In utero exposure to an AR antagonist plus an inhibitor of fetal testosterone synthesis induces cumulative effects on F1 male rats.
Risk assessments are typically conducted on a chemical-by-chemical basis; however, many regulatory bodies are developing frameworks for assessing the cumulative risk of chemical mixtures of chemicals. The current investigation examined how chemicals that disrupt rat sex differentiation via two diverse mechanisms disrupt F1 male rat reproductive development, when administered together orally on days 14-18 of gestation. Experiment 1 used a mixture of 50 mg/kg-d procymidone and 500 mg/kg-d dibutyl phthalate (DBP), whereas experiment 2 used 150 mg/kg-d procymidone and 1125 mg/kg-d DBP (top dose), or 0, 4.17, 8.33, 16.7, 33.3, 50, 66.7, and 83.3% of the top dose. When we compared the dose and response addition predictions to the observed effects we found that dose addition models were more accurate than response addition models, indicating that compounds that act by different mechanisms of toxicity produce cumulative dose-additive effects.
Hotchkiss
A K
AK
Reproductive Toxicology Branch, TAD, NHEERL, ORD, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Rider
C V
CV
Furr
J
J
Howdeshell
K L
KL
Blystone
C R
CR
Wilson
V S
VS
Gray
L E
LE
D000284:Administration, Oral; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001643:Bridged Bicyclo Compounds / Q000633:toxicity; D003993:Dibutyl Phthalate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005659:Fungicides, Industrial / Q000633:toxicity; D005837:Genitalia, Male / Q000187:drug effects / Q000473:pathology; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D009929:Organ Size / Q000187:drug effects; D010968:Plasticizers / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment; D012733:Sex Differentiation / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism
D000726:Androgen Antagonists; D001643:Bridged Bicyclo Compounds; D005659:Fungicides, Industrial; D010968:Plasticizers; D011944:Receptors, Androgen; D003993:Dibutyl Phthalate; C035988:procymidone