title: A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity.
abstract: Alternative methods for full replacement of in vivo tests for systemic endpoints are not yet available. Read across methods provide a means of maximizing utilization of existing data. A limitation for the use of read across methods is that they require analogs with test data. Repeat dose data are more frequently available than are developmental and/or reproductive toxicity (DART) studies. There is historical precedent for using repeat dose data in combination with a database uncertainty factor (UF) to account for missing DART data. We propose that use of the DART decision tree (Wu et al., 2013), in combination with a database UF, provides a path forward for DART data gap filling that better utilizes all of the data. Our hypothesis was that chemical structures identified by the DART tree as being related to structures with known DART toxicity would potentially have lower DART NOAELs compared to their respective repeat dose NOAELs than structures that lacked this association. Our analysis supports this hypothesis and as a result also supports that the DART decision tree can be used as part of weight of evidence in the selection of an appropriate DART database UF factor.
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Mason Business Center, 8700 Mason Montgomery Road, Cincinnati, OH 45040, United States. Electronic address: blackburn.kl@pg.com.
authors.forename: Karen
authors.initials: K
authors.lastname: Blackburn
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Mason Business Center, 8700 Mason Montgomery Road, Cincinnati, OH 45040, United States.
authors.forename: George
authors.initials: G
authors.lastname: Daston
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Mason Business Center, 8700 Mason Montgomery Road, Cincinnati, OH 45040, United States.
authors.forename: Joan
authors.initials: J
authors.lastname: Fisher
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Mason Business Center, 8700 Mason Montgomery Road, Cincinnati, OH 45040, United States.
authors.forename: Cathy
authors.initials: C
authors.lastname: Lester
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Mason Business Center, 8700 Mason Montgomery Road, Cincinnati, OH 45040, United States.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Naciff
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Sharon Woods Innovation Center, 11530 Reed Hartman Highway, Cincinnati, OH 45241, United States.
authors.forename: Echoleah S
authors.initials: ES
authors.lastname: Rufer
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Mason Business Center, 8700 Mason Montgomery Road, Cincinnati, OH 45040, United States.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Stuard
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Winton Hill Business Center, 6110 Center Hill Avenue, Cincinnati, OH 45224, United States.
authors.forename: Kara
authors.initials: K
authors.lastname: Woeller
mesh_terms: D000818:Animals; D016208:Databases, Factual; D003663:Decision Trees; D047108:Embryonic Development / Q000187:drug effects*; D047109:Fetal Development / Q000187:drug effects*; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D019055:No-Observed-Adverse-Effect Level; D012098:Reproduction / Q000187:drug effects*; D018570:Risk Assessment; D013723:Teratogens / Q000633:toxicity*; D018675:Toxicity Tests; D035501:Uncertainty
chemical_list: D015386:Hazardous Substances; D013723:Teratogens
keywords: Developmental toxicity; Reproductive toxicity; Risk assessment; Uncertainty factors