the surrounding environment, leading to human exposure. There is accumulating evidence that these compounds have adverse effects on reproduction and development in humans and animal models. Animal studies have generally characterized the outcome of exposure to a single technical mixture or congener. Here, we determined the impact of exposure of rats prior to mating and during gestation to a mixture representative of congener levels found in North American household dust. Adult female Sprague-Dawley rats were fed a diet containing 0, 0.75, 250 or 750mg/kg of a mixture of flame retardants (polybrominated diphenyl ethers, hexabromocyclododecane) from two weeks prior to mating to gestation day 20. This formulation delivered nominal doses of 0, 0.06, 20 and 60mg/kg body weight/day. The lowest dose approximates high human exposures based on house dust levels and the dust ingestion rates of toddlers. Litter size and resorption sites were counted and fetal development evaluated. No effects on maternal health, litter size, fetal viability, weights, crown rump lengths or sex ratios were detected. The proportion of litters with fetuses with anomalies of the digits (soft tissue syndactyly or malposition of the distal phalanges) was increased significantly in the low (0.06mg/kg/day) dose group. Skeletal analysis revealed a decreased ossification of the sixth sternebra at all exposure levels. Thus, exposure to an environmentally relevant mixture of brominated flame retardants results in developmental abnormalities in the absence of apparent maternal toxicity. The relevance of these findings for predicting human risk is yet to be determined.

Species and sex-dependent toxicokinetics of 1-bromopropane: the role of hepatic cytochrome P450 oxidation and glutathione (GSH).

1. The objectives of the current studies were to evaluate the factors influencing the toxicokinetics of 1-bromopropane (1-BP) in rodents after intravenous (IV) and inhalation exposure. 2. F-344 rats were administered 1-BP via IV bolus injection at 5 and 20 mg/kg and blood concentration determined versus time. F-344 rats and B6C3F1 mice were also exposed to starting inhalation concentrations 70, 240, 800 and 2700 ppm 1-BP in a closed gas uptake system and chamber 1-BP levels were monitored for 6 h. Plasma bromide concentrations were determined to estimate total metabolized dose. Rats were pretreated with chemical inhibitors of cytochrome P450 and glutathione (GSH) synthesis, prior to exposure to 1-BP at 800 ppm within inhalation chambers. 3. Systemic clearance of 1-BP in rat was rapid and decreased with increasing dose. As inhalation chamber concentration of 1-BP increased, the terminal elimination rates decreased. Half-life of 1-BP in rats following inhibition of P450 (9.6 h) or depletion of GSH (4.1 h) increased relative to controls (2.0 h) at 800 ppm. The percentage of 1-BP metabolized decreased with increasing inhalation exposure. Hepatic levels of GSH were significantly lowered regardless of the exposure level in both rats and mice. Chamber concentration-time curves were fit to a two compartment model which was used to estimate metabolic rate constants. 4. These data suggest that in rat, 1-BP clearance is saturable and that elimination is highly dependent on both P450 and GSH-dependent metabolism. This investigation in rodents may provide an understanding of interspecies differences in toxicokinetics and eventually aid translation of animal studies to human risk assessment.

Positive allosteric modulation of α4ß2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from a rat model of nicotine self-administration.

RATIONALE: The α4ß2 subtype of nicotinic acetylcholine receptors (nAChRs) plays a central role in the mediation of nicotine reinforcement. Positive allosteric modulators (PAMs) at α4ß2 nAChRs facilitate the intrinsic efficiency of these receptors, although they do not directly activate the receptors. α4ß2 PAMs are hypothesized to reduce nicotine self-administration in subjects engaged in routine nicotine consumption. The present study tested this hypothesis using a rat model of nicotine self-administration. METHODS: Male Sprague-Dawley rats were trained in daily 1-h sessions to intravenously self-administer nicotine (0.03 mg/kg per infusion, free base) on a fixed-ratio 5 schedule. The effects of the α4ß2 PAM desformylflustrabromine (dFBr), α4ß2 agonist 5-iodo-A-85380, and acetylcholinesterase inhibitor galantamine on nicotine intake were examined. The ability of dFBr and 5-iodo-A-85380 to substitute for nicotine was also assessed. RESULTS: dFBr and 5-iodo-A-85380 dose-dependently reduced nicotine self-administration without changing lever responses for food. Galantamine decreased the self-administration of nicotine and food at high doses. Unlike 5-iodo-A-85380, dFBr failed to substitute for nicotine in supporting self-administration behavior. CONCLUSIONS: These results demonstrated the effectiveness of dFBr in reducing nicotine intake and the inability of dFBr to support self-administration behavior. These findings suggest that positive allosteric modulation of α4ß2 nAChRs may be a promising target for the treatment of nicotine addiction. Moreover, α4ß2 PAMs, in contrast to agonist medications, may have clinical advantages because they may have little liability for abuse because of their lack of reinforcing actions on their own.

Effects of sub-acute and sub-chronic inhalation of 1-bromopropane on neurogenesis in adult rats.

PURPOSE: 1-Bromopropane (1-BP) intoxication is associated with depression and cognitive and memory deficits. The present study tested the hypothesis that 1-BP suppresses neurogenesis in the dentate gyrus, which is involved in higher cerebral function, in adult rats. METHODS: Four groups of 12 male Wistar rats were exposed to 0, 400, 800, 1000 ppm 1-BP, 8 h/day for 7 days. Another four groups of six rats each were exposed to 0, 400, 800 and 1000 ppm 1-BP for 2 weeks followed by 0, 200, 400 and 800 ppm for another 2 weeks, respectively. Another four groups of six rats each were exposed to 0, 200, 400 and 800 ppm 1-BP for 4 weeks. Rats were injected with 5-bromo-2'-deoxy-uridine (BrdU) after 4-week exposure at 1000/800 ppm to examine neurogenesis in the dentate gyrus by immunostaining. We measured factors known to affect neurogenesis, including monoamine levels, and mRNA expression levels of brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR), in different brain regions. RESULTS: BrdU-positive cells were significantly lower in the 800/1000 ppm-4-week group than the control. 1-Week exposure to 1-BP at 800 and 1000 ppm significantly reduced noradrenalin level in the striatum. Four-week exposure at 800 ppm significantly decreased noradrenalin levels in the hippocampus, prefrontal cortex and striatum. 1-BP also reduced hippocampal BDNF and GR mRNA levels. CONCLUSION: Long-term exposure to 1-BP decreased neurogenesis in the dentate gyrus. Downregulation of BDNF and GR mRNA expression and low hippocampal norepinephrine levels might contribute, at least in part, to the reduced neurogenesis.

Report on Carcinogens Monograph on 1-Bromopropane: RoC Monograph 01.

The National Toxicology Program conducted a cancer evaluation on 1 bromopropane for possible listing in the Report on Carcinogens (RoC). The cancer evaluation is captured in the RoC monograph, which was peer reviewed in a public forum. The monograph consists of two components: (Part 1) the cancer evaluation, which reviews the relevant scientific information, assesses its quality, applies the RoC listing criteria to the scientific information, and provides the NTP recommendation for listing status for 1 bromopropane in the RoC, and (Part 2) the substance profile proposed for the RoC, containing the NTP's listing status recommendation, a summary of the scientific evidence considered key to reaching that decision, and data on properties, use, production, exposure, and Federal regulations and guidelines to reduce exposure to 1-bromopropane. This monograph provides an assessment of the available scientific information on 1 bromopropane, including human exposure and properties, disposition and toxicokinetics, cancer studies in experimental animals, and studies of mechanisms and other related effects, including relevant toxicological effects, genetic toxicology, and mechanisms of carcinogenicity. From this assessment, the NTP recommended that 1 bromopropane be listed as reasonably anticipated to be a human carcinogen in the RoC based on sufficient evidence from studies in experimental animals, which found inhalation exposure to 1-bromopropane caused skin tumors in male rats, large intestine tumors in female and male rats, and lung tumors in female mice. Also noted was that 1 bromopropane, either directly or via reactive metabolites, caused molecular alterations that typically are associated with carcinogenesis, including genotoxicity, oxidative stress, and glutathione depletion. These alterations, observed in mainly in vitro and toxicity studies in rodents, are relevant to possible mechanisms of human carcinogenicity and support the relevance of the cancer studies in experimental animals to humans.