Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats.
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.
*Division of the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), PO Box 12233, Research Triangle Park (RTP), North Carolina 27709 and howdeshellkl@niehs.nih.gov.
Kembra L
KL
Howdeshell
*Division of the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), PO Box 12233, Research Triangle Park (RTP), North Carolina 27709 and.
Cynthia V
CV
Rider
Reproductive Toxicology Branch, Toxicology Assessment Division (TAD), National Health and Environmental Effects Research Laboratories, Office of Research and Development, US Environmental Protection Agency (US EPA), RTP, North Carolina 27711.
Vickie S
VS
Wilson
Reproductive Toxicology Branch, Toxicology Assessment Division (TAD), National Health and Environmental Effects Research Laboratories, Office of Research and Development, US Environmental Protection Agency (US EPA), RTP, North Carolina 27711.
Johnathan R
JR
Furr
Reproductive Toxicology Branch, Toxicology Assessment Division (TAD), National Health and Environmental Effects Research Laboratories, Office of Research and Development, US Environmental Protection Agency (US EPA), RTP, North Carolina 27711.
Christy R
CR
Lambright
Reproductive Toxicology Branch, Toxicology Assessment Division (TAD), National Health and Environmental Effects Research Laboratories, Office of Research and Development, US Environmental Protection Agency (US EPA), RTP, North Carolina 27711.
L Earl
LE
Gray
D000367:Age Factors; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D005837:Genitalia, Male / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D005865:Gestational Age; D016015:Logistic Models; D008297:Male; D008954:Models, Biological; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D018570:Risk Assessment; D013739:Testosterone / Q000378:metabolism*; D018675:Toxicity Tests / Q000379:methods*
D000726:Androgen Antagonists; D052244:Endocrine Disruptors; D010795:Phthalic Acids; D013739:Testosterone
dose addition; endocrine disruptors; male reproductive tract; mixture models; phthalates; postnatal developmental toxicity