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DOI10.1093/toxsci/kfv196
Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats
Howdeshell, Kembra L.1; Rider, Cynthia V.1; Wilson, Vickie S.2; Furr, Johnathan R.2; Lambright, Christy R.2; Gray, L. Earl, Jr.2
发表日期2015-12-01
ISSN1096-6080
卷号148期号:2页码:488-502
英文摘要

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 DA(ref)). In addition, we predicted DA (called DA(all)) 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.


英文关键词dose addition;phthalates;postnatal developmental toxicity;male reproductive tract;endocrine disruptors;mixture models
语种英语
WOS记录号WOS:000367195500013
来源期刊TOXICOLOGICAL SCIENCES
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/58743
作者单位1.NIEHS, Div Natl Toxicol Program NTP, Res Triangle Pk, NC 27709 USA;
2.US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Labs, Toxicol Assessment Div TAD,Reprod Toxicol Branch, Res Triangle Pk, NC 27711 USA
推荐引用方式
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Howdeshell, Kembra L.,Rider, Cynthia V.,Wilson, Vickie S.,et al. Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats[J]. 美国环保署,2015,148(2):488-502.
APA Howdeshell, Kembra L.,Rider, Cynthia V.,Wilson, Vickie S.,Furr, Johnathan R.,Lambright, Christy R.,&Gray, L. Earl, Jr..(2015).Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats.TOXICOLOGICAL SCIENCES,148(2),488-502.
MLA Howdeshell, Kembra L.,et al."Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats".TOXICOLOGICAL SCIENCES 148.2(2015):488-502.
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