title: An approach for integrating toxicogenomic data in risk assessment: the dibutyl phthalate case study.
abstract: An approach for evaluating and integrating genomic data in chemical risk assessment was developed based on the lessons learned from performing a case study for the chemical dibutyl phthalate. A case study prototype approach was first developed in accordance with EPA guidance and recommendations of the scientific community. Dibutyl phthalate (DBP) was selected for the case study exercise. The scoping phase of the dibutyl phthalate case study was conducted by considering the available DBP genomic data, taken together with the entire data set, for whether they could inform various risk assessment aspects, such as toxicodynamics, toxicokinetics, and dose-response. A description of weighing the available dibutyl phthalate data set for utility in risk assessment provides an example for considering genomic data for future chemical assessments. As a result of conducting the scoping process, two questions--Do the DBP toxicogenomic data inform 1) the mechanisms or modes of action?, and 2) the interspecies differences in toxicodynamics?--were selected to focus the case study exercise. Principles of the general approach include considering the genomics data in conjunction with all other data to determine their ability to inform the various qualitative and/or quantitative aspects of risk assessment, and evaluating the relationship between the available genomic and toxicity outcome data with respect to study comparability and phenotypic anchoring. Based on experience from the DBP case study, recommendations and a general approach for integrating genomic data in chemical assessment were developed to advance the broader effort to utilize 21st century data in risk assessment.
authors.affiliation: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA. Electronic address: euling.susan@epa.gov.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Euling
authors.forename: Chad M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Weihsueh A
authors.initials: WA
authors.lastname: Chiu
authors.forename: Robert
authors.initials: R
authors.lastname: Benson
mesh_terms: D000818:Animals; D003993:Dibutyl Phthalate / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics; D006801:Humans; D010968:Plasticizers / Q000633:toxicity*; D018570:Risk Assessment / Q000379:methods
chemical_list: D004785:Environmental Pollutants; D010968:Plasticizers; D003993:Dibutyl Phthalate
keywords: 3 beta-hydroxysteroid dehydrogenase/delta-5–delta-4 isomerase type II; ADME; AGD; ALDH2; AR; BBDR model; CNPs; CYP2D6; Cyp11a1/P450scc; Cyp17a1; Cyp2b1; Cyp3a1; DBP; DEG; DEHP; D–R; EDC; Endocrine disrupting chemical; GO; Hsd3b; IRIS; Insl3; Integrated Risk Information System; MBP; MOA; Male development; NIEHS; NOAEL; National Institute of Environmental Health Sciences; PBPK modeling; Phthalates; RT-PCR; Risk assessment; SD; STAR; Scarb1; Science to Achieve Results; Sprague–Dawley; Star; T; TD; TDS; TGx; TK; Testosterone; Toxicogenomic; U.S. Environmental Protection Agency; UDP glucuronosyltransferase 2B1; UF(H); US EPA; Ugt2b1; WOE; absorption, distribution, metabolism, and excretion; aldehyde dehydrogenase-2; androgen receptor; anogenital distance; biologically based dose–response model; copy number polymorphisms; cytochrome P450 2D6; cytochrome P450, family 11, subfamily a, polypeptide 1; cytochrome P450, family 17, subfamily a, polypeptide 1; cytochrome P450, family 2, subfamily b, polypeptide 1; cytochrome P450, family 3, subfamily a, polypeptide 1; di-(2-ethylhexyl) phthalate; dibutyl phthalate; differentially-expressed gene; dose–response; endocrine disrupting chemical; gene ontology; insulin-like 3; mode of action; monobutyl phthalate; no observed adverse effect level; physiologically based pharmacokinetic modeling; reverse transcription-polymerase chain reaction; scavenger receptor class B, member 1; steroidogenic acute regulatory protein; testicular dysgenesis syndrome; testosterone; toxicodynamics; toxicogenomic; toxicokinetics; uncertainty factor for uncertainty in extrapolating animal data to humans (i.e., interspecies uncertainty) (http://www.epa.gov/IRIS/); weight-of-evidence