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Yang C.Z.,Certichem, Inc. | Casey W.,NICEATM | Stoner M.A.,Certichem, Inc. | Kollessery G.J.,Certichem, Inc. | And 3 more authors.
Toxicological Sciences | Year: 2014

Endocrine-disrupting chemicals with estrogenic activity (EA) or anti-EA (AEA) have been extensively reported to possibly have many adverse health effects. We have developed robotized assays using MCF-7:WS8 cell proliferation (or suppression) to detect EA (or AEA) of 78 test substances supplied by the Interagency Coordinating Committee on the Validation of Alternative Methods and the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods for validation studies. We also assayed ICI 182,780, a strong estrogen antagonist. Chemicals to be assayed were initially examined for solubility and volatility to determine optimal assay conditions. For both EA and AEA determinations, a Range-Finder assay was conducted to determine the concentration range for testing, followed by a Comprehensive assay. Test substances with potentially positive results from an EA Comprehensive assay were subjected to an EA Confirmation assay that evaluated the ability of ICI 182,780 to reverse chemically induced MCF-7 cell proliferation. The AEA assays examined the ability of chemicals to decrease MCF-7 cell proliferation induced by nonsaturating concentrations of 17β-estradiol (E2), relative to ICI or raloxifene, also a strong estrogen antagonist. To be classified as having AEA, a saturating concentration of E2 had to significantly reverse the decrease in cell proliferation produced by the test substance in nonsaturating E2. We conclude that our robotized MCF-7 EA and AEA assays have accuracy, sensitivity, and specificity values at least equivalent to validated test methods accepted by the U.S. Environmental Protection Agency and the Organisation for Economic Co-operation and Development. © The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Kollessery G.,University of Nebraska Medical Center | Kollessery G.,Certichem, Inc. | Nordgren T.M.,University of Nebraska Medical Center | Mittal A.K.,University of Nebraska Medical Center | And 2 more authors.
Vaccine | Year: 2011

Vaccines to large B cell lymphoma were made by the covalent attachment of an epitope from the gp70 glycoprotein (SSWDFITV) to the N-termini of the conformationally biased, response-selective C5a agonists EP54 (YSFKPMPLaR) and EP67 (YSFKDMP(MeL)aR). Syngeneic Balb/c mice were immunized with these EP54/EP67-containing vaccines and challenged with a lethal dose of the highly liver metastatic and gp70-expressing lymphoma cell line RAW117-H10 to evaluate the ability of these vaccines to induce protective immune outcomes. All mice immunized with SSWDFITVRRYSFKPMPLaR (Vaccine 2) and SSWDFITVRRYSFKDMP(MeL)aR (Vaccine 3) were protected to a lethal challenge of RAW117-H10 lymphoma (>170 days survival) and exhibited no lymphoma infiltration or solid tumor nodules in the liver relative to unvaccinated controls (<18 days survival). Vaccines 2 and 3 contained the protease-sensitive double-Arg (RR) linker sequence between the epitope and the EP54/EP67 moieties in order to provide a site for intracellular proteases to separate the epitope from the EP54/EP67 moieties once internalized by the APC and, consequently, enhance epitope presentation in the context of MHC I/II. These protected mice exhibited an immune outcome consistent with increased involvement of CD8 + and/or CD4 + T lymphocytes relative to controls and mice that did not survive or showed low survival rates as with Vaccines 1 and 4, which lacked the RR linker sequence. CD8 + T lymphocytes activated in response to Vaccines 2 and 3 express cytotoxic specificity for gp70-expressing RAW117-H10 lymphoma cells, but not antigen-irrelevant MDA-MB231A human breast cancer cells. Results are discussed against the backdrop of the ability of EP54/EP67 to selectively target antigens to and activate C5a receptor-bearing antigen presenting cells and the prospects of using such vaccines therapeutically against lymphoma and other cancers. © 2011 Elsevier Ltd.


Yang C.Z.,Certichem, Inc. | Yaniger S.I.,PlastiPure, Inc. | Jordan V.C.,Georgetown University | Klein D.J.,PlastiPure, Inc. | And 3 more authors.
Environmental Health Perspectives | Year: 2011

Background: Chemicals having estrogenic activity (EA) reportedly cause many adverse health effects, especially at low (picomolar to nanomolar) doses in fetal and juvenile mammals. Objectives: We sought to determine whether commercially available plastic resins and products, including baby bottles and other products advertised as bisphenol A (BPA) free, release chemicals having EA. Methods: We used a roboticized MCF-7 cell proliferation assay, which is very sensitive, accurate, and repeatable, to quantify the EA of chemicals leached into saline or ethanol extracts of many types of commercially available plastic materials, some exposed to common-use stresses (microwaving, ultraviolet radiation, and/or autoclaving). Results: Almost all commercially available plastic products we sampled-independent of the type of resin, product, or retail source-leached chemicals having reliably detectable EA, including those advertised as BPA free. In some cases, BPA-free products released chemicals having more EA than did BPA-containing products. Conclusions: Many plastic products are mischaracterized as being EA free if extracted with only one solvent and not exposed to common-use stresses. However, we can identify existing compounds, or have developed, monomers, additives, or processing agents that have no detectable EA and have similar costs. Hence, our data suggest that EA-free plastic products exposed to common-use stresses and extracted by saline and ethanol solvents could be cost-effectively made on a commercial scale and thereby eliminate a potential health risk posed by most currently available plastic products that leach chemicals having EA into food products.


Stoner M.A.,Certichem, Inc. | Yang C.Z.,Certichem, Inc. | Bittner G.D.,Certichem, Inc. | Bittner G.D.,University of Texas at Austin
Toxicology in Vitro | Year: 2014

Endocrine disrupting chemicals with estrogenic activity (EA) have been associated with various adverse health effects. US agencies (ICCVAM/NICEATM) tasked to assess in vitro transcription activation assays to detect estrogenic receptor (ER) agonists for EA have recently validated a BG1Luc assay in manual format, but prefer robotic formats. We have developed a robotic BG1Luc EA assay to detect EA that demonstrated 100% concordance with ICCVAM meta-analyses and ICCVAM BG1Luc results in manual format for 27 ICCVAM test substances, i.e. no false negatives or false positives. This robotic assay also consistently assessed other, more problematic ICCVAM test substances such as clomiphene citrate, L-thyroxin, and tamoxifen. Agonist responses using this robotic BG1Luc assay were consistently inhibited by the ER antagonist ICI 182,780, confirming that agonist responses were due to binding to ERs rather than to a non-specific agonist response. This robotic assay also detected EA in complex mixtures of substances such as extracts of personal care products, plastic resins or plastic consumer products. This robotic BG1Luc assay had at least as high accuracy and greater sensitivity and repeatability when compared to its manual version or to the other ICCVAM/OECD validated assays for EA (manual BG1Luc and CERI). © 2014 Elsevier Ltd.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 768.82K | Year: 2016

DESCRIPTION provided by applicant Recent scientific investigations have shown that many chemicals used in plastics pharmaceuticals pesticides cosmetics food additives etc are endocrine disrupting chemicals EDCs EDCs interfere in various ways with hormones such as estrogens and androgens and can have significant adverse effects on many behavioral and physiological processes ED effects agonistic or antagonistic sometimes occur at very low picomolar to nanomolar concentrations especially in fetal or developing mammals including humans The prevalence and actions of EDCs in our environment warrant the development of valid testing methods Consequently various governmental bodies e g EPA FDA and ICCVAM and proactive corporations have explicitly expressed a desire to have in vitro robotic assays for EDCs such as for androgenic AnA or anti androgenic Anti AnA activity However no reliable manual or robotic AnA or Anti AnA assays are yet commercially available ICCVAM NICEATM desire single laboratory validation assays of AnA and Anti AnA using a human based cell line To begin to meet these governmental scientific and commercial needs CertiChem CCi is submitting a Fast Track grant to show that it is feasible to develop AnA and Anti AnA assays in manual and medium throughput robotic formats that would be reliable accurate versatile rapid and cost effective CCi proposes to use MDA kb human based cells In our AnA and anti AnA assays these cells will be examined by a transcription reporter gene luciferase assay CCi proposes to examine Test Substances supplied and coded by ICCVAM for AnA and Anti AnA validation to confirm that CCiandapos s assays can accurately assess their AR agonistic and antagonistic activities CCi also proposes to test hydrophilic and hydrophobic extracts of silicone and paper products for AnA and Anti AnA Development of manual and robotic screening assays for AnA and anti AnA is highly desired as part of the mission of NIEHS EPA and ICCVAM as commercially scientificly and socially important Government agencies are now screening a large number of chemicals for hormonal activity including AR agonist and antagonist activities In addition hormonal activity of chemical mixtures extracted from commercial products is of great importance to government agencies NGOs and consumers PUBLIC HEALTH RELEVANCE Recent scientific investigations have shown that many chemicals used in common products such as plastics pesticides cosmetics and food additives have Androgenic and or Anti Androgenic male hormone activity that could potentially interfere with normal androgen actions to produce adverse effects on many behavioral reproductive and physiological processes in humans In this Fast Track SBIR application CertiChem CCi proposes a single lab validation of the MDA kb assays by repeatedly testing Test Substances coded and supplied by ICCVAM an intergovernmental agency that validates in vitro assays to show that our AR agonist and antagonist assays in MDA kb cells are both reliable and accurate Afterward CertiChem will use this assay to test high commercial value consumer products made with silicone or paper


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 872.42K | Year: 2010

This Small Business Innovation Research (SBIR) Phase II project will use state-of-the-art assays to detect estrogenic activity (EA) and anti-EA in antioxidants (AOs). Chemicals like AOs that have EA or Anti-EA (EA**) produce adverse health effects, including reproductive and behavioral disorders and some cancers. AOs have not been examined for EA**, much less AO packages reformulated to have specific levels of EA for specific commercial applications. This project will assess the EA** of 10 additional organic AOs, and 15 EA-**Free/EA**-specified formulations made from combinations of conventional, organic, water-soluble, and oil-soluble AOs that are stable when exposed to common-use stresses. These AO formulations will be used by identified partners to produce animal feeds, cereals and other foodstuffs that are EA**-free or have well-specified levels of EA** providing a clear path to commercialization and additional patents.

The broader impacts of this research are that fetal or juvenile mammals, including humans, are especially sensitive to chemicals having EA** at very low dosages and should not indiscriminately ingest such chemicals. Conversely, other conditions (e.g., menopausal symptoms, some cancers or abnormalities of the prostate) are ameliorated by chemicals having controlled levels of EA**. Hence, this project will minimize the risks of unintentional consumption of chemicals having EA** by using EA**-free AOs in products such as cereals and baby formulas or specified-EA** AOs in products such as fitness drinks and dietary supplements for post-menopausal women.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 500.00K | Year: 2010

This Small Business Innovation Research (SBIR) Phase II project will use state-of-the-art assays to detect estrogenic activity (EA) and anti-EA in antioxidants (AOs). Chemicals like AOs that have EA or Anti-EA (EA**) produce adverse health effects, including reproductive and behavioral disorders and some cancers. AOs have not been examined for EA**, much less AO packages reformulated to have specific levels of EA for specific commercial applications. This project will assess the EA** of 10 additional organic AOs, and 15 EA-**Free/EA**-specified formulations made from combinations of conventional, organic, water-soluble, and oil-soluble AOs that are stable when exposed to common-use stresses. These AO formulations will be used by identified partners to produce animal feeds, cereals and other foodstuffs that are EA**-free or have well-specified levels of EA** providing a clear path to commercialization and additional patents. The broader impacts of this research are that fetal or juvenile mammals, including humans, are especially sensitive to chemicals having EA** at very low dosages and should not indiscriminately ingest such chemicals. Conversely, other conditions (e.g., menopausal symptoms, some cancers or abnormalities of the prostate) are ameliorated by chemicals having controlled levels of EA**. Hence, this project will minimize the risks of unintentional consumption of chemicals having EA** by using EA**-free AOs in products such as cereals and baby formulas or specified-EA** AOs in products such as fitness drinks and dietary supplements for post-menopausal women.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.96K | Year: 2014

? DESCRIPTION (provided by applicant): Personal care products (PCPs) are non-prescription products applied to the body (e.g., hair colorants, shampoos, conditioners, skin lotions, deodorants, suntan lotions, lipstick, makeups, nail polishes, etc.). Daily, the average consumer uses 10 cosmetic products, totaling 126 ingredients, most not listed on the label. Peer- reviewed papers report that ingestion or absorption of chemicals having estrogenic and/or androgenic activity (EA**/AnA**) by mammals (including humans) can possibly cause various adverse health effects including uterine dysfunction, higher rates of some cancers, reduced sperm count, and abnormal brain maturation, disorders of attention, motivation, emotion, cognitive development, and changes inaggressive behavior and sexual orientation. These adverse effects may sometimes occur at very low (picomolar to nanomolar) concentrations, especially on fetal or developing mammals. CertiChem's (CCi's) peer-reviewed papers and preliminary data show that P


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 576.01K | Year: 2016

DESCRIPTION provided by applicant Recent scientific investigations have shown that many chemicals used in plastics pharmaceuticals pesticides cosmetics food additives etc are endocrine disrupting chemicals EDCs EDCs interfere in various ways with hormones such as estrogens and androgens and can have significant adverse effects on many behavioral and physiological processes ED effects agonistic or antagonistic sometimes occur at very low picomolar to nanomolar concentrations especially in fetal or developing mammals including humans The prevalence and actions of EDCs in our environment warrant the development of valid testing methods Consequently various governmental bodies e g EPA FDA and ICCVAM and proactive corporations have explicitly expressed a desire to have in vitro robotic assays for EDCs such as for androgenic AnA or anti androgenic Anti AnA activity However no reliable manual or robotic AnA or Anti AnA assays are yet commercially available ICCVAM NICEATM desire single laboratory validation assays of AnA and Anti AnA using a human based cell line To begin to meet these governmental scientific and commercial needs CertiChem CCi is submitting a Fast Track grant to show that it is feasible to develop AnA and Anti AnA assays in manual and medium throughput robotic formats that would be reliable accurate versatile rapid and cost effective CCi proposes to use MDA kb human based cells In our AnA and anti AnA assays these cells will be examined by a transcription reporter gene luciferase assay CCi proposes to examine Test Substances supplied and coded by ICCVAM for AnA and Anti AnA validation to confirm that CCiandapos s assays can accurately assess their AR agonistic and antagonistic activities CCi also proposes to test hydrophilic and hydrophobic extracts of silicone and paper products for AnA and Anti AnA Development of manual and robotic screening assays for AnA and anti AnA is highly desired as part of the mission of NIEHS EPA and ICCVAM as commercially scientificly and socially important Government agencies are now screening a large number of chemicals for hormonal activity including AR agonist and antagonist activities In addition hormonal activity of chemical mixtures extracted from commercial products is of great importance to government agencies NGOs and consumers PUBLIC HEALTH RELEVANCE Recent scientific investigations have shown that many chemicals used in common products such as plastics pesticides cosmetics and food additives have Androgenic and or Anti Androgenic male hormone activity that could potentially interfere with normal androgen actions to produce adverse effects on many behavioral reproductive and physiological processes in humans In this Fast Track SBIR application CertiChem CCi proposes a single lab validation of the MDA kb assays by repeatedly testing Test Substances coded and supplied by ICCVAM an intergovernmental agency that validates in vitro assays to show that our AR agonist and antagonist assays in MDA kb cells are both reliable and accurate Afterward CertiChem will use this assay to test high commercial value consumer products made with silicone or paper


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.88K | Year: 2009

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). This Small Business Innovation Research Phase I project will confirm that it is feasible to identify food antioxidants (AOs) to make formulations that have no detectable estrogenic activity (EA) or anti-EA (EA-Free) or have well-specified levels of EA (EA-Specified AO formulations). This project is innovative because food AOs have not previously been examined for levels of EA, especially after common-use-stresses of sterilizing or microwaving. CertiChem is uniquely qualified to develop and commercialize EA-free/EA-specified AO formulations because of its exclusive patents and experience in bringing EA-Free products to market. The broader impacts of this research are that CertiChem's data show that most current food AOs have EA in unknown concentrations. CertiChem proposes to develop AO formulations that are EA-Free or have well-specified levels of EA. Chemicals having EA at concentrations used in foodstuffs (mM to uM) often have adverse effects on mammals, including humans. Fetal or juvenile mammals are especially sensitive to effects of chemicals having EA at very low dosages (nM to pM concentrations). Conversely, some conditions in adult humans (e.g., menopause, some cancers or abnormalities of the prostate) are probably ameliorated by chemicals having well-specified levels of EA. CertiChem is raising consumer awareness by actively working with NGOs and legislators to educate the public on health risks or benefits associated with chemicals that have EA. Significant consumer demand for EA-Free products or EA-Specified products is already observed.

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