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!