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Regulatory Toxicology and Pharmacology: RTP

Megumi Akiyama, Yoshihiko Matsui, Junki Kido, Taku Matsushita, Nobutaka Shirasaki
The probability distributions of total potential doses of disinfection byproducts and volatile organic compounds via ingestion, inhalation, and dermal exposure were estimated with Monte Carlo simulations, after conducting physiologically based pharmacokinetic model simulations to takes into account the differences in availability between the three exposures. If the criterion that the 95th percentile estimate equals the TDI (tolerable daily intake) is regarded as protecting the majority of a population, the drinking water criteria would be 140 (trichloromethane), 66 (bromodichloromethane), 157 (dibromochloromethane), 203 (tribromomethane), 140 (dichloroacetic acid), 78 (trichloroacetic acid), 6...
March 16, 2018: Regulatory Toxicology and Pharmacology: RTP
Rit Bahadur Gurung, Dae Hee Kim, Lila Kim, Albert W Lee, Yonglin Gao, Zhenhua Wang
We performed a series of toxicity studies on the safety of 6'-sialyllactose (6'-SL) sodium salt as a food ingredient. 6'-SL sodium salt, up to a maximum dose of 5000 μg/plate, did not increase the number of revertant colonies in five strains of Salmonella typhimurium in the presence or absence of S9 metabolic activation. A chromosomal aberration assay (using Chinese hamster lung cells) found no clastogenic effects at any concentration of 6'-SL sodium salt in the presence or absence of S9 metabolic activation...
March 16, 2018: Regulatory Toxicology and Pharmacology: RTP
Yuzhe Li, Xiaopeng Zhang, Chunlai Liang, Jing Hu, Zhou Yu
Mulberry (Morus alba L.) leaves are of broad popular use for food or remedy purposes due to their bioactive properties, especially antidiabetic activity and antioxidative activity. The present study aimed to assess the toxicological profile of mulberry leaf extract (MLE), through acute, subacute toxicity and genotoxicity tests. Male and female rats received by gavage 15.0 g/kg bw of MLE in the acute toxicity test, and 0, 1.88, 3.75 and 7.50 g/kg bw/d of MLE for subacute toxicity test. In the acute toxicity study, no mortality or behavioral changes were observed, indicating the LD50 is higher than 15...
March 9, 2018: Regulatory Toxicology and Pharmacology: RTP
Carsten Goebel, Thomas L Diepgen, Brunhilde Blömeke, Anthony A Gaspari, Axel Schnuch, Anne Fuchs, Kordula Schlotmann, Maya Krasteva, Ian Kimber
Occupational exposure of hairdressers to hair dyes has been associated with the development of allergic contact dermatitis (ACD) involving the hands. p-Phenylenediamine (PPD) and toluene-2,5-diamine (PTD) have been implicated as important occupational contact allergens. To conduct a quantitative risk assessment for the induction of contact sensitization to hair dyes in hairdressers, available data from hand rinsing studies following typical occupational exposure conditions to PPD, PTD and resorcinol were assessed...
March 9, 2018: Regulatory Toxicology and Pharmacology: RTP
Jeffrey W Habig, Aaron Rowland, Matthew G Pence, Cathy X Zhong
Resistance genes (R-genes) from wild potato species confer protection against disease and can be introduced into cultivated potato varieties using breeding or biotechnology. The R-gene, Rpi-vnt1, which encodes the VNT1 protein, protects against late blight, caused by Phytophthora infestans. Heterologous expression and purification of active VNT1 in quantities sufficient for regulatory biosafety studies was problematic, making it impractical to generate hazard characterization data. As a case study for R-proteins, a weight-of-evidence, tiered approach was used to evaluate the safety of VNT1...
March 9, 2018: Regulatory Toxicology and Pharmacology: RTP
Kevin McAdam, James Murphy, Alison Eldridge, Christopher Proctor, Clive Meredith
The concept of a risk continuum for tobacco and nicotine products has been proposed, which differentiates products according to their propensity to reduce toxicant exposure and risk. Cigarettes are deemed the most risky and medicinal nicotine the least. We assessed whether a Reduced-Toxicant Prototype (RTP) cigarette could sufficiently reduce exposure to toxicants versus conventional cigarettes to be considered a distinct category in the risk continuum. We present findings from both pre-clinical and clinical studies in order to examine the potential for reduced smoke toxicant emissions to lower health risks associated with cigarette smoking...
March 8, 2018: Regulatory Toxicology and Pharmacology: RTP
Sheng Chang, Zhiyou Yang, Na Han, Zhihui Liu, Jun Yin
Ambinine, the major alkaloid of the tuber of Corydalis ambigua var. amurensis, has protective effects on H9 C2 myocardial cells. In the present paper, we observed that ambinine demonstrates activities of both anticoagulation and thrombolysis in vitro by significantly degrading the blood clot and delaying the plasma recalcification time (PRT) in a dose-dependent manner (0.5-2 mg/mL). We further studied its safety profile of acute and subacute toxicity by repeated-dose intravenous injection. The median lethal dosage (LD50 ) of mice given by oral and intravenous administration of ambinine were approximate 800, 41...
March 7, 2018: Regulatory Toxicology and Pharmacology: RTP
Amber B Daniel, Judy Strickland, David Allen, Silvia Casati, Valérie Zuang, João Barroso, Maurice Whelan, M J Régimbald-Krnel, Hajime Kojima, Akiyoshi Nishikawa, Hye-Kyung Park, Jong Kwon Lee, Tae Sung Kim, Isabella Delgado, Ludmila Rios, Ying Yang, Gangli Wang, Nicole Kleinstreuer
Skin sensitization test data are required or considered by chemical regulation authorities around the world. These data are used to develop product hazard labeling for the protection of consumers or workers and to assess risks from exposure to skin-sensitizing chemicals. To identify opportunities for regulatory uses of non-animal replacements for skin sensitization tests, the needs and uses for skin sensitization test data must first be clarified. Thus, we reviewed skin sensitization testing requirements for seven countries or regions that are represented in the International Cooperation on Alternative Test Methods (ICATM)...
March 5, 2018: Regulatory Toxicology and Pharmacology: RTP
Andrew Van Cott, Markus Frericks, Charles Hastings, Naveed Honarvar, Burkhard Flick, Eric Fabian, Bennard van Ravenzwaay
Afidopyropen is a novel insecticide that acts as a TRPV channel modulator in chordotonal organs of target insects. In two carcinogenicity studies with Fischer rats, an increased incidence of uterine adenocarcinomas was observed at 1000 and 3000 ppm. This finding prompted an investigation of the mechanism of the tumor formation as well as the relevance of this mechanism to humans. The mechanistic work took parallel paths: one path investigated the pharmacokinetic properties of the test substance at the doses where the tumors were found; while the second path examined the key mechanistic events that culminated in uterine adenocarcinomas...
March 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Silvia Valero, Eduardo López-Briz, Nieves Vila, Antonio Solana, Mar Melero, Jose Luis Poveda
Assuring healthcare workers security on Hazardous Drugs (HD) compounding is critical in healthcare settings. Our study aims to demonstrate that the use of a Close System drug Transfer Device (CSTD) PhaSeal™ added to a decontamination process reduces antiblastic surface contamination levels in the Compounding Area (CA) of our Pharmacy Department (PD). We selected cyclophosphamide, 5-fluorouracil and iphosphamide to be evaluated. Testing was carried out with a wipe kit and quantified by an independent laboratory...
March 3, 2018: Regulatory Toxicology and Pharmacology: RTP
Deeksha Bhartiya, Amit Kumar, Jasmine Kaur, Suchitra Kumari, Amitesh Kumar Sharma, Dhirendra N Sinha, Harpreet Singh, Ravi Mehrotra
Smokeless tobacco (SLT) products are consumed by millions of people in over 130 countries around the world. Consumption of SLT has been estimated to cause a number of diseases accounting to more than 0.65 million deaths per year. There is sufficient epidemiological evidence on the association of SLT products with nicotine addiction, cancers of oral cavity and digestive systems but there is a lack of understanding of the role of toxic chemicals in these diseases. We provide the first comprehensive in-silico analysis of chemical compounds present in different SLT products used worldwide...
March 2, 2018: Regulatory Toxicology and Pharmacology: RTP
Jun-Won Yun, Ji-Ran You, Yun-Soon Kim, Seung-Hyun Kim, Eun-Young Cho, Jung-Hee Yoon, Euna Kwon, Ja-June Jang, Jin-Sung Park, Hyoung-Chin Kim, Jeong-Hwan Che, Byeong-Cheol Kang
Cinnamomum cassia has been widely used as a natural product to treat diseases in Asia due to its diverse pharmacological functions including anti-inflammatory, anti-oxidant, anti-microbial, anti-diabetic, and anti-tumor effects. Despite its ethnomedicinal benefits, little information regarding its toxicity is currently available. The aim of this study was to evaluate its potential long-term toxicity and genotoxicity in compliance with test guidelines of the Organization for Economic Cooperation and Development...
February 28, 2018: Regulatory Toxicology and Pharmacology: RTP
George Cruzan, James S Bus, Melvin E Andersen, Gary P Carlson, Marcy I Banton, Satinder S Sarang, Robbie Waites
Based on 13 chronic studies, styrene exposure causes lung tumors in mice, but no tumor increases in other organs in mice or rats. Extensive research into the mode of action demonstrates the key events and human relevance. Key events are: metabolism of styrene by CYP2F2 in mouse lung club cells to ring-oxidized metabolites; changes in gene expression for metabolism of lipids and lipoproteins, cell cycle and mitotic M-M/G1 phases; cytotoxicity and mitogenesis in club cells; and progression to preneoplastic/neoplastic lesions in lung...
February 26, 2018: Regulatory Toxicology and Pharmacology: RTP
Atsuko Horibe, Shigenori Odashima, Nobuyuki Hamasuna, Takeshi Morita, Makoto Hayashi
Due to the course of registration of pesticides in Japan, the Food Safety Commission (FSC) has the responsibility to make a risk assessment of residual pesticides and related chemicals through foods. Among the set of safety evaluations for pesticides, genotoxicity assay data are mandatory. The standard test battery for this evaluation consists of a bacterial gene mutation assay, in vitro mammalian chromosomal aberrations and/or other chromosome damage assay, and in vivo rodent micronucleus assay. These assay outcomes are used for mechanistic consideration of carcinogenicity, if any...
February 24, 2018: Regulatory Toxicology and Pharmacology: RTP
Jung-Ho Park, Jae-Woo Lee, Hoonsung Choi, Sun Keun Jung, Jeom Sun Kim, Kyung-Woon Kim, Keon Bong Oh, Hyeon Yang, Sung June Byun
Previously, Escherichia coli harboring the codon-optimized 3D8scFv gene (E. coli 3D8scFv) was developed as a feed additive for use in preventing norovirus infection. Here, we evaluated whether the 3D8scFv gene affects the colonization of E coli when E. coli 3D8scFv passes through the mouse gastrointestinal tract. To determine the colonization ability of E. coli 3D8scFv, E. coli cells with or without the 3D8scFv gene were fed to mice. Total DNA was extracted from the animals' stools, stomach, small intestine and colon...
February 24, 2018: Regulatory Toxicology and Pharmacology: RTP
Chun-Wei Tung, Chia-Chi Wang, Shan-Shan Wang
Integrative testing strategies using adverse outcome pathway (AOP)-based alternative assays for assessing skin sensitizers show the potential for replacing animal testing. However, the application of alternative assays for a large number of chemicals is still time-consuming and expensive. In order to facilitate the assessment of skin sensitizers based on integrative testing strategies, a mechanism-informed read-across assessment method was proposed and evaluated using data from SkinSensDB. First, the prediction performance of two integrated testing strategy models was evaluated giving the highest area under the receiver operating characteristic curve (AUC) values of 0...
February 24, 2018: Regulatory Toxicology and Pharmacology: RTP
Rod A Herman, Gregory S Ladics
The value of criteria used in the weight-of-evidence assessment of allergenic risk of genetically modified (GM) crops has been debated. This debate may originate, in part, from not specifying if the criteria are intended to contribute to the assessment of sensitization risk or elicitation risk. Here, this distinction is explicitly discussed in the context of exposure and hazard. GM crops with structural relationships with known allergens or sourced from an organism known to cause allergy (hazard) are screened for IgE-antibody reactivity using serum from sensitized individuals...
February 23, 2018: Regulatory Toxicology and Pharmacology: RTP
Jacques Descotes, Linda Allais, Philippe Ancian, Henrik Duelund Pedersen, Claire Friry-Santini, Antonio Iglesias, Tina Rubic-Schneider, Hollie Skaggs, Peter Vestbjerg
There is a growing need to consider non-rodent species for the immunological safety evaluation of drug candidates. The EU Framework-6 RETHINK Project demonstrated that the Göttingen Minipig is a relevant animal model for regulatory toxicology studies. Extensive knowledge on the immune system of domestic pigs is available and fewer differences from humans have been identified as compared to other species, such as mice or non-human primates. Minipig data are too scarce to allow for claiming full immunological comparability with domestic pigs...
February 23, 2018: Regulatory Toxicology and Pharmacology: RTP
Hoonhee Seo, Hafij Al Mahmud, Sukyung Kim, Md Imtiazul Islam, Kee-In Lee, Young Sig Gil, Ho-Yeon Song
The infectious disease tuberculosis remains a serious global health issue and is responsible for nearly 1.8 million deaths every year. In our previous study, DFC-2 was confirmed to show anti-tubercular activity against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. To support the safety-in-use of DFC-2 as an anti-tubercular drug, DFC-2 was tested via single- and 28-day repeated-dose oral toxicity study and mutagenicity assays. In the oral toxicity study, a single oral dose of DFC-2 at 2000 mg/kg did not produce deaths or abnormal lesions in the internal organs of rats...
February 20, 2018: Regulatory Toxicology and Pharmacology: RTP
Nikolai L Chepelev, Rémi Gagné, Timothy Maynor, Byron Kuo, Cheryl A Hobbs, Leslie Recio, Carole L Yauk
Acrylamide (AA) exposure causes increased incidence of forestomach, lung, and Harderian gland tumors in male mice. One hypothesized mode of action (MOA) for AA-carcinogenicity includes genotoxicity/mutagenicity as a key event, possibly resulting from AA metabolism to the direct genotoxic metabolite glycidamide. Alternatively, altered calcium signaling (CS) has been proposed as a central key event in the MOA. To examine the plausibility of these proposed MOAs, RNA-sequencing was performed on tumor target tissues: Harderian glands (the most sensitive tumor target tissue in the rodent 2-year cancer bioassay) and lungs of AA-exposed male CD-1 mice...
February 20, 2018: Regulatory Toxicology and Pharmacology: RTP
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