You are here:
Dose addition models based on biologically-relevant reductions in fetal testosterone accurately predict postnatal reproductive tract alterations by a phthalate mixture in rats
Citation:
Howdeshell, K., C. Rider, V. Wilson, J. Furr, C. Lambright, AND E. Gray. 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. Society of Toxicology, RESTON, VA, 148(2):488-502, (2015).
Impact/Purpose:
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 mixture models of dose addition ((DA; requiring individual chemical data) or relative potency factor (RPF; a type of DA based on relative potency of the individual phthalates to reduce fetal T and a reference phthalate)) would predict the effects of a 5 phthalate mixture on fetal testicular gene expression (Insl3, Cyp11a and Star) and 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. These results provide a an example of how key events in an AOP can be used for quantitative risk assessment.
Description:
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 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 GD8-18 (fetal gene expression study) or GD8-postnatal day 3. We compared observed mixture responses to predictions of dose addition based on previsouly published potencies of individual phthalates to reduce fetal T production relative to 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 logistical regression analysis of all 5 indivisual 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.
