Introduction to Brominated Flame Retardants

1. Introduction to Brominated Flame Retardants Linda S. Birnbaum Director, Experimental Toxicology Division NHEERL Research Triangle Park, NC Region 2 Science Day/Non-Regulated Pollutants Workshop NYC – October 25, 2005

2. Flame Retardants • Fires kill >3000, injure >20,000, and cause damages exceeding $11 billion annually in US alone • >175 different types of FRs • Halogenated (~46%) • Phosphorus-containing (24%) • Melamines (4%) • Inorganics (27%)

3. Brominated Flame Retardants • BFRs are the largest market group due to low cost and high efficiency • BFRs account for 38% global demand for bromine • >75 BFRs recognized commercially • Br-BPs, BDEs, CDs, phenols, phthalates,++ • Global, transboundary problem • Persistence • Potential for bioaccumulation • Limited Data Base

4. Global Market Demand for Major BFRs in 2001 (metric tons) [BSEF]

5. TBBPA(Tetrabromobisphenol A) • Reactive & additive • Primary use - Electronics • Acute tox data – oral LD50: 5-10 g/kg • Low chronic toxicity • Not teratogenic or mutagenic • Limited data in biota • Dimethyl-TBBPA • Metabolite eliminated in bile • Little retained in tissues

6. Health Effects of TBBPA • Immunotoxic • Inhibits T cell activation : blocks CD25 (<3µM) • Hepatotoxic • Toxic to primary hepatocytes: destroys mitochondria; membrane dysfunction (inhibits CYP2C9) • Neurotoxic • Inhibits dopamine uptake • Generates free radicals

7. Health Effects of TBBPA (cont.)Endocrine Disruption • AhR Effects • Not relevant for commercial product (Contaminants? Combustion products?) • Thyroid • TBBPA>T4 in relation to binding to transthyretin • Blocks T3 binding to TR • Perturbations observed in vivo • Estrogenic • Inhibits sulfotransferase (decreases estrogen clearance) • Mostly in vitro data

8. Hexabromocylododecane(HBCD) • Additive • Used in Electronics; Textile Backings • Ecotox – • Algae, daphnia, NOEC = 3 ug/L • Fish, LC 50>water solubility; PNEC=.03ug/L • General Toxicity • High absorption; mild irritant and skin sensitizer; liver effects after repeated exposures (rat LOAEL ~13 mg/kg/day) • Need more info: repeated dose studies, repro tox

9. HBCD (cont.) • Neurotoxicity • Developmental neurotoxicant • Blocks dopamine uptake • Concern for occupational settings • Found in human breast milk • Persistent, bioaccumulative, toxic, long range transport • Isomeric composition in environmental samples differs from commercial mixture

10. Polybrominated Diphenyl Ethers (PBDEs) • Major Additive BFRs(~67 metric tons/yr) • DBDE – largest volume (75% in EU) • 97% DBDE; 3% NBDE • Polymers, electronic equipment, textile backing • OBDE • 6%HxBDE; 42%HpBDE;36% OBDE; 13%NBDE;2%DBDE–multiple congeners • unclear if any PeBDE) • Polymers, esp. office equipment • PeBDE • Flexible polyurethane foam (up to 30%) • Cushions; mattresses; carpet padding • Mainly PeBDE+TeBDE, some HxBDE Br Br

11. Properties • Solids with low solubility (< 1ug/kg), high log Kow (>5) • Lower congeners - more bioaccumulative, persistent • Strong adsorption to soil/sediment/sludge • No significant biodegradation in air/water • Bioaccumulation - BCF > 5000 • Long-range transport - Evidence of remote contamination (e.g., Arctic) • Persistence- t 1/2 Atmospheric >2 days;Water >2 mos; Soil, sediment >6 mos

12. Sources of Environmental Release • Polymer Processing • Formulating/applying to textiles • Volatilization and leaching during use • Particulate losses over use/disposal • Incineration • Recycling

13. Pathways of Exposure? • Indoor air >> outdoor air • May account for ~4%, on average, of daily intake by inhalation (could be much higher for some) • BDE209 as well as 47, 99, 100, 153, 154 • House dust • Recent studies in Cape Cod, Northwest, Texas, Europe • Wide range • Recent study: N = 10. Range: 705-69,000 ppb; Mean: 12,100 ppb; Median: 2,500 ppb • Levels in US, UK>>Europe, Japan • Patterns resemble commercial products (Penta, Deca)

14. Breast Milk vs. Dust (BDE 47+99+100+153+154) r=0.76 (p=0.006);not confounded by diet; (T.Webster)

15. Daily US Adult PBDE Dietary Intake (A. Schecter)

16. US Human Breast Milk PBDE levels, 2005, N=62.(A. Schecter)

17. Median Levels of PBDE 47, 99, 153 in Human Milk from Different Countries.

18. PBDEs in Human Samples • Pattern of congeners is different from commercial mixtures (and food) • 47>99 (others: 100,153,183, 209,…) • In some people (and biota) • 153>47 • Large inter-individual differences • People as high as ∑PBDEs ~10 ppm lipid!!!! • Increasing time trends – levels doubling every 2-5 years • PBDEs and PCBs levels are not correlated • different sources and/or time sequence • North American levels ~ 10X Europe/Japan • WHY?

19. (Petreas et al., 2002)

20. Ecotoxicity • PeBDE>>OBDE>DBDE • PeBDE - Highly toxic to invertebrates • Larval development, LOECs in low μg/l range • DE71 – developmentally toxic to fish (1ng/l) • Tail asymmetry; delayed hatching; behavioral changes; learning deficits • ∑PBDEs associated with die-off of Baltic porpoise • Lymphoid depletion • BDE99 - depletion of Vitamin E in duck eggs • BDE 47, 99, 100 - decreases in T4/retinoids, increases in oxidative stress in Kestrals

21. Ecotoxicity (cont.) • DBDE/OBDE • May be low risk to surface water organism and top predators • Concern for waste water, sediment, and soil organisms • Concerns for lower brominated congeners in OBDE, potential for debromination, and generation of PBDDs/PBDFs

22. Mammalian Toxicity in Adult Rodents • Hepatotoxic • Enzyme induction • UDP-glucuronyl transferase • Weak inducer • Cytochrome P450 • Induction of CYP2B,3A • Purified BDEs are NOT CYP1A inducers • DBDE – hepatocarcinogen (high dose)

23. Endocrine Disrupting Effects • AhR Effects • Contamination of commercial PBDEs • Combustion can produce PBDDs/PBDFs • Thyroid Homeostasis • Decrease in T4 • OH-PBDE metabolites bind to transthyretin in vitro • Parent PBDEs - Effects on T4 seen in vivo • Induction of UDP-glucuronyl transferase • Not a low dose effect

24. Endocrine Disrupting Effects (cont.) • Progestins • In vitro – Anti-progesterone • Estrogens • In vivo • BDE99 – decreased E2 • In vitro • OH-PBDEs may be anti-estrogenic • Sulfotransferase inhibition could be estrogenic

25. Endocrine Disrupting Effects (cont.) • Androgens • In vivo • DE71 – decreased weight of seminal vesicles and ventral prostate, decreased LH • BDE99 – decreased Testosterone • In vitro • DE71, BDE100, BDE47 – antiandrogenic (non-competitive inhibition)

26. Developmental Reproductive Effects • DE71– pubertal exposures • Delay in puberty • Effects on male organs • Anti-androgenic in vitro – esp BDEs100, 47 • BDE-99/47– in utero exposures • Delay in puberty • Ovarian toxicity • Male organ effects and decreased sperm

27. Developmental Neurotoxicity • DE-71 – Rats • Deficits in sensory and cognitive function • Altered sex-dependent behaviors • Effects on thyroid, cholinergic, and dopaminergic systems • BDE-99 (47,153,206,208,209) - Mice and rats • Infantile exposure (“Rapid Brain Growth”) - Permanent effects on learning • Perinatal exposure – Delay in sensory-motor development • BDE-99+PCB-52 – Mice • Effects may be more than additive

28. Developmental Neurotoxicity of PBDEs • Mechanisms? • Depression in serum T4 • Anti-cholinergic • Anti-dopamingergic • PBDEs alter cell signaling in vitro • DE71, BDEs 47, 99, 153 • Altered PKC and calcium homeostasis (associated with learning and memory) • Alter phorbol ester binding

29. BDE 47 Toxicokinetics? • BDE47 - Major PBDE in most people and wildlife • Well Absorbed (Oral~Inhalation>Dermal) • Distribution dictated by lipophilicity-Fat • Limited Metabolism -Hydroxylation, Debromination • Excretion – mice and rats differ • Long Half-life-Potential for Bioaccumulation

33. Comparative Urinary Excretion of PBDEs

35. PK of BDE 47,99, 100, and 153 • Well absorbed • Higher urinary elimination in mice than rats • Urine elimination decreases as #Bromine atoms increase • BDE99 is most metabolized • What does this all mean for people?

36. New Information on Deca • Deca is major PBDE in outdoor air (Butt et al., 2004) • Deca can break down in the environment • Photolytic Debromination (Soderstrom et al, 2003) • Matrices affect time course but not outcome • BDE 154 and 183 found in all matrices; BE47 only in silica gel • Deca can break down in fish • Detection of BDE-181 and 190 in carp (congeners not in commercial products) (Rice et al, 2002) • 7 penta to octa metabolites found (Stapleton et al, 2003) • Deca can be absorbed (>10%) and break down in rodents • Debrominated, Hydroxylated, Methoxylated • Reactive Intermediates - Covalent binding • Deca MAY BE developmentally neurotoxic

38. DBDE in Human Samples • Rarely Measured – but its there! • Serum • Levels as high as 200ppb lipid in occupational exposed workers • Breast Milk • Mean~0.9 ppb lipid • Analytical Issues • High background levels in dust lead to laboratory contamination

39. Potential Health Risk of PBDEs • Top 5% of current human exposure in US - >400 ng/g lipid • If humans are 25% lipid, then their “dose” is ~0.1 mg/kg body weight • Significant dose causing DNT • Mice < 0.8 mg BDE99/kg • Rats <0.7 mg BDE47/kg • Preliminary Developmental Repro ~.06mg/kg • Rodent body burdens associated with DNT are only ~10X higher that total PBDE body burdens in people in North America • Margin of exposure for PBDEs appears low • Additional concern: are PBDEs interacting with other PBTs?

40. Conclusions • Growing international concern • P, B, and T • Presence in biota • Presence in human tissues • North American levels much higher than Europe or Japan • Relative Biotic levels are very different from commercial mixtures • Increasing potential for health effects

41. With Special Thanks • NHEERL • Daniele Staskal, Janet Diliberto, Mike Devito, Vicki Richardson, Kevin Crofton, Tammy Stoker, Prasada Kodavanti • EPA HQ • Dan Axelrad, Tala Henry, Hend Galal-Gorchev • NIEHS • Tom Burka, Mike Sanders, Ed Lebetkin, John Prichard • USDA • Heldur Hakk, Janice Huwe • UT • Arnie Schecter • BU • Tom Webster • Cal EPA • Tom McDonald • Duke • Heather Stapleton And all of my colleagues worldwide!