Dioxin and Related Compounds

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Explore dioxins and dioxin-like compounds. • Summarize the structural similarities of cogeners of dioxins and furans. • Understand Toxicity Equivalency Factors (TEF) and Toxicity Equivalents (TEQ) for dioxins and related compounds. • Summarize the known processes and toxicological endpoints of dioxin exposure.

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Principles of Environmental Toxicology Learning Objectives • Explore dioxins and dioxin-like compounds. • Summarize the structural similarities of cogeners of dioxins and furans. Dioxin and Related Compounds • Understand Toxicity Equivalency Factors (TEF) and Toxicity Equivalents (TEQ) for dioxins and related compounds. Principles of Environmental Toxicology • Summarize the known Instructor: Gregory Möller, Ph.D. processes and toxicological University of Idaho endpoints of dioxin exposure. 2 Principles of Environmental Toxicology Principles of Environmental Toxicology Learning Objectives The Organochlorine Legacy • Describe the controversy and data needs • Halogenated organics have been used as concerning low-level dioxin exposure. synthetic pesticides and industrial compounds for since before WWII - stable • Describe the observed effects and major findings of animal studies with dioxin. • Chlorinated compounds can be formed by combustion and natural processes in the • Summarize the environmental and food presence of chlorine (dioxins) sources of dioxins. • Often non-polar and lipophillic, • Summarize the known human they have the ability to be risk estimations for dioxins. sequestered in fat tissue • Summarize the regulatory • Can bioaccumulate up the control approaches for food chain dioxin release. • Can circulate in the “liposphere” 3 4 Principles of Environmental Toxicology Principles of Environmental Toxicology Organochlorine Compounds 2003 NAS Institute of Medicine Analysis • Often related to immune dysfunction, • Dioxins and Dioxin-like Compounds neurological effects, cancer, endocrine in the Food Supply (2003) disruption and other toxicological endpoints – http://newton.nap.edu/catalog/10763.html • Chlorinated compounds all around us • Often the effects of low-level exposure are sub-clinical and “biomolecular” and this complicates the risk assessment for low-level exposure 5 6 1
Principles of Environmental Toxicology Principles of Environmental Toxicology Dioxins Dioxin: Food Supply Exposure NAS IOM NAS IOM • Widespread, low-level contaminants in • Animal production systems animal feeds and the human food supply. – Airborne deposition on grazing areas or water bodies • Animal fats are the primary vector of exposure. – Geographic variability due to sources (incineration) • Dioxins metabolize slowly and accumulate in body fat • Human foods over a lifetime. – Relatively uniform exposure due to food distribution • Data show decline in levels. patterns • Endocrine disruption • Food-consumption patterns is a concern. – High fat diets • Exposure and children’s = higher exposure health and development. – Animal fats, • High public priority to reduce full-fat dairy, fatty fish dioxin levels in girls and 7 young women. 8 Principles of Environmental Toxicology Principles of Environmental Toxicology Chlorinated Dibenzo Dioxins PCDDs 1 9 Cl O Cl O 8 12 3 7 O Cl O Cl 6 4 Cly Clx 2,3,7,8-Tetrachlorodibenzo-p-dioxin TCDD 9 10 Principles of Environmental Toxicology Principles of Environmental Toxicology Chlorinated Dibenzo Furans Polychlorinated Biphenyls Cl Cl Cl Cl Cl Cl Cl Cl O Cl Cl 2,3,7,8-Tetrachlorodibenzo-furan 3,3’,4,4’,5,5’- Hexachlorobiphenyl 11 12 2
Principles of Environmental Toxicology Principles of Environmental Toxicology Background Combining Risks from Dioxins • Dioxins share a “common mechanism of toxicity”. • 75 dioxin cogeners and 135 dibenzofuran congeners. • Toxicity Equivalency Factors (TEF) compare the toxicity of different dioxins. • In general, CDD’s and CDF’s are present in human adipose tissue and fish and bird • TEF are expressed in terms of Toxicity Equivalents samples at a (TEQ). sub - μg/kg level. • TEQ is the amount of TCDD – Many of these being the less or it would take to equal the non-toxic isomers. combined toxic effect of all • In general, relative toxicity: the dioxins found in that mixture. • CCD > CDF >> PCB >> CN 13 14 EPA Banbury Principles of Environmental Toxicology Principles of Environmental Toxicology The TEF Scheme for TEQDF Dioxin Body Burden Levels 14000 Body Burden ng/kg w. body, 25% lipid 10000 2378-TCDD Furan (F) congener TEF Dioxin (D) congener TEF Est. background Non- 2,3,7,8-TCDF 0.1 2,3,7,8-TCDD 1.0 TCDD TEQs 1000 1,2,3,7,8-PeCDF 0.05 1,2,3,7,8-PeCDD 0.5 2,3,4,7,8-PeCDF 0.5 1,2,3,4,7,8-HxCDD 0.1 1,2,3,4,7,8-HxCDF 0.1 1,2,3,6,7,8-HxCDD 0.1 100 1,2,3,6,7,8-HxCDF 0.1 1,2,3,7,8,9-HxCDD 0.1 1,2,3,7,8,9-HxCDF 0.1 1,2,3,4,6,7,8-HpCDD .01 10 2,3,4,6,7,8-HxCDF 0.1 1,2,3,4,6,7,8,9-OCDD .001 1,2,3,4,6,7,8-HpCDF 0.01 1,2,3,4,7,8,9-HpCDF 0.01 A r. r. lor. 00 0 -h ed. ed. B -l 90 1,2,3,4,6,7,8,9-OCDF 0.001 chlo hlo eso eso nd . ch B, m ~19 A, m nd C2 d. c Sev Ha Ha Sev no sev CD A mo nch eso eso nch SF US SF SF Ra BA Sev Sev Ra BA BA 15 16 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Dioxin Exposure Case Studies Background Serum, US 95-97 • Love Canal (1940s-1950s). TEQDFP 2,3,7,8-TCDD – Hazardous waste landfill release. (pg/g lipid) (pg/g lipid) • Times Beach (pre-1982). Median 18.7 1.9 – Chemical mix used to oil streets. Mean 22.1 2.1 • Agent Orange. AP 95th Percentile 38.8 4.2 – Vietnam “Operation Ranch Hand”. • Seveso, Italy (1976). – 2,4,5 Trichlorophenol industrial accident. Adult background intake • BASF/IB (1953, other). estimate 70 pg TEQDF/d – Chlorinated herbicide manufacturing workers. 17 18 EPA 3
Principles of Environmental Toxicology Principles of Environmental Toxicology Dioxin Toxicity Acute Dioxin Poisoning: Chloracne • TCDD characterized as a “human carcinogen” Ukrainian President Viktor Yushchenko Dioxin Poisoning – Other dioxins characterized as “likely human carcinogens”. • Dioxins can alter the fundamental growth and development of cells. • Impact of dioxins on cells results in: – Adverse effects upon reproduction and development. – Suppression of the immune system. – Chloracne (a severe acne-like condition). 19 20 EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Dioxin Exposure Dioxin Exposure, 2 • Dioxins are highly persistent and can • Environmental processes result in widespread, bioaccumulate. low-level exposure of the general population. • 95% of dioxin intake for a typical person comes • Dioxin levels in the environment have declined through dietary intake of animal fats. since the 1970s. • Low exposure: • Dioxin emissions in the US decreased by ~80% – Breathing air containing trace amount of dioxins. between 1987 and 1995. – Ingestion of soil containing dioxins. – Absorption through skin contacting air, soil, or water containing minute levels. 21 22 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology General Population Body Burden General Population Intake • US CDD/CDF range = 8.5 pg TEQ/g lipid to • US CDD/CDF estimate 41 pg TEQDF-WHO98/d or 50.0 pg TEQDF-WHO98/g lipid 0.59 pg TEQDF-WHO98/kg/d • Mean 21.1 pg TEQDF-WHO98/g lipid • US CDD/CDF/PCB estimate 65 pg TEQDF-WHO98/d or 1 pg TEQDF-WHO98/kg/d • Children: US CDD/CDF estimate 54 pg TEQDF-WHO98/d or 3.6 pg TEQDF-WHO98/kg/d – Decrease with age • 5 compounds = 70% load – TCDD, PeCCD, PeCDF HxCDF, PCB 126 23 24 NAS IOM NAS IOM 4
Principles of Environmental Toxicology Principles of Environmental Toxicology Dioxin Effects in Humans Dioxin Effects in Humans • The amount of dioxin found in the tissues of the • 1 in 100 to 1 in 1,000 increased chance of general human population (Body Burden) experiencing cancer related to dioxin exposure approaches (w/in a factor of 10) the levels at in the general population. which adverse effects occur. • Cancer risk in 2000 analysis indicates about • Despite which, there is no clear indication of 10-fold higher chance than increased disease in the estimated in 1994 general population. reassessment. – Limitation of current data and scientific tools. 25 26 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Children and Concern Groups Dioxin Effect Controversy • Fetuses, infants, and children may be more • Enzyme induction and indicators of altered sensitive to dioxin exposure because of rapid cellular function may not clearly indicate toxic growth. response. – Data on risks to children is limited. • Changes in biology and biochemistry from low-exposure: • U.S. Air Force personnel exposed to Agent Orange during the Vietnam War. – Adaptive (w/ little or no adverse impact). • Other populations – Adverse(?). have experienced elevated exposure from: – Industrial accidents. – Unusually high consumption of fish, meat and dairy products. 27 28 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Case Study: Belgium 1999 Belgium: Dioxins and PCBs in Feedstuffs • Transformer oil added to animal feed at feed mills. 5 • Poultry: reduction in egg hatchability, reduced Log dioxins (pg/g fat) 4 weight gain, an increased mortality, edema, ataxia. • PCBs and dioxins in animals products. 3 • 60,000,000 kg of animals destroyed. • Meat product embargo. 2 1 0 -0.5 0 1 2 3 Log PCBs (µg/g fat) 29 30 5
Principles of Environmental Toxicology Principles of Environmental Toxicology Clinicopathologic Concepts Belgium: Dioxins and PCBs in Chicken • Syndrome induced by CDDs in a given species of animal is comparable to that induced by CDFs, PCBs, 4 PBBs, CNs. Log dioxins (pg/g fat) • Pathogenesis of the disease is the same – suggests 3 that these chemicals involve the same receptors. – Typical exposure may be a mixture 2 of isomers and compounds. – Best to view the disease 1 syndrome in terms of etiology rather than specific insult. 0 -1 0 1 2 Log PCBs (µg/g fat) 31 32 Banbury Principles of Environmental Toxicology Principles of Environmental Toxicology Clinicopathologic Syndrome Clinicopathologic Syndrome • Varies from animal species to animal species. • The one organ that uniformly shows Banbury lesions in all species is the thymus. • Skin of primates, rabbits (ears), cattle & some mice – Often weighs 25% less in lethal intoxications. show characteristic follicular dermatitis. • Site of early life formation of lymphocytes and a site of antibody – Chloracne: visible and reversible lesion. production. • Livers of chickens, rabbits (mice) show necrotic • Severe intoxication in birds accompanied by fluid response of lethal severity. accumulation (chick edema). – Guinea pigs, cattle, NH primates: • Interesting feature: enlarged liver, epithilial hyperplasia – Total dose of TCDD required of bile duct/gall bladder. to produce disease is less if • Some animals show the dose is spread over time epithilial lesions: GIT, renal. compared to a single dose. 33 34 Principles of Environmental Toxicology Principles of Environmental Toxicology LD50 Observations • In general, young animals and females LD50 TCDD (μg/kg) Specie may be more susceptible to intoxication (field). Pig (most sensitive) 0.6 – Not observed in lab studies. • Neonatal death, poor survival of young, female Avian (very sensitive) No exact infertility and reproductive failure are indicators of Rat 22-45 field problems. C57bl Mice 114-284 • At lethal dose levels, the time between exposure Monkey R.
Principles of Environmental Toxicology Principles of Environmental Toxicology Observations Metabolism of TCDD • Dog and rat studies. • Except for animals with severe liver necrosis Banbury (chickens, rabbits), cause of death not usually • Major metabolites are hydroxylated compounds. attributed to a specific organ or system pathology. • Most is eliminated as parent compound in feces. • In general, animals exhibit wasting disease. • Chronic rodent bioassays, life-term – Resembles starvation, anorexia. and short duration have addressed the issues of tumor initiation, • In environmental exposures, the disease is complicated promotion, co-carcinogenesis, DNA interaction, mutagenesis by opportunistic infection. and clastogenesis. Banbury 37 38 Principles of Environmental Toxicology Principles of Environmental Toxicology Carcinogenicity - Mutagenicity Suggested Mechanisms • Toxicity and carcinogenicity. Animal Dosage Response Banbury TCDD – Alteration of cell membrane function and cell-cell μg/kg/d communication. Rat SD 0.1 Hepatocellular, squam. carc. – Effect on Vitamin A function. – Membrane lipid peroxidation. Rat SD 0.01 Hepatocellular nodules – Thyroid hormones. No ↑ in tumors Rat SD 0.001 – Hormonal alterations. – DNA modifications. Mouse B6 0.3 Hepatocellular, thyroid tumors Mouse B6 0.07 Hepatocellular tumors No ↑ in tumors Mouse B6 0.03 Banbury 39 40 Principles of Environmental Toxicology Principles of Environmental Toxicology Hepatotoxicity Mechanisms Dioxin: Early Molecular Events 1. Diffusion into the cell. • Experiments suggest O2• (superoxide) formation and EPA 2. Binding of the AhR protein. initiation of peroxidation by Fe2+. 3. Dissociation from hsp90. – Progressive liver damage. 4. Active translocation from cytoplasm. • TCDD inhibits hepatic Se-GSHpx and reduced 5. Association with Arnt protein. glutathione. 6. Conversion of liganded receptor heteromer to enhancer DNA. – Good correlation of GSHpx activity and survival. 7. Enhancer activation. – Lipid peroxidation endpoint. 8. Altered DNA configuration. 9. Histone modification. 10. Recruitment of additional protein. 11. Nucleosome disruption. 12. Increased accessibility of transcriptional promoter. 13. Binding of transcription factors to promoter. 14. Enhanced mRNA and protein synthesis. Banbury 41 42 7
Principles of Environmental Toxicology Principles of Environmental Toxicology Environmental Source Types Effects of TCDD and Related Compounds • Combustion and incineration sources. Effect Human Monkey Rat Fish Avian Marine wildlife mammals • Metals smelting, refining and processing. Enzyme induction + + + + + + • Chemical manufacturing/processing. Acute lethality 0 + + + + + • Reservoir sources (e.g. soils). Wasting syndrome + + + + + • Biological and Teratogenesis, +/- + + + + + photochemical processes. mortality Endocrine effects +/- + + + + + Immunotoxicity +/- + + + + • Significant regulatory Carcinogenicity +/- + + pressure to limit release. Neurotoxicity + + + Porphyria + 0 + Hepatotoxicity + + + + + + 43 44 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology TEQDF Releases - AirUS TEQDF Releases – AirUS, 2 (g TEQ/yr) Incineration 1995 1987 (g TEQ/yr) 1995 1987 EPA EPA Power/Energy Generation Municipal waste 1250 8877 Medical waste/path. 488 2590 Vehicle fuel -leaded 2 37.5 Forest, brush, and straw 208 170 -unleaded 5.9 3.6 fires -diesel 35.5 27.8 Cement kilns (HW) 156 118 Wood comb. -resident 62.8 89.6 Sewage sludge 14.8 6.1 -industrial 27.6 26.4 Crematoria 9.1 5.5 Coal comb. -utility 60.1 50.8 Hazardous 5.8 5 Oil comb. -ind’st./utility 10.7 17.8 Tire combustion 0.11 0.11 Cigarettes 0.8 1 45 46 Principles of Environmental Toxicology Principles of Environmental Toxicology TEQDF Releases – WaterUS TEQDF Releases – AirUS, 3 Releases (g TEQ/yr) to air Releases (g TEQ/yr) to water EPA EPA 1995 1987 1995 1987 Total quantified releases to air 2700 13100 Bleached wood pulp 19.5 356 and paper mills Total quantified 19.9 356 releases to water 47 48 8
Principles of Environmental Toxicology Principles of Environmental Toxicology TEQDF Releases – LandUS TEQDF Releases – OverallUS Releases (g TEQ/yr) to land 1995 1987 EPA EPA 1995 1987 Overall quantified 2830 13560 releases to the Bleached wood pulp and 1.4 14.1 open and paper mill sludge circulating Municipal wastewater 76.6 76.6 environment treatment sludge (g TEQ/yr) Commercially marketed 2.6 2.6 sewage sludge 2,4-Dichlorophenoxy 28.9 33.4 acetic acid Total quantified releases 110 127 49 to land 50 AP Principles of Environmental Toxicology Principles of Environmental Toxicology Unquantified Sources Source Release Reduction • 80% decrease between 1987 and 1995 of dioxin Category Unquantified sources EPA and CDDs/CDFs to air, water and land. Combustion sources Uncontrolled combustion of PCBs – Due to reduction in air emissions from municipal and Agricultural burning medical waste incinerators. Metal smelting and refining Primary Al, Mg, Ni – Regulations promulgated in Chemical Manufacturing Mono- to tetrachlorophenols 1995 for municipal waste Pentachlorophenol combustors and in 1997 for Chlorobenzenes medical waste incinerators Chlorobiphenyls (leaks/spills) should result in greater than Dioxazine dyes and pigments 95% reduction in dioxin 2,4-D emissions from these two Tall oil-based liquid soaps categories. Biological and photochemical processes Composting Reservoir sources (runoff, erosion) Air, Sediments, Water, Biota PCP-treated wood 51 52 EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Control Efforts for Air Control Efforts for Water • The Clean Air Act (CAA) and its amendments • The Clean Water Act (CWA) manages releases EPA EPA requires emission limits based on “maximum through risk-based and technology-based tools. achievable control technology” (MACT). – 1984 ambient water quality for 2,3,7,8-TCDD – a – Changes in 1995 for municipal waste and 1997 for guidance for state water quality criteria. medical waste incinerators should result in greater than • National Pollutant Discharge 95% reduction in dioxin emissions. Elimination System (NPDES) • CAA and the Resources regulates discharge based Conservation and Recovery on state ambient water quality. Act (RCRA) authorize the regulation emissions from facilities that burn HW. 53 54 9
Principles of Environmental Toxicology Principles of Environmental Toxicology Control Efforts for Water, 2 Control Efforts for Water, 3 • Pulp and paper facilities were the largest known • 1992 maximum contaminant level goal (MCLG, a industrial dischargers of dioxin into water. non-enforceable,voluntary health goal) of zero. – 1998 CWA guidelines will reduce dioxin discharge from • Safe Drinking Water Act (SDWA) enforces a pulp and paper facilities by at least 96%. maximum contaminant level (MCL) of • NPDES will places stringent performance 3x10-8 mg/l for TCDD. requirements through combination of technology- based, health-based and state water quality standards. 55 56 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Control Efforts for Land Control Efforts for Products • The Federal Insecticide Fungicide and Rodenticide • Superfund and RCRA Corrective Action programs for Act (FIFRA) and TSCA authorizes control or dioxin (Times Beach and Love Canal). elimination of certain chemicals. • Hazardous Waste Identification and Disposal Rules under RCRA designed to prevent future contamination. – 2,4,5-T and pentachlorophenol (PCP). • The Toxic Substance Control Act (TSCA) authorizes restricted use of dioxin – contaminated pulp and paper sludge. • 1999 regulations limit dioxin content of cement kilns and sludge from POST facilities when by-product material is used as soil additives. 57 58 EPA EPA Principles of Environmental Toxicology Principles of Environmental Toxicology Environmental Media Estimate Levels in Food Food type Total (pg TEQDF/g fresh weight) Media TEQDF concentrations EPA EPA Beef 0.29 Rural soils 1-6 pg/g (ppt) Pork 0.31 Eggs 0.13 Urban soils 7-20 pg/g Milk 0.047 Sediments 1-60 pg/g Dairy products 0.18 AP Marine fish 0.61 pg/m3 Rural air 0.002-0.02 Freshwater fish 2.4 0.02-0.2 pg/m3 Urban air Marine shellfish 0.83 Vegetable fats 0.093 Water NA 59 60 10
Principles of Environmental Toxicology Principles of Environmental Toxicology % Contribution of Food Dioxin Intake Background/Body Burden Changes Children 1-5 Yrs • Body burdens late 1980s Dairy Foods EPA 30 – 80 pg TEQ/g lipid (30 – 80 ppt) 10 Meat 1 – Midpoint of ~55 pg TEQ/g lipid including all dioxins, 30 10 Poultry furans, and dioxin-like PCBs. 4 Fish • High-end estimates (~ 1% of general pop.) may 4 be 3 times higher. Eggs 6 – Based on blood-level data and Fruits & vegetables consumption of fat as surrogate 35 Fats & oils for dioxin intake. • CDD/CDF/PCB body burden in late 1990s 25 ppt (TEQ, lipid basis). 61 62 NAS IOM Principles of Environmental Toxicology Risk • Receptor binding and most early biochemical events are likely to demonstrate low-dose linearity. – If findings imply low-dose linearity in biologically-based cancer models, then the probability of cancer risk will be linearly related to exposure to TCDD at low doses. • Until the mechanistic relationships are better understood, the shape of the dose-response curve for risk can only be inferred with uncertainty. 63 EPA 11