TBBPA. 31 August 2014 Green Science Policy Madrid, Spain. National Institutes of Health U.S. Department of Health and Human Services

Transcription

1 TBBPA Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S. Director, National Institute of Environmental Health Sciences and National Toxicology Program Principle Investigator, National Cancer Institute 31 August 2014 Green Science Policy Madrid, Spain

2 Tetrabromobisphenol A (TBBPA) Global Volume and Use: Highest volume brominated flame retardant ~230,000 metric tons/year Electronics and circuit boards Environment: Considered persistent Air, dust, sludge Human Exposure: Detected in nearly half of human breast milk samples and one third of maternal cord blood samples Carignan CC et al., 2012; Cariou R et al. 2008

3 TBBPA Disposition & Toxicokinetics using WH Rats TBBPA disposition & TK using female rats that developed uterine tumors: After oral administration, absorption is rapid, bioavailability is low (F<5%) Elimination (via fecal route) is extensive by 48 h (delayed at highest dose) 100 TBBPA in plasma (250 mg/kg PO) 120 Dose recovery after TBBPA gavage [TBBPA] (nmol/ml) TBBPA_PO_17 TBBPA_PO_18 TBBPA_PO_19 1 compartment regression Non-compartmental regression Dose recovered (%) mg/kg, 72h (N=4) 250 mg/kg, 72 h (N=3) 1,000 mg/kg, 72 h (N=4) Time (min) Time (h) Knudsen et al., 2014

4 TBBPA: Adverse Health Effects Toxicity: Immunotoxic: Inhibits T cell activation Hepatotoxic: destroys mitochondria, causes membrane dysfunction in hepatocytes Neurotoxic: oxidative stress, inhibits dopamine uptake, generates free radicals, increases calcium Endocrine Disruption: May inhibit estrogen metabolism via SULT1E1 Disrupt androgen signaling to increases testis and pituitary weight Thyroid: receptor agonist/antagonist AhR receptor: weak ligand TBBPA 17β-estradiol (E2) TBBPA Enzymatic Interference Gosavi et al., 2013

5 TBBPA altered gene expression in liver & uterus after 5 doses Expression of Ugt1a1 and Sult2a1 were affected by TBBPA treatment in this study. Competition for conjugating enzymes could result in increased estrogen in tissues. The binding affinities for TBBPA and estradiol to SULT are similar (Gosavi et al., 2013). TBBPA treatment affected expression of Cyp17a1, Cyp1b1, Cyp2b1, and Cyp2b2 in rats. CYP17 and CYP1B are involved in estrogen formation (Roelofs et al., 2013). CYP2B1/2 is induced in rat hepatocytes following tamoxifen exposure (Nuwaysir et al., 1995). Tamoxifen treatment poses risk of uterine cancer in some humans (Ferguson et al., 2004). TBBPA treatment affected expression of Hsd17b2 and Hsd17b4 in rats. Changes in 17β hydroxysteroid dehydrogenase concentrations may lead to increased estradiol (Ito et al., 2006). Comt was down-regulated in liver of TBBPA-treated rats. The transferase inactivates DNA-damaging estrogen catechols (Dawling et al., 2001). The expression of Igf1 was up-regulated in the uterus of TBBPA-treated rats. Activation of the protein may mediate mitotic effects of estradiol (Klotz et al., 2000).

6 TBBPA: Summary of 14-day study results rat & mice No treatment-related mortality, clinical signs, or body weight effect (± 10% of controls) in rats or mice No treatment-related lesions except for minimal kidney cytoplasmic vacuolization in male mice at 500 &1000 mg/kg No treatment-related SMVCE findings Increased liver weights (9-14%) in 500 and 1000 mg/kg rats Increased liver weights (11-13%) in 500 and 1000 mg/kg male mice and 1000 mg/kg female mice Consistent, progressive, dose-related decrease in T4 (rats) increased T4 at 4, 23, 93 days at 93 days ê T4 17%-50% at 100, 500, & 1000 mg/kg No change in TSH or T3

7 National Toxicology Program TBBPA 2-year Study NTP has completed a 2-year bioassay in both rats and mice TBBPA Technical Pathology Tables Uterine tumors and pre-neoplastic uterine lesions in female (WH) rats Liver tumors and neoplastic lesions were found in male and female mice Toxicity-reduced survival in mice that received the highest dose NTP draft technical report has been peer reviewed and is being finalized

8 TBBPA female rat Uterine lesions Original transverse & residual longitudinal review Dose (mg/kg) Endometrium, hyperplasia, atypical 2 13** 11** 13** Uterus - Adenoma Uterus Adenocarcinoma 4** 10 15** 16** Uterus - MMMT Uterus - Adenoma, adenocarcinoma, adenocarcinoma, or MMMT N= 50 **p 0.01 MMMT Malignant mixed Müllerian tumor 6** 11 16** 19**

9 Uterus in control vs. TBBPA treated female rats Normal uterus in vehicle control. Note normal simple tubular endometrial glands (arrows) Uterine adenocarcinoma in 250 mg/ kg rat; cords lined with pleomorphic neoplastic cells. Cells are cuboidal to columnar; multiple nucleoli *No other long-term bioassay has been done in either mice or rats

10 Effects of TBBPA in female rats Female Wistar Han rats received 5 days of 250 mg/kg by gavage Serum T4 was decreased and genes associated with thyroid homeostasis, cell cycle regulation and estrogen metabolism in liver and/or uterus were affected Results indicate TBBPA is an endocrine disruptor with potential to elevate estrogen levels at site of action in TBBPA-treated rats Tox 21: Potent PPARγ antagonist

11 Thank you! NIEHS Strategic Plan Website