Polycyclic Organochlorines: Dioxins, Furans, PCBs

1. Polycyclic Organochlorines:Dioxins, 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 > 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. 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 Toxicity of Dioxins, Furans

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. 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 Toxicity of PCBs - 1

29. 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

30. 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

31. 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

32. Toxicity of PCBs - 5 • Great controversy • Ecotoxicity? • marine mammals • zooplankton and filter feeders • Issues arising: • breast feeding • breast cancer • fish advisories

33. 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

34. 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

35. 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)

36. The Xenoestrogen Hypothesis • Many POPs have weak estrogenic properties, inc. D&Fs, PCBs, pesticides • Concern over: • breast Ca • endometriosis • sperm counts, hypospadias • Phytoestrogens in diet • Increased number of menstrual cycles