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HERO ID
3052883
Reference Type
Journal Article
Title
Dose addition models based on biologically relevant reductions in fetal testosterone accurately predict postnatal reproductive tract alterations by a phthalate mixture in rats
Author(s)
Howdeshell, KL; Rider, CV; Wilson, VS; Furr, JR; Lambright, CR; Gray, LE
Year
2015
Is Peer Reviewed?
Yes
Journal
Toxicological Sciences
ISSN:
1096-6080
EISSN:
1096-0929
Publisher
Oxford University Press
Volume
148
Issue
2
Page Numbers
488-502
Language
English
PMID
26350170
DOI
10.1093/toxsci/kfv196
Web of Science Id
WOS:000367195500013
URL
https://search.proquest.com/docview/1737475190?accountid=171501
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Abstract
Challenges in cumulative risk assessment of anti-androgenic phthalate mixtures include a lack of data on all the individual phthalates and difficulty determining the biological relevance of reduction in fetal testosterone (T) on postnatal development. The objectives of the current study were 2-fold: (1) to test whether a mixture model of dose addition based on the fetal T production data of individual phthalates would predict the effects of a 5 phthalate mixture on androgen-sensitive postnatal male reproductive tract development, and (2) to determine the biological relevance of the reductions in fetal T to induce abnormal postnatal reproductive tract development using data from the mixture study. We administered a dose range of the mixture (60, 40, 20, 10, and 5% of the top dose used in the previous fetal T production study consisting of 300 mg/kg per chemical of benzyl butyl (BBP), di(n)butyl (DBP), diethyl hexyl phthalate (DEHP), di-isobutyl phthalate (DiBP), and 100 mg dipentyl (DPP) phthalate/kg; the individual phthalates were present in equipotent doses based on their ability to reduce fetal T production) via gavage to Sprague Dawley rat dams on GD8-postnatal day 3. We compared observed mixture responses to predictions of dose addition based on the previously published potencies of the individual phthalates to reduce fetal T production relative to a reference chemical and published postnatal data for the reference chemical (called DAref). In addition, we predicted DA (called DAall) and response addition (RA) based on logistic regression analysis of all 5 individual phthalates when complete data were available. DA ref and DA all accurately predicted the observed mixture effect for 11 of 14 endpoints. Furthermore, reproductive tract malformations were seen in 17-100% of F1 males when fetal T production was reduced by about 25-72%, respectively.
Keywords
dose addition; phthalates; postnatal developmental toxicity; male reproductive tract; endocrine disruptors; mixture models
Tags
IRIS
•
BBP (Butyl benzyl phthalate)
Literature Search
Litsearch Jun 2015-Jan 2016
Pubmed
WOS
•
Dibutyl Phthalate (DBP)
Database Searches
LitSearch Jul 2016 - Jan 2017
Prior search overlap
PubMed
WoS
Secondary Literature
Risk assessments
Litsearch June 2015 - Jan 2016
Pubmed
Web of Science
•
Diisobutyl Phthalate (DIBP) Final
Database Searches
December 2015 Update
New for This Search
Pubmed
June 2016 Update
Pubmed
Toxline
Web of Science
January 2017 Update
No Primary Data on Toxic Effects
Mixtures only
•
Phthalates – Targeted Search for Epidemiological Studies
Source – all searches
Pubmed
Excluded
Source - Dec 2016 Update (Private)
Pubmed
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