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Regulatory Toxicology and Pharmacology: RTP

Haleh Saber, Ramadevi Gudi, Michael Manning, Emily Wearne, John K Leighton
As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities...
October 12, 2016: Regulatory Toxicology and Pharmacology: RTP
Jean-Pierre Schaller, Daniela Keller, Laurent Poget, Pascal Pratte, Etienne Kaelin, Damian McHugh, Gianluca Cudazzo, Daniel Smart, Anthony R Tricker, Lydia Gautier, Michel Yerly, Roger Reis Pires, Soazig Le Bouhellec, David Ghosh, Iris Hofer, Eva Garcia, Patrick Vanscheeuwijck, Serge Maeder
The chemical composition, in vitro genotoxicity, and cytotoxicity of the mainstream aerosol from the Tobacco Heating System 2.2 (THS2.2) were compared with those of the mainstream smoke from the 3R4F reference cigarette. In contrast to the 3R4F, the tobacco plug in the THS2.2 is not burnt. The low operating temperature of THS2.2 caused distinct shifts in the aerosol composition compared with 3R4F. This resulted in a reduction of more than 90% for the majority of the analyzed harmful and potentially harmful constituents (HPHCs), while the mass median aerodynamic diameter of the aerosol remained similar...
October 6, 2016: Regulatory Toxicology and Pharmacology: RTP
Christelle Haziza, Guillaume de La Bourdonnaye, Sarah Merlet, Muriel Benzimra, Jacek Ancerewicz, Andrea Donelli, Gizelle Baker, Patrick Picavet, Frank Lüdicke
Smoking conventional cigarettes (CCs) exposes smokers to harmful and potentially harmful constituents (HPHCs). The Tobacco Heating System 2.2 (THS 2.2), a candidate modified risk tobacco product, was developed to reduce or eliminate the formation of HPHCs, while preserving as much as possible the taste, sensory experience, nicotine delivery profile and ritual characteristics of CC. This randomized, controlled, open-label study in confinement for 5 days aimed to demonstrate the reduction in exposure to selected HPHCs, to assess nicotine uptake and subjective effects, in subjects switching to THS 2...
September 29, 2016: Regulatory Toxicology and Pharmacology: RTP
Raja S Settivari, Ricardo Acosta Amado, Marco Corvaro, Nicolo R Visconti, Lynn Kan, Edward W Carney, Darrell R Boverhof, Sean C Gehen
Agrochemical formulations have been underrepresented in validation efforts for implementing alternative eye irritation approaches but represent a significant opportunity to reduce animal testing. This study assesses the utility of the neutral red release assay (NRR) and EpiOcular™ assay (EO) for predicting the eye irritation potential of 64 agrochemical formulations relative to Draize data. In the NRR, formulations with an NRR50 value ≤ 50 mg/mL were categorized as UN GHS Cat 1 and those >250 mg/mL were classified as UN GHS Non Classified (NC)...
September 28, 2016: Regulatory Toxicology and Pharmacology: RTP
Wolfgang Dekant, James Bridges
Quantitative weight of evidence (QWoE) methodology utilizes detailed scoring sheets to assess the quality/reliability of each publication on toxicity of a chemical and gives numerical scores for quality and observed toxicity. This QWoE-methodology was applied to the reproductive toxicity data on diisononylphthalate (DINP), di-n-hexylphthalate (DnHP), and dicyclohexylphthalate (DCHP) to determine if the scientific evidence for adverse effects meets the requirements for classification as reproductive toxicants...
September 28, 2016: Regulatory Toxicology and Pharmacology: RTP
Jun-Won Yun, Jae Hun Ahn, Euna Kwon, Seung-Hyun Kim, Hanna Kim, Ja-June Jang, Woo Ho Kim, Ji Hyang Kim, Su-Youne Han, Jin Tac Kim, Jong-Hoon Kim, Wookhwan Kim, Seung-Yup Ku, Byung-Rok Do, Byeong-Cheol Kang
Umbilical cord-derived mesenchymal stem cells (UC-MSCs) therapy might be an alternative to liver transplantation for acute or chronic liver injury. The aim of this study was to evaluate the efficacy of human UC-MSCs on carbon tetrachloride (CCl4)-induced acute liver injury. In addition, its toxicity, tumorigenicity, and biodistribution were determined. Significant hepatoprotective effects of hUC-MSCs with decreased levels of hepatocellular necrosis and lobular neutrophilic infiltration were found. Regarding the safety of hUC-MSCs, no serious hUC-MSCs-related changes (body weight, food/water consumption, clinical symptom, urinalysis, hematology, clinical chemistry, organ weight, and histopathology) were observed in a 13-week subchronic toxicity study...
September 28, 2016: Regulatory Toxicology and Pharmacology: RTP
Devika Poddalgoda, Kristin Macey, Innocent Jayawardene, Kannan Krishnan
Population-level biomonitoring of tin in urine has been conducted by the U.S. National Health and Nutrition Examination Survey (NHANES) and the National Nutrition and Health Study (ENNS - Étude nationale nutrition santé) in France. The general population is predominantly exposed to inorganic tin from the consumption of canned food and beverages. The National Institute for Public Health and the Environment of the Netherlands (RIVM) has established a tolerable daily intake (TDI) for chronic exposure to inorganic tin based on a NOAEL of 20 mg/kg bw per day from a 2-year feeding study in rats...
September 28, 2016: Regulatory Toxicology and Pharmacology: RTP
Kai-Sheng Liao, Chia-Li Wei, Jyh-Cheng Chen, Hao-Yu Zheng, Wen-Ching Chen, Chia-Hung Wu, Tai-Jing Wang, Yi-Shuan Peng, Po-Yuan Chang, Yun-Wei Lin
Pemetrexed, a multitargeted antifolate agent, has demonstrated clinical activity in non-small cell lung cancer (NSCLC) cells. Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to pemetrexed. Astaxanthin exhibits a wide range of beneficial effects including anti-cancer and anti-inflammatory properties. In this study, we showed that down-regulating of TS expression in two NSCLC cell lines, human lung adenocarcinoma H1650 and squamous cell carcinoma H1703 cells, with astaxanthin were associated with decreased MKK1/2-ERK1/2 activity...
September 28, 2016: Regulatory Toxicology and Pharmacology: RTP
Thomas A Lewandowski, Joel M Cohen
No abstract text is available yet for this article.
September 25, 2016: Regulatory Toxicology and Pharmacology: RTP
Vijay Kumar, Jayantee Kalita, Himangsu K Bora, Usha K Misra
Excess of copper is toxic to different organs. We aim to study the histopathological changes of liver, kidney, and brain following oral CuSO4 exposure for different duration and doses in rat model. Fifty-four males Wistar rats (205 ± 10 g) were included and divided into control (group-I) and experimental (group-II and III) arms. An oral dose of 100 and 200 mg/kgBWt/Day CuSO4 was given to group-II and III respectively and group-I received normal saline by gavage. Six rats from each group were sacrificed on days 30, 60 and 90 for biochemical and histopathological examinations...
September 23, 2016: Regulatory Toxicology and Pharmacology: RTP
Sara Totaro, Giulio Cotogno, Kirsten Rasmussen, Francesca Pianella, Marco Roncaglia, Heidi Olsson, Juan M Riego Sintes, Hugues P Crutzen
The European Commission has established a Nanomaterials Repository that hosts industrially manufactured nanomaterials that are distributed world-wide for safety testing of nanomaterials. In a first instance these materials were tested in the OECD Testing Programme. They have then also been tested in several EU funded research projects. The JRC Repository of Nanomaterials has thus developed into serving the global scientific community active in the nanoEHS (regulatory) research. The unique Repository facility is a state-of-the-art installation that allows customised sub-sampling under the safest possible conditions, with traceable final sample vials distributed world-wide for research purposes...
September 23, 2016: Regulatory Toxicology and Pharmacology: RTP
Ritu Karwasra, Prerna Kalra, T C Nag, Y K Gupta, Surender Singh, Anuj Panwar
Cisplatin (Cis-diaminedichloroplatinum II) is a chemotherapeutic agent having well documented adverse effect as nephrotoxicity. This study was designed to evaluate the nephroprotective role of Boerhaavia diffusa in cisplatin-induced acute kidney injury. Wistar rats (n = 6) were allocated into six groups constituting normal control, cisplatin-induced, Boerhaavia diffusa root extract in doses 50, 100 and 200 mg/kg and Boerhaavia diffusa per se group, administered orally for a period of ten days. Intraperitoneal injection of cisplatin was administered on day 7, to all groups except normal control and Boerhaavia diffusa per se group...
September 22, 2016: Regulatory Toxicology and Pharmacology: RTP
Liesbeth Geraets, Monique M Nijkamp, Wouter Ter Burg
Less than lifetime exposure has confronted risk assessors as to how to interpret the risks for human health in case a chronic health-based limit is exceeded. Intermittent, fluctuating and peak exposures do not match with the basis of the chronic limit values possibly leading to conservative outcomes. This paper presents guidance on how to deal with human risk assessment of less than lifetime exposure. Important steps to be considered are characterization of the human exposure situation, evaluation whether the human less than lifetime exposure scenario corresponds to a non-chronic internal exposure: toxicokinetic and toxicodynamic considerations, and, finally, re-evaluation of the risk assessment...
September 21, 2016: Regulatory Toxicology and Pharmacology: RTP
Jong-Woo Jeong, Changsun Yu, Jong-Hwa Lee, Kyoung-Sik Moon, Eunhee Kim, Sung-Eun Yoo, Tae-Sung Koo
KR33493, a newly developed FAS-associated factor 1 (FAF1) inhibitor for Parkinson's disease, is being evaluated in a Phase I clinical trial. In the present study, the subchronic toxicity of KR33493 in Sprague-Dawley (SD) rats and beagle dogs was investigated at various oral doses for 28 and 14 days, respectively. During the study, food consumption, body weights, organ weights, gross findings, and mortality were examined; and ophthalmoscopy, electrocardiography, hematology, serum biochemistry, urinalysis, histopathology, and toxicokinetics were performed...
September 21, 2016: Regulatory Toxicology and Pharmacology: RTP
Klara Midander, Anneli Julander, Jolinde Kettelarij, Carola Lidén
Metal release from materials immersed in artificial sweat can function as a measure of potential skin exposure. Several artificial sweat models exist that, to various degree, mimic realistic conditions. Study objective was to evaluate metal release from previously examined and well characterized materials in two different artificial sweat solutions; a comprehensive sweat model intended for use within research, based on the composition of human sweat; and the artificial sweat, EN1811, intended for testing compliance with the nickel restriction in REACH...
September 21, 2016: Regulatory Toxicology and Pharmacology: RTP
Benonio T Villalba, Francine R Ianiski, Ane G Vogt, Mikaela P Pinz, Angélica S Reis, Rodrigo A Vaucher, Mauro P Soares, Ethel A Wilhelm, Cristiane Luchese
This study determined whether meloxicam in nanocapsules modifies stomach and liver damage caused by free meloxicam in mice. Male Swiss mice were treated with blank nanocapsules or meloxicam in nanocapsules or free meloxicam (10 mg/kg, intragastrically, daily for five days). On the seventh day, blood was collected to determine biochemical markers (glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, total bilirubin, unconjugated bilirubin, albumin and alkaline phosphatase). Stomachs and livers were removed for histological analysis...
September 21, 2016: Regulatory Toxicology and Pharmacology: RTP
Peter N Lee, John R Gosney
Among lung cancers, a substantial shift over time has occurred in the recorded frequency of adenocarcinoma (AdC) relative to that of squamous cell carcinoma (SqCC). This is evident in many countries, and also in those who have never smoked. We attempted to address the extent to which this increase is real, or an artefact of changing diagnostic practices. We reviewed studies re-evaluating diagnoses using more up-to-date criteria, and studies applying standard criteria to cases collected over a long period. We also describe changes to classifications, and factors affecting diagnostic accuracy and consistency...
September 21, 2016: Regulatory Toxicology and Pharmacology: RTP
Gang Chen, Jiamin Mao, Jianmei Zhao, Yan Zhang, Ting Li, Cheng Wang, Lingfei Xu, Qiaoyun Hu, Xiaoke Wang, Shengyang Jiang, Xiaoke Nie, Qiyun Wu
Arsenic is a widely distributed toxic metalloid in around the world. Inorganic arsenic species are deemed to affect astrocytes functions and to cause neuron apoptosis. Microglia are the key cell type involved in innate immune responses in CNS, and microglia activation has been linked to inflammation and neurotoxicity. In this study, using ELISA and reverse transcriptase PCR (RT-PCR), we showed that Arsenic trioxide up-regulated the expression and secretion of IL-6 in a dose-dependent manner and a time-dependent manner in cultured HAPI microglia cells...
September 21, 2016: Regulatory Toxicology and Pharmacology: RTP
B J Hughes, J Thomas, A M Lynch, S J Borghoff, S Green, T Mensing, S S Sarang, M J LeBaron
In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F1 mice at 1800 ppm. A DNA reactive Mode-of-Action (MOA) for this liver tumor response is not supported by the evidence as MIBK and its major metabolites lack genotoxicity in both in vitro and in vivo studies. Constitutive androstane receptor (CAR) nuclear receptor-mediated activation has been hypothesized as the MOA for MIBK-induced mouse liver tumorigenesis...
September 21, 2016: Regulatory Toxicology and Pharmacology: RTP
Achim Aigner, Roland Buesen, Tim Gant, Nigel Gooderham, Helmut Greim, Jörg Hackermüller, Bruno Hubesch, Madeleine Laffont, Emma Marczylo, Gunter Meister, Jay S Petrick, Reza J Rasoulpour, Ursula G Sauer, Kerstin Schmidt, Hervé Seitz, Frank Slack, Tokuo Sukata, Saskia M van der Vies, Jan Verhaert, Kenneth W Witwer, Alan Poole
The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that ncRNA expression profiling data requires careful evaluation to determine the utility of specific ncRNAs as biomarkers. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify possibly suitable ncRNAs and areas of toxicology where ncRNA expression profiling could address prevailing scientific deficiencies...
September 20, 2016: Regulatory Toxicology and Pharmacology: RTP
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