A 28-day oral dose toxicity study enhanced to detect endocrine effects of a purified technical pentabromodiphenyl ether (pentaBDE) mixture in Wistar rats.
A 28-day subacute oral toxicity study was performed in Wistar rats with a purified preparation of the commercial pentabromodiphenyl ether (pentaBDE), DE-71. The applied OECD407 protocol was enhanced for endocrine and immune parameters, and to enable benchmark dose analysis. A vehicle control group and 7 dose groups were included, which received 0.27, 0.82, 2.47, 7.4, 22.2, 66.7 or 200 mg pentaBDE/kg bw/d (mkd). The liver appeared to be a key target organ, showing a marked increase of weight and centrilobular hepatocellular hypertrophy, probably due to the observed induction of P450 enzymes, notably CYP1A and CYP2B. A marked decrease of circulating total thyroxine (TT4) and an increase of plasma cholesterol were probably secondary to the liver effects. Furthermore, dose-dependently decreased weight of epididymis, seminal vesicles, and prostate, as well as sperm head deformities in males, and induction of CYP17 activity in adrenals in females were observed, all possibly related to anti-androgenic activity. Finally, we observed a substantial increase of large unstained cells in the blood and a decrease of apolar retinoids in the liver. All these effects had benchmark doses at the lower confidence bound (BMDL) in the low- or mid-dose range, but particular sensitive, potentially adverse effects were TT4 decrease (BMDLs 1.1 in males and 1.8 mkd in females), and decrease of hepatic apolar retinoids (BMDLs 0.5 mkd in males and 2.3 mkd in females). These results contribute to refinement of the hazard identification of pentaBDE and improved risk assessment of human exposure to this industrial chemical and environmental pollutant.
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. Leo.van.der.ven@rivm.nl
van de Kuil
Ton
T
Verhoef
Aart
A
Leonards
Pim E G
PE
Slob
Wout
W
Cantón
Rocío F
RF
Germer
Silke
S
Hamers
Timo
T
Visser
Theo J
TJ
Litens
Sabina
S
Håkansson
Helen
H
Fery
Yvonne
Y
Schrenk
Dieter
D
van den Berg
Martin
M
Piersma
Aldert H
AH
Vos
Josephus G
JG
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D005411:Flame Retardants / Q000493:pharmacokinetics / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010647:Phenyl Ethers / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D011075:Polybrominated Biphenyls / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013094:Spermatozoa / Q000187:drug effects / Q000473:pathology; D013963:Thyroid Hormones / Q000097:blood; D036401:Toxicity Tests, Chronic / Q000379:methods
D052244:Endocrine Disruptors; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D010647:Phenyl Ethers; D011075:Polybrominated Biphenyls; D013963:Thyroid Hormones; C086401:pentabromodiphenyl ether