title: Relevance weighting of tier 1 endocrine screening endpoints by rank order.
abstract: Weight of evidence (WoE) approaches are recommended for interpreting various toxicological data, but few systematic and transparent procedures exist. A hypothesis-based WoE framework was recently published focusing on the U.S. EPA's Tier 1 Endocrine Screening Battery (ESB) as an example. The framework recommends weighting each experimental endpoint according to its relevance for deciding eight hypotheses addressed by the ESB. Here we present detailed rationale for weighting the ESB endpoints according to three rank ordered categories and an interpretive process for using the rankings to reach WoE determinations. Rank 1 was assigned to in vivo endpoints that characterize the fundamental physiological actions for androgen, estrogen, and thyroid activities. Rank 1 endpoints are specific and sensitive for the hypothesis, interpretable without ancillary data, and rarely confounded by artifacts or nonspecific activity. Rank 2 endpoints are specific and interpretable for the hypothesis but less informative than Rank 1, often due to oversensitivity, inclusion of narrowly context-dependent components of the hormonal system (e.g., in vitro endpoints), or confounding by nonspecific activity. Rank 3 endpoints are relevant for the hypothesis but only corroborative of Ranks 1 and 2 endpoints. Rank 3 includes many apical in vivo endpoints that can be affected by systemic toxicity and nonhormonal activity. Although these relevance weight rankings (WREL ) necessarily involve professional judgment, their a priori derivation enhances transparency and renders WoE determinations amenable to methodological scrutiny according to basic scientific premises, characteristics that cannot be assured by processes in which the rationale for decisions is provided post hoc.
authors: Applied Pharmacology and Toxicology, Inc, Gainesville, Florida.
authors: Christopher J
authors: CJ
authors: Borgert
authors: Leah D
authors: LD
authors: Stuchal
authors: Ellen M
authors: EM
authors: Mihaich
authors: Richard A
authors: RA
authors: Becker
authors: Karin S
authors: KS
authors: Bentley
authors: John M
authors: JM
authors: Brausch
authors: Katie
authors: K
authors: Coady
authors: David R
authors: DR
authors: Geter
authors: Elliot
authors: E
authors: Gordon
authors: Patrick D
authors: PD
authors: Guiney
authors: Frederick
authors: F
authors: Hess
authors: Catherine M
authors: CM
authors: Holmes
authors: Matthew J
authors: MJ
authors: LeBaron
authors: Steve
authors: S
authors: Levine
authors: Sue
authors: S
authors: Marty
authors: Sandeep
authors: S
authors: Mukhi
authors: Barbara H
authors: BH
authors: Neal
authors: Lisa S
authors: LS
authors: Ortego
authors: David A
authors: DA
authors: Saltmiras
authors: Suzanne
authors: S
authors: Snajdr
authors: Jane
authors: J
authors: Staveley
authors: Abraham
authors: A
authors: Tobia
mesh_terms: D000728:Androgens / Q000819:agonists / Q000378:metabolism; D000818:Animals; D052244:Endocrine Disruptors / Q000032:analysis* / Q000633:toxicity*; D023381:Endpoint Determination; D004967:Estrogens / Q000819:agonists / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013256:Steroids / Q000096:biosynthesis; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000728:Androgens; D052244:Endocrine Disruptors; D004967:Estrogens; D013256:Steroids
keywords: Endocrine Disruptor Screening Program; endocrine disrupters; endocrine screening; regulatory toxicology; weight of evidence