Exposure to tetrabromobisphenol A (TBBPA) in Wistar rats: neurobehavioral effects in offspring from a one-generation reproduction study.
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 3000mg/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 0.5kHz were in the range of 35-70mg/kg body weight with lower bounds (BMDL) of approximately 8mg/kg in males and females. The BMDL values for elevation of hearing thresholds in females were in the range of 1-40mg/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.
Lilienthal
Hellmuth
H
Research Institute of Occupational Medicine, Ruhr University of Bochum, Buerkle de la Camp-Platz 1, 44789 Bochum, Germany. lilien@bgfa.rub.de
Verwer
Cynthia M
CM
van der Ven
Leo T M
LT
Piersma
Aldert H
AH
Vos
Josephus G
JG
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019985:Benchmarking / Q000379:methods; D001835:Body Weight / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects*; D003214:Conditioning, Classical / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D005260:Female; D005411:Flame Retardants / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D018812:Paternal Exposure / Q000009:adverse effects*; D011075:Polybrominated Biphenyls / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
D005411:Flame Retardants; D011075:Polybrominated Biphenyls; C020806:tetrabromobisphenol A