The Experts below are selected from a list of 6483 Experts worldwide ranked by ideXlab platform

Nigel J. Walker - One of the best experts on this subject based on the ideXlab platform.

  • repeated Dose toxicity and relative potency of 1 2 3 4 6 7 hexachloronaphthalene pcn 66 1 2 3 5 6 7 hexachloronaphthalene pcn 67 compared to 2 3 7 8 tetrachlorodibenzo p dioxin tcdd for induction of cyp1a1 cyp1a2 and thymic atrophy in female harlan s
    Toxicology, 2012
    Co-Authors: Michelle J Hooth, Abraham Nyska, Laurene M Fomby, Daphne Vasconcelos, Molly Vallant, Michael J Devito, Nigel J. Walker
    Abstract:

    Abstract In this study we assessed the relative toxicity and potency of the chlorinated naphthalenes 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) and 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemicals were administered in corn oil:acetone (99:1) by gavage to female Harlan Sprague–Dawley rats at dosages of 0 (vehicle), 500, 1500, 5000, 50,000 and 500,000 ng/kg (PCN 66 and PCN 67) and 1, 3, 10, 100, and 300 ng/kg (TCDD) for 2 weeks. Histopathologic changes were observed in the thymus, liver and lung of TCDD treated animals and in the liver and thymus of PCN treated animals. Significant increases in CYP1A1 and CYP1A2 associated enzyme activity were observed in all animals exposed to TCDD, PCN 66 and PCN 67. Dose Response Modeling of CYP1A1, CYP1A2 and thymic atrophy gave ranges of estimated relative potencies, as compared to TCDD, of 0.0015–0.0072, for PCN 66 and 0.00029–0.00067 for PCN 67. Given that PCN 66 and PCN 67 exposure resulted in biochemical and histopathologic changes similar to that seen with TCDD, this suggests that they should be included in the WHO toxic equivalency factor (TEF) scheme, although the estimated relative potencies indicate that these hexachlorinated naphthalenes should not contribute greatly to the overall human body burden of dioxin-like activity.

  • Dose additive carcinogenicity of a defined mixture of dioxin like compounds
    Environmental Health Perspectives, 2004
    Co-Authors: Nigel J. Walker, Donald M. Sells, Amy E. Brix, Abraham Nyska, Patrick W Crockett, Michael P Jokinen, James R Hailey, Micheal Easterling, Joseph K Haseman, Ming Yin
    Abstract:

    Use of the dioxin toxic equivalency factor (TEF) approach in human risk assessments assumes that the combined effects of dioxin-like compounds in a mixture can be predicted based on a potency-adjusted Dose-additive combination of constituents of the mixture. In this study, we evaluated the TEF approach in experimental 2-year rodent cancer bioassays with female Harlan Sprague-Dawley rats receiving 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3′,4,4′,5-pentachlorobiphenyl (PCB-126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a mixture of the three compounds. Statistically based Dose–Response Modeling indicated that the shape of the Dose–Response curves for hepatic, lung, and oral mucosal neoplasms was the same in studies of the three individual chemicals and the mixture. In addition, the Dose Response for the mixture could be predicted from a combination of the potency-adjusted Doses of the individual compounds. Finally, we showed that use of the current World Health Organization dioxin TEF values adequately predicted the increased incidence of liver tumors (hepatocellular adenoma and cholangiocarcinoma) induced by exposure to the mixture. These data support the use of the TEF approach for dioxin cancer risk assessments.

Chad M. Thompson - One of the best experts on this subject based on the ideXlab platform.

  • Development of an oral reference Dose for the perfluorinated compound GenX.
    Journal of applied toxicology : JAT, 2019
    Co-Authors: Chad M. Thompson, Seneca Fitch, Caroline L. Ring, William Rish, John M. Cullen, Laurie C. Haws
    Abstract:

    Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long-chain poly-fluoroalkyl substances, which tend to have long clearance half-lives and are environmentally persistent. Unlike poly-fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non-cancer oral reference Dose (RfD) for GenX based on available repeated Dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark Dose models and Bayesian benchmark Dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2-year bioassay in rats (0.01-0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and Dose-Response Modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for GenX.

  • Benchmark Dose Modeling Estimates of the Concentrations of Inorganic Arsenic That Induce Changes to the Neonatal Transcriptome, Proteome, and Epigenome in a Pregnancy Cohort
    2017
    Co-Authors: Julia E. Rager, Chad M. Thompson, Scott S. Auerbach, Grace A. Chappell, Elizabeth Martin, Rebecca C. Fry
    Abstract:

    Prenatal inorganic arsenic (iAs) exposure influences the expression of critical genes and proteins associated with adverse outcomes in newborns, in part through epigenetic mediators. The Doses at which these genomic and epigenomic changes occur have yet to be evaluated in the context of Dose–Response Modeling. The goal of the present study was to estimate iAs Doses that correspond to changes in transcriptomic, proteomic, epigenomic, and integrated multi-omic signatures in human cord blood through benchmark Dose (BMD) Modeling. Genome-wide DNA methylation, microRNA expression, mRNA expression, and protein expression levels in cord blood were modeled against total urinary arsenic (U-tAs) levels from pregnant women exposed to varying levels of iAs. Dose–Response relationships were modeled in BMDExpress, and BMDs representing 10% Response levels were estimated. Overall, DNA methylation changes were estimated to occur at lower exposure concentrations in comparison to other molecular endpoints. Multi-omic module eigengenes were derived through weighted gene co-expression network analysis, representing co-modulated signatures across transcriptomic, proteomic, and epigenomic profiles. One module eigengene was associated with decreased gestational age occurring alongside increased iAs exposure. Genes/proteins within this module eigengene showed enrichment for organismal development, including potassium voltage-gated channel subfamily Q member 1 (KCNQ1), an imprinted gene showing differential methylation and expression in Response to iAs. Modeling of this prioritized multi-omic module eigengene resulted in a BMD­(BMDL) of 58(45) μg/L U-tAs, which was estimated to correspond to drinking water arsenic concentrations of 51(40) μg/L. Results are in line with epidemiological evidence supporting effects of prenatal iAs occurring at levels

  • development of a chronic noncancer oral reference Dose and drinking water screening level for sulfolane using benchmark Dose Modeling
    Journal of Applied Toxicology, 2013
    Co-Authors: Chad M. Thompson, David W Gaylor, Andrew J Tachovsky, Camarie Perry, Michael Carakostas, Laurie C. Haws
    Abstract:

    Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000–36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference Dose (RfD) based on benchmark Dose Modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark Dose Modeling were 0.01–0.04 mg kg−1 per day, although Modeling of developmental endpoints resulted in higher values, approximately 0.4 mg kg−1 per day. The lowest, most conservative, RfD of 0.01 mg kg−1 per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l−1. It is anticipated that these values, along with the hazard identification and Dose–Response Modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane. Copyright © 2012 John Wiley & Sons, Ltd.

  • genome wide gene expression effects in b6c3f1 mouse intestinal epithelia following 7 and 90 days of exposure to hexavalent chromium in drinking water
    Toxicology and Applied Pharmacology, 2012
    Co-Authors: Anna K Kopec, Laurie C. Haws, Timothy R Zacharewski, Suntae Kim, Agnes L Forgacs, Deborah M Proctor, Mark A Harris, Chad M. Thompson
    Abstract:

    Chronic administration of high Doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90 days of exposure to 0, 0.3, 4, 14, 60, 170 or 520 mg/L SDD in drinking water. Genome-wide microarray analyses identified 6562 duodenal and 4448 jejunal unique differentially expressed genes at day 8, and 4630 and 4845 unique changes, respectively, in the duodenum and jejunum at day 91. Comparative analysis identified significant overlap in duodenal and jejunal differential gene expression. Automated Dose–Response Modeling identified > 80% of the differentially expressed genes exhibited sigmoidal Dose–Response curves with EC50 values ranging from 10 to 100 mg/L SDD. Only 16 genes satisfying the Dose-dependent differential expression criteria had EC50 values < 10 mg/L SDD, 3 of which were regulated by Nrf2, suggesting oxidative stress in Response to SDD at low concentrations. Analyses of differentially expressed genes identified over-represented functions associated with oxidative stress, cell cycle, lipid metabolism, and immune Responses consistent with the reported effects on redox status and histopathology at corresponding SDD drinking water concentrations. Collectively, these data are consistent with a mode of action involving oxidative stress and cytotoxicity as early key events. This suggests that the tumorigenic effects of chronic Cr(VI) oral exposure likely require chronic tissue damage and compensatory epithelial cell proliferation.

Laurie C. Haws - One of the best experts on this subject based on the ideXlab platform.

  • Development of an oral reference Dose for the perfluorinated compound GenX.
    Journal of applied toxicology : JAT, 2019
    Co-Authors: Chad M. Thompson, Seneca Fitch, Caroline L. Ring, William Rish, John M. Cullen, Laurie C. Haws
    Abstract:

    Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long-chain poly-fluoroalkyl substances, which tend to have long clearance half-lives and are environmentally persistent. Unlike poly-fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non-cancer oral reference Dose (RfD) for GenX based on available repeated Dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark Dose models and Bayesian benchmark Dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2-year bioassay in rats (0.01-0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and Dose-Response Modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for GenX.

  • development of a chronic noncancer oral reference Dose and drinking water screening level for sulfolane using benchmark Dose Modeling
    Journal of Applied Toxicology, 2013
    Co-Authors: Chad M. Thompson, David W Gaylor, Andrew J Tachovsky, Camarie Perry, Michael Carakostas, Laurie C. Haws
    Abstract:

    Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000–36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference Dose (RfD) based on benchmark Dose Modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark Dose Modeling were 0.01–0.04 mg kg−1 per day, although Modeling of developmental endpoints resulted in higher values, approximately 0.4 mg kg−1 per day. The lowest, most conservative, RfD of 0.01 mg kg−1 per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l−1. It is anticipated that these values, along with the hazard identification and Dose–Response Modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane. Copyright © 2012 John Wiley & Sons, Ltd.

  • genome wide gene expression effects in b6c3f1 mouse intestinal epithelia following 7 and 90 days of exposure to hexavalent chromium in drinking water
    Toxicology and Applied Pharmacology, 2012
    Co-Authors: Anna K Kopec, Laurie C. Haws, Timothy R Zacharewski, Suntae Kim, Agnes L Forgacs, Deborah M Proctor, Mark A Harris, Chad M. Thompson
    Abstract:

    Chronic administration of high Doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90 days of exposure to 0, 0.3, 4, 14, 60, 170 or 520 mg/L SDD in drinking water. Genome-wide microarray analyses identified 6562 duodenal and 4448 jejunal unique differentially expressed genes at day 8, and 4630 and 4845 unique changes, respectively, in the duodenum and jejunum at day 91. Comparative analysis identified significant overlap in duodenal and jejunal differential gene expression. Automated Dose–Response Modeling identified > 80% of the differentially expressed genes exhibited sigmoidal Dose–Response curves with EC50 values ranging from 10 to 100 mg/L SDD. Only 16 genes satisfying the Dose-dependent differential expression criteria had EC50 values < 10 mg/L SDD, 3 of which were regulated by Nrf2, suggesting oxidative stress in Response to SDD at low concentrations. Analyses of differentially expressed genes identified over-represented functions associated with oxidative stress, cell cycle, lipid metabolism, and immune Responses consistent with the reported effects on redox status and histopathology at corresponding SDD drinking water concentrations. Collectively, these data are consistent with a mode of action involving oxidative stress and cytotoxicity as early key events. This suggests that the tumorigenic effects of chronic Cr(VI) oral exposure likely require chronic tissue damage and compensatory epithelial cell proliferation.

Timothy R Zacharewski - One of the best experts on this subject based on the ideXlab platform.

  • genome wide gene expression effects in b6c3f1 mouse intestinal epithelia following 7 and 90 days of exposure to hexavalent chromium in drinking water
    Toxicology and Applied Pharmacology, 2012
    Co-Authors: Anna K Kopec, Laurie C. Haws, Timothy R Zacharewski, Suntae Kim, Agnes L Forgacs, Deborah M Proctor, Mark A Harris, Chad M. Thompson
    Abstract:

    Chronic administration of high Doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90 days of exposure to 0, 0.3, 4, 14, 60, 170 or 520 mg/L SDD in drinking water. Genome-wide microarray analyses identified 6562 duodenal and 4448 jejunal unique differentially expressed genes at day 8, and 4630 and 4845 unique changes, respectively, in the duodenum and jejunum at day 91. Comparative analysis identified significant overlap in duodenal and jejunal differential gene expression. Automated Dose–Response Modeling identified > 80% of the differentially expressed genes exhibited sigmoidal Dose–Response curves with EC50 values ranging from 10 to 100 mg/L SDD. Only 16 genes satisfying the Dose-dependent differential expression criteria had EC50 values < 10 mg/L SDD, 3 of which were regulated by Nrf2, suggesting oxidative stress in Response to SDD at low concentrations. Analyses of differentially expressed genes identified over-represented functions associated with oxidative stress, cell cycle, lipid metabolism, and immune Responses consistent with the reported effects on redox status and histopathology at corresponding SDD drinking water concentrations. Collectively, these data are consistent with a mode of action involving oxidative stress and cytotoxicity as early key events. This suggests that the tumorigenic effects of chronic Cr(VI) oral exposure likely require chronic tissue damage and compensatory epithelial cell proliferation.

  • automated quantitative Dose Response Modeling and point of departure determination for large toxicogenomic and high throughput screening data sets
    Toxicological Sciences, 2008
    Co-Authors: Lyle D Burgoon, Timothy R Zacharewski
    Abstract:

    Regulatory and homeland security agencies undertake safety and risk assessments to assess the potential hazards of radiation, chemical, biological, and pharmaceutical agents. By law, these assessments must be science-based to ensure public safety and environmental quality. These agencies use Dose-Response Modeling and benchmark Dose methods to identify points of departure across single end points elicited by the agent. Regulatory agencies have also begun to examine toxicogenomic data to identify novel biomarkers of exposure and assess potential toxicity. The ToxResponse Modeler streamlines analyses and point of departure (POD) calculations across hundreds of Responses (e.g., differential gene expression, changes in metabolite levels) through an automated process capable of large-scale Modeling and model selection. The application identifies the best-fit Dose-Response model utilizing particle swarm optimization and calculates the probabilistic POD. The application analyzed a publicly available 2,3,7,8-tetrachlorodibenzo-p-dioxin Dose-Response data set of hepatic gene expression data in C57BL/6 mice to identify putative biomarkers. The Gene Ontology mapped these Responses to specific functions to differentiate adaptive effects from toxic Responses. In principle, safety and risk assessors could use the automated ToxResponse Modeler to analyze any large Dose-Response data set including outputs from high-throughput screening assays to assist with the ranking and prioritization of compounds that warrant further investigation or development.

Chris H Wiggins - One of the best experts on this subject based on the ideXlab platform.

  • Dose Response Modeling in high throughput cancer drug screenings an end to end approach
    Biostatistics, 2021
    Co-Authors: Wesley Tansey, David M Blei, Haoran Zhang, Scott W Linderman, Raul Rabadan, Chris H Wiggins
    Abstract:

    Personalized cancer treatments based on the molecular profile of a patient's tumor are an emerging and exciting class of treatments in oncology. As genomic tumor profiling is becoming more common, targeted treatments for specific molecular alterations are gaining traction. To discover new potential therapeutics that may apply to broad classes of tumors matching some molecular pattern, experimentalists and pharmacologists rely on high-throughput, in vitro screens of many compounds against many different cell lines. We propose a hierarchical Bayesian model of how cancer cell lines respond to drugs in these experiments and develop a method for fitting the model to real-world high-throughput screening data. Through a case study, the model is shown to capture nontrivial associations between molecular features and drug Response, such as requiring both wild type TP53 and overexpression of MDM2 to be sensitive to Nutlin-3(a). In quantitative benchmarks, the model outperforms a standard approach in biology, with $\approx20\%$ lower predictive error on held out data. When combined with a conditional randomization testing procedure, the model discovers markers of therapeutic Response that recapitulate known biology and suggest new avenues for investigation. All code for the article is publicly available at https://github.com/tansey/deep-Dose-Response.

  • Dose Response Modeling in high throughput cancer drug screenings an end to end approach
    arXiv: Applications, 2018
    Co-Authors: Wesley Tansey, David M Blei, Haoran Zhang, Scott W Linderman, Raul Rabadan, Chris H Wiggins
    Abstract:

    Personalized cancer treatments based on the molecular profile of a patient's tumor are an emerging and exciting class of treatments in oncology. As genomic tumor profiling is becoming more common, targeted treatments to specific molecular alterations are gaining traction. To discover new potential therapeutics that may apply to broad classes of tumors matching some molecular pattern, experimentalists and pharmacologists rely on high-throughput, in-vitro screens of many compounds against many different cell lines. We propose a hierarchical Bayesian model of how cancer cell lines respond to drugs in these experiments and develop a method for fitting the model to real-world high-throughput screening data. Through a case study, the model is shown to capture nontrivial associations between molecular features and drug Response, such as requiring both wild type TP53 and overexpression of MDM2 to be sensitive to Nutlin-3(a). In quantitative benchmarks, the model outperforms a standard approach in biology, with ~20% lower predictive error on held out data. When combined with a conditional randomization testing procedure, the model discovers biomarkers of therapeutic Response that recapitulate known biology and suggest new avenues for investigation. All code for the paper is publicly available at this https URL.

  • Dose Response Modeling in high throughput cancer drug screenings a case study with recommendations for practitioners
    arXiv: Applications, 2018
    Co-Authors: Wesley Tansey, David M Blei, Haoran Zhang, Scott W Linderman, Raul Rabadan, Chris H Wiggins
    Abstract:

    Personalized cancer treatments based on the molecular profile of a patient's tumor are becoming a standard of care in oncology. Experimentalists and pharmacologists rely on high-throughput, \textit{in vitro} screenings of many compounds against many different cell lines to build models of drug Response. These models help them discover new potential therapeutics that may apply to broad classes of tumors matching some molecular pattern. We propose a hierarchical Bayesian model of how cancer cell lines respond to drugs in these experiments and develop a method for fitting the model to real-world data. Through a case study, the model is shown both quantitatively and qualitatively to capture nontrivial associations between molecular features and drug Response. Finally, we draw five conclusions and recommendations that may benefit experimentalists, analysts, and clinicians working in the field of personalized medicine for cancer therapeutics.