# Presentation: 120332

## BFRs:  Toxicology and Risk

- Linda S. Birnbaum
- Director, Experimental Toxicology Division
- NHEERL
- US EPA

## Why BFRs?

- Flame retardants save lives
- >75 different BFRs
- 40% of total Br usage
- Worldwide demand ~200,000 metric tons/year
- ~1/2 in US

- Global, transboundary problem
- Persistence
- Potential for bioaccumlation
- Limited Data Base

## Major classes of Concern

- Br-Bisphenols (esp. TBBPA)
- Detected in air, sediment, sludge, biota
- Relatively short half-life, estrogenic, anti-thyroid
- Br-Diphenyl Ethers (e.g., PBDE, OBDE, DBDE)
- Long range transport, PBT
- Anti-thyroid, liver toxicant, developmental neurotoxicant
- Br-Cyclododecanes (e.g., HBCD)
- Long range transport, PBT
- Anti-thyroid, developmentally neurotoxic

## Tetrabromobisphenol A(TBBPA)

## TBBPA(Tetrabromobisphenol A)

- 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 (inhbits CYP2C9)
- Neurotoxic
- Inhibits dopamine uptake
- Generates free radicals

## Health Effects of TBBPA (con)Endocrine Disruption

- AhR Effects
- Not relevant for commercial product (contaminants?)
- Thyroid
- TBBPA>T4 in relation to binding to transthyretin
- Blocks T3 binding to TR
- Perturbations observd *in vivo*
- Estrogenic
- Inhibits sulfotransferase (decreases estrogen clearance)
- Mostly *in vitro* data

## Agency Interest

- Regulated under TSCA – OPPT
- PBDEs under VCCEP
- Concern for Air (LRTRP), Clean water (sediment), Waste (sludge)
- Major Regional Issues
- Region 9 Workshop; Region 5 Grants; GLNPO
- Cross-Agency Workgroup
- Agency “What We Know” Statement

## Hexabromocylododecane(HBCD)

## HBCD(Hexabromocyclododecane)

- 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 (LOEL (rats) ~13 mg/kg/day)
- Need more info: repeated dose studies, repro tox

## HBCD (con)

- Neurotoxicity
- Developmental neurotoxicant
- Blocks dopamine uptake
- Concern for Occupational Settings
- Found in Human Breast Milk
- Persistent, bioaccumulative, toxic, long range transport

## Polybrominated Diphenyl Ethers (PBDEs)

- <date/time>

- Br

- Br

## Composition of Commercial PBDE Mixtures

- DBDE – 97% DBDE; 3% NBDE
- OBDE - 6%HxBDE; 42%HpBDE; 36% 	OBDE; 13%NBDE; 2%DBDE – 	multiple congeners (unclear if any 	PeBDE)
- PeBDE -Mainly PeBDE+TeBDE, some 	HxBDE

## PBDEs (con)Ecotoxicity

- PeBDE>>OBDE>DBDE
- Highly toxic to invertebrates (Larval development, LOECs in low μg/l range)
- 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 of PBDEsin Adult Rodents

- Hepatotoxic
- Enzyme Induction
- UDP-glucuronyl transferase
- Cyotochrome P450
- DBDE – hepatocarcinogen (high dose)

## New Information on Deca

- Deca *CAN* be Absorbed!
- >10% in appropo vehicle
- Deca *CAN* be Metabolized!
- Reactive intermediates; debromination
- Deca *CAN* be found in People!
- Milk and blood
- Deca *MAY* be Developmentally Neurotoxic?
- Similar to BDE-47,99,and 153
- Deca “*may*” be breaking down in fish
- Detection of BDE-181 and 190 in carp (Rice et al, 2002)

## New Information On Penta(SOT, 2003 and Dioxin2003)

- Endocrine
- Reproductive
- Developmental Neurotoxicity

## Endocrine Disrupting Effects

- AhR Effects
- Relevance for commercial BFRs?
- combustion can produce PBDDs/PBDFs
- Thyroid Homeostasis
- OH-PBDE metabolites bind to transthyretin
- Parent PBDEs - Effects on T4 seen *in vivo *
* *induction of UDP-glucuronyl transferase
- Rats and mice; body burdens as low as 0.8 mg/kg
- Estrogen Homeostasis (mostly* in vitro*)
- OH-PBDEs may be anti-estrogenic
- Sulfotransferase inhibition  could be estrogenic

## Developmental Reproductive Effects

- DE71 (NHEERL) – pubertal exposures
- Delay in puberty
- Effects on male organs
- BDE-99 (Switzerland; Germany) – in utero expo.
- Delay in Puberty
- Ovarian Toxicity
- Male Organ Effects and Decreased Sperm

## Developmental Neurotoxicity

- DE-71 – Rats (NHEERL)
- Perinatal Exposure
- Deficits in Sensory and Cognitive Function
- BDE-99  - Mice (Sweden, Italy)
- Infantile Exposure (“Rapid Brain Growth”) - Permanent effects on learning
- Perinatal Exposure – Delay in sensory-motor development
- BDE-99+PCB-52 – Mice (Sweden)
- Effects may be more than Additive

## Pharmacokinetics of PBDEs

- Absorption – DBDE is poorly absorbed
- Distribution – lipid binding is important
- Fat: 47>99>>>209
- Liver: covalent binding from 99,209
- Metabolism – hydroxylation, debromination, O-methylation
- Excretion – feces is major route

## Other Ongoing PBDE Research

- Dose/Response (NHEERL, NIEHS, USDA, Sweden)
- Extrapolation issues
- Half-life
- Metabolism
- Cell Signaling  *in vitro* (NHEERL)
- Altered calcium associated with changes in learning and memory

## Developmental Neurotoxicity of PBDEs

- Both mice and rats
- Mice very sensitive (clear effects at 0.8 mg BDE-99/kg) in infantile period
- Sensory and Cognitive Effects
- Mechanism Unknown
- Depression in serum T4 as low as 0.8 mg/kg
- PBDEs alter cell signaling *in vitro*
- Kodavanti and Derr-Yellin, 2002
- Altered calcium dependent release of arachidonic acid (associated with learning and memory)

## Potential Health Risk of PBDEs

- Comparison of Animal and Human Data
- Body Burden (allows cross-species comparison for PBTs)
- Most Sensitive Effects to Date
- Developmental Neurotoxicity  and Effects on Thyroid Hormones (<0.8mg/kg)
- Preliminary reports on Developmental Reproductive Toxicity at Even Lower Dose (0.06mg/kg)

## Potential Health Risk of PBDEs (con.)

- 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
- Significant dose causing DNT in mice at 0.8 	mg/kg
- Mouse tissue concentrations are only ~10X higher that total PBDE concentrations in human tissues

## Potential Health Risk of PBDEs (con.)

- Margin of exposure for PBDEs appears low
- Additional concern: are PBDEs interacting with other PBTs?