Pub Date : 2020-01-24DOI: 10.1177/2397847319899080
Evangelia E Antoniou, H. Gelbke, J. Ballach, M. Zeegers
Background: Modern industry is developing and so is the consumption of N,N-dimethylformamide (DMF) and the occupational population exposed to DMF. However, chronic occupational and experimental exposure to DMF has been especially linked to liver and gastrointestinal disturbances. Aims: This study aims to systematically review and evaluate with a meta-analysis the influence of DMF exposure on human liver toxicity. Methods: The PubMed/Medline, the ECHA restriction dossier and the Web of Science were searched. Midpoint DMF exposure levels were calculated, and the association between DMF exposure and liver toxicity was investigated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: Of 92 screened articles, 19 articles were included in the review and of them, 10 articles were included in the meta-analysis. No association was observed when the midpoint DMF exposure was less than 20 mg/m3 (OR: 1.58, 95% CIs: 0.68–3.65). A positive association between DMF exposure and liver toxicity was observed when the midpoint DMF exposure was between 21 mg/m3 and 25 mg/m3 (OR: 3.26, 95% CIs: 1.38–7.73). Conclusions: Higher exposure DMF levels are associated with liver toxicity. However, these results tend to overestimate potential risks because the use of midpoint exposures includes and gives weight to populations at the upper end of the exposure distributions and because liver toxicity was defined as a statistical significant difference in liver enzyme levels compared to control groups, which is not identical to biologically relevant effects and adverse health effects.
{"title":"The influence of airborne N,N-dimethylformamide on liver toxicity measured in industry workers: A systematic review and meta-analysis","authors":"Evangelia E Antoniou, H. Gelbke, J. Ballach, M. Zeegers","doi":"10.1177/2397847319899080","DOIUrl":"https://doi.org/10.1177/2397847319899080","url":null,"abstract":"Background: Modern industry is developing and so is the consumption of N,N-dimethylformamide (DMF) and the occupational population exposed to DMF. However, chronic occupational and experimental exposure to DMF has been especially linked to liver and gastrointestinal disturbances. Aims: This study aims to systematically review and evaluate with a meta-analysis the influence of DMF exposure on human liver toxicity. Methods: The PubMed/Medline, the ECHA restriction dossier and the Web of Science were searched. Midpoint DMF exposure levels were calculated, and the association between DMF exposure and liver toxicity was investigated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: Of 92 screened articles, 19 articles were included in the review and of them, 10 articles were included in the meta-analysis. No association was observed when the midpoint DMF exposure was less than 20 mg/m3 (OR: 1.58, 95% CIs: 0.68–3.65). A positive association between DMF exposure and liver toxicity was observed when the midpoint DMF exposure was between 21 mg/m3 and 25 mg/m3 (OR: 3.26, 95% CIs: 1.38–7.73). Conclusions: Higher exposure DMF levels are associated with liver toxicity. However, these results tend to overestimate potential risks because the use of midpoint exposures includes and gives weight to populations at the upper end of the exposure distributions and because liver toxicity was defined as a statistical significant difference in liver enzyme levels compared to control groups, which is not identical to biologically relevant effects and adverse health effects.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78906068","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 : 2020-01-03DOI: 10.1177/2397847319898707
K. Samatha, B. Girish, P. Reddy
The effects of exposure of pregnant rats to cadmium (Cd) on the developmental and behavioral outcomes, reproductive functions, and metabolism of their male progeny were evaluated. Rats (Wistar) were injected intraperitoneally with either 0.5 or 5.0 µg Cd/kg body weight from day 12 to day 19 of pregnancy. The male offspring were evaluated for their developmental outcomes and behavioral changes. All developmental and behavioral parameters assessed were comparable among the different groups. All male pups were allowed to develop until 100 days of age and evaluated for reproductive end points. The results revealed that although the body weights and relative weights of liver, brain, kidney, testis, and epididymis were not altered, reproductive parameters, including daily sperm production, epididymal sperm numbers, and concentrations of motile, viable, and hypo-osmotic tail-swelled sperm declined significantly in rats exposed to 0.5 and 5.0 µg Cd during embryonic development. In addition, plasma testosterone levels and activity levels of testicular steroidogenic enzymes also decreased in these rats. In the fertility study, although each male in the 0.5, 5.0 µg, and control groups produced a copulatory plug and impregnated a female, the mean number of implantations and live fetuses was reduced significantly in females mated with rats exposed to 0.5 and 5.0 µg Cd during the prenatal period. The general metabolism of the animals exposed to Cd during embryonic development was comparable with the controls as evidenced by no significant changes in the activity levels of succinate dehydrogenase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase, glutamate dehydrogenase, aspartate aminotransaminase, and alanine aminotransaminases in the liver, kidney, and testis. The results thus suggest that maternal Cd exposure during embryonic development markedly affected the spermatogenesis, steroidogenesis, and fertility potential, but without alterations in the development, behavior, and metabolism.
{"title":"Embryonic cadmium exposure of male rats alters reproductive functions at adulthood, but without overt alterations in developmental and behavioral outcomes and metabolism","authors":"K. Samatha, B. Girish, P. Reddy","doi":"10.1177/2397847319898707","DOIUrl":"https://doi.org/10.1177/2397847319898707","url":null,"abstract":"The effects of exposure of pregnant rats to cadmium (Cd) on the developmental and behavioral outcomes, reproductive functions, and metabolism of their male progeny were evaluated. Rats (Wistar) were injected intraperitoneally with either 0.5 or 5.0 µg Cd/kg body weight from day 12 to day 19 of pregnancy. The male offspring were evaluated for their developmental outcomes and behavioral changes. All developmental and behavioral parameters assessed were comparable among the different groups. All male pups were allowed to develop until 100 days of age and evaluated for reproductive end points. The results revealed that although the body weights and relative weights of liver, brain, kidney, testis, and epididymis were not altered, reproductive parameters, including daily sperm production, epididymal sperm numbers, and concentrations of motile, viable, and hypo-osmotic tail-swelled sperm declined significantly in rats exposed to 0.5 and 5.0 µg Cd during embryonic development. In addition, plasma testosterone levels and activity levels of testicular steroidogenic enzymes also decreased in these rats. In the fertility study, although each male in the 0.5, 5.0 µg, and control groups produced a copulatory plug and impregnated a female, the mean number of implantations and live fetuses was reduced significantly in females mated with rats exposed to 0.5 and 5.0 µg Cd during the prenatal period. The general metabolism of the animals exposed to Cd during embryonic development was comparable with the controls as evidenced by no significant changes in the activity levels of succinate dehydrogenase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase, glutamate dehydrogenase, aspartate aminotransaminase, and alanine aminotransaminases in the liver, kidney, and testis. The results thus suggest that maternal Cd exposure during embryonic development markedly affected the spermatogenesis, steroidogenesis, and fertility potential, but without alterations in the development, behavior, and metabolism.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77764485","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 : 2020-01-03DOI: 10.1177/2397847319897869
S. Boué, Didier Goedertier, J. Hoeng, A. Kuczaj, Shoaib Majeed, C. Mathis, Anne May, B. Phillips, M. Peitsch, F. Radtke, W. Schlage, W. Tan, P. Vanscheeuwijck
Tobacco harm reduction is increasingly recognized as a promising approach to accelerate the decline in smoking prevalence and smoking-related population harm. Potential modified risk tobacco products (MRTPs) must undergo a rigorous premarket toxicological risk assessment. The ability to reproducibly generate, collect, and use aerosols is critical for the characterization, and preclinical assessment of aerosol-based candidate MRTPs (cMRTPs), such as noncombusted cigarettes, also referred to as heated tobacco products, tobacco heating products, or heat-not-burn (HNB) tobacco products. HNB tobacco products generate a nicotine-containing aerosol by heating tobacco instead of burning it. The aerosols generated by HNB products are qualitatively and quantitatively highly different from cigarette smoke (CS). This constitutes technical and experimental challenges comparing the toxicity of HNB aerosols with CS. The methods and experimental setups that have been developed for the study of CS cannot be directly transposed to the study of HNB aerosols. Significant research efforts are dedicated to the development, characterization, and validation of experimental setups and methods suitable for HNB aerosols. They are described in this review, with a particular focus on the Tobacco Heating System version 2.2. This is intended to support further studies, the objective evaluation and verification of existing evidence, and the development of scientifically substantiated HNB MRTPs.
{"title":"State-of-the-art methods and devices for the generation, exposure, and collection of aerosols from heat-not-burn tobacco products","authors":"S. Boué, Didier Goedertier, J. Hoeng, A. Kuczaj, Shoaib Majeed, C. Mathis, Anne May, B. Phillips, M. Peitsch, F. Radtke, W. Schlage, W. Tan, P. Vanscheeuwijck","doi":"10.1177/2397847319897869","DOIUrl":"https://doi.org/10.1177/2397847319897869","url":null,"abstract":"Tobacco harm reduction is increasingly recognized as a promising approach to accelerate the decline in smoking prevalence and smoking-related population harm. Potential modified risk tobacco products (MRTPs) must undergo a rigorous premarket toxicological risk assessment. The ability to reproducibly generate, collect, and use aerosols is critical for the characterization, and preclinical assessment of aerosol-based candidate MRTPs (cMRTPs), such as noncombusted cigarettes, also referred to as heated tobacco products, tobacco heating products, or heat-not-burn (HNB) tobacco products. HNB tobacco products generate a nicotine-containing aerosol by heating tobacco instead of burning it. The aerosols generated by HNB products are qualitatively and quantitatively highly different from cigarette smoke (CS). This constitutes technical and experimental challenges comparing the toxicity of HNB aerosols with CS. The methods and experimental setups that have been developed for the study of CS cannot be directly transposed to the study of HNB aerosols. Significant research efforts are dedicated to the development, characterization, and validation of experimental setups and methods suitable for HNB aerosols. They are described in this review, with a particular focus on the Tobacco Heating System version 2.2. This is intended to support further studies, the objective evaluation and verification of existing evidence, and the development of scientifically substantiated HNB MRTPs.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79681902","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 : 2020-01-01DOI: 10.1177/2397847320931792
Rim Timoumi, I. Amara, I. B. Salem, Matia Franca Buratti, E. Testai, S. Abid-Essefi
The aim of this study is to evaluate the cytotoxic and the genotoxic effects of triflumuron (TFM) on human colon carcinoma cells (HCT-116). Indeed, TFM is used to protect vegetables, fruits, and domestic animals against a large spectrum of parasites causing animal and human disorders. However, studies revealing its toxicity and its mode of action in mammalian systems remain very limited. We monitored our work with the cytotoxicity assay starting with the cell viability test, the ROS generation, the malondialdehyde (MDA) production, the DNA fragmentation, and the measurement of some antioxidant enzymes activities such as catalase, superoxide dismutase, and the glutathione S-transferase. Also, we measured the mitochondrial transmembrane potential. We showed that TFM induced a dose-dependent cell death. This decrease in cell viability was accompanied by a significant reduction in the mitochondrial membrane potential. We also have shown that TFM induced oxidative stress as revealed by the generation of reactive oxygen species, the increase of the MDA levels, and the activation of the antioxidant enzymes. Moreover, our results indicated that TFM induced DNA damage in HCT-116 cells as monitored by the comet assay. We demonstrate, for the first time, the cytotoxic and the genotoxic potentials of TFM on human cultured cells.
{"title":"The implication of ROS production on triflumuron-induced oxidative stress and genotoxicity in human colon carcinoma (HCT-116) cells","authors":"Rim Timoumi, I. Amara, I. B. Salem, Matia Franca Buratti, E. Testai, S. Abid-Essefi","doi":"10.1177/2397847320931792","DOIUrl":"https://doi.org/10.1177/2397847320931792","url":null,"abstract":"The aim of this study is to evaluate the cytotoxic and the genotoxic effects of triflumuron (TFM) on human colon carcinoma cells (HCT-116). Indeed, TFM is used to protect vegetables, fruits, and domestic animals against a large spectrum of parasites causing animal and human disorders. However, studies revealing its toxicity and its mode of action in mammalian systems remain very limited. We monitored our work with the cytotoxicity assay starting with the cell viability test, the ROS generation, the malondialdehyde (MDA) production, the DNA fragmentation, and the measurement of some antioxidant enzymes activities such as catalase, superoxide dismutase, and the glutathione S-transferase. Also, we measured the mitochondrial transmembrane potential. We showed that TFM induced a dose-dependent cell death. This decrease in cell viability was accompanied by a significant reduction in the mitochondrial membrane potential. We also have shown that TFM induced oxidative stress as revealed by the generation of reactive oxygen species, the increase of the MDA levels, and the activation of the antioxidant enzymes. Moreover, our results indicated that TFM induced DNA damage in HCT-116 cells as monitored by the comet assay. We demonstrate, for the first time, the cytotoxic and the genotoxic potentials of TFM on human cultured cells.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89967683","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 : 2020-01-01DOI: 10.1101/2020.09.25.314138
S. Lazic, Dominic P. Williams
Predicting the safety of a drug from preclinical data is a major challenge in drug discovery, and progressing an unsafe compound into the clinic puts patients at risk and wastes resources. In drug safety pharmacology and related fields, methods and analytical decisions known to provide poor predictions are common and include creating arbitrary thresholds, binning continuous values, giving all assays equal weight, and multiple reuse of information. In addition, the metrics used to evaluate models often omit important criteria and models’ performance on new data are often not assessed rigorously. Prediction models with these problems are unlikely to perform well, and published models suffer from many of these issues. We describe these problems in detail, demonstrate their negative consequences, and propose simple solutions that are standard in other disciplines where predictive modelling is used.
{"title":"Improving drug safety predictions by reducing poor analytical practices","authors":"S. Lazic, Dominic P. Williams","doi":"10.1101/2020.09.25.314138","DOIUrl":"https://doi.org/10.1101/2020.09.25.314138","url":null,"abstract":"Predicting the safety of a drug from preclinical data is a major challenge in drug discovery, and progressing an unsafe compound into the clinic puts patients at risk and wastes resources. In drug safety pharmacology and related fields, methods and analytical decisions known to provide poor predictions are common and include creating arbitrary thresholds, binning continuous values, giving all assays equal weight, and multiple reuse of information. In addition, the metrics used to evaluate models often omit important criteria and models’ performance on new data are often not assessed rigorously. Prediction models with these problems are unlikely to perform well, and published models suffer from many of these issues. We describe these problems in detail, demonstrate their negative consequences, and propose simple solutions that are standard in other disciplines where predictive modelling is used.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80031172","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 : 2019-12-21DOI: 10.1177/2397847319893054
E. Jung, X. Hui, Hanjiang Zhu, Alissa Y. Zhang, Wei Wang, B. Buchholz, H. Maibach
This in vitro skin study determined absorption, diffusion, and binding rates of four [14C]-labeled nanoparticles (NPs): 12 nm Fe3O4, 32 nm Fe3O4@SiO2, 33 nm SiO2, and 78 nm SiO2 in each layer of human cadaver skin. In vitro microdialysis device and flow-through skin diffusion system were used to measure the binding affinity to the stratum corneum (SC) and permeability into/through skin layer of the four NPs with different physical–chemical properties, respectively, in short (30 min) and/or long (24 hours) exposures. Results show that NP size is an important factor affecting NP percutaneous absorption. The 12 nm Fe3O4 NPs reached the SC and viable epidermis; 32 nm Fe3O4@SiO2 core/shell NPs only reached SC. However, 33 nm and 78 nm silica NPs did not permeate SC. Similar patterns were observed for NP binding affinity to SC and dermatopharmacokinetic analysis using the tape stripping method. The binding affinity determination may be a useful method to efficiently screen skin penetration of NPs.
{"title":"Effect of iron and silica nanoparticles’ size on in vitro human skin binding and penetration","authors":"E. Jung, X. Hui, Hanjiang Zhu, Alissa Y. Zhang, Wei Wang, B. Buchholz, H. Maibach","doi":"10.1177/2397847319893054","DOIUrl":"https://doi.org/10.1177/2397847319893054","url":null,"abstract":"This in vitro skin study determined absorption, diffusion, and binding rates of four [14C]-labeled nanoparticles (NPs): 12 nm Fe3O4, 32 nm Fe3O4@SiO2, 33 nm SiO2, and 78 nm SiO2 in each layer of human cadaver skin. In vitro microdialysis device and flow-through skin diffusion system were used to measure the binding affinity to the stratum corneum (SC) and permeability into/through skin layer of the four NPs with different physical–chemical properties, respectively, in short (30 min) and/or long (24 hours) exposures. Results show that NP size is an important factor affecting NP percutaneous absorption. The 12 nm Fe3O4 NPs reached the SC and viable epidermis; 32 nm Fe3O4@SiO2 core/shell NPs only reached SC. However, 33 nm and 78 nm silica NPs did not permeate SC. Similar patterns were observed for NP binding affinity to SC and dermatopharmacokinetic analysis using the tape stripping method. The binding affinity determination may be a useful method to efficiently screen skin penetration of NPs.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86258307","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 : 2019-12-12DOI: 10.1177/2397847319895221
J. Symonds, Chonggang Zhang, Adam Noble, C. Kruger
A safety assessment of the dried whole cell biomass of Euglena gracilis ATCC 12894 was performed by the bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay, and a 90-day repeat oral toxicity study in Wistar rats. E. gracilis ATCC 12894 whole cell biomass has no added excipients and contains 33.8% protein, 28.8% β-glucans, 19.8% fat, 7.1% ash, and 2.8% moisture. The bacterial reverse mutation assay found no evidence of mutagenicity after exposure to E. gracilis ATCC 12894 whole cell biomass, with or without metabolic activity, at levels up to 1581 µg/plate, the limit dose for the assay. Similarly, no evidence of genotoxicity was observed in the micronucleus assay, with or without metabolic activation, up to 320 µg/mL, the limit dose for the assay. The subchronic toxicity study was performed with the following test article dose groups: 0 (control), 1250, 2500, and 5000 mg/kg/day, administered to male and female Wistar rats via oral gavage for 90 days. No test article-related mortalities or adverse events were reported during the study. Histopathological examination revealed some vacuolation in the livers of males in the 5000 mg/kg/day group. This finding was considered adaptive, due to the approximately 20% fat content of whole cell biomass, and was therefore test article-related, but not adverse. No such findings were reported in female rats in the study. The results of the subchronic toxicity study describe a no observed adverse effect level of at least 5000 mg/kg/day.
{"title":"Safety assessment of Euglena gracilis ATCC 12894 whole cell biomass","authors":"J. Symonds, Chonggang Zhang, Adam Noble, C. Kruger","doi":"10.1177/2397847319895221","DOIUrl":"https://doi.org/10.1177/2397847319895221","url":null,"abstract":"A safety assessment of the dried whole cell biomass of Euglena gracilis ATCC 12894 was performed by the bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay, and a 90-day repeat oral toxicity study in Wistar rats. E. gracilis ATCC 12894 whole cell biomass has no added excipients and contains 33.8% protein, 28.8% β-glucans, 19.8% fat, 7.1% ash, and 2.8% moisture. The bacterial reverse mutation assay found no evidence of mutagenicity after exposure to E. gracilis ATCC 12894 whole cell biomass, with or without metabolic activity, at levels up to 1581 µg/plate, the limit dose for the assay. Similarly, no evidence of genotoxicity was observed in the micronucleus assay, with or without metabolic activation, up to 320 µg/mL, the limit dose for the assay. The subchronic toxicity study was performed with the following test article dose groups: 0 (control), 1250, 2500, and 5000 mg/kg/day, administered to male and female Wistar rats via oral gavage for 90 days. No test article-related mortalities or adverse events were reported during the study. Histopathological examination revealed some vacuolation in the livers of males in the 5000 mg/kg/day group. This finding was considered adaptive, due to the approximately 20% fat content of whole cell biomass, and was therefore test article-related, but not adverse. No such findings were reported in female rats in the study. The results of the subchronic toxicity study describe a no observed adverse effect level of at least 5000 mg/kg/day.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"58 34","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91399152","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 : 2019-11-21DOI: 10.1177/2397847319879277
V. Modeste, Alizée Brient, C. Thirion-Delalande, R. Forster, Corinne Aguenou, H. Griffiths, Olivier Cagnac
Protealg® is the dried and ground whole biomass of Galdieria sulphuraria, a microalga naturally rich in protein and phycocyanin, and contains carotenoids. It is expected that Protealg will be consumed as a food ingredient or supplement by the general public. The safety of Protealg was evaluated in an Ames bacterial reverse mutation test, in vitro mammalian cell micronucleus test, and 13-week oral toxicity study in rats at the dose levels of 500, 2000, and 5000 mg/kg/day. The 13-week toxicity study included a 4-week treatment-free period to evaluate recovery. A functional observation battery and ophthalmology examinations were performed, and hematology, blood biochemistry, thyroid hormone, and urinalysis parameters were determined. Seminology parameters and estrus cycle staging were investigated. A macroscopic necropsy examination was performed and tissues were examined microscopically. Protealg showed no evidence of mutagenicity or clastogenic activity. It was well tolerated by rats and no clinical findings indicative of toxicity were observed. There were no significant findings in the in-life or post-mortem investigations. In conclusion, no toxicity was observed after administration of Protealg at dose levels up to 5000 mg/kg/day to rats for 13 weeks, supporting the safety of Protealg for use as a high protein food supplement. The NOAEL was established as 5000 mg/kg/day. Allowing for a margin of exposure of 100-fold, the corresponding anticipated daily intake will be 50 mg/kg/day equivalent to 3.5 g/day for a 70 kg subject. Incorporation levels in various foods will be defined on the basis of appropriate exposure estimations using official recommendations.
{"title":"Safety evaluation of Galdieria high-protein microalgal biomass","authors":"V. Modeste, Alizée Brient, C. Thirion-Delalande, R. Forster, Corinne Aguenou, H. Griffiths, Olivier Cagnac","doi":"10.1177/2397847319879277","DOIUrl":"https://doi.org/10.1177/2397847319879277","url":null,"abstract":"Protealg® is the dried and ground whole biomass of Galdieria sulphuraria, a microalga naturally rich in protein and phycocyanin, and contains carotenoids. It is expected that Protealg will be consumed as a food ingredient or supplement by the general public. The safety of Protealg was evaluated in an Ames bacterial reverse mutation test, in vitro mammalian cell micronucleus test, and 13-week oral toxicity study in rats at the dose levels of 500, 2000, and 5000 mg/kg/day. The 13-week toxicity study included a 4-week treatment-free period to evaluate recovery. A functional observation battery and ophthalmology examinations were performed, and hematology, blood biochemistry, thyroid hormone, and urinalysis parameters were determined. Seminology parameters and estrus cycle staging were investigated. A macroscopic necropsy examination was performed and tissues were examined microscopically. Protealg showed no evidence of mutagenicity or clastogenic activity. It was well tolerated by rats and no clinical findings indicative of toxicity were observed. There were no significant findings in the in-life or post-mortem investigations. In conclusion, no toxicity was observed after administration of Protealg at dose levels up to 5000 mg/kg/day to rats for 13 weeks, supporting the safety of Protealg for use as a high protein food supplement. The NOAEL was established as 5000 mg/kg/day. Allowing for a margin of exposure of 100-fold, the corresponding anticipated daily intake will be 50 mg/kg/day equivalent to 3.5 g/day for a 70 kg subject. Incorporation levels in various foods will be defined on the basis of appropriate exposure estimations using official recommendations.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87838204","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 : 2019-09-16DOI: 10.1177/2397847319874359
S. Owumi, Uche J Dim
We investigated the effect of selenium (Sel), a trace element in diclofenac sodium (DCF), nonsteroidal anti-inflammatory drugs-induced hepatic and renal toxicities in adult rats. Five experimental groups namely control, DCF (10 mg/kg), Sel (0.125 mg/kg), DCF + Sel (0.125 mg/kg), and DCF + Sel (0.25 mg/kg) consisting of 10 rats each were orally treated for 7 consecutive days. Following killing, biomarkers of hepatic and renal toxicities, antioxidant enzyme levels, myeloperoxidase activity, nitric oxide levels, reactive oxygen and nitrogen species (RONS), and lipid peroxidation (LPO) were analyzed spectrophotometrically. Further, the concentration of tumor necrosis factor alpha (TNF-α) was assessed using enzyme-linked immunosorbent assay, and hematological indices: white blood cells (WBC), lymphocytes, and neutrophils and eosinophil counts. Results indicated that DCF-induced increases in biomarkers of hepatic and renal toxicity were significantly (p < 0.05) lessened in serum of rats co-exposed to DCF and Sel in a dose-dependent manner. DCF mediated decrease in antioxidant status, and increases in RONS, LPO, and TNF-α levels were reduced (p < 0.05) in the liver and kidney of rats co-exposed to DCF and Sel. Additionally, Sel reduced hematological abnormalities associated with DCF treatment. Light microscopic examination showed that the severity of histopathological lesions induced by DCF was lessened in rats co-exposed to DCF and Sel. Taken together, Sel supplementation mitigated DCF-induced oxidative stress, inflammation, and hematological abnormalities in the liver and kidney of treated rats.
本文研究了双氯芬酸钠(DCF)中微量元素硒(Sel)和非甾体抗炎药对成年大鼠肝、肾毒性的影响。对照组、DCF (10 mg/kg)、Sel (0.125 mg/kg)、DCF + Sel (0.125 mg/kg)、DCF + Sel (0.25 mg/kg) 5个实验组，每组10只，连续口服7 d。杀死后，用分光光度法分析肝脏和肾脏毒性生物标志物、抗氧化酶水平、髓过氧化物酶活性、一氧化氮水平、活性氧和氮种(RONS)以及脂质过氧化(LPO)。此外，使用酶联免疫吸附法评估肿瘤坏死因子α (TNF-α)的浓度，以及血液学指标:白细胞(WBC)、淋巴细胞、中性粒细胞和嗜酸性粒细胞计数。结果表明，DCF和Sel共暴露大鼠血清中肝脏和肾脏毒性生物标志物的增加呈剂量依赖性，显著减少(p < 0.05)。DCF和Sel共暴露大鼠的肝脏和肾脏中，DCF介导的抗氧化状态下降，以及ron、LPO和TNF-α水平的升高均降低(p < 0.05)。此外，Sel降低了与DCF治疗相关的血液学异常。光镜检查显示，DCF和Sel共暴露大鼠DCF诱导的组织病理学病变严重程度减轻。综上所述，补充Sel减轻了dcf诱导的氧化应激、炎症和治疗大鼠肝脏和肾脏的血液学异常。
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Pub Date : 2019-06-26DOI: 10.1177/2397847319858563
Amaris Jalil, S. B. Reddy, C. Z. Plautz
The herbicidal action of diquat dibromide (DD) on plant cells is due primarily to the initiation of reactive oxygen species (ROS) formation, lipoperoxidation, and apoptotic cell death. It has been demonstrated that oxidative stress also occurs in animal cells exposed to high concentrations of DD; however, observations of DD’s effects on animal cells at concentrations below the reported ROS-initiation threshold suggest that some of these effects may not be attributable to ROS-induced cell death. Our results suggest that DD causes disruption of the Wnt pathway, calcium dysregulation, and cytoskeletal damage during development. Using embryos of the pond snail Lymnaea palustris as our model organism, we observed increased mortality, developmental delay and abnormality, altered motility, calcium dysregulation, decreased heart rate, and arrhythmia in embryos exposed to DD. Sperm extracted from adult snails that were exposed to DD exhibit altered motility, increased abundance, and high mortality. Effects were quantified via real-time imaging, heart rate assessment, flow cytometry, and mortality scoring. We propose that there are two models for the mechanism of DD’s action in animal cells: at low concentrations (≤28 µg/L), apoptotic cell death does not occur, but cytoskeletal elements, calcium regulation, and Wnt signaling are compromised, causing irreversible damage in L. palustris embryos; such damage is partially remediated with antioxidants or lithium chloride. At high concentrations of DD (≥44.4 µg/L), calcium dysregulation may be triggered, leading to the establishment of an intracellular positive feedback loop of ROS formation in the mitochondria, calcium release from the endoplasmic reticulum, calcium efflux, and apoptotic cell death. Permanent cellular damage occurring from exposure to sublethal concentrations of this widespread herbicide underscores the importance of research that elucidates the mechanism of DD on nontarget organisms.
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