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Regulatory Toxicology and Pharmacology: RTP

G Jaccard, D Tafin Djoko, O Moennikes, C Jeannet, A Kondylis, M Belushkin
There has been a sustained effort in recent years to develop products with the potential to present less risk compared with continued smoking as an alternative for adult smokers who would otherwise continue to smoke cigarettes. During the non-clinical assessment phase of such products, the chemical composition and toxicity of their aerosols are frequently compared to the chemical composition and toxicity of the smoke from a standard research cigarette - the 3R4F reference cigarette. In the present study, it is demonstrated that results of these analytical comparisons are similar when considering commercially available cigarette products worldwide...
August 14, 2017: Regulatory Toxicology and Pharmacology: RTP
Jun-Won Yun, Seung-Hyun Kim, Yun-Soon Kim, Ji-Ran You, Eun-Young Cho, Jung-Hee Yoon, Euna Kwon, Sang Ju Lee, Seong Pil Kim, Jae Hoon Seo, Jae Pyung In, Jae Hun Ahn, Ja-June Jang, Jin-Sung Park, Jeong-Hwan Che, Byeong-Cheol Kang
Koji products have been considered as an effective fermented food consumed in East Asia with many health benefits. Particularly, rice koji with Aspergillus terreus (RAT) has been reported to be able to prevent hyperlipidemia and hepatic steatosis through regulating cholesterol synthesis. Despite its biological activities, there is a lack of comprehensive information to give an assurance of its safety. Therefore, the objective of this study was to perform a series of toxicological studies (repeated dose oral toxicity and genotoxicity) according to test guidelines published by the Organization for Economic Cooperation and Development...
August 9, 2017: Regulatory Toxicology and Pharmacology: RTP
Nathan M Drew, Eileen D Kuempel, Ying Pei, Feng Yang
The large and rapidly growing number of engineered nanomaterials (ENMs) presents a challenge to assessing the potential occupational health risks. An initial database of 25 rodent studies including 1929 animals across various experimental designs and material types was constructed to identify materials that are similar with respect to their potency in eliciting neutrophilic pulmonary inflammation, a response relevant to workers. Doses were normalized across rodent species, strain, and sex as the estimated deposited particle mass dose per gram of lung...
August 5, 2017: Regulatory Toxicology and Pharmacology: RTP
Gerhard J Nohynek
No abstract text is available yet for this article.
August 4, 2017: Regulatory Toxicology and Pharmacology: RTP
Sun Joo Hong, Je-Hyeon Lee, Eun Joo Kim, Hea Jung Yang, Jae-Seon Park, Soon-Kwang Hong
Agar, a heterogeneous polymer of galactose, is the main component of the cell wall of marine red algae. It is well established as a safe, non-digestible carbohydrate in Oriental countries. Although neoagarooligosaccharides (NAOs) prepared by the hydrolysis of agar by β-agarase have been reported to exert various biological activities, the safety of these compounds has not been reported to date. For safety evaluation, NAOs containing mainly neoagarotetraose and neoagarohexaose were prepared from agar by enzymatic hydrolysis using β-agarase DagA from Streptomyces coelicolor...
August 3, 2017: Regulatory Toxicology and Pharmacology: RTP
James Bridges, Wolfgang Dekant, James E Klaunig, Anthony R Scialli
No abstract text is available yet for this article.
August 2, 2017: Regulatory Toxicology and Pharmacology: RTP
Patrick Brossard, Rolf Weitkunat, Valerie Poux, Nicola Lama, Christelle Haziza, Patrick Picavet, Gizelle Baker, Frank Lüdicke
Two open-label randomized cross-over studies in Japanese smokers investigated the single-use nicotine pharmacokinetic profile of the Tobacco Heating System (THS) 2.2, cigarettes (CC) and nicotine replacement therapy (Gum). In each study, one on the regular and one on the menthol variants of the THS and CC, both using Gum as reference, 62 subjects were randomized to four sequences: Sequence 1: THS - CC (n = 22); Sequence 2: CC - THS (n = 22); Sequence 3: THS - Gum (n = 9); Sequence 4: Gum - THS (n = 9)...
July 29, 2017: Regulatory Toxicology and Pharmacology: RTP
Daniela E Marin, Gina C Pistol, Mihai A Gras, Mihai L Palade, Ionelia Taranu
Ochratoxin A (OTA) is a secondary metabolite produced by fungi of Aspergillus and Penicillium genra. OTA is mainly nephrotoxic but can also cause hepatotoxicity, mutagenicity, teratogenicity, neurotoxicity and immunotoxicity. As recent studies have highlighted the close relationship between gastrointestinal tract and kidney, as principal organs involved in absorption and respective excretion of xenobiotics, the aim of the present study was to analyze the effect of a subchronic exposure (30 days) to 0.05 mg/kg OTA on immune response and oxidative stress parameters at the level of intestine and kidney of young swine...
July 29, 2017: Regulatory Toxicology and Pharmacology: RTP
E M El Afifi, A M Shahr El-Din, R F Aglan, E H Borai, M M Abo-Aly
Egyptian monazite is a promising resource and investment attractive for production of valuable metals of industrial or nuclear interest such as rare earth elements (REEs), thorium (Th) and uranium (U). The study was focused to establish a baseline framework in viewpoint of radiation protection for the workers in production of REEs from high-grade monazite treated by sodium hydroxide (NaOH) solutions. Radiological hazard indices (cancer, gonadal and other risks) were evaluated, due to emissions (α-, β- and γ-radiations) of radium-isotopes ((228)Ra, (226)Ra, (223)Ra) and lead ((210)Pb)...
July 29, 2017: Regulatory Toxicology and Pharmacology: RTP
Liang Xie, Shuyu Liu, Jinghua Cheng, Lijun Wang, Jing Liu, Jianbin Gong
Previous studies have shown a role of mitochondrial DNA (mtDNA) in innate immunity. However, the specific role of mtDNA in acute myocardial infarction remains elusive. This study was designed to examine the damaging effect of mtDNA on cardiomyocytes. H9c2s cells were incubated with purified mtDNA or nuclear DNA with or without pretreatment by chloroquine, an inhibitor of Toll-like receptor 9(TLR9). The cell viability was tested by MTT. To demonstrate the toxicity of mtDNA, mtDNA fragments were injected into rats 10 min before ischemia for 30 min and reperfusion for 24 h...
July 27, 2017: Regulatory Toxicology and Pharmacology: RTP
S M G Goody, K E Cannon, M Liu, M J Kallman, J P Martinolle, L Mazelin-Winum, A Giarola, P Ardayfio, J Moyer, G Teuns, T J Hudzik
Given the serious nature of suicidal ideation and behavior (SIB) and the possibility of treatment-emergent SIB, pharmaceutical companies are now applying more proactive approaches in clinical trials and are considering the value of nonclinical models to predict SIB. The current review summarizes nonclinical approaches to modeling three common risk factors associated with SIB: aggression, impulsivity, and anhedonia. For each risk factor, a general description, advantages and disadvantages, species considerations, nonclinical to clinical translation, and pharmacological validation with respect to treatments associated with SIB are summarized...
July 27, 2017: Regulatory Toxicology and Pharmacology: RTP
Duncan Turnbull, Joseph V Rodricks, Gregory F Mariano, Farah Chowdhury
This report evaluates the scientific literature on caffeine with respect to potential cardiovascular outcomes, specifically relative risks of total cardiovascular disease (CVD), coronary heart disease (CHD) and acute myocardial infarction (AMI), effects on arrhythmia, heart failure, sudden cardiac arrest, stroke, blood pressure, hypertension, and other biomarkers of effect, including heart rate, cerebral blood flow, cardiac output, plasma homocysteine levels, serum cholesterol levels, electrocardiogram (EKG) parameters, heart rate variability, endothelial/platelet function and plasma/urine catecholamine levels...
July 26, 2017: Regulatory Toxicology and Pharmacology: RTP
Sean M Hays, Christopher R Kirman
2-ethylhexyl-2,3,4,5 tetrabromobenzoate (TBB) is used as a flame retardant. Biomonitoring for TBB exposures include the metabolite, tetrabromobenzoic acid (TBBA), in urine. We derived a Reference Dose (RfD) for TBB and a Biomonitoring Equivalent (BE) for TBBA in urine. Three longer-term studies of oral gavage dosing of a commercial mixture BZ-54 (which includes 70% TBB) in rats were evaluated for deriving the RfD. The 95% lower confidence limits on the BMD associated with a 1 SD change from the mean (BDMLSD) values ranged from 77 to 134 mg/kg-day...
July 25, 2017: Regulatory Toxicology and Pharmacology: RTP
Julie E Goodman, Erin M Kennedy, Mara Seeley
The current 100 ppb short-term National Ambient Air Quality Standard for NO2, and EPA's determination of a causal association for respiratory effects, are based in part on controlled human exposure studies evaluating airway hyper-responsiveness (AHR). A meta-analysis by Goodman et al. (2009) found increased AHR at 100 ppb NO2 but no clear concentration-response relationship up to 600 ppb, and an overall lack of an AHR effect for studies involving exercise or exposure to allergens. Several factors have been suggested to explain why effects on AHR are observed while people are at rest, but not during exercise or after exposure to allergens...
July 25, 2017: Regulatory Toxicology and Pharmacology: RTP
Shitalkumar Patel, Laxit Bhatt, Rajesh Patel, Chitrang Shah, Vipul Patel, Jitendra Patel, Rajesh Sundar, Upendra Bhatnagar, Mukul Jain
A number of drugs belonging to different therapeutic classes cause increase in QT interval duration, and this change has been associated with ventricular arrhythmias. Investigation of changes in QT intervals in toxicity studies in dogs is therefore of potential value. Estimation of a direct effect of drugs on the duration of the QT interval can be confused by drug-induced increases in heart rate. The objective of this evaluation was to identify an appropriate correction formula by comparing different formulae that could appropriately correct changes in QT interval in conscious beagle dogs in toxicology studies...
July 25, 2017: Regulatory Toxicology and Pharmacology: RTP
Peter N Lee, John S Fry, Janette S Hamling
We present analyses relating cigarette type to lung cancer based on a case-control study in five European countries. The analyses involved 3561 cases and 2301 controls with diseases not associated with smoking. Subjects completed a detailed questionnaire, including a lifetime smoking history. Analyses included never smokers, and those who smoked for at least 80% of the "critical period" from 2 to 20 years before diagnosis, ignoring those who ever smoked pipes or cigars, or chewed tobacco. The main analysis compares risk in those who, in the critical period, smoked ultra-low tar (ULT) cigarettes (machine yield ≤3 mg tar/cigarette) for 8 + years, with those who only smoked full flavour (FF) cigarettes (≥10 mg tar/cigarette)...
July 25, 2017: Regulatory Toxicology and Pharmacology: RTP
Ricardo D Ekmay, Craig N Coon, Gregory S Ladics, Rod A Herman
Currently, risk assessment of the allergenic potential of novel proteins relies heavily on evaluating protein digestibility under normal conditions based on the theory that allergens are more resistant to gastrointestinal digestion than non-allergens. There is also proposed guidance for expanded in vitro digestibility assay conditions to include vulnerable sub-populations. One of the underlying rationales for the expanded guidance is that current in vitro assays do not accurately replicate the range of physiological conditions...
July 24, 2017: Regulatory Toxicology and Pharmacology: RTP
Donna R Farmer, Thomas C Edrington, Colton R Kessenich, Cunxi Wang, Jay S Petrick
Many insect-protected crops express insecticidal crystal (Cry) proteins derived from the soil bacterium Bacillus thuringiensis (Bt), including both naturally-occurring Cry proteins and chimeric Cry proteins created through biotechnology. The Cry51Aa2 protein is a naturally-occurring Cry protein that was modified to increase its potency and expand its insect activity spectrum through amino acid sequence changes. The improved Cry51Aa2 variant, Cry51Aa2.834_16, and other developmental variants belong to the ETX_MTX2 family of proteins but share a low level of sequence similarity to other members of this family...
July 24, 2017: Regulatory Toxicology and Pharmacology: RTP
Paul Baldrick
Examination of content of 35 Investigator Brochures (IBs) for small molecules (including some for oncology) used to support First-In-Human studies over a 2 year period (2014-2016) showed that a mean of 37 nonclinical studies were performed per molecule with pharmacology, ADME and toxicology testing contributing 43%, 32% and 24% of the studies, respectively. Examination of 11 IBs for biopharmaceuticals (monoclonal antibodies) over the same time frame showed that the mean number of nonclinical studies was 17 studies per molecule with pharmacology, ADME and toxicology testing contributing 82%, 6% and 12% of the studies, respectively...
July 24, 2017: Regulatory Toxicology and Pharmacology: RTP
M Lusso, I Gunduz, A Kondylis, G Jaccard, L Ruffieux, F Gadani, K Lion, A Adams, W Morris, T Danielson, U Warek, J Strickland
Research conducted during past decades to reduce the level of the tobacco specific nitrosamine N-nitrosonornicotine (NNN) and its precursor nornicotine in tobacco yielded identification of three tobacco genes encoding for cytochrome P450 nicotine demethylases converting nicotine to nornicotine. We carried out trials to investigate the effect of using tobaccos containing three non-functional nicotine demethylase genes on the selective reduction of NNN in cigarette tobacco filler and mainstream smoke. Our results indicate that the presence of non-functional alleles of the three genes reduces the level of nornicotine and NNN in Burley tobacco by 70% compared to the level observed in currently available low converter (LC) Burley tobacco varieties...
July 20, 2017: Regulatory Toxicology and Pharmacology: RTP
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