Pub Date : 2019-06-14DOI: 10.1177/2397847319855285
S. Owumi, Eseroghene S. Najophe
Toxicological effects from chemical interaction may result in weaker or stronger effects. The present study investigated the influence of acute oral co-exposure to dichloromethane (DCM) and ethanol (EtOH) in rats. Four groups of rats were treated for seven consecutive days with corn oil, DCM at 150 mg/kg alone, EtOH at 5 g/kg alone, and both DCM and EtOH, respectively. Subsequently, biomarkers of hepatic and renal functions, cellular antioxidant defense systems, and oxidative stress indices were analyzed in the liver and kidney samples. Results indicated that the significant (p < 0.05) elevations in the biomarkers of hepatic and renal toxicity following exposure of rats to DCM alone and EtOH alone were aggravated in the co-exposure group. Further, the significant reductions in the antioxidant status and the increase in lipid peroxidation in the liver and kidney of rats following exposure to DCM alone and EtOH alone were aggravated in the co-exposure group. Histological alterations of rats treated with DCM alone and EtOH alone were worsened in the co-exposure group. In summary, co-exposure to DCM and EtOH elicited more harmful effects on the liver and kidney than the individual chemical exposure, which is attributable to the intensified oxidative stress in the treated rats.
{"title":"Dichloromethane and ethanol co-exposure aggravates oxidative stress indices causing hepatic and renal dysfunction in pubertal rats.","authors":"S. Owumi, Eseroghene S. Najophe","doi":"10.1177/2397847319855285","DOIUrl":"https://doi.org/10.1177/2397847319855285","url":null,"abstract":"Toxicological effects from chemical interaction may result in weaker or stronger effects. The present study investigated the influence of acute oral co-exposure to dichloromethane (DCM) and ethanol (EtOH) in rats. Four groups of rats were treated for seven consecutive days with corn oil, DCM at 150 mg/kg alone, EtOH at 5 g/kg alone, and both DCM and EtOH, respectively. Subsequently, biomarkers of hepatic and renal functions, cellular antioxidant defense systems, and oxidative stress indices were analyzed in the liver and kidney samples. Results indicated that the significant (p < 0.05) elevations in the biomarkers of hepatic and renal toxicity following exposure of rats to DCM alone and EtOH alone were aggravated in the co-exposure group. Further, the significant reductions in the antioxidant status and the increase in lipid peroxidation in the liver and kidney of rats following exposure to DCM alone and EtOH alone were aggravated in the co-exposure group. Histological alterations of rats treated with DCM alone and EtOH alone were worsened in the co-exposure group. In summary, co-exposure to DCM and EtOH elicited more harmful effects on the liver and kidney than the individual chemical exposure, which is attributable to the intensified oxidative stress in the treated rats.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73751751","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 : 2019-05-15DOI: 10.1177/2397847319849648
Carr J. Smith, T. Perfetti, J. King
In 2018, the National Institutes of Health estimated that 1,735,350 new cancer cases were diagnosed in the United States and 609,640 patients died from various forms of cancer. The vast majority of those cancer deaths occurred from cancers derived from epithelial cells, that is, carcinomas. The most lethal cancers in American women based upon estimated deaths occurred in the lung and bronchus (352,209), breast (205,675), colon and rectum (123,617), pancreas (96,571), and ovary (71,141). The largest cancer killers in men occurred in the lung and bronchus (427,587), prostate (140,086), colon and rectum (135,542), pancreas (100,599), and liver (80,526). Histologically different carcinomas are initiated, clonally expanded, and progressed in association with particular changes in genes and also epigenetic alterations. Currently employed genotoxicity testing protocols emphasize testing for the initiating (mutational) potential of the test agent. While 2-year chronic rodent cancer bioassays test for the entire spectrum of carcinogenic transformation and development, the high doses used in these assays induce cytotoxicity leading to increased cellular proliferation rates and high false-positive rates of tumor induction in non-genotoxic chemicals. The low cancer induction from high radiation exposures experienced by atomic bomb survivors in Hiroshima and Nagasaki, Japan, and the epidemiological evidence showing that cigarette smoking duration and not intensity is associated with lung cancer risk both support a more important role for tumor promotion rather than initiation in the clinical presentation of human carcinomas. Cancer hazard assessment testing protocols and weight-of-the-evidence analysis of agent-specific cancer risk should be better aligned with the pathogenesis of human carcinoma.
{"title":"Rodent 2-year cancer bioassays and in vitro and in vivo genotoxicity tests insufficiently predict risk or model development of human carcinomas","authors":"Carr J. Smith, T. Perfetti, J. King","doi":"10.1177/2397847319849648","DOIUrl":"https://doi.org/10.1177/2397847319849648","url":null,"abstract":"In 2018, the National Institutes of Health estimated that 1,735,350 new cancer cases were diagnosed in the United States and 609,640 patients died from various forms of cancer. The vast majority of those cancer deaths occurred from cancers derived from epithelial cells, that is, carcinomas. The most lethal cancers in American women based upon estimated deaths occurred in the lung and bronchus (352,209), breast (205,675), colon and rectum (123,617), pancreas (96,571), and ovary (71,141). The largest cancer killers in men occurred in the lung and bronchus (427,587), prostate (140,086), colon and rectum (135,542), pancreas (100,599), and liver (80,526). Histologically different carcinomas are initiated, clonally expanded, and progressed in association with particular changes in genes and also epigenetic alterations. Currently employed genotoxicity testing protocols emphasize testing for the initiating (mutational) potential of the test agent. While 2-year chronic rodent cancer bioassays test for the entire spectrum of carcinogenic transformation and development, the high doses used in these assays induce cytotoxicity leading to increased cellular proliferation rates and high false-positive rates of tumor induction in non-genotoxic chemicals. The low cancer induction from high radiation exposures experienced by atomic bomb survivors in Hiroshima and Nagasaki, Japan, and the epidemiological evidence showing that cigarette smoking duration and not intensity is associated with lung cancer risk both support a more important role for tumor promotion rather than initiation in the clinical presentation of human carcinomas. Cancer hazard assessment testing protocols and weight-of-the-evidence analysis of agent-specific cancer risk should be better aligned with the pathogenesis of human carcinoma.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86738765","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 : 2019-05-14DOI: 10.1177/2397847319849521
S. Owumi, S. Nwozo, Eseroghene S. Najophe
Exposure to the fungicide carbendazim (CBZ) has been associated with hepatorenal dysfunction. Quercetin, a naturally occurring polyphenolic phytochemical, reportedly possesses beneficial health effects. However, there is paucity of scientific information on the impact of quercetin on CBZ-induced hepatorenal damage. The present study investigated the protective mechanism of quercetin in CBZ-induced hepatic and renal damage in rats. The treatment groups consisted of control, CBZ alone (50 mg/kg), quercetin alone (20 mg/kg), and rats co-treated with CBZ and quercetin for 14 consecutive days. Quercetin co-treatment significantly (p < 0.05) abated CBZ-induced increase in biomarkers of hepatorenal damage when compared to CBZ alone. Also, quercetin abrogated CBZ-mediated decrease in antioxidant status as well as the increase in reactive oxygen and nitrogen species and lipid peroxidation in the treated rats. Furthermore, quercetin significantly suppressed CBZ-mediated increase in interleukin-1β, tumor necrosis factor alpha, and caspase-3 activity in the liver and kidney of the rats. Histopathological examination demonstrated that the severity of CBZ-induced hepatic and renal injury was ameliorated in rats co-treated with quercetin. Taken together, quercetin-mediated hepatorenal protection in CBZ-treated rats involves antioxidant, anti-inflammatory, and antiapoptotic mechanisms.
{"title":"Quercetin abates induction of hepatic and renal oxidative damage, inflammation, and apoptosis in carbendazim-treated rats","authors":"S. Owumi, S. Nwozo, Eseroghene S. Najophe","doi":"10.1177/2397847319849521","DOIUrl":"https://doi.org/10.1177/2397847319849521","url":null,"abstract":"Exposure to the fungicide carbendazim (CBZ) has been associated with hepatorenal dysfunction. Quercetin, a naturally occurring polyphenolic phytochemical, reportedly possesses beneficial health effects. However, there is paucity of scientific information on the impact of quercetin on CBZ-induced hepatorenal damage. The present study investigated the protective mechanism of quercetin in CBZ-induced hepatic and renal damage in rats. The treatment groups consisted of control, CBZ alone (50 mg/kg), quercetin alone (20 mg/kg), and rats co-treated with CBZ and quercetin for 14 consecutive days. Quercetin co-treatment significantly (p < 0.05) abated CBZ-induced increase in biomarkers of hepatorenal damage when compared to CBZ alone. Also, quercetin abrogated CBZ-mediated decrease in antioxidant status as well as the increase in reactive oxygen and nitrogen species and lipid peroxidation in the treated rats. Furthermore, quercetin significantly suppressed CBZ-mediated increase in interleukin-1β, tumor necrosis factor alpha, and caspase-3 activity in the liver and kidney of the rats. Histopathological examination demonstrated that the severity of CBZ-induced hepatic and renal injury was ameliorated in rats co-treated with quercetin. Taken together, quercetin-mediated hepatorenal protection in CBZ-treated rats involves antioxidant, anti-inflammatory, and antiapoptotic mechanisms.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79296300","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 : 2019-04-24DOI: 10.1177/2397847319844782
S. Quamar, Jayant Kumar, Awanish Mishra, S. Flora
An increase in copper concentration in body may lead to hepatolenticular degeneration which is considered as one clinical feature of Wilson’s disease. Chelation therapy using d-penicillamine is the preferred medical treatment for reducing the toxic effects of copper. However, a few shortcomings associated with d-penicillamine led us to search of an alternative antidote for copper toxicity. Monoisoamyl-2, 3-dimercaptosuccinic acid (MiADMSA), a potent arsenic chelator under clinical trial, has been reported to reduce system copper level. Thus, the present study was envisaged to explore the ameliorative effect of MiADMSA against copper toxicity. Copper pre-exposed animals (CuSO4.5H2O; 100 mg/kg; p.o., for 6 weeks) were segregated in different groups and were administered equimolar dose (0.3 mEq/kg/day; p.o.) of d-penicillamine and MiADMSA for 5 days. The effect of different treatments on spontaneous locomotor activity, muscle coordination, depression like behaviour and contextual fear memory was analysed using neurobehavioural battery test. Biochemical variables related to oxidative stress, zinc and copper concentration were determined in liver, kidney and brain. The results suggested that copper exposure led to oxidative stress in liver, kidney and blood, along with moderate effects in brain. Treatment with d-penicillamine and MiADMSA reduced liver copper load. MiADMSA produced more pronounced beneficial effect compared to d-penicillamine by increasing brain GPx activity. Our study suggests that MiADMSA might be equally effective as d-penicillamine in depleting body copper load. More detailed studies using different doses are required to suggest whether MiADMSA could be an alternative for d-penicillamine in reducing oxidative injury, neurobehavioural changes and depleting body copper burden.
{"title":"Oxidative stress and neurobehavioural changes in rats following copper exposure and their response to MiADMSA and d-penicillamine","authors":"S. Quamar, Jayant Kumar, Awanish Mishra, S. Flora","doi":"10.1177/2397847319844782","DOIUrl":"https://doi.org/10.1177/2397847319844782","url":null,"abstract":"An increase in copper concentration in body may lead to hepatolenticular degeneration which is considered as one clinical feature of Wilson’s disease. Chelation therapy using d-penicillamine is the preferred medical treatment for reducing the toxic effects of copper. However, a few shortcomings associated with d-penicillamine led us to search of an alternative antidote for copper toxicity. Monoisoamyl-2, 3-dimercaptosuccinic acid (MiADMSA), a potent arsenic chelator under clinical trial, has been reported to reduce system copper level. Thus, the present study was envisaged to explore the ameliorative effect of MiADMSA against copper toxicity. Copper pre-exposed animals (CuSO4.5H2O; 100 mg/kg; p.o., for 6 weeks) were segregated in different groups and were administered equimolar dose (0.3 mEq/kg/day; p.o.) of d-penicillamine and MiADMSA for 5 days. The effect of different treatments on spontaneous locomotor activity, muscle coordination, depression like behaviour and contextual fear memory was analysed using neurobehavioural battery test. Biochemical variables related to oxidative stress, zinc and copper concentration were determined in liver, kidney and brain. The results suggested that copper exposure led to oxidative stress in liver, kidney and blood, along with moderate effects in brain. Treatment with d-penicillamine and MiADMSA reduced liver copper load. MiADMSA produced more pronounced beneficial effect compared to d-penicillamine by increasing brain GPx activity. Our study suggests that MiADMSA might be equally effective as d-penicillamine in depleting body copper load. More detailed studies using different doses are required to suggest whether MiADMSA could be an alternative for d-penicillamine in reducing oxidative injury, neurobehavioural changes and depleting body copper burden.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80228065","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 : 2019-02-21DOI: 10.1177/2397847319831368
Fathiah A Zubaidi, Fathiah A Zubaidi, Y. Choo, G. Tan, P. Myron, C. CornelIa
Background: Methamphetamine (MA) and phentermine (PTM) are critical isomeric compounds that often coexist in biological specimen in toxicology cases which have similar nominal mass. The dependency of high-resolution mass spectrometer and special chiral stationary phase column for separation of isomeric compound impedes screening throughput especially in meeting high sampling demand. Aim: In the absence of such equipment for identification, we introduce the flow injection analysis (FIA)-MRM3 technique and demonstrated its capabilities for quick identification of both isomeric compounds without liquid chromatography (LC) separation through the addition of selectivity criteria in the MRM3 mode. Method: 20 to 100 ng/mL of MA and PTM, respectively, in whole blood sample (WBS) and dried blood stain (DBS) were used to develop the method for the identification and relative quantification. Twenty whole blood samples which were reported positive of the drugs were randomly selected and were individually stained onto the Flinders Technology Associates (FTA) card for DBS study. Results: The peaks from the two isomeric compounds were successfully discerned for all the tested specimens using the FIA-MRM3 spectrometry technique. The limit of detection (LOD) and limit of quantification (LOQ) for MA and PTM were comparable to normal liquid chromatography-tandem mass spectrometry runs at 2.23 and 2.07 ng/mL, respectively, for WBS (n = 30). For DBS, the LOD and LOQ were 3.40 and 2.86 ng/mL, respectively. The accuracy and inter-day precision for DBS and WBS were in the range of 99.97–111.19% and 7.17–9.55%, respectively. Conclusion: These results demonstrated that the technique is highly adoptable in the screening of isomeric compounds of similar masses in a simple and rapid analysis.
{"title":"High-throughput flow injection analysis-MRM3 (FIA-MRM3) spectrometry for alternative fast screening of the isomeric methamphetamine and phentermine in blood for forensic toxicology cases in Malaysia","authors":"Fathiah A Zubaidi, Fathiah A Zubaidi, Y. Choo, G. Tan, P. Myron, C. CornelIa","doi":"10.1177/2397847319831368","DOIUrl":"https://doi.org/10.1177/2397847319831368","url":null,"abstract":"Background: Methamphetamine (MA) and phentermine (PTM) are critical isomeric compounds that often coexist in biological specimen in toxicology cases which have similar nominal mass. The dependency of high-resolution mass spectrometer and special chiral stationary phase column for separation of isomeric compound impedes screening throughput especially in meeting high sampling demand. Aim: In the absence of such equipment for identification, we introduce the flow injection analysis (FIA)-MRM3 technique and demonstrated its capabilities for quick identification of both isomeric compounds without liquid chromatography (LC) separation through the addition of selectivity criteria in the MRM3 mode. Method: 20 to 100 ng/mL of MA and PTM, respectively, in whole blood sample (WBS) and dried blood stain (DBS) were used to develop the method for the identification and relative quantification. Twenty whole blood samples which were reported positive of the drugs were randomly selected and were individually stained onto the Flinders Technology Associates (FTA) card for DBS study. Results: The peaks from the two isomeric compounds were successfully discerned for all the tested specimens using the FIA-MRM3 spectrometry technique. The limit of detection (LOD) and limit of quantification (LOQ) for MA and PTM were comparable to normal liquid chromatography-tandem mass spectrometry runs at 2.23 and 2.07 ng/mL, respectively, for WBS (n = 30). For DBS, the LOD and LOQ were 3.40 and 2.86 ng/mL, respectively. The accuracy and inter-day precision for DBS and WBS were in the range of 99.97–111.19% and 7.17–9.55%, respectively. Conclusion: These results demonstrated that the technique is highly adoptable in the screening of isomeric compounds of similar masses in a simple and rapid analysis.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81779611","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 : 2019-01-03DOI: 10.1177/2397847318820768
A. Hayes, Roman Li, J. Hoeng, A. Iskandar, Manuel C Peistch, M. Dourson
Assessing the risk of chemical mixtures is an intricate process that should integrate published laboratory data; comparisons with the composition, toxicity, and functionality of similar mixtures; complete analytical characterization of the mixture components; and in silico modeling. Various tiered assessment protocols have been proposed to address this need, and these protocols may be adapted on a case-by-case basis for both mixture-based and component-based evaluations. Emerging technologies have enabled rapid mixture testing in alternative animal models, such as human organotypic cultures and zebrafish. In addition, quantitative modeling that uses systems toxicology approaches can identify exposure-induced cellular and molecular alterations that would not be detected by standard toxicology assays. This review summarizes the approaches to risk assessment of complex chemical mixtures as presented at the Eighth International Congress of the Asian Society of Toxicology, June 2018.
{"title":"New approaches to risk assessment of chemical mixtures","authors":"A. Hayes, Roman Li, J. Hoeng, A. Iskandar, Manuel C Peistch, M. Dourson","doi":"10.1177/2397847318820768","DOIUrl":"https://doi.org/10.1177/2397847318820768","url":null,"abstract":"Assessing the risk of chemical mixtures is an intricate process that should integrate published laboratory data; comparisons with the composition, toxicity, and functionality of similar mixtures; complete analytical characterization of the mixture components; and in silico modeling. Various tiered assessment protocols have been proposed to address this need, and these protocols may be adapted on a case-by-case basis for both mixture-based and component-based evaluations. Emerging technologies have enabled rapid mixture testing in alternative animal models, such as human organotypic cultures and zebrafish. In addition, quantitative modeling that uses systems toxicology approaches can identify exposure-induced cellular and molecular alterations that would not be detected by standard toxicology assays. This review summarizes the approaches to risk assessment of complex chemical mixtures as presented at the Eighth International Congress of the Asian Society of Toxicology, June 2018.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76483482","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 : 2019-01-03DOI: 10.1177/2397847318820719
Hadi Tabarraei, J. Hassan, Sh Mosavi
In this study, the toxicity of thymol, the essential oil (EO) of thyme plant, cumin seeds, and caraway seeds on rainbow trout (Oncorhynchus mykiss) was investigated and compared through a static method. The acute and short-term exposure study were conducted at a pH of 7.4 and a temperature of 15°C. In Acute toxicity test, concentrations of agents that killed 50% of rainbow trout (LC50) within 96-h for EOs of thyme, thymol, cumin, and caraway were 6.6, 2.6, 35, and 14 mg L−1, respectively. Changes in fish behavior were restless, aimless swimming, and imbalances that were the same for all agents in acute toxicity test. In short-term study, histopathological changes consisted of hyperemia and edema in most organs. But most of the changes were observed in gill and brain of fish that included cellular hyperplasia and fusion of lamellae in the gills and necrosis and inflammation in the brain in addition to hyperemia and edema. The results showed that EOs used in this study were likely to exert their effects through competition with oxygen insolubility in the water and, for this reason, most of the changes were seen in the gills and brain that are more sensitive to the amounts of oxygen. This study concluded that the acute toxicity of these EOs is significant and the use of these substances in the aquatic industry should be cautious.
{"title":"Determination of LD50 of some essential oils and histopathological changes in short-term exposure to one of them in rainbow trout (Oncorhynchus mykiss)","authors":"Hadi Tabarraei, J. Hassan, Sh Mosavi","doi":"10.1177/2397847318820719","DOIUrl":"https://doi.org/10.1177/2397847318820719","url":null,"abstract":"In this study, the toxicity of thymol, the essential oil (EO) of thyme plant, cumin seeds, and caraway seeds on rainbow trout (Oncorhynchus mykiss) was investigated and compared through a static method. The acute and short-term exposure study were conducted at a pH of 7.4 and a temperature of 15°C. In Acute toxicity test, concentrations of agents that killed 50% of rainbow trout (LC50) within 96-h for EOs of thyme, thymol, cumin, and caraway were 6.6, 2.6, 35, and 14 mg L−1, respectively. Changes in fish behavior were restless, aimless swimming, and imbalances that were the same for all agents in acute toxicity test. In short-term study, histopathological changes consisted of hyperemia and edema in most organs. But most of the changes were observed in gill and brain of fish that included cellular hyperplasia and fusion of lamellae in the gills and necrosis and inflammation in the brain in addition to hyperemia and edema. The results showed that EOs used in this study were likely to exert their effects through competition with oxygen insolubility in the water and, for this reason, most of the changes were seen in the gills and brain that are more sensitive to the amounts of oxygen. This study concluded that the acute toxicity of these EOs is significant and the use of these substances in the aquatic industry should be cautious.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78838225","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 : 2019-01-01DOI: 10.1177/2397847319889535
C. Berry, S. Cohen, A. Hayes, N. Kaminski
In late 2016, an examination of the 60 studies constituting the 2-year National Toxicology Program (NTP) inhalation study database conducted for the purpose of evaluating the clinical relevance to humans of chemical induction of bronchioloalveolar carcinomas in mice was initiated. From an anecdote of unknown origin that tumor concordance between rats and mice was reported to be 70%, therefore, the very high level of discordance in tumor formation and tumor site between rats and mice that the inhalation data actually showed was a surprising but interesting outcome. Further examination of the NTP inhalation database led to an initial publication in 2017. The inability to extrapolate the results from the inhalation route to the other routes of exposure (feed, gavage, drinking water, dermal, intraperitoneal injection) in the NTP database motivated Smith and Perfetti to analyze the studies on these other routes of exposure in terms of rat–mouse tumor incidence and site concordance and correlation of rodent tumorigenicity with Ames test results and, similarly, with other tests of genotoxicity as reported by the NTP. Over the last several years, Smith and his colleagues have closely followed the deliberations of the NTP expert panel regarding the potential genotoxicity and tumorigenicity of 1-bromopropane. From this experience, the emphasis placed by the NTP on historical data rather than on more recently conducted, state-of-the-art, GLP genotoxicity assays was striking. In the analysis of the feed, gavage, drinking water, dermal, and intraperitoneal injection 2-year NTP studies, Smith and Perfetti found a poor correlation between positive Ames test results and the development of rodent tumors and, concomitantly, a similarly poor correlation between negative Ames test results and the absence of rodent tumors. The inability to determine the quality of the Ames tests and other tests of genetic toxicity confounded the evaluation of whether the Ames test data were actually displaying poor predictive power or whether the Ames test data contained an inherently high error rate that interfered with the statistical analysis. Given the limitations of the data in the NTP database, Smith and Perfetti shifted the focus of the analysis to the molecular determinants of rodent tumorigenicity. Smith and Perfetti had a long-standing collaborative relationship with Dr Corwin Hansch, the originator of the QSAR concept and methodology, and following his passing, with his former postdoctoral fellow Dr Rajni Garg and her former postdoctoral fellow Dr Gene Ko. In collaboration with Drs Garg and Ko, Smith and Perfetti correlated the following for all the chemicals in the NTP database: Ames mutagenicity, structural alerts of carcinogenicity, Hansch QSAR parameters (ClogP, CMR, MgVol), tumor site concordance/multiplicity, and tumorigenicity rank. One of the conclusions was that since the clinical relevance of rodent tumors to human tumors cannot be determined from this data set,
{"title":"The NTP 2-year bioassay: Controversies in counting rodent tumors to predict human cancer","authors":"C. Berry, S. Cohen, A. Hayes, N. Kaminski","doi":"10.1177/2397847319889535","DOIUrl":"https://doi.org/10.1177/2397847319889535","url":null,"abstract":"In late 2016, an examination of the 60 studies constituting the 2-year National Toxicology Program (NTP) inhalation study database conducted for the purpose of evaluating the clinical relevance to humans of chemical induction of bronchioloalveolar carcinomas in mice was initiated. From an anecdote of unknown origin that tumor concordance between rats and mice was reported to be 70%, therefore, the very high level of discordance in tumor formation and tumor site between rats and mice that the inhalation data actually showed was a surprising but interesting outcome. Further examination of the NTP inhalation database led to an initial publication in 2017. The inability to extrapolate the results from the inhalation route to the other routes of exposure (feed, gavage, drinking water, dermal, intraperitoneal injection) in the NTP database motivated Smith and Perfetti to analyze the studies on these other routes of exposure in terms of rat–mouse tumor incidence and site concordance and correlation of rodent tumorigenicity with Ames test results and, similarly, with other tests of genotoxicity as reported by the NTP. Over the last several years, Smith and his colleagues have closely followed the deliberations of the NTP expert panel regarding the potential genotoxicity and tumorigenicity of 1-bromopropane. From this experience, the emphasis placed by the NTP on historical data rather than on more recently conducted, state-of-the-art, GLP genotoxicity assays was striking. In the analysis of the feed, gavage, drinking water, dermal, and intraperitoneal injection 2-year NTP studies, Smith and Perfetti found a poor correlation between positive Ames test results and the development of rodent tumors and, concomitantly, a similarly poor correlation between negative Ames test results and the absence of rodent tumors. The inability to determine the quality of the Ames tests and other tests of genetic toxicity confounded the evaluation of whether the Ames test data were actually displaying poor predictive power or whether the Ames test data contained an inherently high error rate that interfered with the statistical analysis. Given the limitations of the data in the NTP database, Smith and Perfetti shifted the focus of the analysis to the molecular determinants of rodent tumorigenicity. Smith and Perfetti had a long-standing collaborative relationship with Dr Corwin Hansch, the originator of the QSAR concept and methodology, and following his passing, with his former postdoctoral fellow Dr Rajni Garg and her former postdoctoral fellow Dr Gene Ko. In collaboration with Drs Garg and Ko, Smith and Perfetti correlated the following for all the chemicals in the NTP database: Ames mutagenicity, structural alerts of carcinogenicity, Hansch QSAR parameters (ClogP, CMR, MgVol), tumor site concordance/multiplicity, and tumorigenicity rank. One of the conclusions was that since the clinical relevance of rodent tumors to human tumors cannot be determined from this data set, ","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73406752","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 : 2019-01-01DOI: 10.1177/2397847319855087
R. Maronpot, Y. Ramot, Mihoko Koyanagi, Nicola Dias, D. Cameron, Samuel Eniola, A. Nyska, S. Hayashi
Background: Alpha-glycosyl isoquercitrin (AGIQ) is widely used as an anti-oxidative food additive in many products. Nevertheless, information on its safety and toxicity is still very limited. A 90-day toxicity study in rats and comprehensive genotoxic studies have proven AGIQ to be safe. Aim: The goal of this study was to assess the safety of use of AGIQ in infant formula. To test for potential adverse effects on growth or other safety issues specific for young animals, we performed a 10-day and a 4-week study in preweaning Göttingen minipigs. Method: Newborn minipigs were treated four times per day with oral AGIQ (0, 100, 300, or 1000 mg/kg/day) for 10 days or 4 weeks. Results: All animals remained in good health throughout both studies, and there were no treatment-related signs of toxicity or abnormal findings in blood parameters. In the 4-week study, yellow coloration of the bones was seen in all animals in the high-dose group with no related histological findings. Hepatocellular and sinusoidal/Kupffer cell iron deposition was seen in the liver of all animals in both studies, as expected after the routine administration of supplemental iron to newborn animals. There was sufficient evidence of systemic exposure based on plasma levels of AGIQ metabolites. Conclusion: Taken together, these findings show that oral administration of AGIQ in reconstituted milk supplement to preweaning Göttingen minipigs for 4 weeks at up to 1000 mg/kg/day does not result in any adverse treatment-related effects and further support the safety of AGIQ as a food additive.
{"title":"Ten-day and four-week toxicity and toxicokinetics studies of alpha-glycosyl isoquercitrin in juvenile Göttingen minipigs","authors":"R. Maronpot, Y. Ramot, Mihoko Koyanagi, Nicola Dias, D. Cameron, Samuel Eniola, A. Nyska, S. Hayashi","doi":"10.1177/2397847319855087","DOIUrl":"https://doi.org/10.1177/2397847319855087","url":null,"abstract":"Background: Alpha-glycosyl isoquercitrin (AGIQ) is widely used as an anti-oxidative food additive in many products. Nevertheless, information on its safety and toxicity is still very limited. A 90-day toxicity study in rats and comprehensive genotoxic studies have proven AGIQ to be safe. Aim: The goal of this study was to assess the safety of use of AGIQ in infant formula. To test for potential adverse effects on growth or other safety issues specific for young animals, we performed a 10-day and a 4-week study in preweaning Göttingen minipigs. Method: Newborn minipigs were treated four times per day with oral AGIQ (0, 100, 300, or 1000 mg/kg/day) for 10 days or 4 weeks. Results: All animals remained in good health throughout both studies, and there were no treatment-related signs of toxicity or abnormal findings in blood parameters. In the 4-week study, yellow coloration of the bones was seen in all animals in the high-dose group with no related histological findings. Hepatocellular and sinusoidal/Kupffer cell iron deposition was seen in the liver of all animals in both studies, as expected after the routine administration of supplemental iron to newborn animals. There was sufficient evidence of systemic exposure based on plasma levels of AGIQ metabolites. Conclusion: Taken together, these findings show that oral administration of AGIQ in reconstituted milk supplement to preweaning Göttingen minipigs for 4 weeks at up to 1000 mg/kg/day does not result in any adverse treatment-related effects and further support the safety of AGIQ as a food additive.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86810537","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 : 2019-01-01DOI: 10.1177/2397847319850167
Carr J. Smith, T. Perfetti
Chemical-induced pulmonary carcinogenesis in humans is usually a multi-decade process. The average age at diagnosis of lung cancer in cigarette smokers, and mesothelioma in asbestos workers, is approximately 70. The carcinogenic process consists of genetic changes to normal cells usually sequenced as initiation (mutations), promotion (clonal expansion of initiated cells), and progression (carcinoma in situ to invasive carcinoma to metastatic carcinoma). Angiogenesis, the sprouting of new vessels from preexisting capillaries, plays an important role in the progression of small avascular tumors to vascularized invasive carcinomas and metastatic carcinomas. While the overall carcinogenic process is multi-decade, the transition from avascular to vascularized carcinoma is believed to take place over the course of a much more limited time span. Tumor progression is a late-stage event in carcinogenesis. About 70% of human cancers including lung cancer express hypoxia-inducible factor (HIF)-1 in the absence of cobalt exposure. Cobalt compounds administered to transformed cell lines and primary cultures of human endothelial cells, smooth muscle cells, and mesenchymal stem cells can elicit overexpression of HIF-1. Cobalt-induced expression of HIF-1 would not be expected to interact with either the avascular initiation or promotion phases of carcinoma development. Humans exposed long-term to cobalt leaching from implants do not have an elevated cancer risk, and neither do goats ingesting up to 667 times the recommended daily human cobalt dietary requirement throughout their 15- to 18-year life span. In vitro hypoxia-mimetic characteristics of cobalt compounds do not correlate with the absence of increased risk following long-term systemic exposure to cobalt in humans.
{"title":"In vitro cobalt-stimulated hypoxia-inducible factor-1 overexpression does not correlate with cancer risk from cobalt exposure in humans","authors":"Carr J. Smith, T. Perfetti","doi":"10.1177/2397847319850167","DOIUrl":"https://doi.org/10.1177/2397847319850167","url":null,"abstract":"Chemical-induced pulmonary carcinogenesis in humans is usually a multi-decade process. The average age at diagnosis of lung cancer in cigarette smokers, and mesothelioma in asbestos workers, is approximately 70. The carcinogenic process consists of genetic changes to normal cells usually sequenced as initiation (mutations), promotion (clonal expansion of initiated cells), and progression (carcinoma in situ to invasive carcinoma to metastatic carcinoma). Angiogenesis, the sprouting of new vessels from preexisting capillaries, plays an important role in the progression of small avascular tumors to vascularized invasive carcinomas and metastatic carcinomas. While the overall carcinogenic process is multi-decade, the transition from avascular to vascularized carcinoma is believed to take place over the course of a much more limited time span. Tumor progression is a late-stage event in carcinogenesis. About 70% of human cancers including lung cancer express hypoxia-inducible factor (HIF)-1 in the absence of cobalt exposure. Cobalt compounds administered to transformed cell lines and primary cultures of human endothelial cells, smooth muscle cells, and mesenchymal stem cells can elicit overexpression of HIF-1. Cobalt-induced expression of HIF-1 would not be expected to interact with either the avascular initiation or promotion phases of carcinoma development. Humans exposed long-term to cobalt leaching from implants do not have an elevated cancer risk, and neither do goats ingesting up to 667 times the recommended daily human cobalt dietary requirement throughout their 15- to 18-year life span. In vitro hypoxia-mimetic characteristics of cobalt compounds do not correlate with the absence of increased risk following long-term systemic exposure to cobalt in humans.","PeriodicalId":23155,"journal":{"name":"Toxicology Research and Application","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82713412","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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