DIOXINAS Y FURANOS

1. DIOXINAS Y FURANOS Prof. Jesús Olivero Verbel. Ph.D. Grupo de Química Ambiental y Computacional Universidad de Cartagena

2. DIOXINAS, FURANOS PCBs PFOS

3. ¿Qué son los COPs? Tóxicos, Persistentes, Bioacumulables, Contaminantes globales Tóxicas: en muy bajas concentraciones afectan la salud de las personas, animales y el medio ambiente. Persistentes: tienen muy lenta degradación física, química o microbiológica. Bioacumulables: por sus características físico-químicas se acumulan en tejidos grasos, biomagnificándose al subir en la cadena alimenticia. Contaminantes globales: se dispersan por el medio ambiente por medio de corrientes de aire, marinas, ríos y en los seres vivos, encontrándose en el agua, sedimentos, animales y personas incluso en zonas remotas.

4. ¿Cuáles son? • Plaguicidas organoclorados: Aldrin, Clordano, DDT, Dieldrin, Endrin, Heptacloro, Hexaclorobenceno, Mirex yToxafeno, • Bifenilos Policlorados (PCBs) usado como aceite dieléctrico en transformadores y acumuladores y otros usos. • Dioxinas y Furanos: subproductos no intencionales generados por combustión y en algunos procesos industriales cuyos insumos contienen cloro.

5. Objetivo: Proteger la salud humana y el medio ambiente frente a los Contaminantes Orgánicos Persistentes (Art.1) Convenio de Estocolmo

6. What Are “Dioxins”? A family of structurally related chemicals which have a common mechanism of action and induce a common spectrum of biological responses.

7. Cl Cl O Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl O O Cl Cl 2,3,7,8-Tetrachlorodibenzo-p-dioxin 3,3',4,4',5,5'-Hexachlorobiphenyl 2,3,7,8-Tetrachlorodibenzofuran Dioxin-Like Compounds Furans 135 congeners 10 toxic Dioxins 75 congeners 7 toxic PCBs 209 congeners 12 toxic 2,3,7,8-TCDF 1,2,3,7,8-PeCDF 2,3,4,7,8-PeCDF 1,2,3,4,7,8-HxCDF 1,2,3,6,7,8-HxCDF 1,2,3,7,8,9-HxCDF 2,3,4,6,7,8-HxCDF 1,2,3,4,6,7,8-HpCDF 1,2,3,4,7,8,9-HpCDF 1,2,3,4,6,7,8,9-OCDF 3,3',4,4'-TeCB 3,3',4,4',5-PeCB 3,3',4,4',5,5'-HxCB 2,3,7,8-TCDD 1,2,3,7,8-PeCDD 1,2,3,4,7,8-HxCDD 1,2,3,6,7,8-HxCDD 1,2,3,7,8,9-HxCDD 1,2,3,4,6,7,8-HpCDD 1,2,3,4,6,7,8,9-OCDD

8. Dioxinas

9. Furanos

10. Introduction Methods Results Summary Methods Results . a a b b b 10 b b b b b 9 b b a a Molecular structure of 1,2,3,4,6,7-hexa-CN Molecular structure of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Naftalenos Policlorados Naftalenos Pol

11. 2,3,7,8-Tetrachlorodibenzo-p-dioxin“The Most Toxic Man-Made Compound” • Prototype for family of structurally related compounds • Common mechanism of action • Common spectrum of biological responses • Environmentally and biologically persistent (Basis for TEQ approach)

12. 1899 – Chloracne Characterized 1929 – PCBs produced commercially 1947 – “X” Disease in cattle 1957 – Chick Edema Disease; TCDD identified in TCPs 1962-1970 – Agent Orange use in Southeast Asia 1971 – Times Beach; TCDD causes birth defects in mice 1976 – Seveso, Italy 1978 – Kociba rat cancer study 1981 – Capacitor fire in Binghamton, NY 1985 – 1st US EPA health assessment of TCDD 1991 – NIOSH cancer mortality study of US workers 1999 – Belgium dioxin poisoning; Viennese poisoning Why the Interest in Dioxins?

13. “Dioxins” Polyhalogenated Dibenzo-p-dioxins and furans Never produced intentionally Unwanted byproducts of industrial and combustion processes Polyhalogenated Biphenyls, Naphthalenes, Azo/azoxybenzenes Commercially produced Major industrial chemicals Limited number of congeners have dioxin-like properties Lateral halogenation > 3 Halogens Chlorinated, brominated, and mixed chloro-bromocongeners

14. Dioxin-Like Compounds • Semivolatile • Lipophilic • Hydrophobic • Persistent • Bioaccumulating • Toxics

15. PCBs • Large Family of Chemicals • 209 Possible Congeners • Small Subset Are “Dioxins” • NEVER have PCBs without Dioxin-like PCBs • Majority Have Own, Inherent, Toxicities • Multiple, Overlapping, Structural Classes • Can Interact Additively, Synergistically, and/or Antagonistically With Dioxins and With Other PCB Congeners

16. TCDD is NEVER Found Alone • Complex Mixtures Exist both Environmentally and in Animal and Human Tissues • TCDD is only a Small Part of Total Chemical Mass • We have the Most Toxicological Information about TCDD.

17. Toxic Equivalency Factors (TEFs) • Developed for Risk Assessment • Interpret Complex Database Derived from Analysis of Samples Containing Mixtures of Dioxin-like Chemicals • Express Quantitatively the Toxicity of a Chemical in terms of an Equivalent concentration of TCDD (Relative Potency) • ∑([Chemical] x TEF)PCDD/PCDF/PCB=TEQ

19. Five Compounds Make up about 80+% of the Total TEQ in Human Tissues • Four of 17 Toxic PCDD/PCDF Congeners • 2,3,7,8-TCDD • 1,2,4,7,8,-PeCDD • 1,2,3,6,7,8-HxCDD • 2,3,4,7,8-PeCDF • One of the 12 Toxic PCBs • PCB 126

21. Major Past Sources of Dioxins (20th Century Problem) • Chloralkali Facilities • Chlorinated herbicide and biocide Production. • Leaded Gasoline • Municipal, Medical, and Hazardous Waste Incineration. • Chlorine Bleaching of Paper and Pulp Products.

22. Recently Identified Sources • Open Burning of Household Waste • Uncontrolled Combustion • Forest Fires and Volcanos • Metal Refining

24. PCBs From Factory to the Fetus Dioxins and PCBs: Pathways of Exposure and Neurodevelopmental Effects AIR Dioxins PCBs: Transformers Landfills Hazardous Waste Sites Dioxins: PVC Manufacturing Medical/Municipal Incinerator PCBs SOIL WATER FOOD

25. How do Dioxins Move in the Environment • If emitted into air, undergo atmospheric transport and deposition on land or water. • If emitted into water, bind to sediment. • Recycle in environment. • Bioaccumulate up the food chain. • Resistance to physical, chemical, and biological degradation.

26. Dioxin Environmental Mobility • Dioxins are less mobile than Hg or the more volatile PCBs. • Dioxins do not appear to exhibit global retort, or • strong “grasshopper” effect. • Dioxins are continually exchanged among media and • should be viewed as a complex system of stocks and flows.

27. How are People Exposed? • Dioxins are omnipresent • Majority of exposure (>95%) is via micro-contamination of food • Meat, fish, dairy. • Sensitive Subpopulations with High Exposure • Subsistence Fishers and Hunters • Nursing Infants • Occupational Workers • Oral, dermal, and inhalation exposures

28. How You are Exposed Makes Little Difference • Dioxins are well absorbed from the GI tract and lungs • Skin absorption is limited and slow. • Dioxins primarily lodge in the liver and fat. • Dioxins are primarily eliminated after metabolism, which is VERY slow.

29. Why do the Body Burdens Increase Over Time? • Persistence • Resistance to Biological, Chemical, and Physical Degradation • Long Half-Lives in Animals and People • More Body Fat-Longer Half-Life • Half-Life is Dose-Dependent. • Bioaccumulation • Due to Persistence in Animal tissues Higher Trophic Organisms have Higher Concentrations. • Older Organisms have Higher Body Burdens than Young.

31. 95% of Background Exposure From Commercial Food Supply Vegetable fat Soil ingestion Soil dermal contact Other meats Freshwaterfish and Poultry shellfish 6% Pork 5% 19% Marine fish and shellfish Beef 7% 14% 1% Inhalation 4% 16% Eggs 21% Milk Dairy

32. Dioxin/PCB Exposure Trends • Environmental Levels • Peaked in late ’60s/early ’70s – decline since confirmed by sediment data • Decline also supported by Emissions Inventory – shows significant decrease from ’87 to ‘;95 (~80%) • Human tissue data suggest mid-90s levels approximately half of 1980 • 55  25 ppt TEQ lipid (~5ng/kg ww) • Decrease continues • Success of Regulatory Agenda!

33. Mean and Range of TEQs By Age Group

34. Wildlife and Domestic Animals Great Lakes fish, birds, mammals Baltic seals, Dolphins Developmental/reproductive effects Immunological effects Effects observed at environmental levels Cows, Horses, Sheep, Chickens Effects observed during poisoning episodes. Laboratory Animals Fish Amphibians Turtles Birds Rats Mice Guinea Pigs Hamsters Rabbits Dogs Non-human primates Adverse Effects

35. BIOCHEMICAL Induction of Drug Metabolizing Genes Cyp1A1/2, 1B1; GST; UDPGT; ALDH… Induction of Proliferation Genes. Induction of Cytokines TNF, IL-6, IL-1β Induction of Oxidative Stress Induction of Growth factors/receptors TGFs, EGFR… Modulation of Hormones/Receptors TOXIC Lethality/Wasting Gonadal/Lymphoid Atrophy Hyperplasia/Metaplasia Endocrine Disruption Carcinogenicity Repro/Developmental toxicity Functional Devpt. Toxicity Dermal Toxicity Immunotoxicity Neurotoxicity Hepatic Toxicity Cardiovascular Toxicity Bone/Teeth Toxicity Effects of Dioxins

36. Multiple Effects Multiple Tissues Both Sexes Multiple Species Throughout Vertebrata Molecular/ Biochemical Metabolic/ Cellular Tissue/Organ Growth/ Differentiation Wasting/Death Effects of Dioxins

37. Dioxin Effects Require the “Ah Receptor” • Highly conserved protein • throughout Vertebrates • Related Proteins in Invertebrates • Member of Growing Family of Key Regulatory Proteins • Development, Aging, Hypoxia, Daily Rhythms • Necessary, but Not Sufficient, for All of the Effects of Dioxins

38. AIP,.. TCDD, ... hsp90 Other Proteins AhR hsp90 Arnt HIFa, Sim,... Transport Mechanism Rb, RelA,… AIP,.. hsp90 O O O O Cl Cl Cl Cl Cl Cl Cl Cl phosphorylation/ dephosphorylation Cl Cl Cl Cl Cl Cl Cl Cl O O O O hsp90 chromatin Co-activators Co-repressors Differentiation and Proliferation AhR BTFs Arnt BTFs DRE TATA Changes in protein levels (e.g., CYPIA1, IL-1, ...) Altered gene expression mRNA Mechanism of Action AhR-interacting protein Basic Transcription Factor

39. Introduction Methods Results Summary PCNs

40. Cardiovascular Disease Diabetes Cancer Porphyria Endometriosis Decreased Testosterone Chloracne Biochemical Enzyme Induction Receptor Changes Developmental Thyroid Status Immune Status Neurobehavior Cognition Dentition Reproductive Effects Altered Sex Ratio Delayed Breast Devpt Dioxins’ Effects in People

41. Unfortunate Poisoning Episodes • PCBs/PCDFs • Japan (“Yusho”) • Taiwan (“Yucheng”) • PBBs/PBNs • Michigan • TCDD • Seveso, Italy • Vienna, Austria • Ukraine • Clear Evidence of Adverse Health Effects

42. Chloracne Classic Toxic Effect • “Hallmark of Dioxin Toxicity” • High-Dose Response • Genetic Polymorphism • Occurs in People, Monkeys, Cows, Rabbits, and Mice • Associated with multiple problems with skin, teeth, hair and nails following prenatal exposure

43. La exposición a dioxinas genera Cloroacné!

44. HEALTH EFFECTS IN “HIGHLY” EXPOSED POPULATIONS • Exposures Are Not As High As We Once Thought:10-100X Background (“Ambient”) • Occupational Populations • Chloracne, Cancer, Heart Disease, Diabetes, ... • Poisoning Episodes • Chloracne. Cancer, Heart Disease, Diabetes, Reproductive, Developmental, Hormonal and Immune Effects

45. EFFECTS SEEN IN ADULTS AT BACKGROUND EXPOSURES • Type II Diabetes • Decreased Glucose Tolerance • Hyperinsulinemia • Mechanistic Plausibility • Endometriosis • Hormone Disruption and Immune Suppression • Animal Models • Cancer????

46. HEALTH OUTCOMES IN PRENATALLY-EXPOSED CHILDREN • Studies in the US (Michigan, North Carolina, Lake Oswego); Japan; the Netherlands; Sweden; Finland • Low Birthweight • Cognitive and Behavioral Impairment • Immune System Effects • Hormonal Changes (Thyroid Effects) • Altered Dentition

47. Dioxin Effects of Greatest Concern • Developmental Alterations Occurring at “High End” of Background Population • Decreased neuro-optimality and IQ • Altered Behavior • Altered Immune System • Altered Hormone Systems • Altered Growth

48. ORGANOFLUORINES F is the most electronegative element. C-F bond is the strongest of known covalent bonds. e.g., C-F bond can withstand boiling with 100% sulfuric acid without any defluorination. Perfluorinated (fully fluorinated) alkanes are anthropogenic.

49. STRUCTURES OF PERFLUORINATED SURFACTANTS MONITORED (1) PFOS: Perfluorooctanesulfonate O PFOS is the ultimate degradation product of POSF-based compounds and the compound found in the environment - - - S O C8F17 O

50. ORGANOFLUORINE SURFACTANTS Surfactants:Surface-active agents; due to selective adsorption at the interface. Amphiphilic or amphipathic :Implies attraction to two different kinds of media. Surfactant structure consists of ‘hydrophilic’ and ‘hydrophobic’ parts. Thehydrophobic portion repels not only water but also oil and fat. So, fluorinated surfactants exhibit both water and oil repellency when adsorbed on substrates such as textiles or paper.