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Regulatory Toxicology and Pharmacology: RTP

Stephen W Borron, Susan H Watts, Jessica Herrera, Joshua Larson, Salvador Baeza, Richard L Kingston
The ill-defined term "energy drink" includes a disparate group of products (beverages, shots, concentrates, and workout powders) having large differences in caffeine content and concentration and intended use. Hence, inaccurate conclusions may be drawn when describing adverse events associated with "energy drinks". The FDA is considering new regulation of these products but product specificity is needed to evaluate safety. To help address this, we queried Texas Poison Center Network data for single substance exposures to "energy drinks" from 2010 to 2014, then analyzed adverse events by product type...
May 21, 2018: Regulatory Toxicology and Pharmacology: RTP
Cheng You, Dennis K J Lin, S Stanley Young
Since the London Great Smog of 1952 was estimated to have killed over 4000 people, scientists have studied the relationship between air quality and acute mortality. Currently, the association between air quality and acute deaths is usually taken as evidence for causality. As air quality has markedly improved since 1952, do contemporary datasets support this view? We use a large dataset, eight air basins in California for the years 2004-2007, to examine the possible association of ozone and PM2.5 with acute deaths after statistically removing seasonal and weather effects...
May 18, 2018: Regulatory Toxicology and Pharmacology: RTP
Melvin E Andersen, George Cruzan, Michael B Black, Salil N Pendse, Darol E Dodd, James S Bus, Satinder S Sarang, Marcy I Banton, Robbie Waites, Debra B Layko, Patrick D McMullen
Both CD-1 and C57BL/6 wildtype (C57BL/6-WT) mice show equivalent short-term lung toxicity from exposures to styrene, while long-term tumor responses are greater in CD-1 mice. We analyzed lung gene expression from styrene exposures lasting from 1-day to 2-years in male mice from these two strains, including a Cyp2f2(-/-) knockout (C57BL/6-KO) and a Cyp2F1/2A13/2B6 transgenic mouse (C57BL/6-TG). With short term exposures (1-day to 1-week), CD-1 and C57BL/6-WT mice had thousands of differentially expressed genes (DEGs), consistent with changes in pathways for cell proliferation, cellular lipid metabolism, DNA-replication and inflammation...
May 16, 2018: Regulatory Toxicology and Pharmacology: RTP
Thomas Visalli, Nancy Bower, Tushar Kokate, Paul A Andrews
Toxicity studies in juvenile animals (JAS) are sometimes performed to support clinical trials in pediatric oncology patients, and there are differing conclusions on the value of JAS for pediatric drug development. This manuscript provides a review of the pediatric clinical data for 25 molecularly-targeted and 4 biologic anticancer therapeutics. Other publications that evaluated the value of JAS in pediatric drug development focus on differences in toxicity between juvenile animals and adult animals. The present paper examines pediatric-specific clinical findings to focus on dose setting in pediatric oncology patients and safety monitoring in terms of the potential value of JAS...
May 12, 2018: Regulatory Toxicology and Pharmacology: RTP
Shiying Zou, Tianqi Lang, Xu Liu, Kunlun Huang, Xiaoyun He
Genetically modified (GM) maize, DAS-40278-9, expresses the aryloxyalkanoate dioxygenase-1 (AAD-1) protein, which confers tolerance to 2,4-dichlorophenoxyacetic acid (2,4-D) and aryloxyphenoxypropionate (AOPP) herbicides. The aad-1 gene, which expresses the AAD-1 protein, was derived from Gram-negative soil bacterium, Sphingobium herbicidovorans. A 90-day sub-chronic toxicity study was conducted on rats as a component of the safety evaluation of DAS-40278-9 maize. Rats were given formulated diets containing maize grain from DAS-40278-9 or a non-GM near isogenic control comparator at an incorporation rate of 12...
May 12, 2018: Regulatory Toxicology and Pharmacology: RTP
Youyou Zhang, Xiaowei Zhou, Jie Zhang, Chuhuai Guan, Liang Liu
Cantharides poisoning may cause serious adverse reactions or even death.We attempt to retrieval articles automatically and manually with the key words of "cantharides" and " poisoning " or " side effects ", then summarized and analyzed the cases of cantharides poisoning from 1996 to 2016 in China, to provide some reference for clinical drug use and forensic identification. Finally, 91 cases were conformance to require; general data, clinical data, prognosis, autopsy results were analyzed...
May 10, 2018: Regulatory Toxicology and Pharmacology: RTP
Dai Yuki
The objectives of this clinical study were to demonstrate a reduction in exposure to selected harmful and potentially harmful constituents (HPHCs), and to assess product use behavior, in Japanese healthy adult smokers who switched to a novel tobacco vapor product (NTV). 60 smokers were randomly assigned for 5 days to either (a) a group who switched to an NTV (n = 20), (b) a group who continued to smoke their own brand of conventional cigarettes (CC, n = 20) or (c) a smoking abstinence group (SA, n = 20)...
May 5, 2018: Regulatory Toxicology and Pharmacology: RTP
Chad M Thompson, Mina Suh, Grace Chappell, Susan Borghoff, Robert Ellis-Hutchings, Karin Wiench, Lavorgie Finch, Deborah M Proctor
Chronic repeated gavage dosing of high concentrations of ethyl acrylate (EA) causes forestomach tumors in rats and mice. For two decades, there has been general consensus that these tumors are unique to rodents because of: i) lack of carcinogenicity in other organs, ii) specificity to the forestomach (an organ unique to rodents which humans do not possess), iii) lack of carcinogenicity by other routes of exposure, and iv) obvious site of contact toxicity at carcinogenic doses. In 1986, EA was classified as possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC)...
May 5, 2018: Regulatory Toxicology and Pharmacology: RTP
Matthew Clark
Although lack of efficacy is an important cause of late stage attrition in drug development the shortcomings in the translation of toxicities observed during the preclinical development to observations in clinical trials or post-approval is an ongoing topic of research. The concordance between preclinical and clinical safety observations has been analyzed only on relatively small data sets, mostly over short time periods of drug approvals. We therefore explored the feasibility of a big-data analysis on a set of 3290 approved drugs and formulations for which 1,637,449 adverse events were reported for both humans animal species in regulatory submissions over a period of more than 70 years...
May 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Shinkichi Ishikawa, Kazushi Matsumura, Nobumasa Kitamura, Kanae Ishimori, Yuichiro Takanami, Shigeaki Ito
Recent advancements in in vitro exposure systems and cell culture technology enable direct exposure to cigarette smoke (CS) of human organotypic bronchial epithelial cultures. MucilAir organotypic bronchial epithelial cultures were exposed, using a Vitrocell exposure system, to mainstream aerosols from the 3R4F cigarette or from a recently developed novel tobacco vapor product (NTV). The exposure aerosol dose was controlled by dilution flow and the number of products smoked; there were five exposure conditions for 3R4F smoke and three for NTV vapor...
May 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Nigel S B Rawson
The objectives of this analysis were to assess whether consistency in Health Canada's (HC's) approval times identified in 2011 has been sustained and to compare HC's approval times with those of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Between 2002 and 2016, 460 new drugs were approved by at least one of the agencies: 351 (76.3%), 319 (69.3%) and 392 (85.2%) by HC, the EMA and the FDA, respectively - all three approved 252 (54.8%). Overall medians and inter-quartile ranges of approval times for HC, the EMA and the FDA were 364 days (343-651), 371 days (322-434) and 304 days (209-455), respectively...
May 3, 2018: Regulatory Toxicology and Pharmacology: RTP
David W Roberts, Anne Marie Api
Prediction of skin sensitisation potential and potency by non-animal methods is the target of many active research programmes. Although the aim is to predict sensitisation potential and potency in humans, data from the murine local lymph node assay (LLNA) constitute much the largest source of quantitative data on in vivo skin sensitisation. The LLNA has been the preferred in vivo method for identification of skin sensitising chemicals and as such is potentially valuable as a benchmark for assessment of non-animal approaches...
May 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Dandan Yan, Yunjian Zhang, Liegang Liu, Nian Shi, Hong Yan
The cause of late onset Parkinson's disease (PD) remains unknown. Evidence suggested that lifelong exposure to pesticides might contribute to the development of neurodegenerative diseases, but the results were controversial. Relevant studies were identified by searching PubMed and Web of Science through September 2017. We included cohort and case-control studies reporting relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) of three or more categories of pesticide exposure and PD. Ten articles with 13 reports (3 for cumulative exposure, 10 for duration exposure) were included...
May 2, 2018: Regulatory Toxicology and Pharmacology: RTP
Michael L Dourson
The Integrated Risk Information System (IRIS) of the U.S. Environmental Protection Agency (EPA) has an important role in protecting public health. Originally it provided a single database listing official risk values equally valid for all Agency offices, and was an important tool for risk assessment communication across EPA. Started in 1986, IRIS achieved full standing in 1990 when it listed 500 risk values, the effort of two senior EPA groups over 5 years of monthly face-to-face meetings, to assess combined risk data from multiple Agency offices...
May 2, 2018: Regulatory Toxicology and Pharmacology: RTP
Ediberto Garcia, Daniel Newfang, Jayme P Coyle, Charles L Blake, John W Spencer, Leonard G Burrelli, Giffe T Johnson, Raymond D Harbison
Three independently conducted asbestos exposure evaluations were conducted using wire gauze pads similar to standard practice in the laboratory setting. All testing occurred in a controlled atmosphere inside an enclosed chamber simulating a laboratory setting. Separate teams consisting of a laboratory technician, or technician and assistant simulated common tasks involving wire gauze pads, including heating and direct wire gauze manipulation. Area and personal air samples were collected and evaluated for asbestos consistent with the National Institute of Occupational Safety Health method 7400 and 7402, and the Asbestos Hazard Emergency Response Act (AHERA) method...
April 30, 2018: Regulatory Toxicology and Pharmacology: RTP
Zhi-Yong Qian, Shu-Jing Zhang, Li Zhang, Jing Zhang, Ying-Hua Liu, Qing-Hong Zhou, Shu-Qing Jiang, Shu-Fei Li
A 90-day feeding study in rats was conducted to evaluate the subchronic oral toxicity of genetically modified (GM) DAS-81419-2 soybean. Wistar rats were fed with diets containing toasted soybean meal produced from DAS-81419-2 soybean grain that expresses the Cry1F, Cry1Ac, and Pat proteins or containing conventional soybean at doses of 30.0%, 15.0%, 7.5%, or 0% (control group) for 90 consecutive days. The general behavior, body weight and food consumption were observed. At the middle and end of the experiment, blood, serum, and urine samples were collected for biochemical assays...
April 28, 2018: Regulatory Toxicology and Pharmacology: RTP
Lin-Chau Chang, Thomas E Colonna
The rapid progress in "omics", such as genomics, metabolomics, microbiomics, has paved the path for precision medicine and revolutionized the development of drugs and devices promising to meet unmet medical needs. The aim of the present study was to investigate the current regulatory framework established by the United States Food and Drug Administration (USFDA) and to identify challenges and concerns through study of related literatures in the PubMed database. We found that efforts were made to facilitate the implementation of precision medicine through organizational reform, publication of guidance documents, and continuous post-market surveillance...
April 28, 2018: Regulatory Toxicology and Pharmacology: RTP
Toshime Igarashi, Hideki Serizawa, Katsumi Kobayashi, Hiroshi Suzuki, Mariko Matsumoto, Takako Iso, Tomoko Kawamura, Kaoru Inoue, Atsushi Ono, Takashi Yamada, Akihiko Hirose
4-Benzylphenol (CAS No. 101-53-1), a structural analog of bisphenol F, has estrogenic activity in vitro and in vivo, as is the case with bisphenol F. 4-Benzylphenol is used in plastics and during organic synthesis. Since its safety is largely unknown, we conducted toxicity tests as part of screening risk assessment in an existing chemical safety survey program. Based on results of the Ames test and the chromosomal aberration test using Chinese hamster lung cells (OECD TG 471 and 473), 4-benzylphenol was determined to be non-genotoxic in vitro...
April 26, 2018: Regulatory Toxicology and Pharmacology: RTP
Deborah M Proctor, Mina Suh, Grace Chappell, Susan J Borghoff, Chad M Thompson, Karin Wiench, Lavorgie Finch, Robert Ellis-Hutchings
The utility of rodent forestomach tumor data for hazard and risk assessment has been examined for decades because humans do not have a forestomach, and these tumors occur by varying modes of action (MOAs). We have used the MOA for ethyl acrylate (EA) to develop an Adverse Outcome Pathway (AOP) for forestomach tumors caused by non-genotoxic initiating events. These tumors occur secondary to site of contact induced epithelial cytotoxicity and regenerative repair-driven proliferation. For EA, the critical initiating event (IE) is epithelial cytotoxicity, and supporting key events (KEs) at the cellular and tissue level are increased cell proliferation (KE1) resulting in sustained hyperplasia (KE2), with the adverse outcome of forestomach papillomas and carcinomas...
April 20, 2018: Regulatory Toxicology and Pharmacology: RTP
John L Vahle, Ulf Anderson, Eric A G Blomme, Jean-Christophe Hoflack, Daniel P Stiehl
Toxicogenomics held great promise as an approach to enable early detection of toxicities induced by xenobiotics; however, there remain questions regarding the impact of the discipline on pharmaceutical nonclinical safety assessment. To understand the current state of toxicogenomics in the sector, an industry group surveyed companies to determine the frequency of toxicogenomics use in in vivo studies at various stages of drug discovery and development and to assess how toxicogenomics use has evolved over time...
April 18, 2018: Regulatory Toxicology and Pharmacology: RTP
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