Available online at www.sciencedirect.com Toxicology 246 (2008) 45–54 Exposure to tetrabromobisphenol A (TBBPA) in Wistar rats: Neurobehavioral effects in offspring from a one-generation reproduction study Hellmuth Lilienthal a,∗ , Cynthia M. Verwer b , Leo T.M. van der Ven c , Aldert H. Piersma c , Josephus G. Vos c,1 a Neurotoxicology Group, BGFA-Research Institute of Occupational Medicine, Ruhr University of Bochum, Buerkle de la Camp-Platz 1, 44789 Bochum, Germany b Department of Animals, Science and Society, School of Veterinary Medicine, Utrecht University, P.O. Box 80.166, 3508 TD Utrecht, The Netherlands c Laboratory for Health Protection Research, National Institute for Public Health and Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands Received 4 October 2007; received in revised form 9 January 2008; accepted 10 January 2008 Available online 19 January 2008 Abstract Within the framework of an EU project on risk assessment of brominated flame retardants, TBBPA was studied for neurobehavioral effects in rats. To permit benchmark dose analysis, eight dose levels were chosen ranging from 0 to 3000 mg/kg body weight. Exposure of parental rats started 10 and 2 weeks before mating in males and females, respectively, and was continued throughout mating, gestation and lactation. After weaning, exposure was continued in the offspring throughout life. Previous studies had indicated TBBPA-induced effects on thyroid hormones. Because of the known implication of thyroid hormones in neurodevelopment, the present experiments tested if TBBPA exposure affects thyroid-dependent neurobehavioral functions in offspring, such as auditory responses and conditioned fear. Sweet preference was included because of sex-specific effects in littermates. No statistically significant effects were found on context or cue conditioned fear or sweet preference. Auditory responses were examined with brainstem auditory evoked potentials (BAEPs) at approximately 50–110 days of age. BAEP thresholds and wave IV latency were increased in exposed female rats in the low frequency range. In male rats, thresholds were unaffected, but absolute latency of wave IV and interpeak latencies II–IV showed exposure-related increases at low frequencies. The outcome pattern suggests a predominant cochlear effect of TBBPA in females while in males neural effects are more apparent. According to benchmark analysis, the critical effect doses (CED) for prolongations of wave IV latency at 0.5 kHz were in the range of 35–70 mg/kg body weight with lower bounds (BMDL) of approximately 8 mg/kg in males and females. The BMDL values for elevation of hearing thresholds in females were in the range of 1–40 mg/kg body weight, depending on frequency. The benchmark doses for effects on the BAEP were similar to values for decreases in circulating thyroid hormones. The comparison of the exposure level at which the most sensitive effect was found with current human exposure levels yielded a margin of exposure of about 5, according to a recent risk assessment. Further investigations are needed to examine exposure pathways, fate in the body and effects of TBBPA. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Tetrabromobisphenol A; Brominated flame retardants; Brainstem auditory evoked potentials; Behavior; Benchmark analysis; Rats 1. Introduction Tetrabromobisphenol A (TBBPA) is the most widely used brominated flame retardant (BFR) with an annual demand of about 130,000 metric tonnes in 2002 of which approximately ∗ Corresponding author. Tel.: +49 234 361 7978; fax: +49 234 302 4505. E-mail addresses: lilien@bgfa.rub.de (H. Lilienthal), cynthia.verwer@rivm.nl (C.M. Verwer), L.van.der.ven@rivm.nl (L.T.M. van der Ven), a.h.piersma@rivm.nl (A.H. Piersma). 1 Joseph Vos is deceased. 85% are used in East Asia (BSEF, 2004). TBBPA-containing materials are used in the manufacturing of office and home elec- tronic equipment, such as computer boards, printers, copiers, mobile phones, televisions, and washing machines. Covalent binding to plastic polymers is found in the majority of all appli- cations, however, additive use accounts for approximately 10%. TBBPA has been detected in sewage sludge, aquatic animals (Morris et al., 2004), and human serum samples (Thomsen et al., 2002). Investigation of concentrations in serum taken from hos- pital patients in Norway revealed slight increases from 1985 to 1999 with the highest values (average 0.71 ng/g lipids) detected 0300-483X/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.tox.2008.01.007