Introduction to Brominated Flame
RetardantsLinda S. Birnbaum
Director, Experimental Toxicology DivisionNHEERL
Research Triangle Park, NC
Region 2 Science Day/Non-Regulated Pollutants Workshop
NYC – October 25, 2005
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%)
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
Global Market Demand for Major BFRs in 2001
(metric tons) [BSEF]
America Europe Asia RestoW Total
TBBPA 18,000 11,600 89,400 600 119,700
HBCD 2,800 9,500 3,900 500 16,700
DBDE 24,500 7,600 23,000 1,050 56,100
OBDE 1,500 610 1,500 180 3,790
PBDE 7,100 150 150 100 7,500
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
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
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
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
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
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
O
Br Br
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
Sources of Environmental Release
• Polymer Processing• Formulating/applying to textiles• Volatilization and leaching during
use• Particulate losses over
use/disposal Incineration Recycling
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)
Breast Milk vs. Dust(BDE 47+99+100+153+154)
r=0.76 (p=0.006);not confounded by diet; (T.Webster)
0
0.5
1
1.5
2
2.5
2 2.5 3 3.5 4 4.5 5
Log of PBDEs in Dust (ug/g)
Log
of P
BD
Es in
Bre
ast
Milk
(pen
ta c
onge
ners
onl
y)
Daily US Adult PBDE Dietary Intake (A. Schecter)
723
88 101
451
82 77
0
100
200
300
400
500
600
700
800
Meat Fish Dairy
PB
DE
inta
ke p
g/kg
bw
per
day
20-39 Males 20-39 Fem ales
US Human Breast Milk PBDE levels, 2005, N=62.
(A. Schecter)
0
50
100
150
200
250
300
350
400
4501 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70
PB
DE
s ng
/g o
r ppb
, lip
id
Median Levels of PBDE 47, 99, 153 in Human Milk from Different Countries.
25
13
1.4 0.8 1.7 1
4.5 5.13
0.5 0.2 0.2 0.4 0.06
10.1
2.1 1.3 0.3 0.5 0.5 0.3
17
0.2 0.09
0
5
10
15
20
25
30
USA EWG 2003 (n = 20)
USA, TX,2004 (n = 59)
Canada2002 (n = 92)
Canada1992 (n = 72)
Germany2000
(n = 7)
Sw eden2000 (n = 40)
Finland1994-98
(n = 11)
Hanoi,V ietnam2004 (n = 2)
PBD
E le
vels
(ng/
g. p
pb. l
ipid
)BDE 47 BDE 99 BDE 153
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?
(Petreas et al., 2002)
ΣPBDE in Humans, Seals and Fish from the SF Bay Area
0
500
1000
1500
2000
2500
3000
Humans Fish Seals
ng/g
lipi
d
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
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
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)
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
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
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)
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
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
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
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
Cumulative Urinary Excretion:Effect of Dose
0 1 2 3 4 5 60
10
20
30
40
50
60
0.1 mg/kg1.0 mg/kg10 mg/kg100 mg/kg
Day
% B
DE 4
7 Do
se in
Urin
e
Percent BDE 47 Remaining inBody Over Time
0.0 2.5 5.0 7.5 10.0 12.50
25
50
75
100
AdultPup
*
**
* ^
Day
% D
ose
Rem
aini
ng
24 hr Urine Concentrations
22 29 40 700
1000
200022294070
**
^
Day
ng/g
Comparative Urinary Excretion of PBDEs
Cumulative Excretion via Urine
0 1 2 3 4 5 60
10
20
30
40
50BDE 47BDE 99BDE 100BDE 153
16%
40%
6%2%
Day
% D
ose
PBDE Brain Concentrations
47 99 100 1530
25
50
75
100
125
a
a
b
cb
cc
dd
d
ng/g
(wet
wei
ght)
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?
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
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
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?
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
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!
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