Pub Date : 2021-01-01DOI: 10.1177/23978473211030653
P. Pressman, R. Clemens, Thomas Blackburn, A. Hayes
The fatty acid amide hydrolase (FAAH) inhibitors likely represent a novel therapeutic yet complex target with the potential to impact various disease processes that present significant unmet medical needs. Despite a history of significant adverse events and still ill-defined risks associated with FAAH inactivation, potential clinical results of FAAH inhibitors for the management of human diseases suggest strongly that the research not be abandoned. In the present commentary we argue that the way to move forward safely and effectively may lie in universal expansion of clinical trials guidelines and toxicology protocols to include targeted genomic screening of clinical trial subjects. Generalization to the safety testing of many new pharmaceutical agents may be the silver lining of an otherwise dark cloud.
{"title":"A commentary on drug safety and genomics: Promising new agents may require expansion of guidelines for subject screening in clinical trials","authors":"P. Pressman, R. Clemens, Thomas Blackburn, A. Hayes","doi":"10.1177/23978473211030653","DOIUrl":"https://doi.org/10.1177/23978473211030653","url":null,"abstract":"The fatty acid amide hydrolase (FAAH) inhibitors likely represent a novel therapeutic yet complex target with the potential to impact various disease processes that present significant unmet medical needs. Despite a history of significant adverse events and still ill-defined risks associated with FAAH inactivation, potential clinical results of FAAH inhibitors for the management of human diseases suggest strongly that the research not be abandoned. In the present commentary we argue that the way to move forward safely and effectively may lie in universal expansion of clinical trials guidelines and toxicology protocols to include targeted genomic screening of clinical trial subjects. Generalization to the safety testing of many new pharmaceutical agents may be the silver lining of an otherwise dark cloud.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79076123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1177/23978473211021072
T. Langston, J. Randazzo, U. Kogel, J. Hoeng, F. Martin, B. Titz, E. Guedj, T. Schneider, B. Prabhakar, J. Zhang, M. Oldham, Km Lee
The objectives of this study were to increase PG exposure above concentrations tested by Suber et al. and use systems toxicology analysis of lung tissue to understand molecular events. Sprague Dawley rats were exposed to filtered air (sham), propylene glycol/water (PG/W; 90:10) or a propylene glycol/vegetable glycerin/water (PG/VG/W; 50:40:10) reference. The reference group was added at the high dose to observe any changes that might be associated with a carrier more in line with e-vapor products. Macroscopic examinations and terminal organ weights revealed no observations associated with exposure to PG/W or reference. Food consumption and body weights were unaffected by PG/W or reference when compared to sham. No exposure related alterations were observed in serum chemistry, hematology, coagulation, urinalysis or BALF cytology and clinical chemistry. Although clinical observations of dried red material around the nose in the high dose PG/W group were reported, histopathology showed no nasal hemorrhaging which was previously reported by Suber et al. Non-adverse PG/W and reference related findings of minimal mucous cell hyperplasia were noted in nasal cavity section II. No other exposure-related findings were noted in the primary or recovery necropsies. A systems toxicology analysis on lung tissue showed no statistically significant differentially expressed transcripts or proteins compared to the sham group. The endpoints measured from the PG/W high dose group did not differ significantly from those in the more common carrier PG/VG/W. As anticipated, exposure to PG aerosols was slightly irritating but well tolerated. Accordingly, the highest PG exposure (5 mg/L, 6 hrs/day) was regarded as the NOAEC, corresponding to a PG delivered dose of 1,152 mg/kg/day in rats.
{"title":"Thirteen-week nose-only inhalation exposures of propylene glycol aerosols in Sprague Dawley rats with a lung systems toxicology analysis","authors":"T. Langston, J. Randazzo, U. Kogel, J. Hoeng, F. Martin, B. Titz, E. Guedj, T. Schneider, B. Prabhakar, J. Zhang, M. Oldham, Km Lee","doi":"10.1177/23978473211021072","DOIUrl":"https://doi.org/10.1177/23978473211021072","url":null,"abstract":"The objectives of this study were to increase PG exposure above concentrations tested by Suber et al. and use systems toxicology analysis of lung tissue to understand molecular events. Sprague Dawley rats were exposed to filtered air (sham), propylene glycol/water (PG/W; 90:10) or a propylene glycol/vegetable glycerin/water (PG/VG/W; 50:40:10) reference. The reference group was added at the high dose to observe any changes that might be associated with a carrier more in line with e-vapor products. Macroscopic examinations and terminal organ weights revealed no observations associated with exposure to PG/W or reference. Food consumption and body weights were unaffected by PG/W or reference when compared to sham. No exposure related alterations were observed in serum chemistry, hematology, coagulation, urinalysis or BALF cytology and clinical chemistry. Although clinical observations of dried red material around the nose in the high dose PG/W group were reported, histopathology showed no nasal hemorrhaging which was previously reported by Suber et al. Non-adverse PG/W and reference related findings of minimal mucous cell hyperplasia were noted in nasal cavity section II. No other exposure-related findings were noted in the primary or recovery necropsies. A systems toxicology analysis on lung tissue showed no statistically significant differentially expressed transcripts or proteins compared to the sham group. The endpoints measured from the PG/W high dose group did not differ significantly from those in the more common carrier PG/VG/W. As anticipated, exposure to PG aerosols was slightly irritating but well tolerated. Accordingly, the highest PG exposure (5 mg/L, 6 hrs/day) was regarded as the NOAEC, corresponding to a PG delivered dose of 1,152 mg/kg/day in rats.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74504644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1177/2397847320985255
Dr. Keneth Iceland Kasozi, Eric Oloya Otim, Herbert Izo Ninsiima, G. Zirintunda, A. Tamale, J. Ekou, Grace Henry Musoke, Robert Muyinda, Kevin Matama, Regan Mujinya, H. Matovu, F. Ssempijja, E. Eze, Mauryn Atino, B. Udechukwu, Ronald Kayima, P. Etiang, E. T. Ayikobua, Stellamaris Kembabazi, I. Usman, Sheu Oluwadare Sulaiman, Phyllis Candy Natabo, Grace Nambatya Kyeyune, G. Batiha, O. Otim
Background: Environmental contamination with elevated levels of copper (Cu), cobalt (Co), iron (Fe), zinc (Zn), lead (Pb), chromium (Cr6+), cadmium (Cd), and nickel (Ni)—all states of which are found in Uganda—raises health risk to the public. Pb, Cr6+, Cd, and Ni for instance are generally considered nonessential to cellular functions, notwithstanding the importance of the oxidative state of the metals in bioavailability. As such, we aimed in this study (i) to evaluate heavy metal concentrations in four vegetables from a typical open-air market in Uganda, (ii) to assess the safety of consuming these vegetables against the World Health Organization (WHO) recommended limits of heavy metals consumption, and (iii) to formulate a model of estimated daily intake (EDI) among consumers in the country. Methods: This was a cross-sectional study conducted in five georeferenced markets of Bushenyi district in January 2020. Amaranthus, cabbages, scarlet eggplants, and tomatoes were collected from open markets, processed, and analyzed by atomic absorption spectrometry. Modeled EDI, principal component (PCA) and cluster analysis (CA) were conducted to identify relationships in the samples. Results: The levels of essential elements in the four vegetables were found to fall from Co > Cu > Fe > Zn. Those of non-essential metals were significantly higher and followed the pattern Cd > Cr > Pb > Ni. The highest EDI values were those of Cu in scarlet eggplants, Zn in amaranthus, Fe in amaranthus, Co in amaranthus, Pb in cabbages, total Cr in scarlet eggplant, Cd in cabbages and tomatoes, and Ni in cabbages. In comparison to international limits, EDIs for Zn, Cu, Co and Fe were low while Ni in cabbages were high. PCA showed high variations in scarlet eggplant and amaranthus. The study vegetables were found to be related with each other, not according to the location of the markets from where they were obtained, but according to their species by CA. Conclusion: The presence of non-essential elements above WHO limits raises policy challenges for the consumption and marketing of vegetables in the study area. Furthermore, low EDIs of essential elements in the vegetables create demand for nutritious foods to promote healthy communities.
背景:铜(Cu)、钴(Co)、铁(Fe)、锌(Zn)、铅(Pb)、铬(Cr6+)、镉(Cd)和镍(Ni)水平升高的环境污染——所有这些都在乌干达发现——增加了公众的健康风险。例如，铅、Cr6+、Cd和Ni通常被认为对细胞功能不是必需的，尽管金属的氧化状态在生物利用度中很重要。因此，在本研究中，我们的目标是(i)评估乌干达一个典型露天市场的四种蔬菜中的重金属浓度，(ii)根据世界卫生组织(WHO)建议的重金属消费限制评估食用这些蔬菜的安全性，以及(iii)制定该国消费者估计每日摄入量(EDI)的模型。方法:采用横断面研究方法，于2020年1月在busshenyi区5个地理参考市场进行调查。从露天市场采集苋菜、卷心菜、鲜红茄子和西红柿，进行加工，并用原子吸收光谱法进行分析。通过建模EDI、主成分(PCA)和聚类分析(CA)来确定样本之间的关系。结果:4种蔬菜中必需元素含量顺序为Co > Cu > Fe > Zn。非必需金属含量显著高于其他金属，表现为Cd > Cr > Pb > Ni。EDI值最高的是红色茄子中的Cu、苋菜中的Zn、苋菜中的Fe、苋菜中的Co、卷心菜中的Pb、红色茄子中的总Cr、卷心菜和西红柿中的Cd和卷心菜中的Ni。与国际标准相比，白菜中Zn、Cu、Co和Fe的EDIs较低，而Ni较高。主成分分析表明，红茄子和苋菜品种变异较大。CA发现，研究蔬菜之间存在相关性，但不是根据获得蔬菜的市场位置，而是根据它们的品种。结论:非必需元素高于世卫组织限制的存在，为研究地区蔬菜的消费和销售带来了政策挑战。此外，蔬菜中基本元素的低edi创造了对营养食品的需求，以促进健康社区。
{"title":"An analysis of heavy metals contamination and estimating the daily intakes of vegetables from Uganda","authors":"Dr. Keneth Iceland Kasozi, Eric Oloya Otim, Herbert Izo Ninsiima, G. Zirintunda, A. Tamale, J. Ekou, Grace Henry Musoke, Robert Muyinda, Kevin Matama, Regan Mujinya, H. Matovu, F. Ssempijja, E. Eze, Mauryn Atino, B. Udechukwu, Ronald Kayima, P. Etiang, E. T. Ayikobua, Stellamaris Kembabazi, I. Usman, Sheu Oluwadare Sulaiman, Phyllis Candy Natabo, Grace Nambatya Kyeyune, G. Batiha, O. Otim","doi":"10.1177/2397847320985255","DOIUrl":"https://doi.org/10.1177/2397847320985255","url":null,"abstract":"Background: Environmental contamination with elevated levels of copper (Cu), cobalt (Co), iron (Fe), zinc (Zn), lead (Pb), chromium (Cr6+), cadmium (Cd), and nickel (Ni)—all states of which are found in Uganda—raises health risk to the public. Pb, Cr6+, Cd, and Ni for instance are generally considered nonessential to cellular functions, notwithstanding the importance of the oxidative state of the metals in bioavailability. As such, we aimed in this study (i) to evaluate heavy metal concentrations in four vegetables from a typical open-air market in Uganda, (ii) to assess the safety of consuming these vegetables against the World Health Organization (WHO) recommended limits of heavy metals consumption, and (iii) to formulate a model of estimated daily intake (EDI) among consumers in the country. Methods: This was a cross-sectional study conducted in five georeferenced markets of Bushenyi district in January 2020. Amaranthus, cabbages, scarlet eggplants, and tomatoes were collected from open markets, processed, and analyzed by atomic absorption spectrometry. Modeled EDI, principal component (PCA) and cluster analysis (CA) were conducted to identify relationships in the samples. Results: The levels of essential elements in the four vegetables were found to fall from Co > Cu > Fe > Zn. Those of non-essential metals were significantly higher and followed the pattern Cd > Cr > Pb > Ni. The highest EDI values were those of Cu in scarlet eggplants, Zn in amaranthus, Fe in amaranthus, Co in amaranthus, Pb in cabbages, total Cr in scarlet eggplant, Cd in cabbages and tomatoes, and Ni in cabbages. In comparison to international limits, EDIs for Zn, Cu, Co and Fe were low while Ni in cabbages were high. PCA showed high variations in scarlet eggplant and amaranthus. The study vegetables were found to be related with each other, not according to the location of the markets from where they were obtained, but according to their species by CA. Conclusion: The presence of non-essential elements above WHO limits raises policy challenges for the consumption and marketing of vegetables in the study area. Furthermore, low EDIs of essential elements in the vegetables create demand for nutritious foods to promote healthy communities.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89611067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1177/23978473211001580
Ce Clark, AF Chall, J. Stagg, V. Sittaramane, R. Quirino, A. Mixson, W. E. Gato
Carbon nanotubes bound to tumor specific antibodies offer specific treatment for cancer cells without affecting surrounding tissue. The present study seeks to affirm the initial results of CNTs in cancer therapy by investigating the toxicological effect in mice injected with CNT-Ab followed by microwave hypothermia. We were particularly interested in evaluating the biodistribution, toxicity, and immune response that may be elicited from CNT-Ab exposure in mice. 4–5 week old mice (C57BL/6) were injected with various concentrations and combinations of multiwalled carbon nanotubes (MWCNT) conjugated with specific prostate-specific membrane antigen (PMSA) antibodies. After 1-week post-injection, mice were sacrificed followed by the collection of blood separated into serum, liver, kidney and other tissues for further analysis. Serum total protein concentration across the treatment groups was varied. No significant changes in albumin levels were detected when compared to the control group (No Treatment). Group YE (.125 mg/ml anti-PSMA-MWCNT + Microwave) was found to have consistently high blood serum analyte levels, indicating impaired liver and kidney function. Likewise, groups YB (Microwave only), YF [.5 mg/ml anti-PSMA-MWCNT (No Microwave)], and YG (.5 mg/ml plain MWCNT + Microwave) seemed to show indications of impaired liver function. Analysis of gene expression revealed a significant impact on the NF-KB inflammatory response pathway. NF-KB gene was up-regulated relative to controls in all treatment groups. These results seem to suggest marginal toxicity from the injection of CNT-Ab followed by microwave hyperthermia in mice subjects.
{"title":"Investigating the toxicology of intramuscular injected multiwalled carbon nanotubes conjugated antibody (CNT-Ab) in mice followed by microwave hyperthermia","authors":"Ce Clark, AF Chall, J. Stagg, V. Sittaramane, R. Quirino, A. Mixson, W. E. Gato","doi":"10.1177/23978473211001580","DOIUrl":"https://doi.org/10.1177/23978473211001580","url":null,"abstract":"Carbon nanotubes bound to tumor specific antibodies offer specific treatment for cancer cells without affecting surrounding tissue. The present study seeks to affirm the initial results of CNTs in cancer therapy by investigating the toxicological effect in mice injected with CNT-Ab followed by microwave hypothermia. We were particularly interested in evaluating the biodistribution, toxicity, and immune response that may be elicited from CNT-Ab exposure in mice. 4–5 week old mice (C57BL/6) were injected with various concentrations and combinations of multiwalled carbon nanotubes (MWCNT) conjugated with specific prostate-specific membrane antigen (PMSA) antibodies. After 1-week post-injection, mice were sacrificed followed by the collection of blood separated into serum, liver, kidney and other tissues for further analysis. Serum total protein concentration across the treatment groups was varied. No significant changes in albumin levels were detected when compared to the control group (No Treatment). Group YE (.125 mg/ml anti-PSMA-MWCNT + Microwave) was found to have consistently high blood serum analyte levels, indicating impaired liver and kidney function. Likewise, groups YB (Microwave only), YF [.5 mg/ml anti-PSMA-MWCNT (No Microwave)], and YG (.5 mg/ml plain MWCNT + Microwave) seemed to show indications of impaired liver function. Analysis of gene expression revealed a significant impact on the NF-KB inflammatory response pathway. NF-KB gene was up-regulated relative to controls in all treatment groups. These results seem to suggest marginal toxicity from the injection of CNT-Ab followed by microwave hyperthermia in mice subjects.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87994118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1177/23978473211055361
T. Vo, Jwar Meetro, B. Lynch, S. Tafazoli, Akio Ichihara, G. Chikamatsu
β-Fructofuranosidase (β-D-fructofuranoside fructohydrolase; EC 3.2.1.26) is used in the production of fructo-oligosaccharides that are commonly used by the food industry as prebiotics for their purported health benefits. The β-fructofuranosidase discussed herein is obtained from a novel source organism that is a non-genetically modified strain of Aspergillus brunneoviolaceus, which phylogenetically belongs to the Aspergillus section Nigri. The safety of β-fructofuranosidase was evaluated in a series of toxicology studies as prescribed by Tier 1 toxicity testing by the European Food Safety Authority, including an evaluation of the mutagenicity and genotoxicity potential using the in vitro bacterial reverse mutation and mammalian chromosomal aberration assays, as well as systemic toxicity in a 90-day oral subchronic toxicity study in Sprague-Dawley rats. β-Fructofuranosidase was demonstrated to lack mutagenic or genotoxic potential based on the results of the in vitro assays due to absence of increased revertant colonies in the bacterial reverse mutation test and incidence of chromosome aberrations in the chromosomal aberration assay. Administration of β-fructofuranosidase by gavage at doses up to 1200 mg total organic solids (TOS)/kg body weight/day for 90 days did not elicit any systemic toxic effects in rats based on a lack of adverse effect in any study parameter, and therefore the no-observed-adverse-effect level of β-fructofuranosidase was concluded to be 1200 mg TOS/kg body weight/day, the highest dose tested. The results of the toxicology studies on β-fructofuranosidase from A. brunneoviolaceus demonstrate this species to be a safe and suitable source of enzymes for use by the food industry.
β- d -果糖呋喃苷水解酶;EC 3.2.1.26)用于生产低聚果糖，低聚果糖通常被食品工业用作益生元，因为它们据称对健康有益。本文讨论的β-果糖呋喃苷酶是从一种新的来源生物中获得的，该生物是一种非转基因的棕色新紫罗兰曲霉菌株，在系统发育上属于黑曲霉段。根据欧洲食品安全局一级毒性测试的规定，β-果糖呋喃苷酶的安全性在一系列毒理学研究中进行了评估，包括使用体外细菌反向突变和哺乳动物染色体畸变试验评估其致突变性和遗传毒性潜力，以及在Sprague-Dawley大鼠进行的90天口服亚慢性毒性研究中的全身毒性。根据体外实验的结果，由于在细菌反向突变试验中没有增加的可逆菌落和在染色体畸变试验中没有增加的染色体畸变发生率，β-果糖呋喃苷酶被证明缺乏致突变性或遗传毒性潜力。由于在任何研究参数中均未发现不良反应，因此在90天内，以1200 mg总有机固体(TOS)/kg体重/天的剂量给药β-果糖呋喃苷酶未引起大鼠的任何全身毒性作用，因此β-果糖呋喃苷酶未观察到的不良反应水平被推断为1200 mg TOS/kg体重/天，这是所测的最高剂量。从褐紫拟南芥中提取的β-果糖呋喃糖苷酶的毒理学研究结果表明，褐紫拟南芥是一种安全、适宜用于食品工业的酶源。
{"title":"Safety assessment of β-fructofuranosidase from Aspergillus brunneoviolaceus","authors":"T. Vo, Jwar Meetro, B. Lynch, S. Tafazoli, Akio Ichihara, G. Chikamatsu","doi":"10.1177/23978473211055361","DOIUrl":"https://doi.org/10.1177/23978473211055361","url":null,"abstract":"β-Fructofuranosidase (β-D-fructofuranoside fructohydrolase; EC 3.2.1.26) is used in the production of fructo-oligosaccharides that are commonly used by the food industry as prebiotics for their purported health benefits. The β-fructofuranosidase discussed herein is obtained from a novel source organism that is a non-genetically modified strain of Aspergillus brunneoviolaceus, which phylogenetically belongs to the Aspergillus section Nigri. The safety of β-fructofuranosidase was evaluated in a series of toxicology studies as prescribed by Tier 1 toxicity testing by the European Food Safety Authority, including an evaluation of the mutagenicity and genotoxicity potential using the in vitro bacterial reverse mutation and mammalian chromosomal aberration assays, as well as systemic toxicity in a 90-day oral subchronic toxicity study in Sprague-Dawley rats. β-Fructofuranosidase was demonstrated to lack mutagenic or genotoxic potential based on the results of the in vitro assays due to absence of increased revertant colonies in the bacterial reverse mutation test and incidence of chromosome aberrations in the chromosomal aberration assay. Administration of β-fructofuranosidase by gavage at doses up to 1200 mg total organic solids (TOS)/kg body weight/day for 90 days did not elicit any systemic toxic effects in rats based on a lack of adverse effect in any study parameter, and therefore the no-observed-adverse-effect level of β-fructofuranosidase was concluded to be 1200 mg TOS/kg body weight/day, the highest dose tested. The results of the toxicology studies on β-fructofuranosidase from A. brunneoviolaceus demonstrate this species to be a safe and suitable source of enzymes for use by the food industry.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77914654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1177/23978473211038632
N. Todorovic, V. Štajer, L. Rátgéber, J. Betlehem, P. Acs, S. Ostojić
We investigated the effects of 7-day supplementation with three different dosages of citrulline nitrate (CN) on blood pressure at rest and after exercise, biochemical safety markers, and self-reported outcome measures of adverse events in healthy men. 12 apparently healthy young men (age 25.9 ± 4.0 years; weight 78.6 ± 10.0 kg, height 181.0 ± 7.0 cm) volunteered to participate in this double-blind, randomized, placebo-controlled cross-over trial. The dosages of CN were 1.5 g per day (low dose), 3.0 g per day (medium dose), and 6.0 g per day (high dose). No significant differences were found for systolic and diastolic blood pressure and heart rate at rest and after exercise between varying doses of CN and placebo (p > 0.05). In addition, hematological indices, biochemical variables, and clinical enzyme profiles were not affected by either intervention (p > 0.05), and the type and frequency of side effects were comparable to the placebo group. Citrulline nitrate was safe and well tolerated when administered for 7 days in dosages up to 6 g per day.
我们研究了在健康男性中，补充三种不同剂量的硝酸瓜氨酸(CN) 7天对休息和运动后血压、生化安全指标和不良事件自我报告结局测量的影响。健康青年男性12例(年龄25.9±4.0岁);体重78.6±10.0 kg，身高181.0±7.0 cm)自愿参加本双盲、随机、安慰剂对照交叉试验。CN的剂量为1.5 g / d(低剂量)、3.0 g / d(中剂量)和6.0 g / d(高剂量)。不同剂量的CN与安慰剂在静息和运动后的收缩压、舒张压和心率方面无显著差异(p > 0.05)。此外，两种干预均未影响血液学指标、生化指标和临床酶谱(p > 0.05)，副作用的类型和频率与安慰剂组相当。以每天6克的剂量给药7天，硝酸瓜氨酸是安全且耐受性良好的。
{"title":"Effects of 7-day supplementation with escalating doses of citrulline nitrate on resting and post-exercise blood pressure and safety biomarkers in healthy men: A randomized controlled trial","authors":"N. Todorovic, V. Štajer, L. Rátgéber, J. Betlehem, P. Acs, S. Ostojić","doi":"10.1177/23978473211038632","DOIUrl":"https://doi.org/10.1177/23978473211038632","url":null,"abstract":"We investigated the effects of 7-day supplementation with three different dosages of citrulline nitrate (CN) on blood pressure at rest and after exercise, biochemical safety markers, and self-reported outcome measures of adverse events in healthy men. 12 apparently healthy young men (age 25.9 ± 4.0 years; weight 78.6 ± 10.0 kg, height 181.0 ± 7.0 cm) volunteered to participate in this double-blind, randomized, placebo-controlled cross-over trial. The dosages of CN were 1.5 g per day (low dose), 3.0 g per day (medium dose), and 6.0 g per day (high dose). No significant differences were found for systolic and diastolic blood pressure and heart rate at rest and after exercise between varying doses of CN and placebo (p > 0.05). In addition, hematological indices, biochemical variables, and clinical enzyme profiles were not affected by either intervention (p > 0.05), and the type and frequency of side effects were comparable to the placebo group. Citrulline nitrate was safe and well tolerated when administered for 7 days in dosages up to 6 g per day.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81640378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-11-18DOI: 10.1177/23978473211047164
Lysandra Castro, Jingli Liu, Linda Yu, Alanna D Burwell, Trey O Saddler, Lindsay A Santiago, William Xue, Julie F Foley, Michael Staup, Norris D Flagler, Min Shi, Linda S Birnbaum, Dixon Darlene
Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that induces endometrial adenocarcinoma and other uterine tumors in Wistar Han rats; however, early molecular events or biomarkers of TBBPA exposure remain unknown. We investigated the effects of TBBPA on growth factor receptor activation (phospho-RTK) in uteri of rats following early-life exposures. Pregnant Wistar Han rats were exposed to TBBPA (0, 0.1, 25, 250 mg/kg/day) via oral gavage on gestation day 6 through weaning of pups (PND 21). Pups were exposed in utero, through lactation, and by daily gavage from PND 22 to PND 90. Uterine horns were collected (at PND 21, PND 33, PND 90) and formalin-fixed or frozen for histologic, immunohistochemical, phospho-RTK arrays, or western blot analysis. At PND 21, the phosphor-RTKs, FGFR2, FGFR3, TRKC and EPHA1 were significantly increased at different treatment concentrations. Several phospho-RTKs were also significantly overexpressed at PND 33 which included epithelial growth factor receptor (EGFR), Fibroblast Growth Factor Receptor 3-4 (FGFR2, FGFR3, FGFR4), insulin-like growth factor receptor 1 (IGF1R), INSR, AXL, MERTK, PDGFRa and b, RET, Tyrosine Kinase with Immunoglobulin Like and EGF Like Domains 1 and 2 (TIE1; TIE2), TRKA, VEGFR2 and 3, and EPHA1 at different dose treatments. EGFR, an RTK overexpressed in endometrial cancer in women, remained significantly increased for all treatment groups at PND 90. Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) and IGF1R were overexpressed at PND 33 and remained increased through PND 90, although ERBB2 was statistically significant at PND 90. The phospho-RTKs, FGFR3, AXL, DTK, HGFR, TRKC, VEGFR1 and EPHB2 and 4 were also statistically significant at PND 90 at different dose treatments. The downstream effector, phospho-MAPK44/42 was also increased in uteri of treated rats. Our findings show RTKs are dysregulated following early life TBBPA exposures and their sustained activation may contribute to TBBPA-induced uterine tumors observed in rats later in life.
{"title":"Differential Receptor Tyrosine Kinase Phosphorylation in the Uterus of Rats Following Developmental Exposure to Tetrabromobisphenol A.","authors":"Lysandra Castro, Jingli Liu, Linda Yu, Alanna D Burwell, Trey O Saddler, Lindsay A Santiago, William Xue, Julie F Foley, Michael Staup, Norris D Flagler, Min Shi, Linda S Birnbaum, Dixon Darlene","doi":"10.1177/23978473211047164","DOIUrl":"https://doi.org/10.1177/23978473211047164","url":null,"abstract":"<p><p>Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that induces endometrial adenocarcinoma and other uterine tumors in Wistar Han rats; however, early molecular events or biomarkers of TBBPA exposure remain unknown. We investigated the effects of TBBPA on growth factor receptor activation (phospho-RTK) in uteri of rats following early-life exposures. Pregnant Wistar Han rats were exposed to TBBPA (0, 0.1, 25, 250 mg/kg/day) via oral gavage on gestation day 6 through weaning of pups (PND 21). Pups were exposed <i>in utero,</i> through lactation, and by daily gavage from PND 22 to PND 90. Uterine horns were collected (at PND 21, PND 33, PND 90) and formalin-fixed or frozen for histologic, immunohistochemical, phospho-RTK arrays, or western blot analysis. At PND 21, the phosphor-RTKs, FGFR2, FGFR3, TRKC and EPHA1 were significantly increased at different treatment concentrations. Several phospho-RTKs were also significantly overexpressed at PND 33 which included epithelial growth factor receptor (EGFR), Fibroblast Growth Factor Receptor 3-4 (FGFR2, FGFR3, FGFR4), insulin-like growth factor receptor 1 (IGF1R), INSR, AXL, MERTK, PDGFRa and b, RET, Tyrosine Kinase with Immunoglobulin Like and EGF Like Domains 1 and 2 (TIE1; TIE2), TRKA, VEGFR2 and 3, and EPHA1 at different dose treatments. EGFR, an RTK overexpressed in endometrial cancer in women, remained significantly increased for all treatment groups at PND 90. Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) and IGF1R were overexpressed at PND 33 and remained increased through PND 90, although ERBB2 was statistically significant at PND 90. The phospho-RTKs, FGFR3, AXL, DTK, HGFR, TRKC, VEGFR1 and EPHB2 and 4 were also statistically significant at PND 90 at different dose treatments. The downstream effector, phospho-MAPK44/42 was also increased in uteri of treated rats. Our findings show RTKs are dysregulated following early life TBBPA exposures and their sustained activation may contribute to TBBPA-induced uterine tumors observed in rats later in life.</p>","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"5 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774279/pdf/nihms-1761644.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39716002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1177/23978473211031467
O. Babalola, J. C. Truter, J. V. van Wyk
The emergence of widespread morphological malformations in the reproductive system of wildlife is generating increasing concerns. This concern is because the observed malformities may be linked to pollution by pesticides and other chemicals. The amphibian declines, for example, have been linked to pesticide pollution among other factors. Using an extended Xenopus Metamorphosis Assay protocol, until the tadpoles metamorphosized, the exposure impacts of three glyphosate formulations, namely, Roundup, Kilo Max and Enviro Glyphosate, were assessed on the reproductive system of Xenopus laevis, vis-a-vis the body mass, sex ratios and morphological malformations as endpoints. The exposure concentrations ranged between 0.2–0.6 mg/L, 0.9–28 mg/L and 90–280 mg/L for Roundup, Enviro Glyphosate, and Kilo Max, respectively. Both Kilo Max and Enviro Glyphosate formulations significantly reduced the body mass of the metamorphs compared to the control. In sex ratios, only Kilo Max altered the percentage sex ratio of the treated frogs at a ratio of 68:32 (F:M) compared to 50:50 ratio in the control. In reproductive malformations, the three formulations showed abnormality index range of 22.3–49%, 17.5–37.5% and 20–30% for the Kilo Max, Enviro Glyphosate and Roundup formulations, respectively, compared to 7.5% in the control. Observed reproductive malformations include mixed sex, translucence, aplasia, segmented hypertrophy and segmented aplasia and translucence. This result indicates that some of the glyphosate formulations have the capacity to cause widespread reproductive malformations in a way that could reduce the reproductive fitness of the amphibian. Care must therefore be taken to reduce the application rate of these formulations, particularly in aquatic environments.
{"title":"Impacts of three glyphosate formulations on gonadal development of Xenopus laevis","authors":"O. Babalola, J. C. Truter, J. V. van Wyk","doi":"10.1177/23978473211031467","DOIUrl":"https://doi.org/10.1177/23978473211031467","url":null,"abstract":"The emergence of widespread morphological malformations in the reproductive system of wildlife is generating increasing concerns. This concern is because the observed malformities may be linked to pollution by pesticides and other chemicals. The amphibian declines, for example, have been linked to pesticide pollution among other factors. Using an extended Xenopus Metamorphosis Assay protocol, until the tadpoles metamorphosized, the exposure impacts of three glyphosate formulations, namely, Roundup, Kilo Max and Enviro Glyphosate, were assessed on the reproductive system of Xenopus laevis, vis-a-vis the body mass, sex ratios and morphological malformations as endpoints. The exposure concentrations ranged between 0.2–0.6 mg/L, 0.9–28 mg/L and 90–280 mg/L for Roundup, Enviro Glyphosate, and Kilo Max, respectively. Both Kilo Max and Enviro Glyphosate formulations significantly reduced the body mass of the metamorphs compared to the control. In sex ratios, only Kilo Max altered the percentage sex ratio of the treated frogs at a ratio of 68:32 (F:M) compared to 50:50 ratio in the control. In reproductive malformations, the three formulations showed abnormality index range of 22.3–49%, 17.5–37.5% and 20–30% for the Kilo Max, Enviro Glyphosate and Roundup formulations, respectively, compared to 7.5% in the control. Observed reproductive malformations include mixed sex, translucence, aplasia, segmented hypertrophy and segmented aplasia and translucence. This result indicates that some of the glyphosate formulations have the capacity to cause widespread reproductive malformations in a way that could reduce the reproductive fitness of the amphibian. Care must therefore be taken to reduce the application rate of these formulations, particularly in aquatic environments.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81292143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1177/2397847321999760
S. Salian-Mehta, Jolaine M Wilson, H. Burr, Abigail Greenstein, K. Murray, W. West, N. Poy
Contract Research Organizations (CROs) conducting toxicology studies on behalf of biopharmaceutical sponsors and others routinely provide supportive care for animals to minimize pain and distress on studies. A large number of guidance documents govern the care of experimental animals, however there is currently no uniform approach on the communication between sponsor and their CRO partners in providing a standard definition of and strategies for administering supportive care in toxicity studies. This survey was conducted by the CRO Outreach Working Group (WG), a part of the 3Rs Translational and Predictive Sciences (TPS) Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium), to better understand the provision of supportive care on nonclinical studies. The survey aimed to define supportive care strategies, identify alternatives to supportive care, and understand regulatory feedback and implications about supportive care decisions. The survey was distributed to members of the 3Rs Leadership Group of the IQ Consortium and several CRO partners, representing 35 organizations as potential respondents. The results of the survey from 13 respondents provided positive feedback that helped in highlighting the existing best practices for supportive care. Areas of enhancements identified included greater consistency in the inclusion of sponsor veterinarians on project teams for externalized studies, the timing of initiation of supportive care, and increased sharing of regulatory outcomes. Suggested best practices include creating a plan of action for veterinary care prior to study start, and enhancing information sharing regarding expected toxicities from previous study findings. Improved communication regarding supportive care will pave the way for enhanced 3Rs initiatives, refining the existing animal care paradigm and helping to ensure the most ethical toxicology study designs.
{"title":"Supportive care for animals on toxicology studies: An industrial best practices survey conducted by the IQ 3Rs TPS CRO Outreach Working Group","authors":"S. Salian-Mehta, Jolaine M Wilson, H. Burr, Abigail Greenstein, K. Murray, W. West, N. Poy","doi":"10.1177/2397847321999760","DOIUrl":"https://doi.org/10.1177/2397847321999760","url":null,"abstract":"Contract Research Organizations (CROs) conducting toxicology studies on behalf of biopharmaceutical sponsors and others routinely provide supportive care for animals to minimize pain and distress on studies. A large number of guidance documents govern the care of experimental animals, however there is currently no uniform approach on the communication between sponsor and their CRO partners in providing a standard definition of and strategies for administering supportive care in toxicity studies. This survey was conducted by the CRO Outreach Working Group (WG), a part of the 3Rs Translational and Predictive Sciences (TPS) Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium), to better understand the provision of supportive care on nonclinical studies. The survey aimed to define supportive care strategies, identify alternatives to supportive care, and understand regulatory feedback and implications about supportive care decisions. The survey was distributed to members of the 3Rs Leadership Group of the IQ Consortium and several CRO partners, representing 35 organizations as potential respondents. The results of the survey from 13 respondents provided positive feedback that helped in highlighting the existing best practices for supportive care. Areas of enhancements identified included greater consistency in the inclusion of sponsor veterinarians on project teams for externalized studies, the timing of initiation of supportive care, and increased sharing of regulatory outcomes. Suggested best practices include creating a plan of action for veterinary care prior to study start, and enhancing information sharing regarding expected toxicities from previous study findings. Improved communication regarding supportive care will pave the way for enhanced 3Rs initiatives, refining the existing animal care paradigm and helping to ensure the most ethical toxicology study designs.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79773168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1177/2397847321995875
Ashutosh Kumar, U. Kogel, M. Talikka, Céline Merg, E. Guedj, Yang Xiang, A. Kondylis, B. Titz, N. Ivanov, J. Hoeng, M. Peitsch, Joshua Allen, Amit Gupta, A. Skowronek, K. M. Lee
Cigarette smoking causes serious diseases, including lung cancer, atherosclerotic coronary artery disease, peripheral vascular disease, chronic bronchitis, and emphysema. While cessation remains the most effective approach to minimize smoking-related disease, alternative non-combustible tobacco-derived nicotine-containing products may reduce disease risks among those unable or unwilling to quit. E-vapor aerosols typically contain significantly lower levels of smoke-related harmful and potentially harmful constituents; however, health risks of long-term inhalation exposures are unknown. We designed a 7-month inhalation study in C57BL/6 mice to evaluate long-term respiratory toxicity of e-vapor aerosols compared to cigarette smoke and to assess the impact of smoking cessation (Cessation group) or switching to an e-vapor product (Switching group) after 3 months of exposure to 3R4F cigarette smoke (CS). There were no significant changes in in-life observations (body weights, clinical signs) in e-vapor groups compared to the Sham Control. The 3R4F CS group showed reduced respiratory function during exposure and had lower body weight and showed transient signs of distress post-exposure. Following 7 months of exposure, e-vapor aerosols resulted in no or minimal increase in pulmonary inflammation, while exposure to 3R4F CS led to impairment of lung function and caused marked lung inflammation and emphysematous changes. Biological changes observed in the Switching group were similar to the Cessation group. 3R4F CS exposure dysregulated the lung and nasal tissue transcriptome, while these molecular effects were substantially lower in the e-vapor group. Results from this study demonstrate that in comparison with 3R4F CS, e-vapor aerosols induce substantially lower biological responses including pulmonary inflammation and emphysematous changes, and that complete switching from CS to e-vapor products significantly reduces biological changes associated with CS in C57BL/6 mice.
{"title":"A 7-month inhalation toxicology study in C57BL/6 mice demonstrates reduced pulmonary inflammation and emphysematous changes following smoking cessation or switching to e-vapor products","authors":"Ashutosh Kumar, U. Kogel, M. Talikka, Céline Merg, E. Guedj, Yang Xiang, A. Kondylis, B. Titz, N. Ivanov, J. Hoeng, M. Peitsch, Joshua Allen, Amit Gupta, A. Skowronek, K. M. Lee","doi":"10.1177/2397847321995875","DOIUrl":"https://doi.org/10.1177/2397847321995875","url":null,"abstract":"Cigarette smoking causes serious diseases, including lung cancer, atherosclerotic coronary artery disease, peripheral vascular disease, chronic bronchitis, and emphysema. While cessation remains the most effective approach to minimize smoking-related disease, alternative non-combustible tobacco-derived nicotine-containing products may reduce disease risks among those unable or unwilling to quit. E-vapor aerosols typically contain significantly lower levels of smoke-related harmful and potentially harmful constituents; however, health risks of long-term inhalation exposures are unknown. We designed a 7-month inhalation study in C57BL/6 mice to evaluate long-term respiratory toxicity of e-vapor aerosols compared to cigarette smoke and to assess the impact of smoking cessation (Cessation group) or switching to an e-vapor product (Switching group) after 3 months of exposure to 3R4F cigarette smoke (CS). There were no significant changes in in-life observations (body weights, clinical signs) in e-vapor groups compared to the Sham Control. The 3R4F CS group showed reduced respiratory function during exposure and had lower body weight and showed transient signs of distress post-exposure. Following 7 months of exposure, e-vapor aerosols resulted in no or minimal increase in pulmonary inflammation, while exposure to 3R4F CS led to impairment of lung function and caused marked lung inflammation and emphysematous changes. Biological changes observed in the Switching group were similar to the Cessation group. 3R4F CS exposure dysregulated the lung and nasal tissue transcriptome, while these molecular effects were substantially lower in the e-vapor group. Results from this study demonstrate that in comparison with 3R4F CS, e-vapor aerosols induce substantially lower biological responses including pulmonary inflammation and emphysematous changes, and that complete switching from CS to e-vapor products significantly reduces biological changes associated with CS in C57BL/6 mice.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77947820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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