DOCSLIB.ORG

Genomics and Toxic Substances: Part I—Toxicogenomics by Gary E

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genomics and Toxic Substances: Part I—Toxicogenomics by Gary E Copyright © 2003 Environmental Law Institute®, Washington, DC. reprinted with permission from ELR®, http://www.eli.org, 1-800-433-5120. 1-2003 ELR 33 ELR 10071 NEWS&ANALYSIS Genomics and Toxic Substances: Part I—Toxicogenomics by Gary E. Marchant dvances in genomics, the study of the structure and ticle will address the application of toxicogenomics to Afunction of our genetic make-up, are fundamentally toxic torts and environmental regulation; a subsequent transforming toxicology, the science of how toxic sub- companion article will address toxicogenetic applications. stances affect our bodies. These changes will inevitably spill After first describing the scientific background of toxico- over into the legal regimes that frequently rely on toxicolog- genomics, this Article explores some potential uses of ical data, including toxic torts and environmental regula- toxicogenomic data in regulation and litigation involving tion.1 Genomic data, and the techniques with which they are toxic substances. generated, have the potential to make toxic torts and envi- ronmental regulation more effective, efficient, and fair, but Scientific Background at the same time will present many new doctrinal, eviden- tiary, and ethical challenges. Toxicogenomics is defined “as the study of the relationship Two key applications of genomic data for toxic torts and between the structure and activity of the genome (the cellu- environmental regulation are2: (i) the study of the expres- lar complement of genes) and the adverse biological effects sion of genes in cells or tissues in response to exposure to a of exogenous agents.”4 A major focus of toxicogenomics is toxicant, known as toxicogenomics; and (ii) the identifica- to characterize changes in gene expression in cells or tissues tion of genetic variations affecting susceptibility to toxic after exposure to toxic substances.5 Such exposure invari- agents, sometimes referred to as toxicogenetics.3 This Ar- ably results, either directly or indirectly, in characteristic changes in gene expression6 These gene expression changes The author is Associate Professor and Executive Director, Center for the Study of Law, Science, and Technology, Arizona State University College 4. Marilyn J. Aardema & James T. MacGregor, Toxicology and Ge- of Law. J.D. (1990); M.P.P. (1990); Ph.D. (Genetics) (1986). Portions of netic Toxicology in the New Era of “Toxicogenomics”: Impact of this Article were presented at a National Institutes of Environmental “-Omics” Technologies, 499 Mutation Res. 13, 15 (2002). Health Sciences conference on Toxicogenomics in December 2001, and at presentations in 2002 to the Woodrow Wilson International Center for 5. A small proportion of the genes in any cell are “turned on” or “ex- Scholars, the Environmental Law Institute, and faculty colloquia at Seton pressed” in a given cell at any one time. Although different types of Hall Law School and Arizona State University College of Law. The author cells, e.g., skin, blood, nerve cells, within a body contain identical genetic information, they have very different functional and struc- appreciates the many helpful comments and questions from the partici- tural properties primarily because they have different subsets of pants at those events, including some particularly valuable suggestions genes that are expressed. One estimate is that approximately 25% of from Andrew Askland and Michael Saks. all genes are active (turned on) in a given cell type, and that on aver- 1. See, e.g., P. Trinia Simmons & Christopher J. Portier, Toxico- age about 5% of genes that are active in one cell type are different genomics: The New Frontier in Risk Analysis,23Carcinogenesis from the genes turned on in another cell type. Toby G. Rossman, 903, 903 (2002) (“the complete sequence of the human genome will Cloning Genes Whose Levels of Expression Are Altered by Metals: cause a fundamental paradigm shift in the science of risk assess- Implications for Human Health Research,38Am. J. Ind. Med. 335, ment”); Wendy Yap & David Rejeski, Environmental Policy in the 335 (2000). In addition to these differences in gene expression be- Age of Genetics, Issues in Sci. & Tech., Fall 1998, at 33. tween cell types, the gene expression in any one cell type varies over 2. Many other types of genetic data may be useful in environmental time in response to external stimuli. A gene is expressed by a process regulation and toxic torts, including deoxyribonucleic acid (DNA) called transcription, in which a replicate of the functional DNA se- adducts, chromosomal aberrations, DNA breakage studies, reporter quence of the gene is created (known as messenger RNA (mRNA)), gene assays, and mutational spectra associated with specific chemi- which then moves from the cell nucleus into the cell cytoplasm to cals. See generally Stefano Bonassi & William W. Au, Biomarkers produce a protein, the primary functional and structural units of the in Molecular Epidemiology Studies for Health Risk Prediction, 511 cell. In addition to characterizing these gene expression changes, Mutation Res. 73 (2002). These applications are outside the scope “toxicogenomics” also generally encompasses other types of data of this Article. including profiling the proteins (proteomics) or metabolites (metabonomics) in a cell or tissue. See Aardema & MacGregor, su- 3. Emile F. Nuwaysir et al., Microarrays and Toxicology: The Advent pra note 4, at 14. of Toxicogenetics,24Molecular Carcinogenesis 153, 158 (1999); Richard J. Albertini, Developing Sustainable Studies on En- 6. See Nuwaysir et al., supra note 3, at 153 (“Almost without excep- vironmental Health, 510 Mutation Res. 317, 323 (2001). tion, gene expression is altered during toxicity, as either a direct or Toxicogenetics therefore involves the toxicological implications of indirect result of a toxicant exposure.”); Spencer Farr & Robert T. single genes, whereas the focus of toxicogenomics is on the entire Dunn, Concise Review: Gene Expression Applied to Toxicology,50 genome. A “genome” refers to the complete set of genes contained Toxicological Sci. 1, 1 (1999) (“The fundamental assumption of within a cell. This same distinction between focusing on one or a few toxicogenetics is that there are no toxicologically relevant outcomes susceptibility genes (toxicogenetics) versus studying the expression in vitro or in vivo, with the possible exception of rapid necrosis, that of the whole genome (toxicogenomics) in response to exposure to do not require differential gene expression.”); Russell S. Thomas et toxic substances also applies in the related field of genomic ap- al., Identification of Toxicologically Predictive Gene Sets Using proaches to pharmaceuticals. See Allen D. Roses, Pharmaco- cDNA Microarrays,60Molecular Pharmacology 1189, genetics,10Hum. Molecular Genetics 2261, 2261 (2001) 1189-90 (2001) (“[T]oxicity is commonly manifested as inflamma- (“[P]harmacognetics is defined as the study of variability in drug tion, proliferation, apoptosis, necrosis, and/or cellular differentia- responses attributed to hereditary factors in different populations. tion. All of these toxic endpoints are intimately linked to specific al- Pharmacogenomics is the determination and analysis of the ge- terations in gene expression.”); Albertini, supra note 3, at 321 (“It nome (DNA) and its products (RNA and proteins) as they relate to has long been known that cells almost always respond to noxious drug response.”). stimuli by altering gene expression.”). 33 ELR 10072 ENVIRONMENTAL LAW REPORTER 1-2003 Copyright © 2003 Environmental Law Institute®, Washington, DC. reprinted with permission from ELR®, http://www.eli.org, 1-800-433-5120. may sometimes be the cause or in other cases the conse- quences known as complementary DNA (cDNA) that can quence of the early stages of a toxic response.7 be “tagged” with a flourescent marker.14 The cDNA sample Gene expression changes can be analyzed by collecting is then added to the microarray, and cDNA sequences will and characterizing messenger ribonucleic acid (mRNA) us- bind (or hybridize) to sites on the microarray that contain ing a deoxyribonucleic acid (DNA) microarray. A DNA DNA with a matching sequence. A laser scans the micro- microarray (sometimes also referred to as a gene chip or array and generates flourescent spots at the locations where DNA chip) consists of a set of many different single- the cDNA binds, and the intensity of the signal at each spot stranded genetic sequences fixed to a substrate, such as a will be proportional to the abundance of matching mRNA in glass slide or membrane, in a defined pattern. The genetic the original sample isolated from the treated or control markers can consist of short (500 to 2,000 base pair) DNA cells.15 Sophisticated computer programs are available to sequences that are complementary to, and thus bind to, “read” the microarrays and produce digital graphic read- genes of potential interest. Fifty thousand or more of these outs of the genes being expressed in the cells of interest. specific DNA sequences can be spotted (or printed) onto the DNA microarrays thus permit the almost instantaneous and fixed substrate in precise locations or spots on a grid, with simultaneous genome-wide detection of the expression of each spot on the array containing several million identical thousand of genes, even if the function of some of the genes copies of a DNA segment from a specific gene.8 Alterna- is unknown.16 tively, shorter synthesized DNA sequences, called This genome-wide or “global” gene expression analysis oligonucleotides, can be constructed directly onto the is a major advancement over previous methodologies which substrate using a process called photolithography.9 At only permitted analysis of the expression of one or two indi- least 20 companies have commercialized DNA micro- vidual genes at a time.17 Toxicity usually involves the induc- array products,10 and at least 1 manufacturer has already re- tion (up regulation) and repression (down regulation) of leased a commercial gene chip containing the entire hu- man genome.11 14. Jennifer Medlin, Array of Hope for Gene Technology, 109 Envtl. DNA microarrays can be used to identify and character- Health Persp. A34, A35-36 (2001).
Load more

Recommended publications
  • Toxicogenomics Applications of New Functional Genomics Technologies in Toxicology
    \-\w j Toxicogenomics Applications of new functional genomics technologies in toxicology Wilbert H.M. Heijne Proefschrift ter verkrijging vand egraa dva n doctor opgeza gva nd e rector magnificus vanWageninge n Universiteit, Prof.dr.ir. L. Speelman, in netopenbaa r te verdedigen op maandag6 decembe r200 4 des namiddagst e half twee ind eAul a - Table of contents Abstract Chapter I. page 1 General introduction [1] Chapter II page 21 Toxicogenomics of bromobenzene hepatotoxicity: a combined transcriptomics and proteomics approach[2] Chapter III page 48 Bromobenzene-induced hepatotoxicity atth etranscriptom e level PI Chapter IV page 67 Profiles of metabolites and gene expression in rats with chemically induced hepatic necrosis[4] Chapter V page 88 Liver gene expression profiles in relation to subacute toxicity in rats exposed to benzene[5] Chapter VI page 115 Toxicogenomics analysis of liver gene expression in relation to subacute toxicity in rats exposed totrichloroethylen e [6] Chapter VII page 135 Toxicogenomics analysis ofjoin t effects of benzene and trichloroethylene mixtures in rats m Chapter VII page 159 Discussion and conclusions References page 171 Appendices page 187 Samenvatting page 199 Dankwoord About the author Glossary Abbreviations List of genes Chapter I General introduction Parts of this introduction were publishedin : Molecular Biology in Medicinal Chemistry, Heijne etal., 2003 m NATO Advanced Research Workshop proceedings, Heijne eral., 2003 81 Chapter I 1. General introduction 1.1 Background /.1.1 Toxicologicalrisk
    [Show full text]
  • Genomic Dose Response
    Genomic Dose Response: The Picture NTP Genomic Dose Response Modeling Expert Panel Meeting October 23, 2017 Russell Thomas Director National Center for Computational Toxicology The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA Scott May Want To Rethink Asking Me To Be The “Big Picture Guy”… National Center for Computational Toxicology It is a Well Known Fact that Toxicology Continues to Have a Data Problem US National Research Council, 1984 Size of Estimate Mean Percent Category Category In the Select Universe Pesticides and Inert Ingredients of Pesticides 3,350 Formulations 10 24 2 26 38 Cosmetic Ingredients 3,410 2 14 10 18 56 Drugs and Excipients Used in Drug Formulations 1,815 18 18 3 36 25 Food Additives 8,627 • Major challenge is too many 5 14 1 34 46 Chemicals in Commerce: chemicals and not enough At Least 1 Million 12,860 Pounds/Year data 11 11 78 Chemicals in Commerce: • Total # chemicals = 65,725 Less than 1 Million 13,911 Pounds/Year • Chemicals with no toxicity 12 12 76 data of any kind = ~46,000 Chemicals in Commerce: Production Unknown or 21,752 Inaccessible 10 8 82 Complete Partial Minimal Some No Toxicity Health Health Toxicity Toxicity Information Hazard Hazard Information Information Available Assessment Assessment Available Available 2 Possible Possible (But Below Minimal) National Center for Computational Toxicology It is a Well Known Fact that Toxicology Continues to Have a Data Problem 70 60 50 40 30 20 Percent of Chemicals <1% 10 0 Acute Cancer Gentox Dev Tox Repro Tox EDSP Tier 1 Modified from Judson et al., EHP 2009 3 National Center for Computational Toxicology For Those With Data, Have We Been Truly Predictive or Just Protective? …data compiled from 150 compounds with 221 human toxicity events reported.
    [Show full text]
  • Next-Generation Sequencing Data for Use in Risk Assessment Bruce Alexander Merrick
    Available online at www.sciencedirect.com Current Opinion in ScienceDirect Toxicology Next-generation sequencing data for use in risk assessment Bruce Alexander Merrick Abstract fluorescently labeled nucleotides and capillary electro- Next-generation sequencing (NGS) represents several phoresis that gave rise to automated sequencing in- powerful platforms that have revolutionized RNA and DNA struments such as the Applied Biosystems, Inc. model analysis. The parallel sequencing of millions of DNA molecules 370A sequencers and others, on the basis of Sanger can provide mechanistic insights into toxicology and provide chemistries [2]. Read length per each sample was at 500e new avenues for biomarker discovery with growing relevance 800 nucleotides, and sample throughput was limited. for risk assessment. The evolution of NGS technologies has improved over the last decade with increased sensitivity and Sanger-based DNA sequencing instruments are accuracy to foster new biomarker assays from tissue, blood, considered first-generation platforms. Instruments that and other biofluids. NGS technologies can identify transcrip- perform multiple sequencing reactions simultaneously tional changes and genomic targets with base pair precision in in a ‘massively parallel’ fashion have been dubbed, response to chemical exposure. Furthermore, there are ‘NextGeneration’ or NextGen Sequencing [3]. How several exciting movements within the toxicology community NGS came about compared with other genomic plat- that incorporate NGS platforms into new strategies for more forms is interlinked with microarray technology rapid toxicological characterizations. These include the Tox21 (Figure 1). Both platforms can provide whole genomic in vitro high-throughput transcriptomic screening program, approaches to research problems. Microarrays are a development of organotypic spheroids, alternative animal fluorescent probe hybridization-based technology with models, mining archival tissues, liquid biopsy, and epige- origins in the mid-1990s that are now a mature genomic nomics.
    [Show full text]
  • In Vitro RNA-Seq-Based Toxicogenomics Assessment Shows
    www.nature.com/scientificreports OPEN In vitro RNA-seq-based toxicogenomics assessment shows reduced biological efect of tobacco Received: 11 August 2017 Accepted: 5 January 2018 heating products when compared Published: xx xx xxxx to cigarette smoke Linsey E. Haswell, Sarah Corke, Ivan Verrastro, Andrew Baxter, Anisha Banerjee, Jason Adamson, Tomasz Jaunky, Christopher Proctor, Marianna Gaça & Emmanuel Minet The battery of regulatory tests used to evaluate the risk of novel tobacco products such as heated tobacco products (THPs) presents some limitations including a bias towards the apical endpoint tested, and limited information on the mode of action. This is driving a paradigm shift to more holistic systems biology approaches. In this study, we used RNA-sequencing to compare the transcriptomic perturbations following acute exposure of a 3D airway tissue to the aerosols from two commercial THPs and a reference 3R4F cigarette. 2809 RNAs were diferentially expressed for the 3R4F treatment and 115 and 2 RNAs for the two THPs (pFDR < 0.05, FC > 1.5), respectively. The relationship between the identifed RNA features and gene ontologies were mapped showing a strong association with stress response, xenobiotics metabolism, and COPD-related terms for 3R4F. In contrast, fewer ontologies were found enriched for the THPs aerosols. “Response to wounding” was a common COPD-related term over-represented for the two THPs but at a reduced signifcance. Quantifcation of a cytokine panel post-exposure confrmed a pro-infammatory efect of cigarette smoke but not for THPs. In conclusion, THPs have a reduced impact on gene expression compared to 3R4F. Te health risk associated with smoking cigarettes and tobacco regulations have been driving a wave of develop- ment and innovation in next generation tobacco and nicotine delivery systems1.
    [Show full text]
  • IPA Analysis of Metabolomics Data Including Cross-Platform Integration with Transcriptomics Data from a Diabetic Mouse Model
    IPA Analysis of Metabolomics Data Including Cross-Platform Integration with Transcriptomics Data from a Diabetic Mouse Model CONTENTS Overview ........................................................................................................................................................................ 3 Introduction ................................................................................................................................................................... 3 Metabolomics Background ........................................................................................................................................ 3 Integration of Metabolomic and Transcriptomic data .............................................................................................. 5 The Ingenuity Platform .............................................................................................................................................. 5 Case Study Background ............................................................................................................................................. 5 Methods ........................................................................................................................................................................ 6 Establishing a Metabolite profile for db/db mice and identification of exploratory biomarkers .............................. 6 IPA-Metabolomics™ Analysis: ...................................................................................................................................
    [Show full text]
  • Toxicogenomics: Toward the Future of Toxic Tort Causation
    NORTH CAROLINA JOURNAL OF LAW & TECHNOLOGY VOLUME 5, ISSUE 1: FALL 2003 Toxicogenomics: Toward the Future of Toxic Tort Causation Jon R. Pierce and Terrence Sexton1 I. Introduction Plaintiff suspects that a chemical in her city’s water supply has caused her to develop a rare form of liver cancer. Defendant, a company in Plaintiff’s city, has been discharging the chemical into the water for a number of years. Both parties in the toxic tort litigation are at the mercy of an unevenly developed and often- insufficient body of science to establish or rebut the required causation element. This article will examine the current causation paradigm in toxic tort litigation, pointing out its specific weaknesses. The article will then introduce an emerging discipline, toxicogenomics, which will eventually make it possible to specifically describe the molecular pathways leading from exposure to injury, and in so doing will greatly improve the reliability of causation evidence in toxic tort cases to the benefit of both plaintiffs and defendants. To illustrate its potential usefulness, this article will walk through a hypothetical toxicogenomics experiment involving a suspected liver toxin. The article will conclude by suggesting that judges controlled by Daubert v. Merrell Dow Pharmaceuticals, Inc.2 would be wise not to admit such evidence until more research can definitively link the described molecular pathways to the specific injury. 1 Jon R. Pierce, J.D. Candidate, University of North Carolina School of Law, 2004. Terrence Sexton is a trial attorney with the international law firm of Shook Hardy & Bacon LLP. He represents clients nationwide in cases involving toxic torts, products liability, white collar crime and commercial disputes.
    [Show full text]
  • Transcriptomics in Toxicogenomics, Part III: Data Modelling for Risk Assessment
    nanomaterials Review Transcriptomics in Toxicogenomics, Part III: Data Modelling for Risk Assessment Angela Serra 1,2 , Michele Fratello 1,2 , Luca Cattelani 1,2 , Irene Liampa 3 , Georgia Melagraki 4 , Pekka Kohonen 5,6 , Penny Nymark 5,6 , Antonio Federico 1,2 , Pia Anneli Sofia Kinaret 1,2,7 , Karolina Jagiello 8,9, My Kieu Ha 10,11,12, Jang-Sik Choi 10,11,12, Natasha Sanabria 13 , Mary Gulumian 13,14, Tomasz Puzyn 8,9 , Tae-Hyun Yoon 10,11,12 , Haralambos Sarimveis 3 , Roland Grafström 5,6, Antreas Afantitis 4 and Dario Greco 1,2,7,* 1 Faculty of Medicine and Health Technology, Tampere University, FI-33014 Tampere, Finland; angela.serra@tuni.fi (A.S.); michele.fratello@tuni.fi (M.F.); luca.cattelani@tuni.fi (L.C.); antonio.federico@tuni.fi (A.F.); pia.kinaret@helsinki.fi (P.A.S.K.) 2 BioMediTech Institute, Tampere University, FI-33014 Tampere, Finland 3 School of Chemical Engineering, National Technical University of Athens, 157 80 Athens, Greece; [email protected] (I.L.); [email protected] (H.S.) 4 Nanoinformatics Department, NovaMechanics Ltd., Nicosia 1065, Cyprus; [email protected] (G.M.); [email protected] (A.A.) 5 Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; [email protected] (P.K.); [email protected] (P.N.); [email protected] (R.G.); 6 Division of Toxicology, Misvik Biology, 20520 Turku, Finland 7 Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland 8 QSAR Lab Ltd., Aleja Grunwaldzka 190/102, 80-266 Gdansk, Poland; [email protected]
    [Show full text]
  • Review TOXICITY STUDIES of DRUGS AND
    Bulgarian Journal of Veterinary Medicine, 2016 ONLINE FIRST ISSN 1311-1477; DOI: 10.15547/bjvm.983 Review TOXICITY STUDIES OF DRUGS AND CHEMICALS IN ANIMALS: AN OVERVIEW S. A. SAGANUWAN Department of Veterinary Physiology, Pharmacology and Biochemistry, College of Veterinary Medicine, University of Agriculture, Makurdi, Benue State, Nigeria Summary Saganuwan, S. A., 2016. Toxicity studies of drugs and chemicals in animals: An overview. Bulg. J. Vet. Med. (online first). Toxicity study is the investigation of either short or long-term toxic effects of a drug or chemical on animals. The toxicity is dose-dependent as asserted by Paracelsus over 500 years ago. However, short-term toxic effect is determined using median lethal dose (LD50) first introduced by Trevan in 1927 and revised many times. Presently there is a growing preponderance of rejection of scientific papers on acute toxicity study, simply because of the belief that in the current hazard and safety as- sessment of drugs and chemicals, LD50 values are no longer used. In view of this, literature search was carried out with a view to investigating the relevance of LD50 in development and assessment of drugs and chemicals. The findings revealed that in the past, many animals had been used for LD50 determination. OECD has reduced the number of test animals to 5–15 and presently it is further re- duced to 2–6. Acute toxicity study is being carried out in medicinal plants research and in the study of patent medicine. Although the application of LD50 has been drastically reduced, it is still applied and accepted in some parts of the world.
    [Show full text]
  • Public Data Sources to Support Systems Toxicology Applications Allan Peter Davis1, Jolene Wiegers1, Thomas C
    Available online at www.sciencedirect.com Current Opinion in ScienceDirect Toxicology Public data sources to support systems toxicology applications Allan Peter Davis1, Jolene Wiegers1, Thomas C. Wiegers1 and Carolyn J. Mattingly1,2 Abstract metabolic pathways, interaction networks, and/or bio- Public databases provide a wealth of freely available infor- logical processes; and the outcome can be the perturbed mation about chemicals, genes, proteins, biological networks, biological system trying to return back to a normal state phenotypes, diseases, and exposure science that can be in- (resilience) or a new, and potentially, adverse state due tegrated to construct pathways for systems toxicology appli- to toxicity [2]. The toxicant may trigger multiple cations. Relating this disparate information from public different pathways simultaneously by interacting with repositories, however, can be challenging because databases different biological mediators, complicating under- use a variety of ways to represent, describe, and make avail- standing about the specific connectivity between indi- able their content. The use of standard vocabularies to anno- vidual events, mediators, and outcomes. As well, in the tate key data concepts, however, allows the information to be real world, humans are typically exposed simultaneously more easily exchanged and combined for discovery of new to mixtures of chemicals and drugs, further complicating findings. We explore some of the many public data sources understanding of toxic mechanisms of actions [3,4]. currently available to support systems toxicology and demon- strate the value of standardizing data to help construct The goal of systems toxicology is to discern and organize chemical information pathways. exposure and toxicogenomic events to help formalize an understanding for drug therapy, risk assessment, expo- Addresses e 1 Department of Biological Sciences, North Carolina State University, sure hazards, and toxicity to humans [5 9].
    [Show full text]
  • OECD Environment, Health and Safety Publications
    OECD Environment, Health and Safety Publications Series on Testing and Assessment No. 39 DRAFT GUIDANCE DOCUMENT ON ACUTE INHALATION TOXICITY TESTING Environment Directorate Organisation for Economic Co-operation and Development 28 November 2008 1 Also published in the Series on Testing and Assessment: No. 1, Guidance Document for the Development of OECD Guidelines for Testing of Chemicals (1993; reformatted 1995, revised 2006) No. 2, Detailed Review Paper on Biodegradability Testing (1995) No. 3, Guidance Document for Aquatic Effects Assessment (1995) No. 4, Report of the OECD Workshop on Environmental Hazard/Risk Assessment (1995) No. 5, Report of the SETAC/OECD Workshop on Avian Toxicity Testing (1996) No. 6, Report of the Final Ring-test of the Daphnia magna Reproduction Test (1997) No. 7, Guidance Document on Direct Phototransformation of Chemicals in Water (1997) No. 8, Report of the OECD Workshop on Sharing Information about New Industrial Chemicals Assessment (1997) No. 9, Guidance Document for the Conduct of Studies of Occupational Exposure to Pesticides during Agricultural Application (1997) No. 10, Report of the OECD Workshop on Statistical Analysis of Aquatic Toxicity Data (1998) No. 11, Detailed Review Paper on Aquatic Testing Methods for Pesticides and industrial Chemicals (1998) No. 12, Detailed Review Document on Classification Systems for Germ Cell Mutagenicity in OECD Member Countries (1998) No. 13, Detailed Review Document on Classification Systems for Sensitising Substances in OECD Member Countries 1998) No. 14, Detailed Review Document on Classification Systems for Eye Irritation/Corrosion in OECD Member Countries (1998) No. 15, Detailed Review Document on Classification Systems for Reproductive Toxicity in OECD Member Countries (1998) 2 No.
    [Show full text]
  • Prioritizing Candidate Diseases-Related Metabolites Based
    Wang et al. BMC Bioinformatics 2019, 20(Suppl 18):574 https://doi.org/10.1186/s12859-019-3127-4 RESEARCH Open Access Prioritizing candidate diseases-related metabolites based on literature and functional similarity Yongtian Wang1, Liran Juan2, Jiajie Peng3, Tianyi Zang1* and Yadong Wang1* From Biological Ontologies and Knowledge bases workshop at IEEE BIBM 2018 Madrid, Spain. 3-6 December 2018 Abstract Background: As the terminal products of cellular regulatory process, functional related metabolites have a close relationship with complex diseases, and are often associated with the same or similar diseases. Therefore, identification of disease related metabolites play a critical role in understanding comprehensively pathogenesis of disease, aiming at improving the clinical medicine. Considering that a large number of metabolic markers of diseases need to be explored, we propose a computational model to identify potential disease-related metabolites based on functional relationships and scores of referred literatures between metabolites. First, obtaining associations between metabolites and diseases from the Human Metabolome database, we calculate the similarities of metabolites based on modified recommendation strategy of collaborative filtering utilizing the similarities between diseases. Next, a disease-associated metabolite network (DMN) is built with similarities between metabolites as weight. To improve the ability of identifying disease-related metabolites, we introduce scores of text mining from the existing database of chemicals and proteins into DMN and build a new disease-associated metabolite network (FLDMN) by fusing functional associations and scores of literatures. Finally, we utilize random walking with restart (RWR) in this network to predict candidate metabolites related to diseases. Results: We construct the disease-associated metabolite network and its improved network (FLDMN) with 245 diseases, 587 metabolites and 28,715 disease-metabolite associations.
    [Show full text]
  • Exploring Mechanistic Toxicity of Mixtures Using PBPK Modeling and Computational Systems Biology
    Agency for Toxic Substances & Disease Registry Exploring mechanistic toxicity of mixtures using PBPK modeling and computational systems biology Patricia Ruiz, PhD Simulation Science Section Office of Innovation and Analytics ICCVAM Communities of Practice January 2021 The findings and conclusions in this presentation are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry. Outline . Background . Single and Multiple Chemical Risk Assessment . Current State of Affairs . Methods . Results and discussion . Conclusions Background Exposome Adverse health . Often toxicity assessment of a outcomes single chemical is conducted . Three approaches can be used for mixtures risk assessment: Whole mixture, similar mixture and the components-based hazard index (HI)[ATSDR, 2018]. Molecular initiating event Toxicity effect Modified from Kortenkamp et al.,Science(2018). DOI: 10.1126/science.aat9219 HAZARD QUOTIENTS (HQ) The HQ for each chemical component of a mixture is calculated for only its critical effect using its exposure level (E) and health guidance value (HGV) HQ = E /HGV Hazard Quotients (HQ) and Hazard Index (HI) Component Based Hazard Index (Hl)= E1 /HGV1 + E2 /HGV2 + .. En /HGVn Assessments Hazard Mixture HGV Exposure Component Quotient A 2 1 0.5 HQ = E /HGV B 16 8 0.5 C 1 1 1.0 D 30 10 0.3 Hl (MIXTURE) 2.3 Current State of Affairs Chemical Library RNA RNA . Integration of Data Library Phenotype Chemical from Multiple Streams databases databases DNA Expression array Microbiome . Transcripts Microbiota Systems Biology databases databases Genomics Bio- Gene . Adverse Outcome monitoring databases databases Pathways array Population data Proteins Proteins Clinical databases databases proteomics Clinical data Modified from resource: Leung et al., 2013.
    [Show full text]