Endocrine effects of tetrabromobisphenol-A (TBBPA) in Wistar rats as tested in a one-generation reproduction study and a subacute toxicity study.
Endocrine effects of the brominated flame retardant tetrabromobisphenol-A (TBBPA) were studied in a one-generation reproduction assay in Wistar rats via repeated dietary exposure, applying eight dose groups at 0-3-10-30-100-300-1,000-3,000 mg/kg body weight/day (mkd). This design enables dose-response analysis and calculation of benchmark doses (BMDL). This reproduction study was preceded by a 28-day repeat dose subacute toxicity study, at 0-30-100-300 mkd. Major effects in the reproduction study included decreased circulating thyroxine (T4) with BMDLs of 31 (m) and 16 (f) mkd, and increased weight of testis and male pituitary (BMDLs of 0.5 and 0.6 mkd). The hypothyroxinemia correlated to a cluster of developmental parameters including delayed sexual development in females, decreased pup mortality, and effects on brainstem auditory evoked potentials [Lilienthal, H., Verwer, C.M., Van der Ven, L.T.M., Piersma, A.H., Vos, J.G., 2008. Neurobehavioral effects of tetrabromobisphenol A (TBBPA) in rats after pre- and postnatal exposure. Toxicology]. A second cluster of parameters in F1 animals was correlated to increased testis weight, and included female gonad weight, endometrium height, CYP19/aromatase activity in the ovary, and plasma testosterone levels in males. These two correlation clusters suggest a dual action of TBBPA. The only effects in the subacute study were decreased circulating T4 and increased T3 levels in males (BMDLs 48 and 124mkd), and non-significant trends for these parameters in females, suggesting that the other effects in the reproduction study were induced during development. Combined with data of human exposure to environmental TBBPA, the margin of exposure for highly exposed populations can be calculated at 2.6, and current use of TBBPA may therefore be a matter of concern for human health.
Van der Ven
Leo T M
LT
Laboratory for Health Protection Research, National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. L.van.der.ven@rivm.nl
Van de Kuil
Ton
T
Verhoef
Aart
A
Verwer
Cynthia M
CM
Lilienthal
Hellmuth
H
Leonards
Pim E G
PE
Schauer
Ute M D
UM
Cantón
Rocío F
RF
Litens
Sabina
S
De Jong
Frank H
FH
Visser
Theo J
TJ
Dekant
Wolfgang
W
Stern
Natalia
N
Håkansson
Helen
H
Slob
Wout
W
Van den Berg
Martin
M
Vos
Josephus G
JG
Piersma
Aldert H
AH
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011075:Polybrominated Biphenyls / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects*; D013963:Thyroid Hormones / Q000097:blood; D014018:Tissue Distribution; D018675:Toxicity Tests / Q000379:methods
D052244:Endocrine Disruptors; D011075:Polybrominated Biphenyls; D013963:Thyroid Hormones; C020806:tetrabromobisphenol A