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1 Introduction
Pages 11-20

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From page 11...
... The Tox21 program is a collaborative effort among EPA's National Center for Computational Toxicology, the National Toxicology Program, the National Institutes of Health National Center for Advancing Translational Sciences, and the US Food and Drug Administration. The program's work focuses on understanding chemically induced biological effects and developing predictive models of human biological response.
From page 12...
... Some definitions of low dose include language similar to that found in the EPA definition that obliquely defines a point of reference: "doses lower than those typically used in standard testing protocols." Those phrases help define an upper exposure range because the highest dose used in many guideline-driven animal tox 1 Low-dose effects were defined as "biologic changes that occur in the range of human exposures or at doses lower than those typically used in the standard testing paradigm of the US EPA for evaluating reproductive and developmental toxicity" (Melnick et al.
From page 13...
... Ultimately, the committee defined low dose as external or internal exposure that falls within the range estimated to occur in humans. Human exposure estimates may be based on environmental or biomarker measurements and/or computational models; ideally, the estimates account for toxicokinetic processes.
From page 14...
... Disagreements include the degree to which a biological change from normal is adverse; whether some effects are adaptive and have little effect on an organism; defining the degree to which functional capacity is so impaired as to be considered adverse; and uncertainties about the reliability and sensitivity of precursor effects to predict adverse outcomes. NONMONOTONIC DOSE-RESPONSE CURVES A conventional assumption of toxicology is that the dose-response relationship between a chemical and an adverse health effect will have a monotonic shape: that is, the slope of the curve does not change sign.
From page 15...
... From a methodologic standpoint, two sets of guidelines for performing systematic reviews for environmental health assessments were considered by the committee: the Navigation Guide (Woodruff and Sutton 2014) and the National Toxicology Program's Office of Health Assessment and Translation (OHAT)
From page 16...
... ; ideally, the estimates account for toxicoki netic processes. If no human exposure estimates are available, low dose is defined on a case-by-case basis relative to an explicitly specified exposure in a particular context, such as "below the US EPA reference dose (RfD)
From page 17...
... Thus, the committee performed three independent systematic reviews and updated one existing systematic review. The approach used by the committee for its independent reviews was the OHAT method, whereas the authors of the existing review followed the Navigation Guide method.
From page 18...
... Literature Screening DistillerSRd DistillerSR DistillerSR DistillerSR e Data Extraction HAWC HAWC HAWC DRAGONf Risk-of-Bias Evaluation OHATg OHAT OHAT Navigation Guideh Data Analysis and OHAT OHAT OHAT Navigation Guide Evidence Integration Confidence Rating OHAT (based on OHAT (based on OHAT (based on Navigation Guide and Level of Evidence GRADEi)
From page 19...
... 2011. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 (updated March 2011)
From page 20...
... 2001. National Toxicology Program's Report of the Endocrine Disruptors Low Dose Peer Review.


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