3,963 results match your criteria Regulatory Toxicology and Pharmacology [Journal]


Acute and sub-chronic oral toxicity studies of hesperidin isolated from orange peel extract in Sprague Dawley rats.

Regul Toxicol Pharmacol 2019 Apr 13. Epub 2019 Apr 13.

Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Paud Road, Pune, 411038, India. Electronic address:

Citrus sinensis contains glycoside hesperetin-7-rhamnoglucoside (hesperidin) which harbor an array of therapeutic potentials including antioxidant, anticancer, and anti-inflammatory. However, a systematic examination of safety is needed before its utilization. Hence, the present investigation is aimed to evaluate acute and sub-chronic toxicity of hesperidin isolated from the citrus fruit. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.04.001DOI Listing

Analysis of exposure margins in developmental toxicity studies for detection of human teratogens.

Regul Toxicol Pharmacol 2019 Apr 11;105:62-68. Epub 2019 Apr 11.

Merck & Co, Inc., West Point, PA, USA.

The draft Step 2 ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high-dose in reproductive and developmental toxicity studies. To help determine an appropriate exposure margin for embryofetal developmental toxicity testing, a retrospective analysis was undertaken to determine what threshold would have been sufficient to detect hazards to embryofetal development in rats and rabbits for 18 known and 4 presumed human teratogens. The analysis showed that using a high dose that provided at least a 6-fold exposure margin in the developmental toxicity studies would have been sufficient to detect the teratogenic hazard with relevance for humans for all these therapeutics. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S02732300193009
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http://dx.doi.org/10.1016/j.yrtph.2019.04.005DOI Listing
April 2019
1 Read

User-oriented independent analysis of the toxic load model's ability to predict the effects of time-varying toxic inhalation exposures.

Regul Toxicol Pharmacol 2019 Apr 9. Epub 2019 Apr 9.

Institute for Defense Analyses, 4850 Mark Center Drive, Alexandria, VA, 22311-1882, USA.

Toxic industrial chemicals and chemical warfare agents present an acute inhalation hazard to exposed populations. The hazardous materials consequence assessment modeling community requires toxicity models to estimate these hazards. One popular phenomenological toxicity model is the toxic load model. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.04.003DOI Listing

Eye hazard classification according to UN GHS / EU CLP and the severity of eye symptoms caused by accidental exposures to detergents and cleaning products.

Regul Toxicol Pharmacol 2019 Apr 9;105:69-76. Epub 2019 Apr 9.

Toxicological Information Centre, Department of Occupational Medicine, First Faculty of Medicine, Charles University and General University Hospital Prague, Czech Republic.

The use of lower cut-off values/concentration limits for the calculation of mixture classification in UN GHS/EU CLP versus the previous regulatory scheme (EU Dangerous Preparations Directive, DPD), has resulted in an increased number of classifications in the highest eye hazard category. Herein, a semi-quantitative categorisation of severity of eye effects, following accidental human exposures to detergents, was compared to the classification category of the products. Three schemes were evaluated: EU DPD; EU CLP (based on all available data and information, including weight of evidence); and EU CLP (based entirely on the calculation method). Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.04.004DOI Listing

The implementation of RAAF in the OECD QSAR Toolbox.

Regul Toxicol Pharmacol 2019 Apr 7;105:51-61. Epub 2019 Apr 7.

Laboratory of Mathematical Chemistry (LMC), As. Zlatarov University, Bourgas, Bulgaria. Electronic address:

The Read-Across Assessment Framework (RAAF) was developed by the European Chemicals Agency (ECHA) as an internal tool providing a framework for a consistent, structured and transparent assessment of grouping of chemicals and read-across. Following a RAAF-based evaluation, also developers and users of read-across predictions outside ECHA can judge whether their read-across rationale is sufficiently robust from a regulatory perspective. The aim of this paper is to describe the implementation of RAAF functionalities in the OECD QSAR Toolbox report. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.018DOI Listing

Overgeneralization by Anderson et al. and Luz et al. regarding safety of fluorotelomer-based chemistry.

Regul Toxicol Pharmacol 2019 Apr 5. Epub 2019 Apr 5.

Environmental Defense Fund, Washington, DC, 20009, USA.

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http://dx.doi.org/10.1016/j.yrtph.2019.04.002DOI Listing

Evaluation of toxicokinetics of nonylphenol in the adult female Sprague-Dawley rats using a physiologically based toxicokinetic model.

Regul Toxicol Pharmacol 2019 Apr 5;105:42-50. Epub 2019 Apr 5.

Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China. Electronic address:

The physiologically based toxicokinetic (PBTK) model was firstly developed in female rats to quantitatively evaluate toxicokinetics of nonylphenol (NP). Changes in NP serum concentrations over time of single oral NP administration experiments in Sprague-Dawley rats and literature data were collected to establish and calibrate the PBTK model in the SimBiology framework. The calibrated model predicted the serum and tissue NP concentrations of repeat oral NP administration for model evaluation. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.019DOI Listing
April 2019
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Effect of plant extracts on the genotoxicity of 1'-hydroxy alkenylbenzenes.

Regul Toxicol Pharmacol 2019 Mar 29;105:36-41. Epub 2019 Mar 29.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.

Food-borne alkenylbenzenes are potential risks for human health because they are known to induce liver tumors in rodent bioassays at high dose levels. This carcinogenicity is ascribed to the conversion of their 1'-hydroxymetabolites to the ultimate DNA reactive and carcinogenic 1'-sulfoxymetabolites. The aim of this study was to investigate the in vitro genotoxicity of some botanical extracts used as Plant Food Supplements (PFS) and to compare it with the individual substances, estragole, safrole and their 1'-hydroxy-derivative activity. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.017DOI Listing
March 2019
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Use of stem cells as alternative methods to animal experimentation in predictive toxicology.

Regul Toxicol Pharmacol 2019 Mar 28;105:15-29. Epub 2019 Mar 28.

Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, Republic of Korea. Electronic address:

Despite a major role of experimental animals in development of biomedical research, there has been historical controversy surrounding animal research. Along with a strategy of 3Rs, various in vitro methods have been suggested to replace potentially painful animal experiments. In this review, we summarize the use of stem cells as an alternative of animal experimentation in predictive toxicology. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.016DOI Listing

Response to "Overgeneralization by Anderson et al. and Luz et al. regarding safety of fluorotelomer-base chemistry".

Regul Toxicol Pharmacol 2019 Mar 27. Epub 2019 Mar 27.

Integral Consulting Inc, 7030 E Genesee Street, Suite 105, Fayetteville, NY, 13066, USA.

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http://dx.doi.org/10.1016/j.yrtph.2019.03.015DOI Listing

Evaluation of the avian acute oral and sub-acute dietary toxicity test for pesticide registration.

Regul Toxicol Pharmacol 2019 Mar 25;105:30-35. Epub 2019 Mar 25.

PETA International Science Consortium Ltd, London, UK.

The United States Environmental Protection Agency (USEPA), as well as other international regulatory agencies, require pesticide registrants to submit toxicity data that are used to conduct ecological risk assessments. While the USEPA has required both an acute oral and sub-acute dietary test in birds, trends in the use of data from these tests over the past 20 years have suggested that the avian sub-acute dietary test generally does not contribute to risk assessment conclusions. To address this question, a retrospective analysis was conducted to evaluate 119 pesticides with publicly available ecological risk assessments that were registered into commerce between 1998 and 2017. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S02732300193008
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http://dx.doi.org/10.1016/j.yrtph.2019.03.013DOI Listing
March 2019
1 Read

Toxicological evaluation of carcinogenicity of the pyrethroid imiprothrin in rats and mice.

Regul Toxicol Pharmacol 2019 Mar 21;105:1-14. Epub 2019 Mar 21.

Havlik-Wall Professor of Oncology, Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135, Omaha, NE, 68198-3135, USA.

The carcinogenic potential of a non-genotoxic pyrethroid imiprothrin was examined in rats and mice. There was no carcinogenicity in rats up to a maximum dose of 5000 ppm of the diet. There was a higher (p = 0. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.012DOI Listing

Acute and genetic toxicity of GS-E3D, a new pectin lyase-modified red ginseng extract.

Regul Toxicol Pharmacol 2019 Jun 21;104:157-162. Epub 2019 Mar 21.

Department of Nanofusion Technology, Hoseo University, Asan, 31499, South Korea. Electronic address:

Korean red ginseng and its extract have been used as traditional medicines and functional foods in countries worldwide. Pectin lyase-modified red ginseng extract (GS-E3D) was newly developed as a dietary supplement for obesity, diabetes-related renal dysfunction, etc. In this study, the safety of GS-E3D on acute toxicity and genotoxicity was evaluated. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.010DOI Listing

Fragrance inhalation and adverse health effects: The question of causation.

Regul Toxicol Pharmacol 2019 Jun 21;104:151-156. Epub 2019 Mar 21.

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.

The toxicology of fragrance materials is largely well understood. Although most are benign, a minority have the potential to cause adverse health effects, notably allergic contact dermatitis resulting from skin sensitization. As a consequence, industry guidelines have banned certain materials and strictly limited the use of others. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.011DOI Listing
June 2019
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Micronutrient and heavy metal concentrations in basil plant cultivated on irradiated and non-irradiated sewage sludge- treated soil and evaluation of human health risk.

Regul Toxicol Pharmacol 2019 Jun 17;104:141-150. Epub 2019 Mar 17.

Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G.C., Evin, Tehran, Iran.

Gamma irradiation is regarded as a promising alternative method for sewage sludge (SS) treatment. To evaluate the human health risk and effects of gamma irradiated and non-irradiated SS (SSGI and SSNI, respectively) on micronutrient and heavy metal concentrations in basil (Ocimum basilicum L.) as a test plant, a greenhouse experiment based on completely randomized design was conducted with control (without SS and irradiation) and 15, 30 and 60 g kg of SSNI as well as SSGI (irradiated with doses of 5, 10 and 20 kGy) with three replicates. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.009DOI Listing

Evaluation of behavioral profiles in mice fed with milk supplemented diets derived from human lactoferrin gene-modified cows.

Regul Toxicol Pharmacol 2019 Jun 16;104:133-140. Epub 2019 Mar 16.

Key Laboratory of Food Safety Risk Assessment of Ministry of Health, China National Center for Food Safety Risk Assessment, Beijing 100021, PR China. Electronic address:

To date, many safety assessments of genetically modified (GM) food have been done, but there was still considerable skepticism about the safety of genetic modified foods because no study could be designed to discover all of the potential effects. Since behavioral endpoints could provide one of the most sensitive strategies to reveal subtle functional deficits. In the present study, behavioral profiles in mice fed with milk derived from human lactoferrin gene-modified cows were investigated to enrich the toxicological data of GM food. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.008DOI Listing

Flavonoids protect colon against radiation induced colitis.

Regul Toxicol Pharmacol 2019 Jun 13;104:128-132. Epub 2019 Mar 13.

Zonguldak Bulent Ecevit University Faculty of Medicine, Department of Public Health, Zonguldak, Turkey.

Radiation induced colitis is one the most common clinical issue for patients receiving radiotherapy. For this reason, we aimed to investigate the effect of antioxidant-effective flavonoids hesperidin and quercetin on the intestinal damage induced by radiation in this study. TNF-alpha, interleukin-10 (IL-10), heat shock protein 70 (HSP 70) and caspase 3, 8, 9 markers of apoptotic pathways were measured in the colon tissues of irradiated acute intestinal damage by enzyme-linked immunosorbent assay (ELISA). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S02732300193007
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http://dx.doi.org/10.1016/j.yrtph.2019.03.006DOI Listing
June 2019
6 Reads

Sex differences in subacute manganese intoxication: Oxidative parameters and metal deposition in peripheral organs of adult Wistar rats.

Regul Toxicol Pharmacol 2019 Jun 13;104:98-107. Epub 2019 Mar 13.

Programa de Pós-Graduação em Biociências e Saúde (PPGBS), Área de Ciências da Vida e Saúde, Universidade do Oeste de Santa Catarina (UNOESC), Campus de Joaçaba, SC, Brazil. Electronic address:

Introduction: Manganese (Mn) is an essential element required for several biological systems. However, it is toxic in excessive accumulation. The toxic effects following Mn overexposure is well known in the CNS but other studies evaluating other target tissues remain scarce. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.005DOI Listing

Toxicological assessment of Tobacco Heating System 2.2: Findings from an independent peer review.

Regul Toxicol Pharmacol 2019 Jun 14;104:115-127. Epub 2019 Mar 14.

PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000, Neuchâtel, Switzerland.

Offering safer alternatives to cigarettes, such as e-cigarettes and heated tobacco products, to smokers who are not willing to quit could reduce the harm caused by smoking. Extensive and rigorous scientific studies are conducted to assess the relative risk of such potentially modified risk tobacco products compared with that of smoking cigarettes. In addition to the peer review of publications reporting individual studies, we aimed to gauge the plausibility of the evidence to the scientific community and appreciate likely necessary additions prior to regulatory submission. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.007DOI Listing

Critical issues and alternatives for the establishment of chemical water quality criteria for livestock.

Regul Toxicol Pharmacol 2019 Jun 11;104:108-114. Epub 2019 Mar 11.

School of Technology, University of Campinas, Rua Pascoal Marmo 1888, 13484-332, Limeira, SP, Brazil. Electronic address:

Good water quality for livestock is essential for animal health, supply of safe food and food production economy. Few countries have established water quality criteria for livestock for chemical contaminants. For those that have them, the values are quite variable among each other for the same substance due to differences in the approach for the acceptable daily intakes and algorithms for the calculation. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.003DOI Listing

Oxidative stress, DNA damage, and mutagenicity induced by the extractable organic matter of airborne particulates on bacterial models.

Regul Toxicol Pharmacol 2019 Jun 11;104:59-73. Epub 2019 Mar 11.

Environmental Pollution Control Laboratory, Department of Chemistry, Aristotle University of Thessaloniki, GR-54124, Thessaloniki, Greece. Electronic address:

The biological activity induced by the extractable organic matter (EOM) of size-segregated airborne Particulate Matter (PM) from two urban sites, urban traffic (UT) and urban background (UB), was assessed by using bacterial assays. The Gram-negative Escherichia coli (E. coli) coliform bacterium was used to measure the intracellular formation of Reactive Oxygen Species (ROS) by employing the Nitroblue tetrazolium (NBT) reduction assay and the lipid peroxidation by malondialdehyde (MDA) measurement. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.004DOI Listing

Assessment of priority tobacco additives per the requirements in the EU Tobacco Products Directive (2014/40/EU): Part 2: Smoke chemistry and in vitro toxicology.

Regul Toxicol Pharmacol 2019 Jun 8;104:163-199. Epub 2019 Mar 8.

Philip Morris International, Philip Morris Products SA, Rue des Usines 90, 2000, Neuchâtel, Switzerland.

This publication is part of a series of three publications and describes the non-clinical assessment performed to fulfill the regulatory requirement per Art. 6 (2) of the EU Tobacco Products Directive 2014/40/EU under which Member States shall require manufacturers and importers of cigarettes and Roll Your Own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies (European Comission, 2016). This publication contains the results of a literature search, comprehensive smoke chemistry, additive transfer, and in vitro toxicity studies for the 13 priority additives (carob bean extract, cocoa powder, fenugreek extract, fig juice concentrate, geraniol, glycerol, guaiacol, guar gum, liquorice extract powder, maltol, l-menthol (synthetic), propylene glycol, and sorbitol) commissioned by the members of the Priority Additives Tobacco Consortium to independent Contract Research Organizations. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.002DOI Listing
June 2019
3 Reads

Evaluation of the efficacy in cosmetic products safety: Comparison with biochemical substrates.

Regul Toxicol Pharmacol 2019 Jun 8;104:56-58. Epub 2019 Mar 8.

Mugla Sitki Kocman University, Faculty of Science, Department of Chemistry, 48000, Kotekli-Mugla, Turkey.

Chemicals used in cosmetics must interact with the enzymes for their consumption after entering our bodies. The area at which the interaction realizes on the enzyme is known as the active center. This center is three dimensional and optically active. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.03.001DOI Listing

Factors effecting the induction of rat forestomach hyperplasia induced by Swedish oral smokeless tobacco (snus).

Regul Toxicol Pharmacol 2019 Jun 4;104:21-28. Epub 2019 Mar 4.

Vinča Institute of Nuclear Sciences, Department of Physical Chemistry, University of Belgrade, POB 522, 11000, Belgrade, Serbia. Electronic address:

Long term exposure to oral smokeless tobacco may induce lesions in the oral cavity characterized by a hyperplastic epithelium. The possible role of nicotine and the physical properties of oral tobacco for developing these lesions, as well as of dysplasia and neoplasia is unclear. Low nitrosamine Swedish snus as well as non-genotoxic butylated hydroxyanisole induces increased cellular proliferation in the rat forestomach epithelia. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.015DOI Listing
June 2019
1 Read

Developing OECD test guidelines for regulatory testing of nanomaterials to ensure mutual acceptance of test data.

Regul Toxicol Pharmacol 2019 Jun 1;104:74-83. Epub 2019 Mar 1.

European Commission, Joint Research Centre, Ispra, via E. Fermi 2749, 21027, Ispra, (VA), Italy. Electronic address:

The OECD Working Party on Manufactured Nanomaterials (WPMN) provides a global forum for discussion of nano-safety issues. Together with the OECD Test Guidelines Programme (TGP) the WPMN has explored the need for adaptation of some of the existing OECD Test Guidelines (TGs) and Guidance Documents (GDs) as well as developing new TGs and GDs to specifically address NM issues. An overview is provided of progress in the TGP and WPMN, and information on supporting initiatives, regarding the development of TGs for nanomaterials addressing Physical Chemical Properties, Effects on Biotic Systems, Environmental Fate and Behaviour, and Health Effects. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.008DOI Listing
June 2019
3 Reads
2.031 Impact Factor

Toxicological evaluations of colostrum ultrafiltrate.

Regul Toxicol Pharmacol 2019 Jun 1;104:39-49. Epub 2019 Mar 1.

Toxi-Coop Zrt, Magyar Jakobinusok Tere 4/B, H-1122 Budapest, Hungary. Electronic address:

Colostrum has been consumed safely for many years as a food collected directly from cows. More recently, an ultrafiltrated bovine colostrum product has been developed; however, its safety in toxicology studies has not been extensively evaluated. To assess the safety of bovine colostrum ultrafiltrate, in accordance with internationally accepted standards, the genotoxic potential was investigated in a bacterial reverse mutation test, an in vitro chromosomal aberration test, and an in vivo mammalian micronucleus test. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S02732300193006
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http://dx.doi.org/10.1016/j.yrtph.2019.02.017DOI Listing
June 2019
11 Reads
2.031 Impact Factor

The activity of methacrylate esters in skin sensitisation test methods: A review.

Authors:
Ian Kimber

Regul Toxicol Pharmacol 2019 Jun 28;104:14-20. Epub 2019 Feb 28.

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. Electronic address:

Skin sensitisation associated with allergic contact dermatitis is an important occupational and environmental disease. The identification of skin sensitisation hazards was traditionally performed using animal tests; originally guinea pig assays and subsequently the murine local lymph node assay (LLNA). More recently there has, for a variety of reasons, been an increased interest in, and requirement for, non-animal assays. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.014DOI Listing
June 2019
2 Reads

Systemic toxicity of di (2-ethylhexyl) adipate (DEHA) in rats following 28-day intravenous exposure.

Regul Toxicol Pharmacol 2019 Jun 28;104:50-55. Epub 2019 Feb 28.

Baxter Healthcare Corporation, PreClinical, Roundlake, United States.

Di (2-ethylhexyl) adipate (DEHA) is a potential plasticizer alternative for di-2-ethylhexyl phthalate (DEHP). Toxicity of DEHA has been studied mostly via oral exposure but not assessed after repeated intravenous exposure. The present study shows the toxicity effects after intravenous administration for 28 consecutive days and the reversibility of the effects following a 14-day recovery period. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S02732300193006
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http://dx.doi.org/10.1016/j.yrtph.2019.02.016DOI Listing
June 2019
2 Reads

Assessment of priority tobacco additives per the requirements of the EU Tobacco Products Directive (2014/40/EU): Part 3, Smoking behavior and plasma nicotine pharmacokinetics.

Regul Toxicol Pharmacol 2019 Jun 26;104:29-38. Epub 2019 Feb 26.

British American Tobacco, Research & Development, Regents Park Road, Southampton, SO158TL, United Kingdom.

This publication is part of a series of 3 publications and describes the clinical assessment performed to fulfill the regulatory requirement per Art. 6 (2) of the EU Tobacco Products Directive 2014/40/EU under which Member States require manufacturers and importers of cigarettes and Roll Your Own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies (European Union, 2016). In our clinical study, two distinct end points were investigated, namely measuring plasma nicotine pharmacokinetics as a measure of nicotine uptake, and analyses of changes in smoker puffing behavior as a measure of cigarette smoke inhalation. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.012DOI Listing
June 2019
3 Reads

Toxicity studies for the use of prodrug of voriconazole in rats.

Regul Toxicol Pharmacol 2019 Jun 25;104:8-13. Epub 2019 Feb 25.

China Pharmaceutical University, Nanjing, 210009, China.

It has been reported that voriconazole is used to treat infections caused by invasive aspergillosis, fluconazole-resistant Candida, Actinoplanes and Fusarium. This study was performed to investigate the safety of prodrug of voriconazole (POV) and explore the distribution and metabolism of POV in vivo. The POV for injection was formulated into POV injection. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.013DOI Listing

Assessment of priority tobacco additives per the requirements of the EU Tobacco Products Directive (2014/40/EU): Part 1: Background, approach, and summary of findings.

Regul Toxicol Pharmacol 2019 Jun 21;104:84-97. Epub 2019 Feb 21.

Philip Morris International, Philip Morris International Management SA, Avenue de Rhodanie 50, 1001, Lausanne, Switzerland.

This paper is part of a series of 3 publications and describes the non-clinical and clinical assessment performed to fulfill the regulatory requirement per Art. 6 (2) of the EU Tobacco Products Directive 2014/40/EU; under which Member States shall require manufacturers and importers of cigarettes and roll-your-own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies. The Directive requires manufacturers and importers of cigarettes and Roll Your Own tobacco to examine for each additive whether it; contributes to and increases the toxicity or addictiveness of tobacco products to a significant or measurable degree; if it leads to a characterizing flavor of the product; if it facilitates inhalation or nicotine uptake, and if it results in the formation of CMR (carcinogenic, mutagenic and reprotoxic) constituents and if these substances increase the CMR properties of the respective tobacco product to a significant or measurable degree. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.011DOI Listing
June 2019
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A case study on the application of an expert-driven read-across approach in support of quantitative risk assessment of p,p'-dichlorodiphenyldichloroethane.

Regul Toxicol Pharmacol 2019 Apr 19;103:301-313. Epub 2019 Feb 19.

National Center for Environmental Assessment (NCEA), U.S. Environmental Protection Agency, Cincinnati, OH, 45268, USA.

Deriving human health risk estimates for environmental chemicals has traditionally relied on in vivo toxicity databases to characterize potential adverse health effects and associated dose-response relationships. In the absence of in vivo toxicity information, new approach methods (NAMs) such as read-across have the potential to fill the required data gaps. This case study applied an expert-driven read-across approach to identify and evaluate analogues to fill non-cancer oral toxicity data gaps for p,p'-dichlorodiphenyldichloroethane (p,p'-DDD), an organochlorine contaminant known to occur at contaminated sites in the U. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.010DOI Listing
April 2019
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Effect of acute exposure in swiss mice (Mus musculus) to a fibrinolytic protease produced by Mucor subtilissimus UCP 1262: An histomorphometric, genotoxic and cytological approach.

Regul Toxicol Pharmacol 2019 Apr 18;103:282-291. Epub 2019 Feb 18.

Laboratory of Bioactive Technology, Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Rua Dom Manoel de Medeiros, s / n, Dois Irmãos, 52171-900, Recife, Pernambuco, Brazil. Electronic address:

The fibrinolytic enzyme produced by Mucor subtilissimus UCP 1262 was obtained by solid fermentation and purified by ion exchange chromatography using DEAE-Sephadex A50. The enzyme toxicity was evaluated using mammalian cell lineages: HEK-293, J774.A1, Sarcoma-180 and PBMCs which appeared to be viable at a level of 80%. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.009DOI Listing
April 2019
1 Read
2.031 Impact Factor

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

Regul Toxicol Pharmacol 2019 Jun 16;104:1-7. Epub 2019 Feb 16.

Charles River, Ashland, OH, USA.

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. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.034DOI Listing
June 2019
3 Reads

Toxicological assessment compilation of selected examples of raw materials for homeopathic medicinal products.

Regul Toxicol Pharmacol 2019 Apr 13;103:253-273. Epub 2019 Feb 13.

Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany.

The considerable number of homeopathic medicinal products (HMP) on the German market and the staggering breadth of active substances of various origin along with the specific legal requirements of adequate safety principles posed the need to compile data on toxicologically evaluated raw materials. In line with the European regulatory framework, HMP applications must consider appropriate safety standards in analogy to conventional human medicinal products. This review presents an option for a systematic and scientifically substantiated approach for regulatory use. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.007DOI Listing
April 2019
2 Reads

Evaluation of developmental toxicity of Methyl Chloride (Chloromethane) in rats, mice, and rabbits.

Regul Toxicol Pharmacol 2019 Apr 10;103:274-281. Epub 2019 Feb 10.

Triskelion, Utrechtseweg 48, 3704, HE, Zeist, the Netherlands.

Methyl Chloride (MeCl; Chloromethane) is a high production volume chemical (>1000 t/a) and is used as an industrial solvent. Based on cardiac lesions reported in developmental toxicity studies in mice, but not in rats, manufacturers decided to classify MeCl as a developmental toxicant, cat. 2. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.001DOI Listing
April 2019
1 Read

Acute toxicity and genotoxicity evaluations of Nattokinase, a promising agent for cardiovascular diseases prevention.

Regul Toxicol Pharmacol 2019 Apr 8;103:205-209. Epub 2019 Feb 8.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address:

Cardiovascular diseases (CVDs) are the leading cause of death in the world; however, current agents for CVDs prevention are still limited. Owing to the serious bleeding risk of Aspirin, FDA recently recommended against it from preventing first heart attacks. Nattokinase (NK), a serine protease possessing many key beneficial effects on cardiovascular system, is being pursued as a promising alternative agent. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.006DOI Listing
April 2019
2 Reads
2.031 Impact Factor

Regulatory effect of decreasing therapeutic duplication of respiratory drugs using a prescription database between 2012 and 2015.

Regul Toxicol Pharmacol 2019 Apr 8;103:218-228. Epub 2019 Feb 8.

School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, South Korea. Electronic address:

Duplicative drug use increases the risk of adverse drug reactions and expends healthcare resources unnecessarily. No epidemiological evidence of the prevalence of therapeutic duplication (TD) involving respiratory system drugs exists. Therefore, we describe the prescription patterns of these drugs and estimate changes in TD rates following implementation of a new regulation in 2013. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.003DOI Listing

A 90-day subchronic toxicology screen of genetically modified rice Lac-3 and its effects on the gut microbiota in Sprague-Dawley rats.

Regul Toxicol Pharmacol 2019 Apr 7;103:292-300. Epub 2019 Feb 7.

College of Food Science and Nutritional Engineering, China Agricultural University, No.17 Qinghua East Road, Beijing, 100083, China; Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, P.R, Beijing, 100083, China. Electronic address:

A 90-day subchronic toxicology screen of genetically modified (GM) rice Lac-3 expressing human lactoferrin (hLF) and its effects on the gut microbiota were studied in comparison to non-GM rice fed to Sprague-Dawley (SD) rats. Three different dietary concentrations (17.5%, 35% and 70%, w/w) of the GM rice or its corresponding non-GM rice were used. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S02732300193005
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http://dx.doi.org/10.1016/j.yrtph.2019.02.005DOI Listing
April 2019
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Subacute toxicity and toxicokinetics study of DHP107, an oral paclitaxel formulation with once-weekly dosing in mice.

Regul Toxicol Pharmacol 2019 Apr 7;103:196-204. Epub 2019 Feb 7.

Department of Toxicological Evaluation and Research, Korea Institute of Toxicology (KIT), Daejeon, Republic of Korea; Human and Environmental Toxicology, University of Science and Technology, Daejeon, Republic of Korea. Electronic address:

DHP107, an oral formulation of paclitaxel, is effectively and systemically absorbed in intestinal endothelial cells. Although the in vivo efficacy of DHP107 has been reported, the potential toxicity of DHP107 has not been evaluated. Therefore, this study was conducted to evaluate the toxicity and toxicokinetics of DHP107 orally administered to ICR mice at 25, 50, and 100 mg/kg via once-weekly dosing for six weeks. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S02732300193004
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http://dx.doi.org/10.1016/j.yrtph.2019.02.004DOI Listing
April 2019
7 Reads

Toxicology study of long-term administration of rhKGF-2 eye drops on rabbit corneas.

Regul Toxicol Pharmacol 2019 Apr 5;103:189-195. Epub 2019 Feb 5.

Wenzhou Medical University, Chashan University Park, Wenzhou, 325035, China. Electronic address:

Keratinocyte growth factor -2 promotes corneal repair. Its mechanism of action involves regulating regeneration and migration of corneal cells, as well as activating corneal limbal stem cells. However, KGF-2 being a carcinogenic growth factor and its potential adverse effect in over dosage long-term treatment had not yet been reported. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.02.002DOI Listing
April 2019
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Toxicological comparison of cigarette smoke and e-cigarette aerosol using a 3D in vitro human respiratory model.

Regul Toxicol Pharmacol 2019 Apr 2;103:314-324. Epub 2019 Feb 2.

Imperial Brands PLC, 121 Winterstoke Road, Bristol, BS3 2LL, UK.

With the growing prevalence of e-cigarettes as an alternative to conventional cigarettes amongst smokers worldwide, there is a need for new methods to evaluate their relative toxicological profile as part of a safety assessment. Initiatives to replace, reduce and refine animal testing have led to developments of new methodologies utilizing organotypic, in vitro tissue models. Here we use a respiratory epithelial model, EpiAirway, to examine the biological effects of nicotine-containing blu PLUS + e-cigarettes, with or without blueberry flavoring, in comparison to conventional cigarette smoke. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.036DOI Listing
April 2019
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Evaluation of aspartame cancer epidemiology studies based on quality appraisal criteria.

Regul Toxicol Pharmacol 2019 Apr 2;103:352-362. Epub 2019 Feb 2.

Intertek Regulatory & Scientific Consultancy, 2233 Argentia Rd., Suite 201, Mississauga, ON, L5N 2X7, Canada.

Given the widespread use of the low-calorie sweetener aspartame over the last 30 years, the current work was undertaken to evaluate aspartame epidemiology studies looking at cancer endpoints against quality appraisal criteria. The quality appraisal tool used was from the National Heart, Lung and Blood Institute (NHLBI) of the National Institute of Health. Studies identified included nine case-control studies and five prospective cohort studies. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.033DOI Listing

Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017.

Regul Toxicol Pharmacol 2019 Apr 1;103:174-180. Epub 2019 Feb 1.

Center of Consultation, Center for Drug Evaluation (CDE), Taipei, Taiwan. Electronic address:

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.037DOI Listing
April 2019
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Emission level of seven mainstream smoke toxicants from cigarette with variable tobacco leaf constituents.

Regul Toxicol Pharmacol 2019 Apr 30;103:181-188. Epub 2019 Jan 30.

Molecular Genetics Key Laboratory of China Tobacco, Guizhou Academy of Tobacco Science, Guiyang 550081, PR China. Electronic address:

[Introduction] Seven smoke constituents, including hydrogen cyanide (HCN), ammonia (NH), phenol, benzo[α]pyrene (B[a]P), carbon monoxide (CO)¸ crotonaldehyde, and 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK), are proposed be the most relevant constituents for smoking-related diseases. [Methods] Different combinations of leaf stalk positions, varieties and locations were used to create variable chemistry of cigarette filler and smoke. Experimental cigarettes were measured for emission level of seven smoke toxicants and content of seventy-three filler components. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.032DOI Listing
April 2019
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An evaluation of the USEPA Proposed Approaches for applying a biologically based dose-response model in a risk assessment for perchlorate in drinking water.

Regul Toxicol Pharmacol 2019 Apr 29;103:237-252. Epub 2019 Jan 29.

ToxStrategies, Research Triangle Park, NC, USA.

The United States Environmental Protection Agency's (USEPA) 2017 report, "Draft Report: Proposed Approaches to Inform the Derivation of a Maximum Contaminant Level Goal for Perchlorate in Drinking Water", proposes novel approaches for deriving a Maximum Contaminant Level Goal (MCLG) for perchlorate using a biologically-based dose-response (BBDR) model. The USEPA (2017) BBDR model extends previously peer-reviewed perchlorate models to describe the relationship between perchlorate exposure and thyroid hormone levels during early pregnancy. Our evaluation focuses on two key elements of the USEPA (2017) report: the plausibility of BBDR model revisions to describe control of thyroid hormone production in early pregnancy and the basis for linking BBDR model results to neurodevelopmental outcomes. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.028DOI Listing

Acute and sub-chronic 90-day oral toxicity study of Perilla seed oil in rodents and Beagle dogs.

Regul Toxicol Pharmacol 2019 Apr 29;103:229-236. Epub 2019 Jan 29.

Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Key Laboratory of Structure-based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address:

Perilla seeds are used as food and traditional medicine in China. This study aimed to investigate the toxicity profile of Perilla seed oil (PSO), which is the main constituent of Perilla seeds in rodents and Beagle dogs. No significant treatment-associated toxicity or mortality was observed at PSO dosages of up to 50 g/kg and 20 g/kg in KM mice and Wistar rats, respectively, suggesting that PSO was well tolerated by the experimental rodents. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.035DOI Listing
April 2019
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Improving risk assessment approaches for chemicals with both endogenous and exogenous exposures.

Regul Toxicol Pharmacol 2019 Apr 28;103:210-215. Epub 2019 Jan 28.

Olin Corporation (retired), Midland, MI, 48674, USA; LHP Tox Consult, LLC, Midland, MI, 48640, USA.

To conduct risk assessments of exogenous chemicals for which there are also endogenous exposures, knowledge of the chemistry and biology of both types of exposures needs to be integrated into problem formulation and carried through to risk characterization. This issue is framed in a risk assessment context, highlighting the importance of quantifying increments of dose from all sources of the same or similar chemicals interacting with biological targets; understanding the influence of endogenous chemical concentrations on disease risk; and assessing total dose to targets in evaluating risk from incremental environmental exposures. Examples of recent assessments illustrate the importance of addressing this issue. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.029DOI Listing
April 2019
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A study in a rat initiation-promotion bladder tumour model demonstrated no promoter/progressor potential of dapagliflozin.

Regul Toxicol Pharmacol 2019 Apr 25;103:166-173. Epub 2019 Jan 25.

Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. Electronic address:

Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is indicated to improve glycaemic control in adults of type 2 diabetes. In nonclinical studies, dapagliflozin was neither genotoxic nor carcinogenic. However, in some clinical studies, an increased incidence of bladder cancer was observed in the dapagliflozin group vs. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.031DOI Listing
April 2019
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A comprehensive toxicological safety assessment of an extract of Ageratum conyzoides.

Regul Toxicol Pharmacol 2019 Apr 23;103:140-149. Epub 2019 Jan 23.

Toxi-Coop Zrt., Magyar Jakobinusok tere 4/B, H-1122, Budapest, Hungary. Electronic address:

A battery of toxicological studies was conducted to aid in the safety assessment of an ethanolic extract of Ageratum conyzoides for use as an ingredient in food. In accordance with internationally accepted standards, a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, an in vivo mammalian micronucleus test, and a 90-day repeated-dose oral toxicity study in rats were performed. In the first three applied test systems, no evidence of mutagenicity, clastogenicity or genotoxicity was revealed. Read More

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http://dx.doi.org/10.1016/j.yrtph.2019.01.027DOI Listing
April 2019
3 Reads
2.031 Impact Factor