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

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Polycyclic OrganochlorinesDioxins, Furans, PCBs

• Tee L. Guidotti
• The George Washington University Medical Center

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Chemistry
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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

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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

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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

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Dioxins and Furans
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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)

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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)

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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

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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)

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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Polychlorinated Biphenyls

• PCBs

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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

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PCBs

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

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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

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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

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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

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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

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Toxicity of PCBs - 1

• Animal Models
• Hepatotoxicity
• Neuropathy
• Repro effects
• ?Ab response
• Cancer (hepatic, GI, leukemia, lymphoma)
• Xenoestrogen effects

• Humans and Primates
• Chloracne
• Hepatotoxicity
• hepatocellular injury, possibly jaundice
• porphyrin metabolism
• ?Otitis media
• Reduced neuro development

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Toxicity of PCBs - 2

• Coplanar PCBs interact with Ah receptor
• Biotransformation enriches non-co-planar
• Non-coplanar PCBs may show different patterns of
  toxicity
• neurotoxicity
• stimulation of insulin release, ?biosynthesis
• xenoestrogen effects
• neutrophil inactivation

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Toxicity of PCBs - 3

• Fish-Eaters
• Great Lakes - Jacobson studies
• Sweden, east v. west coast
• Netherlands, North Sea
• Consistent and strongly suggestive
• depressed neurocognitive function
• associated with PCB-contaminated fish consumption
  at reasonable amounts

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Toxicity of PCBs - 4

• Organochlorine ecosystem contamination
• northern latitudes
• susceptible population - Inuit
• contaminated fish
• marine mammals
• breast feeding
• elevated rate of otitis media, meningitis
• immunsuppression
• associated with PCB 77, 126, 169

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Toxicity of PCBs - 5

• Great controversy
• Ecotoxicity?
• marine mammals
• zooplankton and filter feeders
• Issues arising
• breast feeding
• breast cancer
• fish advisories

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Carcinogenesis of PCBs

• Highly controversial
• IARC classifies 2A probable
• EPA, ATSDR treat as human carcinogens
• Evidence suggests certain types
• hepatocellular Ca
• ?cholangiosarcoma and biliary tract
• ?leukemia
• ?non-Hodgkins lymphoma

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Problems in studying PCBs

• Most human toxicity information comes from Yusho
  incident
• very high level of exposure
• contamination by furans
• Susceptible populations are confounded
• PCBs track with other organochlorines
• Ubiquitous distribution in industrial society
• Analytical methods difficult, expensive

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Toxic Equivalency Factors

• Most common system is WHO/IPCS
• TEFs are based on potency compared to
  2,3,7,8-TCDD 1
• Applied to PCBs, dioxins, furans, other
• Database incomplete, not systematic
• Most TEFs derive from potency for enzyme
  induction (CYP1A1)

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The Xenoestrogen Hypothesis

• Many POPs have weak estrogenic properties, inc.
  DFs, PCBs, pesticides
• Concern over
• breast Ca
• endometriosis
• ?sperm counts, ?hypospadias
• Phytoestrogens in diet
• Increased number of menstrual cycles