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Regulatory Toxicology and Pharmacology: RTP

Arne Burzlaff, Carol Beevers, Helen Pearce, Melvyn Lloyd, Kevin Klipsch
The potential of molybdenum substances to cause genotoxic effects has been studied previously. However, a review of existing in vitro data, including an assessment of relevance and reliability, has shown that inconsistent results have been observed in the past. To resolve the inconsistencies, new studies were performed with the highly soluble sodium molybdate dihydrate according to OECD test guidelines. In a bacterial reverse mutation assay sodium molybdate dihydrate did not induce reverse mutations in five strains of Salmonella typhimurium...
March 23, 2017: Regulatory Toxicology and Pharmacology: RTP
Diana Isela Araujo-Espino, Ana Lourdes Zamora-Perez, Guillermo Moisés Zúñiga-González, Rosalinda Gutiérrez Hernández, Gabriela Morales-Velazquez, Blanca Patricia Lazalde-Ramos
Jatropha dioica Sessé ex Cerv. is a medicinal plant credited with low cytotoxicity in vitro. Thus, the objective of this work was to evaluate the possible genotoxic and cytotoxic effect in vivo of the J. dioica aqueous extract by means of micronucleus assay in mouse peripheral blood. Four different J. dioica aqueous extract dose-units were evaluated (30, 60, 100, and 300 mg/kg). The extract was administered orally to male Balb-C-strain mice every 24 h during 5 days. Blood samples were taken at 0, 24, 48, 72, 96, and 120 h from the mouse's tail and were performed in duplicate extensions...
March 22, 2017: Regulatory Toxicology and Pharmacology: RTP
Andrew Hill, Oscar M Camacho
In 2012 the US FDA suggested the use of mathematical models to assess the impact of releasing new nicotine or tobacco products on population health outcomes. A model based on system dynamics methodology was developed to project the potential effects of a new nicotine product at a population level. A model representing traditional smoking populations (never, current and former smokers) and calibrated using historical data was extended to a two-product model by including electronic cigarettes use statuses. Smoking mechanisms, such as product initiation, switching, transition to dual use, and cessation, were represented as flows between smoking statuses (stocks) and the potential effect of smoking renormalisation through a feedback system...
March 22, 2017: Regulatory Toxicology and Pharmacology: RTP
Brett J West
No abstract text is available yet for this article.
March 21, 2017: Regulatory Toxicology and Pharmacology: RTP
Helena Cowley, Qin Yan, Lee Koetzner, Laurie Dolan, Erik Nordwald, Aaron B Cowley
Nephure™ is a proprietary oxalate decarboxylase (OxDC) enzyme being developed as a food ingredient. In this study, the safety of Nephure™ was evaluated in a bacterial mutagenicity assay and in a sub-chronic (13-week) oral toxicity study in rats. Nephure™ did not show any mutagenic properties in the mutagenicity assay. In the 13-week sub-chronic oral toxicity study in which 10 Sprague Dawley rats per sex were administered 0, 118, 235 and 475 mg/kg bw/day (8260, 16450 and 33,250 Units/kg bw/day, respectively) of Nephure™ by gavage, male and female rats did not show any test article-related clinical observations or effects on body weight, body weight gain, food consumption, food efficiency, ophthalmology, functional observational battery parameters or motor activity...
March 18, 2017: Regulatory Toxicology and Pharmacology: RTP
Christina L Zuch de Zafra, Vito G Sasseville, Steven Matsumoto, Christian Freichel, Mark Milton, Timothy K MacLachlan, Cindy Farman, Iona Raymond, Swati Gupta, Ronald Newton, Elke-Astrid Atzpodien, Evan A Thackaberry
The nonclinical safety evaluation of therapeutic drug candidates is commonly conducted in two species (rodent and non-rodent) in keeping with international health authority guidance. Biologic drugs typically have restricted species cross-reactivity, necessitating the evaluation of safety in non-human primates and thus limiting the utility of lower order species. Safety studies of cross-reactive ocular biologic drug candidates have been conducted in rabbits as a second toxicology species, despite the fact that rabbits are not a rodent species...
March 16, 2017: Regulatory Toxicology and Pharmacology: RTP
Afa K Palu, John R Wadsworth, David Kasteler, Jacob Smith
No abstract text is available yet for this article.
March 15, 2017: Regulatory Toxicology and Pharmacology: RTP
Huimin Deng, Zhonghao Li, Zhaoyang Bian, Fei Yang, Shanshan Liu, Ziyan Fan, Ying Wang, Gangling Tang
The World Health Organization Study Group on Tobacco Product Regulation (WHO TobReg) proposed mandated ceilings on 9 prioritized mainstream cigarette smoke constituents determined from the market-specific median of nicotine-normalized yield distributions. Considering the requirements for assessing and reporting of compliance with ceilings, it is of great importance to estimate the measurement uncertainty. To have a better understanding of influence of measurement uncertainty on the WHO recommended regulation for cigarette smoke constituents, in the present study, the measurement uncertainties were evaluated systematically based on series of collaborative studies reported by three different authorities over the years from 2012 to 2016, according to the approaches guided in ISO/TS 21748...
March 12, 2017: Regulatory Toxicology and Pharmacology: RTP
Lynne T Haber, Hudson K Bates, Bruce C Allen, Melissa J Vincent, Adriana R Oller
Nickel (Ni) is in the earth's crust and can be found in environmental compartments such as water, soil, and air, as well as food. This paper presents an assessment of the oral nickel toxicity data in support of non-cancer health-based oral exposure limits or toxicity reference values (TRVs). This paper derives TRVs for three populations of interest: adults, toddlers, and people who have been dermally sensitized to nickel. The adult/lifetime TRV of 20 μg Ni/kg-day is based on post-implantation loss/perinatal mortality in a 2-generation reproductive study in rats...
March 11, 2017: Regulatory Toxicology and Pharmacology: RTP
Mizuho Nonaka, Kouhei Amakasu, Yukie Saegusa, Misaki Naota, Takuya Nishimura, Kumiko Ogawa, Akiyoshi Nishikawa
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has been conducting a prospective evaluation period to validate the criteria for waiving some carcinogenicity studies in rats. Before the waiving strategy is practiced in ICH, it is crucial to elucidate whether non-neoplastic lesions are found only in 2-year rat carcinogenicity studies. To confirm possible importance of 2-year bioassays for evaluating chronic toxicity but not carcinogenicity, we retrospectively surveyed 59 pharmaceuticals approved by the Ministry of Health, Labour and Welfare (MHLW) from 2007 to 2010 in Japan for non-neoplastic lesions observed in carcinogenicity studies...
March 10, 2017: Regulatory Toxicology and Pharmacology: RTP
S Stanley Young
Ever since the London Great Smog of 1952 is estimated to have killed over 4000 people, scientists have studied the relationship between air quality and acute mortality. There are many hundreds of papers examining the question. There is a serious statistical problem with most of these papers. If there are many questions under consideration, and there is no adjustment for multiple testing or multiple modeling, then unadjusted p-values are totally unreliable making claims unreliable. Our idea is to determine the statistical reliability of eight papers published in Environmental Health Perspectives that were used in meta-analysis papers appearing in Lancet and JAMA...
March 8, 2017: Regulatory Toxicology and Pharmacology: RTP
Valéria Garrido, Caroline Barros, Vanessa A Melchiades, Rainomar Raimundo Fonseca, Sergio Pinheiro, Patrícia Ocampo, Valéria L Teixeira, Diana N Cavalcanti, Viveca Giongo, Norman A Ratcliffe, Gerlinde Teixeira, Izabel Christina N P Paixão
This study examined in rats the subchronic toxicity and anti- HSV-1activity after oral administration of dolabelladienetriol (D1), a diterpene isolated from the seaweed Dictyota pfaffii. In subchronic toxicity (SCT) tests, female rats received D1 by gavage 15 mg/kg/day (n = 5) for 50 days, and general behavior, death, hematological, biochemical and histological changes in the liver, kidney, stomach, and duodenum were determined. For the anti-HSV-1 activity, female mice were infected and treated orally with a dose of 20 mg/kg (n = 5) twice a day with D1 and any lesions in the skin were then recorded for 18 days...
March 8, 2017: Regulatory Toxicology and Pharmacology: RTP
Alison C Eldridge, Kevin G McAdam, Tatiana R Betson, Marcos V Gama, Christopher J Proctor
The WHO Tobacco Product Regulation Study Group (TobReg) has proposed three regulatory models for cigarettes, each creating mandatory limits for emissions of nine smoke toxicants. One approach proposes country-specific limits, using median or 1.25× median toxicant/nicotine emission ratios. A second model provides fixed toxicant-ratio limits. The third model limits were three times the lowest toxicant emission on a market. Currently, the practical implications of these models are largely unknown. An impact assessment was conducted using cigarette data from 79 countries to identify four diverse test markets...
March 8, 2017: Regulatory Toxicology and Pharmacology: RTP
Liliani Carolini Thiesen, Luisa Mota da Silva, José Roberto Santin, Tania Mari Bellé Bresolin, Sérgio Faloni de Andrade, Clarissa de Medeiros Amorim, Lidia Merlin, Rilton Alves de Freitas, Rivaldo Niero, Daisy Janice Aguilar Netz
We investigated the hepatoprotective effect of methanolic extract from Maytenus robusta leaves in mice and HepG2 cells. The administration of CCl4 in mice promoted a deep destruction of the histological lobular structure and increased the alanine aminotransferase (ALT) serum levels by 46.25% compared with the control group (p < 0.05). The M. robusta extract reduced the hepatic histological changes and normalization the ALT levels. The antioxidant effect of M. robusta in liver tissue promoted the reduction in 31...
March 8, 2017: Regulatory Toxicology and Pharmacology: RTP
Joanne A Lasrado, Kristin M Nieman, Brenda A Fonseca, Kristen D Sanoshy, Arianne L Schild, Kelli A Herrlinger
Spearmint (Mentha spicata L.) and spearmint extracts are Generally Recognized as Safe (GRAS) for use as flavoring in beverages, pharmaceuticals, and confectionaries. Studies of spearmint extracts in humans and animals have reported conflicting results with respect to toxicity. Since the chemical composition of these extracts was not reported and the spearmint source material was different, the relevance of these existing data to evaluating the risks associated with ingestion of a dried aqueous spearmint extract standardized to rosmarinic acid is not clear...
March 7, 2017: Regulatory Toxicology and Pharmacology: RTP
Stephanie Born, David V Gauvin, Suman Mukherjee, Richard Briscoe
Suvorexant (Belsomra(®)) is a dual orexin receptor antagonist approved for the treatment of insomnia. Because of its pharmacology within the central nervous system, intended therapeutic indication, and first-in-class status, an assessment of suvorexant abuse liability potential was required prior to marketing approval. The nonclinical abuse liability potential studies for suvorexant included: 1) rat drug-dependence model to assess physical dependence following abrupt cessation; 2) rat drug-discrimination model to examine the potential similarity of the interoceptive or subjective effects of suvorexant to those elicited by zolpidem and morphine; 3) self-administration model to assess the relative reinforcing efficacy of suvorexant in rhesus monkeys conditioned to self-administer methohexital...
March 6, 2017: Regulatory Toxicology and Pharmacology: RTP
James S Bus
The International Agency for Research on Cancer (IARC) has formulated 10 key characteristics of human carcinogens to incorporate mechanistic data into cancer hazard classifications. The analysis used glyphosate as a case example to examine the robustness of IARC's determination of oxidative stress as "strong" evidence supporting a plausible cancer mechanism in humans. The IARC analysis primarily relied on 14 human/mammalian studies; 19 non-mammalian studies were uninformative of human cancer given the broad spectrum of test species and extensive use of formulations and aquatic testing...
March 6, 2017: Regulatory Toxicology and Pharmacology: RTP
Martin Bopst, Elke-Astrid Atzpodien
The non-clinical safety profile of aleglitazar, a peroxisome proliferator activated receptor alpha/gamma agonist, and its major human metabolite M6 was studied in a complete package consisting of drug metabolism and pharmacokinetics characterization, safety pharmacology, genotoxicity, repeat dose toxicity, reproductive toxicity and carcinogenicity studies. These studies identified the following main targets similar to other PPAR agonists: red blood cell parameters, liver, heart, kidney, ovaries, testes, bone marrow, adipose tissue, and fluid accumulation...
March 6, 2017: Regulatory Toxicology and Pharmacology: RTP
David Basketter, Alan Poole, Ian Kimber
Asthma resulting from sensitisation of the respiratory tract to chemicals is an important occupational health issue, presenting many toxicological challenges. Most importantly there are no recognised predictive methods for respiratory allergens. Nevertheless, it has been found that all known chemical respiratory allergens elicit positive responses in assays for skin sensitising chemicals. Thus, chemicals failing to induce a positive response in skin sensitisation assays such as the local lymph node assay (LLNA) lack not only skin sensitising activity, but also the potential to cause respiratory sensitisation...
March 6, 2017: Regulatory Toxicology and Pharmacology: RTP
Zemin Wang, Xilin Li, James E Klaunig
Chronic dietary exposure to Triclosan (TCS) produced increased incidence of liver tumors in mice. The mechanism for liver tumor induction has been attributed to activation of either peroxisome proliferator activated receptor α (PPARα) or constitutive androstane receptor (CAR). To further define the mechanism of TCS induced liver tumors, male CD-1 and C57BL/6 mice were treated with TCS at 0, 10, 100 and 200 mg/kg diet/day for 14 or 28 days. In addition, a recovery group and positive control groups for CAR or PPARα activation with either phenobarbital or diethylhexyl-phthalate were included in the 14-day study...
March 4, 2017: Regulatory Toxicology and Pharmacology: RTP
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