Polycyclic Organochlorines:Dioxins, Furans, PCBs

Tee L. Guidotti

The George Washington University Medical Center

Chemistry

Class Ring structure Halide

PCBs Single bond Cl

PBBs Single bond Br

Dioxins Two etherbridges

Cl

Furans (dibenzo) Single bond,Ether bridge

Cl

Pentachlorophenol Single ring Cl

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

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

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

Dioxins and Furans

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)

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)

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

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)

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

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

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

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

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

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)

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

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

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

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

Polychlorinated Biphenyls

PCBs

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

PCBs

• Many desirable properties– low flammability– electrically nonconductive– good heat exchange– lubricating– solvent

• Ban on new manufacture

• Hazardous waste, old transformers

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

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

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

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

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

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

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

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

Toxicity of PCBs - 5

• Great controversy

• Ecotoxicity?– marine mammals– zooplankton and filter feeders

• Issues arising: – breast feeding– breast cancer– fish advisories

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

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

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)

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