Publications by authors named "George P Daston"

62 Publications

FutureTox IV Workshop Summary: Predictive Toxicology for Healthy Children.

Toxicol Sci 2021 Apr;180(2):198-211

U.S. Environmental Protection Agency, ORD, Research Triangle Park, North Carolina, USA.

FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high-throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact animals (U.S. Environmental Protection Agency [EPA], Strategic plan to promote the development and implementation of alternative test methods within the tsca program, 2018, https://www.epa.gov/sites/production/files/2018-06/documents/epa_alt_strat_plan_6-20-18_clean_final.pdf). There are challenges to implementing NAMs to evaluate chemicals for developmental toxicity compared with adult toxicity. This forum article reviews the 2018 workshop activities, highlighting challenges and opportunities for applying NAMs for adverse pregnancy outcomes (eg, preterm labor, malformations, low birth weight) as well as disorders manifesting postnatally (eg, neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). DART is an important concern for different regulatory statutes and test guidelines. Leveraging advancements in such approaches and the accompanying efficiencies to detecting potential hazards to human development are the unifying concepts toward implementing NAMs in DART testing. Although use of NAMs for higher level regulatory decision making is still on the horizon, the conference highlighted novel testing platforms and computational models that cover multiple levels of biological organization, with the unique temporal dynamics of embryonic development, and novel approaches for estimating toxicokinetic parameters essential in supporting in vitro to in vivo extrapolation.
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http://dx.doi.org/10.1093/toxsci/kfab013DOI Listing
April 2021

Incorporation of in vitro techniques for botanicals dietary supplement safety assessment - Towards evaluation of developmental and reproductive toxicity (DART).

Food Chem Toxicol 2020 Oct 6;144:111539. Epub 2020 Jul 6.

Procter & Gamble Technical Centre, Whitehall Lane, Egham, Surrey, TW20 9AW, UK. Electronic address:

As complex mixtures, botanicals present unique challenges when assessing safe use, particularly when endpoint gaps exist that cannot be fully resolved by existing toxicological literature. Here we explore in vitro gene expression as well receptor binding and enzyme activity as alternative assays to inform on developmental and reproductive toxicity (DART) relevant modes of action, since DART data gaps are common for botanicals. Specifically, botanicals suspected to have DART effects, in addition to those with a significant history of use, were tested in these assays. Gene expression changes in a number of different cell types were analysed using the connectivity mapping approach (CMap) to identify modes of action through a functional read across approach. Taken together with ligand affinity data obtained using a set of molecular targets customised towards known DART relevant modes of action, it was possible to inform DART risk using functional analogues, potency comparisons and a margin of internal exposure approach.
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http://dx.doi.org/10.1016/j.fct.2020.111539DOI Listing
October 2020

New ideas for non-animal approaches to predict repeated-dose systemic toxicity: Report from an EPAA Blue Sky Workshop.

Regul Toxicol Pharmacol 2020 Jul 23;114:104668. Epub 2020 Apr 23.

School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK. Electronic address:

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a 'Blue Sky Workshop' on new ideas for non-animal approaches to predict repeated-dose systemic toxicity. The aim of the Workshop was to formulate strategic ideas to improve and increase the applicability, implementation and acceptance of modern non-animal methods to determine systemic toxicity. The Workshop concluded that good progress is being made to assess repeated dose toxicity without animals taking advantage of existing knowledge in toxicology, thresholds of toxicological concern, adverse outcome pathways and read-across workflows. These approaches can be supported by New Approach Methodologies (NAMs) utilising modern molecular technologies and computational methods. Recommendations from the Workshop were based around the needs for better chemical safety assessment: how to strengthen the evidence base for decision making; to develop, standardise and harmonise NAMs for human toxicity; and the improvement in the applicability and acceptance of novel techniques. "Disruptive thinking" is required to reconsider chemical legislation, validation of NAMs and the opportunities to move away from reliance on animal tests. Case study practices and data sharing, ensuring reproducibility of NAMs, were viewed as crucial to the improvement of non-animal test approaches for systemic toxicity.
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http://dx.doi.org/10.1016/j.yrtph.2020.104668DOI Listing
July 2020

Bisphenol exposure, hazard and regulation.

Toxicology 2019 09 10;425:152243. Epub 2019 Jul 10.

Victor Mills Society Research Fellow, Procter & Gamble Company, Mason, OH 45040, USA. Electronic address:

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http://dx.doi.org/10.1016/j.tox.2019.152243DOI Listing
September 2019

Use of connectivity mapping to support read across: A deeper dive using data from 186 chemicals, 19 cell lines and 2 case studies.

Toxicology 2019 07 21;423:84-94. Epub 2019 May 21.

Mason Business Center, The Procter & Gamble Company, Cincinnati, OH, 45040, USA.

We previously demonstrated that the Connectivity Map (CMap) (Lamb et al., 2006) concept can be successfully applied to a predictive toxicology paradigm to generate meaningful MoA-based connections between chemicals (De Abrew et al., 2016). Here we expand both the chemical and biological (cell lines) domain for the method and demonstrate two applications, both in the area of read across. In the first application we demonstrate CMap's utility as a tool for testing biological relevance of source chemicals (analogs) during a chemistry led read across exercise. In the second application we demonstrate how CMap can be used to identify functionally relevant source chemicals (analogs) for a structure of interest (SOI)/target chemical with minimal knowledge of chemical structure. Finally, we highlight four factors: promiscuity of chemical, dose, cell line and timepoint as having significant impact on the output. We discuss the biological relevance of these four factors and incorporate them into a work flow.
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http://dx.doi.org/10.1016/j.tox.2019.05.008DOI Listing
July 2019

Is omphalocele a non-specific malformation in New Zealand White rabbits?

Reprod Toxicol 2018 06 14;78:29-39. Epub 2018 Mar 14.

Charles River, 's-Hertogenbosch, The Netherlands.

We evaluated the incidence of omphalocele, a malformation that occurs sporadically in many studies. We assembled data on external malformations using all treatment groups from every study published in three major journals over the past 35 years using New Zealand White rabbits. Fifty-eight papers were included: 4905 litters and 36,977 fetuses. Omphalocele was reported in 43% and was among the most common defects, occurring at a rate of 1.10% (litter) and 0.16% (fetus). The defect did not appear to be treatment-related, although it may have been in two studies, based on rate and dose-responsiveness. Removing these two studies from the analysis, the defect was still prevalent (0.77% litter, 0.11% fetal incidence). Three studies evaluated the effects of food restriction and omphalocele was observed with food restriction in two of them, suggesting that decreased maternal weight gain or food consumption may be causal. Otherwise, it appears to be spontaneous and common.
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http://dx.doi.org/10.1016/j.reprotox.2018.03.006DOI Listing
June 2018

A unified birth defects research.

Birth Defects Res 2017 01;109(1)

Hôpital Universitaire Necker-Enfants Malades, Paris, France.

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http://dx.doi.org/10.1002/bdra.23595DOI Listing
January 2017

FutureTox III: Bridges for Translation.

Toxicol Sci 2017 01 25;155(1):22-31. Epub 2016 Oct 25.

US Environmental Protection Agency, Research Triangle Park, North Carolina.

Future Tox III, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2015. Building upon Future Tox I and II, Future Tox III was focused on developing the high throughput risk assessment paradigm and taking the science of in vitro data and in silico models forward to explore the question-what progress is being made to address challenges in implementing the emerging big-data toolbox for risk assessment and regulatory decision-making. This article reports on the outcome of the workshop including 2 examples of where advancements in predictive toxicology approaches are being applied within Federal agencies, where opportunities remain within the exposome and AOP domains, and how collectively the toxicology community across multiple sectors can continue to bridge the translation from historical approaches to Tox21 implementation relative to risk assessment and regulatory decision-making.
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http://dx.doi.org/10.1093/toxsci/kfw194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080854PMC
January 2017

Grouping 34 Chemicals Based on Mode of Action Using Connectivity Mapping.

Toxicol Sci 2016 06 29;151(2):447-61. Epub 2016 Mar 29.

*Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.

Connectivity mapping is a method used in the pharmaceutical industry to find connections between small molecules, disease states, and genes. The concept can be applied to a predictive toxicology paradigm to find connections between chemicals, adverse events, and genes. In order to assess the applicability of the technique for predictive toxicology purposes, we performed gene array experiments on 34 different chemicals: bisphenol A, genistein, ethinyl-estradiol, tamoxifen, clofibrate, dehydorepiandrosterone, troglitazone, diethylhexyl phthalate, flutamide, trenbolone, phenobarbital, retinoic acid, thyroxine, 1α,25-dihydroxyvitamin D3, clobetasol, farnesol, chenodeoxycholic acid, progesterone, RU486, ketoconazole, valproic acid, desferrioxamine, amoxicillin, 6-aminonicotinamide, metformin, phenformin, methotrexate, vinblastine, ANIT (1-naphthyl isothiocyanate), griseofulvin, nicotine, imidacloprid, vorinostat, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) at the 6-, 24-, and 48-hour time points for 3 different concentrations in the 4 cell lines: MCF7, Ishikawa, HepaRG, and HepG2 GEO (super series accession no.: GSE69851). The 34 chemicals were grouped in to predefined mode of action (MOA)-based chemical classes based on current literature. Connectivity mapping was used to find linkages between each chemical and between chemical classes. Cell line-specific linkages were compared with each other and to test whether the method was platform and user independent, a similar analysis was performed against publicly available data. The study showed that the method can group chemicals based on MOAs and the inter-chemical class comparison alluded to connections between MOAs that were not predefined. Comparison to the publicly available data showed that the method is user and platform independent. The results provide an example of an alternate data analysis process for high-content data, beneficial for predictive toxicology, especially when grouping chemicals for read across purposes.
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http://dx.doi.org/10.1093/toxsci/kfw058DOI Listing
June 2016

Dose- and Time-Dependent Transcriptional Response of Ishikawa Cells Exposed to Genistein.

Toxicol Sci 2016 05 10;151(1):71-87. Epub 2016 Feb 10.

*Mason Business Center, The Procter and Gamble Company, Mason, Ohio 45040.

To further define the utility of the Ishikawa cells as a reliable in vitro model to determine the potential estrogenic activity of chemicals of interest, transcriptional changes induced by genistein (GES) in Ishikawa cells at various doses (10 pM, 1 nM, 100 nM, and 10 μM) and time points (8, 24, and 48 h) were identified using a comprehensive microarray approach. Trend analysis indicated that the expression of 5342 unique genes was modified by GES in a dose- and time-dependent manner (P ≤ 0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest dose of GES evaluated (10 μM). The GES' estrogenic activity was identified by comparing the Ishikawa cells' response to GES versus 17 α-ethynyl estradiol (EE, at equipotent doses, ie, 10 μM vs 1 μM, respectively) and was defined by changes in the expression of 284 unique genes elicited by GES and EE in the same direction, although the magnitude of the change for some genes was different. Further, comparing the response of the Ishikawa cells exposed to high doses of GES and EE versus the response of the juvenile rat uterus exposed to EE, we identified 66 unique genes which were up- or down regulated in a similar manner in vivo as well as in vitro Genistein elicits changes in multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response and offer an in vitro model to assess this mode of action.
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http://dx.doi.org/10.1093/toxsci/kfw024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914796PMC
May 2016

Obituary. Edward W. Carney, 1959-2015.

Birth Defects Res B Dev Reprod Toxicol 2015 Apr 11;104(2):53-4. Epub 2015 Jun 11.

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http://dx.doi.org/10.1002/bdrb.21141DOI Listing
April 2015

Assessment of health risks resulting from early-life exposures: Are current chemical toxicity testing protocols and risk assessment methods adequate?

Crit Rev Toxicol 2015 Mar 17;45(3):219-44. Epub 2015 Feb 17.

The Procter & Gamble Company , Cincinnati, OH , USA.

Abstract Over the last couple of decades, the awareness of the potential health impacts associated with early-life exposures has increased. Global regulatory approaches to chemical risk assessment are intended to be protective for the diverse human population including all life stages. However, questions persist as to whether the current testing approaches and risk assessment methodologies are adequately protective for infants and children. Here, we review physiological and developmental differences that may result in differential sensitivity associated with early-life exposures. It is clear that sensitivity to chemical exposures during early-life can be similar, higher, or lower than that of adults, and can change quickly within a short developmental timeframe. Moreover, age-related exposure differences provide an important consideration for overall susceptibility. Differential sensitivity associated with a life stage can reflect the toxicokinetic handling of a xenobiotic exposure, the toxicodynamic response, or both. Each of these is illustrated with chemical-specific examples. The adequacy of current testing protocols, proposed new tools, and risk assessment methods for systemic noncancer endpoints are reviewed in light of the potential for differential risk to infants and young children.
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http://dx.doi.org/10.3109/10408444.2014.993919DOI Listing
March 2015

A novel transcriptomics based in vitro method to compare and predict hepatotoxicity based on mode of action.

Toxicology 2015 Feb 2;328:29-39. Epub 2014 Dec 2.

Mason Business Center, The Procter & Gamble Company, Cincinnati, OH 45040, USA.

High-content data have the potential to inform mechanism of action for toxicants. However, most data to support this notion have been generated in vivo. Because many cell lines and primary cells maintain a differentiated cell phenotype, it is possible that cells grown in culture may also be useful in predictive toxicology via high-content approaches such as whole-genome microarray. We evaluated global changes in gene expression in primary rat hepatocytes exposed to two concentrations of ten hepatotoxicants: acetaminophen (APAP), β-naphthoflavone (BNF), chlorpromazine (CPZ), clofibrate (CLO), bis(2-ethylhexyl)phthalate (DEHP), diisononyl phthalate (DINP), methapyrilene (MP), valproic acid (VPA), phenobarbital (PB) and WY14643 at two separate time points. These compounds were selected to cover a range of mechanisms of toxicity, with some overlap in expected mechanism to address the question of how predictive gene expression analysis is, for a given mode of action. Gene expression microarray analysis was performed on cells after 24h and 48h of exposure to each chemical using Affymetrix microarrays. Cluster analysis suggests that the primary hepatocyte model was capable of responding to these hepatotoxicants, with changes in gene expression that appear to be mode of action-specific. Among the different methods used for analysis of the data, a combination method that used pathways (MOAs) to filter total probesets provided the most robust analysis. The analysis resulted in the phthalates clustering closely together, with the two other peroxisome proliferators, CLO and WY14643, eliciting similar responses at the whole-genome and pathway levels. The Cyp inducers PB, MP, CPZ and BNF also clustered together. VPA and APAP had profiles that were unique. A similar analysis was performed on externally available (TG-GATES) in vivo data for 6 of the chemicals (APAP, CLO, CPZ, MP, MP and WY14643) and compared to the in vitro result. These results indicate that transcription profiling using an in vitro assay may offer pertinent biological data to support predictions of in vivo hepatotoxicity potential.
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http://dx.doi.org/10.1016/j.tox.2014.11.008DOI Listing
February 2015

Exposure-based validation list for developmental toxicity screening assays.

Birth Defects Res B Dev Reprod Toxicol 2014 Dec 4;101(6):423-8. Epub 2014 Dec 4.

Procter & Gamble, Cincinnati, Ohio.

Validation of alternative assays requires comparison of the responses to toxicants in the alternative assay with in vivo responses. Chemicals have been classified as "positive" or "negative" in vivo, despite the fact that developmental toxicity is conditional on magnitude of exposure. We developed a list of positive and negative developmental exposures, with exposure defined by toxicokinetic data, specifically maternal plasma Cmax . We selected a series of 20 chemicals that caused developmental toxicity and for which there were appropriate toxicokinetic data. Where possible, we used the same chemical for both positive and negative exposures, the positive being the Cmax at a dose level that produced significant teratogenicity or embryolethality, the negative being the Cmax at a dose level not causing developmental toxicity. It was not possible to find toxicokinetic data at the no-effect level for all positive compounds, and the negative exposure list contains Cmax values for some compounds that do not have developmental toxicity up to the highest dose level tested. This exposure-based reference list represents a fundamentally different approach to the evaluation of alternative tests and is proposed as a step toward application of alternative tests in quantitative risk assessment.
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http://dx.doi.org/10.1002/bdrb.21132DOI Listing
December 2014

Effects of transplacental 17-α-ethynyl estradiol or bisphenol A on the developmental profile of steroidogenic acute regulatory protein in the rat testis.

Birth Defects Res B Dev Reprod Toxicol 2012 Aug 2;95(4):318-25. Epub 2012 Jul 2.

Mason Business Center, The Procter and Gamble Company, Mason, OH, USA.

Previous research from our laboratory has determined the transcript profiles for developing fetal rat female and male reproductive tracts following transplacental exposure to estrogens. Prenatal exposure to bisphenol A (BPA) or 17-α-ethynyl estradiol (EE) significantly affects steroidogenic acute regulatory (StAR) protein transcript levels in the developing male rat reproductive tract. The purpose of this study was to establish the intratesticular distribution and temporal expression pattern of StAR, a key gene involved in steroidogenesis. Beginning on gestation day (GD) 11, pregnant Sprague-Dawley rats were exposed daily to 10μg/kg/day EE and fetal testes were harvested at GD16, 18, or 20. Quantitative reverse transcriptase PCR (QRT-PCR) demonstrated no significant difference in StAR transcript levels present at GD16. However, at GD18, StAR transcripts were significantly decreased following exposure. Immunohistochemistry demonstrated similar StAR protein levels in interstitial region of GD16 testes and an obvious decrease in StAR protein levels in the interstitial region of GD18 testes. Moreover, starting at GD11 additional dams were dosed with 0.001 or 0.1 μg/kg/day EE or 0.02, 0.5, 400 mg/kg/day BPA via subcutaneous injections. QRT-PCR validated previous microarray dose-related decreases in StAR transcripts at GD20, whereas immunohistochemistry results demonstrated decreases in StAR protein levels in the interstitial region at the highest EE and BPA doses only. Neither EE nor BPA exposure caused morphological changes in the developing seminiferous cords, Sertoli cells, gonocytes, or the interstitial region or Leydig cells at GD16-20. High levels of estrogens decrease StAR expression in the fetal rat testis during late gestation.
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http://dx.doi.org/10.1002/bdrb.21020DOI Listing
August 2012

Developmental toxicity testing for safety assessment: new approaches and technologies.

Birth Defects Res B Dev Reprod Toxicol 2011 Oct 18;92(5):413-20. Epub 2011 Jul 18.

National Center for Computational Toxicology, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.

The ILSI Health and Environmental Sciences Institute's Developmental and Reproductive Toxicology Technical Committee held a 2-day workshop entitled "Developmental Toxicology-New Directions" in April 2009. The fourth session of this workshop focused on new approaches and technologies for the assessment of developmental toxicology. This session provided an overview of the application of genomics technologies for developmental safety assessment, the use of mouse embryonic stem cells to capture data on developmental toxicity pathways, dynamical cell imaging of zebrafish embryos, the use of computation models of development pathways and systems, and finally, high-throughput in vitro approaches being utilized by the EPA ToxCast program. Issues discussed include the challenges of anchoring in vitro predictions to relevant in vivo endpoints and the need to validate pathway-based predictions with targeted studies in whole animals. Currently, there are 10,000 to 30,000 chemicals in world-wide commerce in need of hazard data for assessing potential health risks. The traditional animal study designs for assessing developmental toxicity cannot accommodate the evaluation of this large number of chemicals, requiring that alternative technologies be utilized. Though a daunting task, technologies are being developed and utilized to make that goal reachable.
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http://dx.doi.org/10.1002/bdrb.20315DOI Listing
October 2011

Laboratory models and their role in assessing teratogenesis.

Authors:
George P Daston

Am J Med Genet C Semin Med Genet 2011 Aug 15;157C(3):183-7. Epub 2011 Jul 15.

Miami Valley Innovation Center, The Procter & Gamble Company, Cincinnati, OH 45253, USA.

Laboratory models have an important role in identifying exposures with teratogenic potential, determining mechanisms of abnormal development, and supporting or refuting the biological plausibility of associations identified in human studies. Laboratory animals are the most widely used models, but are rapidly being supplemented by in vitro tools. Testing paradigms that have been in place since the mid-1960s for pharmaceuticals, and soon thereafter for industrial chemicals and pesticides, have been used to evaluate the potential developmental toxicity of thousands of agents. These models have served as the principal basis for regulatory decisions about acceptable exposure levels and restrictions on use of certain drugs during pregnancy.
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http://dx.doi.org/10.1002/ajmg.c.30312DOI Listing
August 2011

A different approach to validating screening assays for developmental toxicity.

Birth Defects Res B Dev Reprod Toxicol 2010 Dec;89(6):526-30

Procter & Gamble, Cincinnati, Ohio, USA.

Background: There continue to be many efforts around the world to develop assays that are shorter than the traditional embryofetal developmental toxicity assay, or use fewer or no mammals, or use less compound, or have all three attributes. Each assay developer needs to test the putative assay against a set of performance standards, which traditionally has involved testing the assays against a list of compounds that are generally recognized as "positive" or "negative" in vivo. However, developmental toxicity is highly conditional, being particularly dependent on magnitude (i.e. dose) and timing of exposure, which makes it difficult to develop lists of compounds neatly assigned as developmental toxicants or not.

Approach: Here we offer an alternative approach for the evaluation of developmental toxicity assays based on exposures. Exposures are classified as "positive" or "negative" in a system, depending on the compound and the internal concentration. Although this linkage to "internal dose" departs from the recent approaches to validation, it fits well with widely accepted principles of developmental toxicology.

Conclusions: This paper introduces this concept, discusses some of the benefits and drawbacks of such an approach, and lays out the steps we propose to implement it for the evaluation of developmental toxicity assays.
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http://dx.doi.org/10.1002/bdrb.20276DOI Listing
December 2010

Predicting developmental toxicity through toxicogenomics.

Birth Defects Res C Embryo Today 2010 Jun;90(2):110-7

Miami Valley Innovation Center, The Procter & Gamble Company, Cincinnati, Ohio 45253, USA.

Global analysis of gene expression in target cells or tissues in response to a toxicant holds significant promise for predictive toxicology. Toxicants elicit a characteristic pattern of gene expression that is dependent on mechanism of action. These mechanism-specific transcript profiles can be used as the basis for predictive toxicology. Potential applications include prioritizing chemicals for testing and customizing testing approaches based on the chemical. Results that are useful in this predictive context can be obtained from animal or in vitro models. Gene expression analysis can also be used to elucidate the shape of the dose-response curve at exposure levels below the no observed adverse effect level, an important need in risk assessment. In this review, we will illustrate each of these points using our research on estrogen and an estrogenic mode of action as a model for how to use gene expression data in a predictive way. Although gene expression in response to estrogens is tissue, life stage, and sex specific, it is feasible to identify transcript profiles that are diagnostic of this mode of action.
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http://dx.doi.org/10.1002/bdrc.20178DOI Listing
June 2010

Computational toxicology: realizing the promise of the toxicity testing in the 21st century.

Environ Health Perspect 2010 Aug 18;118(8):1047-50. Epub 2010 May 18.

Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599-7431, USA.

Background: The National Academies' Standing Committee on Use of Emerging Science for Environmental Health Decisions held a meeting (21-22 September 2009 in Washington, DC) titled "Computational Toxicology: From Data to Analyses to Applications." This commentary reflects on the presentations and roundtable discussions from the meeting that were designed to review the state of the art in the field and the practical applications of the new science and to provide focus to the field.

Objectives: The meeting considered two topics: the emerging data streams amenable to computational modeling and data mining, and the emerging data analysis and modeling tools.

Discussion: Computational toxicology is a subdiscipline of toxicology that aims to use the mathematical, statistical, modeling, and computer science tools to better understand the mechanisms through which a given chemical induces harm and, ultimately, to be able to predict adverse effects of the toxicants on human health and/or the environment. The participants stressed the importance of computational toxicology to the future of environmental health sciences and regulatory decisions in public health; however, many challenges remain to be addressed before the findings from high-throughput screens and in silico models may be considered sufficiently robust and informative.

Conclusions: Many scientists, regulators, and the general public believe that new and better ways to assess human toxicity are now needed, and technological breakthroughs are empowering the field of toxicity assessment. Even though the application of computational toxicology to environmental health decisions requires additional efforts, the merger of the power of computers with biological information is poised to deliver new tools and knowledge.
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http://dx.doi.org/10.1289/ehp.1001925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920091PMC
August 2010

The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent.

Toxicology 2010 Apr 17;270(2-3):137-49. Epub 2010 Feb 17.

Miami Valley Innovation Center, The Procter and Gamble Company, PO Box 538707 #805, Cincinnati, OH 45253-8707, United States.

A reliable in vitro model to determine the potential estrogenic activity of chemicals of interest is still unavailable. To further investigate the usefulness of a human-derived cell line, we determined the transcriptional changes induced by bisphenol A (BPA) in Ishikawa cells at various doses (1 nM, 100 nM, 10 microM, and 100 microM) and time points (8, 24 and 48 h) by comparing the response of approximately 38,500 human genes and ESTs between treatment groups and controls (vehicle-treated). By trend analysis, we determined that the expression of 2794 genes was modified by BPA in a dose- and time-dependent manner (p< or =0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest doses of BPA evaluated (10-100 microM), while the genomic response of the cells exposed to low doses of BPA was essentially negligible. By comparing the Ishikawa cells' response to BPA vs.17 alpha-ethynyl estradiol we determined that the change in the expression of 307 genes was identical in the direction of the change, although the magnitude of the change for some genes was different. Further, the response of Ishikawa cells to high doses of BPA shared similarities to the estrogenic response of the rat uterus, specifically, 362 genes were regulated in a similar manner in vivo as well as in vitro. Gene ontology analysis indicated that BPA results in changes to multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response after exposure to chemicals with varied estrogenic activity, and offer an in vitro model to assess this mode of action.
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http://dx.doi.org/10.1016/j.tox.2010.02.008DOI Listing
April 2010

Introduction to special issue on developmental and reproductive toxicology in China.

Authors:
George P Daston

Birth Defects Res B Dev Reprod Toxicol 2010 Feb;89(1)

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http://dx.doi.org/10.1002/bdrb.20239DOI Listing
February 2010

Application of key events analysis to chemical carcinogens and noncarcinogens.

Crit Rev Food Sci Nutr 2009 Sep;49(8):690-707

Department of Experimental Medicine and Toxicology, Imperial College London, London W12 0NN, UK.

The existence of thresholds for toxicants is a matter of debate in chemical risk assessment and regulation. Current risk assessment methods are based on the assumption that, in the absence of sufficient data, carcinogenesis does not have a threshold, while noncarcinogenic endpoints are assumed to be thresholded. Advances in our fundamental understanding of the events that underlie toxicity are providing opportunities to address these assumptions about thresholds. A key events dose-response analytic framework was used to evaluate three aspects of toxicity. The first section illustrates how a fundamental understanding of the mode of action for the hepatic toxicity and the hepatocarcinogenicity of chloroform in rodents can replace the assumption of low-dose linearity. The second section describes how advances in our understanding of the molecular aspects of carcinogenesis allow us to consider the critical steps in genotoxic carcinogenesis in a key events framework. The third section deals with the case of endocrine disrupters, where the most significant question regarding thresholds is the possible additivity to an endogenous background of hormonal activity. Each of the examples suggests that current assumptions about thresholds can be refined. Understanding inter-individual variability in the events involved in toxicological effects may enable a true population threshold(s) to be identified.
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http://dx.doi.org/10.1080/10408390903098673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840875PMC
September 2009

The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol.

Toxicol Sci 2009 Jan 20;107(1):40-55. Epub 2008 Oct 20.

Miami Valley Innovation Center, The Procter and Gamble Company, Cincinnati, Ohio 45253, USA.

We have determined the gene expression profile induced by 17 alpha-ethynyl estradiol (EE) in Ishikawa cells, a human uterine-derived estrogen-sensitive cell line, at various doses (1 pM, 100 pM, 10 nM, and 1 microM) and time points (8, 24, and 48 h). The transcript profiles were compared between treatment groups and controls (vehicle-treated) using high-density oligonucleotide arrays to determine the expression level of approximately 38,500 human genes. By trend analysis, we determined that the expression of 2560 genes was modified by exposure to EE in a dose- and time-dependent manner (p
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http://dx.doi.org/10.1093/toxsci/kfn219DOI Listing
January 2009

Identification and characterization of toxicity of contaminants in pet food leading to an outbreak of renal toxicity in cats and dogs.

Toxicol Sci 2008 Nov 9;106(1):251-62. Epub 2008 Aug 9.

The Procter & Gamble Company, Cincinnati, Ohio 45253, USA.

This paper describes research relating to the major recall of pet food that occurred in Spring 2007 in North America. Clinical observations of acute renal failure in cats and dogs were associated with consumption of wet pet food produced by a contract manufacturer producing for a large number of companies. The affected lots of food had been formulated with wheat gluten originating from China. Pet food and gluten were analyzed for contaminants using several configurations of high-performance liquid chromatography (HPLC) and mass spectrometry (MS), which revealed a number of simple triazine compounds, principally melamine and cyanuric acid, with lower concentrations of ammeline, ammelide, ureidomelamine, and N-methylmelamine. Melamine and cyanuric acid, have been tested and do not produce acute renal toxicity. Some of the triazines have poor solubility, as does the compound melamine cyanurate. Pathological evaluation of cats and dogs that had died from the acute renal failure indicated the presence of crystals in kidney tubules. We hypothesized that these crystals were composed of the poorly soluble triazines, a melamine-cyanuric acid complex, or a combination. Sprague dawley rats were given up to 100 mg/kg ammeline or ammelide alone, a mixture of melamine and cyanuric acid (400/400 mg/kg/day), or a mixture of all four compounds (400 mg/kg/day melamine, 40 mg/kg/day of the others). Neither ammeline nor ammelide alone produced any renal effects, but the mixtures produced significant renal damage and crystals in nephrons. HPLC-MS/MS confirmed the presence of melamine and cyanuric acid in the kidney. Infrared microspectroscopy on individual crystals from rat or cat (donated material from a veterinary clinic) kidneys confirmed that they were melamine-cyanuric acid cocrystals. Crystals from contaminated gluten produced comparable spectra. These results establish the causal link between the contaminated gluten and the adverse effects and provide a mechanistic explanation for how two apparently innocuous compounds could have adverse effects in combination, that is, by forming an insoluble precipitate in renal tubules leading to progressive tubular blockage and degeneration.
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http://dx.doi.org/10.1093/toxsci/kfn160DOI Listing
November 2008

Gene expression, dose-response, and phenotypic anchoring: applications for toxicogenomics in risk assessment.

Authors:
George P Daston

Toxicol Sci 2008 Oct 6;105(2):233-4. Epub 2008 Aug 6.

Central Product Safety, Procter & Gamble, Cincinnati, Ohio 45253, USA.

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http://dx.doi.org/10.1093/toxsci/kfn138DOI Listing
October 2008

CERHR bisphenol A: review and commentaries.

Authors:
George P Daston

Birth Defects Res B Dev Reprod Toxicol 2008 Jun;83(3):151

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http://dx.doi.org/10.1002/bdrb.20159DOI Listing
June 2008

Lack of effect of butylparaben and methylparaben on the reproductive system in male rats.

Birth Defects Res B Dev Reprod Toxicol 2008 Apr;83(2):123-33

Charles River Preclinical Services, Horsham, PA 19044, USA.

Background: Parabens are widely used preservatives in cosmetics and pharmaceutical products, and approved as food additives. Parabens have been considered safe for these uses for many years. Recently, adverse effects on male reproductive parameters in rats have been reported when parabens were given orally for 8 weeks starting at three weeks of age. Our studies used two representative parabens, methyl- and butylparaben, to try to replicate these studies and thereby evaluate potential reproductive effects in male Wistar rats.

Methods: Diets containing 0, 100, 1000 or 10,000 ppm of either butyl- or methylparaben were fed to male rats for eight weeks. Rats were 22 days of age at the start of exposure. Parameters evaluated included organ weights, histopathology of reproductive tissues, sperm production, motility, morphology and reproductive hormone levels (butylparaben only).

Results: None of the parameters evaluated for either paraben showed compound- or dosage-dependent adverse effects. Metabolism experiments of butylparaben indicate that it is rapidly metabolized by non-specific esterases to p-hydroxybenzoic acid and butanol, neither of which is estrogenic.

Conclusions: Exposure to methyl- or butylparaben in the diet for eight weeks did not affect any male reproductive organs or parameters at exposures as high as 10,000 ppm, corresponding to a mean daily dose of 1,141.1+/-58.9 or 1,087.6+/-67.8 mg/kg/day for methyl- and butylparaben, respectively. The rapid metabolism of parabens by esterases probably explains why these weakly estrogenic substances elicit no in vivo effects when administered by relevant exposure routes (i.e., topical and oral).
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http://dx.doi.org/10.1002/bdrb.20153DOI Listing
April 2008

Casimer T. Grabowski: 1927-2007.

Birth Defects Res B Dev Reprod Toxicol 2008 Apr;83(2):149-50

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http://dx.doi.org/10.1002/bdrb.20151DOI Listing
April 2008

Skeletal malformations and variations in developmental toxicity studies: interpretation issues for human risk assessment.

Birth Defects Res B Dev Reprod Toxicol 2007 Dec;80(6):421-4

Miami Valley Innovation Center, Procter & Gamble, Cincinnati, Ohio 45253, USA.

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http://dx.doi.org/10.1002/bdrb.20135DOI Listing
December 2007