Polycyclic%20Organochlorines:%20Dioxins,%20Furans,%20PCBs - PowerPoint PPT Presentation

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Polycyclic%20Organochlorines:%20Dioxins,%20Furans,%20PCBs

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Non-primate animal models 'wasting' syndrome. hepatotoxicity. immunotoxicity ... Human studies and primate models. chloracne. Ca risk ?peripheral neuropathy ... – PowerPoint PPT presentation

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Title: Polycyclic%20Organochlorines:%20Dioxins,%20Furans,%20PCBs

1
Polycyclic OrganochlorinesDioxins, Furans, PCBs

Tee L. Guidotti
The George Washington University Medical Center

2
Chemistry
3
Features in Common, esp. PCBs and Dioxins/Furans

Highly lipophilic
bioaccumulation
bioconcentration
Persistent organic pollutant
adsorbs onto clay particles
sorbs and desorbs on surface of vegetation
long-range seasonal transport
accumulation in Arctic of organochlorines

4
Features in Common, esp. PCBs and Dioxins/Furans

Structural similarities lead to similar toxicity
profiles among dioxins, furans and some
coplanar PCBs
Principal toxic outcome in human beings for the
class is chloracne
acneiform skin rash, very persistent
preauricular distribution characteristic
refractory to treatment

5
Chloracne and polycyclic halogenated organics

Chloracne is non-specific may be cased by
polychlorinated dibenzofurans and dioxins
polybrominated dibenzofurans and dioxins
polychloronaphthalenes
polychlorobiphenyls
polybromobiphenyls
tetrachloroazobenzenes

6
Dioxins and Furans
7
Dioxins and Furans

Comparable toxicity, dioxin gt furan
Both produced in minute quantities from natural
combustion
Both produced in significant quantities from
chemical synthesis as contaminant
runaway chemical reactions
combustion (PVC plastics)
effluent (Cl pulp bleaching)

8
Dioxins and Furans

75 dioxins, 135 furans
Mono-, di-, octa- chloro dioxins and furans show
little toxicity
Most toxic of family are
2,3,7,8-tetrachlorodibenzodioxin (TCDD)
2,3,7,8-tetrachlorodibenzofuran (TCDF)
1,2,3,7,8-pentachlorodibenzodioxin (PCDD)
2,3,4,7,8-pentachlorodibenzofuran (PCDF)

9
Dioxins and Furans - Fate and Disposition

Photolysis occurs in sunlight
molecule may be held on surface of plant
light quanta sufficient to break bridging bonds
t1/2 may be only hours in such situations
Persistent organic pollutants
persists in soil, t1/2 may be 10 y below surface
fortunately do not migrate well in water
slow photolysis under cold conditions

10
Toxicokinetics of Dioxins and Furans - 1

May be absorbed by any route of exposure
inhalation
ingestion
transcutaneous absorption
transplacental
expressed in breast milk - infants at risk
Distribution
typical fat depots for lipophilic substance
(next)

11
Toxicokinetics of Dioxins and Furans - 2

Distribution (continued)
blocked by BBB, poor entry into brain
circulating levels represent what is mobilized
from depot
may be mobilized with weight loss
adipose levels are detectable in individuals
without exceptional exposure
adipose levels not routinely used clinical

12
Toxicokinetics of Dioxins and Furans - 3

Metabolism
very slow in vivo
t1/2 approximately 7 years
mostly hepatic
Phase I metabolism is hydroxylation or
methylation
Phase II metabolism is glu, sulf conjugation
potent induction of both I and II enzymes

13
Toxicokinetics of Dioxins and Furans - 4

Excretion
biliary, subject to enterohepatic circulation
TCDD metabolites in urine and bile
TCDD (unchanged) excreted into bile, enters feces
mobilizes into breast milk, which is a
significant route of excretion in lactating women

14
Toxicodynamics of Dioxins, Furans

Exposure-response ratio for most effects is
poorly characterized
Very potent (ppq) in animal models
Human toxicity
difficult to demonstrate at same exposure levels
appears to be a species difference, Ah receptor
affinity
Cancer risk

15
Mechanisms of TCDD toxicity - 1

Interacts with an intracellular receptor Ah
Function of this receptor is probably related to
endocrine control mechanisms
estrogenic and thyroid function
enzyme induction
? Downregulates tumor suppressor genes
modulates protein kinase C, allowing
proliferation

16
Mechanisms of TCDD toxicity - 2

The Ah receptor
also binds aryl hydrocarbons(PAHs)
forms heterodimer with a transport protein the
aromatic receptor nuclear transporter (ARNT)
dioxin-Ah-ARNT complex is transported into
nucleus
binds there to dioxin-responsive elements
(DREs) (next)

17
Mechanisms of TCDD toxicity - 3

In nucleus, dioxin-Ah-ANRT
binds to DRES
activates transcription of a variety of proteins,
including cytochromes, cell cycle regulators,
cytokines
Many alleles with different binding efficiencies
probably the explanation for species differences

18
Toxicity of Dioxins, Furans

Non-primate animal models
wasting syndrome
hepatotoxicity
immunotoxicity
hematopoietic failure
repro toxicity
neuropathy
endocrinopathy

Human studies and primate models
chloracne
?Ca risk
?peripheral neuropathy
porphyria cutanea tarda

19
Immunotoxicity of TCDD

Extensively studied as a model for
immunotoxicology
thymic atrophy
pancytopenia
suppression of cellular immunity
No consistent findings or syndrome in humans
May be related to thyroxin-like effects

20
Cancer Risk Associated with TCDD

Most potent promoter known for rat liver Ca, also
potent for lung and skin
Classified by IARC as 2B possibly
limited evidence for human carcinogenicity
sufficient evidence for animal carcinogenicity
Cancers implicated in human studies
soft tissue sarcomas
non-Hodgkins lymphoma

21
Polychlorinated Biphenyls

PCBs

22
PCBs

209 compounds in class, with varied toxicity
profiles
May have one to ten chlorines
PCB formulations are mixtures
20 PCBs generally present in forumalations
average 3 to 5 chlorines
Hydrophobic, lipophilic
Very stable chemically

23
PCBs

Many desirable properties
low flammability
electrically nonconductive
good heat exchange
lubricating
solvent
Ban on new manufacture
Hazardous waste, old transformers

24
PCBs

In addition to chlorine substitution, chlorine
positioning plays a major role in toxicity
para resembles thyroxine
ortho non-co-planar configuration
para, meta co-planar configuration
Co-planar PCBs resemble TCDD, bind to Ah receptor
Co-planar ? non-co-planar in environment

25
Toxicokinetics of PCBs

Absorption by any route
low volatility but may be adsorbed on particles
heavy skin exposure common in past
transplacental, breast milk important routes
Distribution
lipophilic, higher Cl ? affinity for adipose
adipose depot
may mobilize with weight loss

26
Toxicokinetics of PCBs

Metabolism
primarily hepatic metabolism
very slow
higher Cl ? resistance to metabolism
induction of Phase I, II enzymes
Excretion
bile, feces
breast milk

27
Toxicodynamics of PCBs

Generalizations regarding toxicity
much less potent than dioxins, furans, by factor
of 10,000 or 100,000
higher chlorine content associated with greater
toxicity
coplanar PCBs associated with higher TCDD-like
toxicity, activity resembling dioxins and furans
non-coplanar associated with other toxicity

28
Toxicity of PCBs - 1