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Pesticides and Trace Organics

ENS3320 Biochemical toxicology. Pesticides and Trace Organics. Introduction Pesticides and their toxic effects Trace Organics: chemicals and their receptors Toxic effects and risk Assessment of trace organics Electronic w astes & PBDE Concluding remarks. 1. Introduction.

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Pesticides and Trace Organics

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  1. ENS3320Biochemical toxicology Pesticides and Trace Organics Introduction Pesticides and their toxic effects Trace Organics: chemicals and their receptors Toxic effects and risk Assessment of trace organics Electronic wastes & PBDE Concluding remarks

  2. 1. Introduction SOURCES OF TRACE ORGANICS Combustion of organic substances; by products Manufacturing of pollutant chemicals Bio-magnification in food chains Daily products: Meat (beef and fish), milk, egg. Agent Orange & By-products of chlorine related chemicals, including pesticides. Waste incineration, Metal processing, Fossil fuel combustion (vehicle emission).

  3. 1.3 Introduction POPs, persistent organic pollutants. • Lipid soluble, hard to remove, easy to accumulate, magnification via food chains with high concentrations in tertiary consumers. • Examples, polychlorinated Aromatic hydrocarbons (PAHs), Polycyclic biphenyls (PCBs), Dichloro-Diphenyl Trichloroethane (DDT), PBDE (Polybrominated Diphenyl Ether), Dioxins (TCDD) and furans. • Environmental estrogens, mimic estrogenic compounds in animal body, endocrine disrupters. • Related to gene mutations and cancer.

  4. Pesticides Aldrin Dieldrin Endrin Chlordane DDT Heptachlor Mirex Toxaphene Hexachlorobenzene (HCB) Industrial Chemicals PCBs (Polychlorinated Biphenyls) HCB Unwanted By-products PCDDs (Poly Chlorinated Dibenzo Dioxins) PCDFs (Polychlorinated Dibenzo Furans) PCBs HCB 1.4Introduction The UNEP 12 POPs

  5. 1.5 Introduction Toxicity Scale of Example Substance LD50, mg/kg (approximate) Substance DEHP (plasticizer), di(2 ethylhexyl)phthalate) • 100,000 • 10,000 • 1,000 • 100 • 10 • 1 • 0.1 • 0.001 • 0.00001 Practically non toxic, > 1.5 X 10 4 mg/kg Ethanol Sodium Chloride Slightly toxic, 5 X 10 3 to 1.5 X 10 4mg/kg Malathion Chlordane Heptachlor Parathion Moderate toxic, 500 to 5000 mg/kg Tetrodotoxin Dioxin Very toxic, 50 to 500 mg/kg Botulinus toxin

  6. 2. Pesticides Including herbicides, fungicides, rodenticides and substances used to control pests. Control = intended for preventing, destroying, repelling or mitigating any pests Usage: agricultural pesticides, public health pesticides, wood preservatives, anti-fouling paints, household products, etc Four main types: [1] Organochlorine, [2] organophosphate, [3] carbamate and [4] pyrethroid pesticides.

  7. 2.1 Organochlorine pesticide Commonly used in the past, but many have been removed from the market due to their health and environmental effects and their biomagnifiable properties (e.g. DDT and chlordane). OCs and their metabolites resist degradation by chemical, physical or biological means. Persistent and have half-live ranging from months to years and in some cases decades. DDT is the most notorious organochlorine (OC) insecticide widely used in agricultural production around the world even today.

  8. General effects of organochlorine pesticides toxic to humans and other animals and are highly toxic to most aquatic life. They can have serious short-term and long-term impacts at low concentrations. sub-lethal effects such as immune system and reproductive damage of some of these pesticides may also be significant build up in the fatty tissues of humans, plants and animals. Most of them are attracted to fatty tissues and organs and are accumulated significantly through food-chain (bio-magnification) and hence large animals in high trophic levels accumulate most.

  9. DDT (Dichloro diphenyl trichloroethane) http://en.wikipedia.org/wiki/Rachel_Carson Raised public awareness about the dangers of pesticides, with a specific focus on persistent OCs and DDT due to the publication of Silent Spring by Rachel Carson (1907-1964), leading to the establishment of USEPA. Banned in many countries in the 1970s in response to public concern and mounting scientific evidence linking DDT with damage to wildlife.

  10. DDT(dichlorodiphenyltrichloroethane) • Banned in the United States in 1972, but is now being used in many countries including China to kill mosquitoes to avoid malaria. • DDT is an organochlorine slowly transformed to 1,1-dichloro-2,2-bis(p-dichlorodiphenyl)ethylene (DDE) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD), and ultimately transformed into bis(dichlorodiphenyl) acetic acid (DDA) at a very slow rate. • DDA are readily excreted in urine, but DDE tends to bio-concentrate and accumulate in food webs. • Fish, milk contaminated with DDT or metabolites DDE are major sources for human uptake.

  11. Toxic effects of DDT • Toxic to many types of aquatic organisms, even at low concentrations. It has moderately to slightly toxic to studied mammalian species via the oral route. • Chronic effects on the nervous system, liver, kidneys, and immune systems in experimental animals. • Adverse effects on the liver, kidney and immune system due to DDT exposure have not been demonstrated in humans. • Evidence for mutagenicity and genotoxicity is contradictory, but carcinogenicity is equivocal. • Confirmed to be environmental estrogen.

  12. Examples of Organochlorine Pesticides 1) DDT: DichloroDiphenyllTrichloroethane 2) Endosulfan 3) Methoxychlor 4) Heptachlor

  13. Methoxychlor (MXC) • Protect crops, ornamentals, livestock, and pets against fleas, mosquitoes, cockroaches, and other insects, as a replacement for DDT • Readily metabolized, non-accumulative • No acute or chronic effects has been reported on human • Used extensively to protect crops, ornamentals, livestock, and pets against fleas, mosquitoes, cockroaches, and other insects, • Xenoestrogen and endocrine disruptor

  14. Endosulfan and its toxic effects • USEPA Category Ib – Highly Hazardous • Beta- (very persistence, half life = 800 days) and alpha- isomer • Acutely neuro-toxic to both insects and mammals and affects CNS: Epilepsy • Hyperactivity, tremors, convulsions, lack of coordination, difficulty breathing, nausea and vomiting, diarrhea, lethal effects • Chronic endocrine disruptor: Hypothyroidism • Environmental estrogen • Reproductive and developmental toxicity

  15. 2.2 Organophosphate Pesticides Most OPs are insecticides. Developed during the early 19th century, but their effects on insects, which are similar to their effects on humans, were discovered in 1932. Not persistent in the environment. They degrade rapidly by hydrolysis on exposure to sunlight, air, and soil. An attractive alternative to the persistent organochlorine pesticides, such as DDT and aldrin

  16. General effects of Organophosphate Organophosphate pesticides irreversibly inactivate acetylcholinesterase, which is essential to nerve function in insects, humans, and many other animals. Many organophosphates, in particular Chlorpyrifos,are highly toxic to fish. It is necessary to exercise extreme care and caution not to contaminate fish bearing water bodies.

  17. Examples of organophosphate pesticides Chlorpyrifos Malathion Dichlorvos Parathion

  18. Dimethoxyphosphinothioyl)thio)butanedioic acid Ref: PAN Pesticide Database Malathion CAS121-75-5 • The most commonly used insecticide • EPA estimates that annual use of it is over 30 million pounds • Inhibits a CNS enzyme called acetylcholinesterase (AChE) • Cause over-excitation of synaptic neuron • Confirmed mutagen, suspected carcinogen • Other effects: immune system, sperm activity and hormone system

  19. 2.3 Carbamate Pesticides Carbamates are effective insecticides by virtue of their ability to inhibit acetylcholinesterase (AChE) in the nervous system. The carbamylation of the enzyme is unstable, and the regeneration of AChE is relatively rapid compared with that from a phosphorylated enzyme. They are less dangerous with regard to human exposure than organophosphorus pesticides.

  20. Examples of Carbamate Pesticides Aldicarb Carbofuran Acute intoxication symptoms:dizziness, sweating, laboured breathing, unconsciousness, vomiting, pupillary constriction, muscle cramp, excessive salivation Carbaryl

  21. Aldicarb, 2-methyl-2-(methylthio)-propionaldehyde O-methylcarbamoyloxime Ref: PAN Pesticide Database Aldicarb CAS116-06-3 • Control mites, nematodes and aphids by applying directly to the soil • USEPA estimated that 5.2-5.6 million pounds of aldicarb were used nationwide • Reversibly inactivate acetylcholinesterase • Highly toxic insecticide (more potent than malathion) • Little evidence on mutagenicity / carcinogenicity • Suppress immune system

  22. 2.4 Pyrethroid Pesticides Natural Pyrethrins is a botanical insecticide made from Chrysanthemum flowers while Pyrethroids such as Cypermethrin and tetramethrin are its synthetic chemical analogues. Provide rapid knockdown effects on insects but with only little residual activity. To increase their effectiveness, a synergist - Piperonyl butoxide (PBO) is often added to the formulations. Toxic to fish and other aquaticorganisms, they must be used carefully so as not to contaminate the waterbodies.

  23. Examples of Pyrethroid Pesticides Cypermethrin Tetramethrin Allethrin

  24. 2.5 Take home exercises • Make a table to summarize the types of chemicals, general properties of pesticides and their biological targets. • Compare and explain the chemical structures and toxic targets of OPs and OCs. • Are carbamates safer than Ops and OCs? Why?

  25. 3. Trace Organics: chemicals and their receptors Polychlorinated aromatic hydrocarbons, PAHs • Products of tobacco smoke and combustion of fossil fuels • Benzo-a-pyrene as a representative chemical • They undergo primary (Phase I) and secondary (Phase II) detoxification steps and metabolism • Could become DNA adducts causing DNA damage and point mutation • As chemical carcinogens, leading to mutation of oncogenes and cancer.

  26. 3. Trace Organics: chemicals and their receptors Dioxins • Polychlorinated dibenzo-p-dioxins form a group of 75 congeners, including the most toxic compound TCDD, 2,3,7,8- tetrachloro dibenzo-p-dioxin. EPA limit in drinking water is 0.00003 mg/L (ppm). • FDA limits for seafood: 50 ppt. • Waste water discharge limit: 0.5 ppt. • Air: 4-5 ppt or 45 ppt , related to climatic conditions. • US daily intake (estimated): 20 X 10 –12 g/kg bw. WHO data: 1 – 4 pg/kg/day (tolerable daily intake).

  27. o Cl x Cl y o o Cl Cl o Cl Cl 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) The most toxic dioxin ! 3. Trace Organics: chemicals and their receptors Dibenzo-para-dioxin structure formula and numbers of chlorinated isomers No. of chlorines (x+y) No. of isomers 1 2 2 10 3 14 4 22 5 14 6 10 7 2 8 1 Total 75 Adapted from IARC et al, 1997

  28. 3. Trace Organics: chemicals and their receptors A wider group of related compounds considered as dioxin-like: PCDFs (polychlorinated dibenzo furans), PCBs (polychlorinated biphenyls), diphenyl ethers, naphthalenes, etc. 1 9 O 3’ 3 2 2’ 2 8 4 4’ 7 3 Cly Clx O Clx Cly 4 6 5 6 6’ 5’ Polychlorinated dibenzodioxins (PCDDs) Polychlorinated biphenyls (PCBs) 9 1 2 8 3 7 O Clx Cly 4 6 Polychlorinated dibenzofurans (PCDFs) Benzo[a]pyrene

  29. 3. Trace Organics: chemicals and their receptors 1 9 O Cl Cl 2 8 7 3 Cl O Cl 6 Benzo-[a]-pyrene 4 TCDD, 2,3,7,8 Tetrachloride Dibenzo Dioxin NH 3-methylcholanthrene NH Indolo[3,2-b]carbazole found in plants and diets CH3

  30. 3. Trace Organics: chemicals and their receptors Characteristics of dioxins • Low vapor pressure and water solubility; lipid soluble • Persistent, chemically stable • Bio-accumulated in lipid, highly lipophilic • long half-life (5-10 years in human) • high affinity on Aryl hydrocarbon receptor (AhR)

  31. Mechanism of intracellular actions of dioxins and dioxin-like compounds 3. Trace Organics: chemicals and their receptors n: nuclear pore factors p23 Hsp90 n dioxin unoccupied AHR Ah receptor CYP1A1 Hsp90 ER n CYP1A gene induction ARNT AHR AAA AAA heterodimer n AHR AHR DRE n ARNT ARNT Cytosol Nucleus CYP 450

  32. 3. Trace Organics: chemicals and their receptors Anti-estrogenic effects of TCDD • It was found that testosterone (a male hormone) levels DECREASED in small numbers of workers occupationally exposed to TCDD with serum TCDD concentrations of 20 pg/g blood lipid (Egeland et al., 1994). • Speculative of lower sperm counts in European countries to be related to higher dioxin levels. • Lower T4:thyroxine binding globulin ratio and plasma thyroid stimulating hormone levels related to high PCDD and TEQ.

  33. 3. Trace Organics: chemicals and their receptors Estrogen Receptors • Environmental estrogens stir debate. • Would chemical compounds being modified in living organisms become estrogen receptors mimics? • Would those chemical compounds, when accumulated, cause deficiency in reproductive system in making estrogenic effects in males (lower sperm count) or lower the estrogenicity in females (reduced egg production)? • Evidence found in mice, marine organisms and fish. How about human beings? Ans: Not fully understood.

  34. 3. Trace Organics: chemicals and their receptors Proved Xenoestrogen • Chlorinated organic compounds, e.g. Atrazine, Chlordane, DDT, Endosulfan, Methoxychlor, PCBs. • Plastics, e.g. Bisphenol A, nonylphenol (plastic softener). • Pharmaceuticals, e.g. Cimetidine (dopamine receptor blocker for ulcer treatment), synthetic estrogens (for birth control). • Aromatic hydrocarbons (from vehicle exhaust).

  35. 3. Trace Organics: chemicals and their receptors Environmental Estrogens!? Estrogens PCBs

  36. 3. Trace Organics: chemicals and their receptors Adapted from Kuiper et al., 1998. Sci. & Med. 5(4):36-45.

  37. 3. Trace Organics: chemicals and their receptors Inactive Receptor Active Receptor Estrogens Anti-estrogens Hormone Binding Region DNA Binding Region Other estrogenic compound Target Gene

  38. Adapted from Kuiper et al., 1998. Sci. & Med. 5(4):36-45. Tamoxifen: a partial anti-estrogen in use as a breast cancer therapeutic 3. Trace Organics: chemicals and their receptors

  39. Environmental estrogens are able to bind to estrogen receptors as mimic to enhance or reduce (anti-estrogenic) the activation of target genes. ERs forming homo- (αα or ββ) heterodimers (αβ) Other estrogenic compound Target Gene Estrogen, e.g. 17β estradiol. 3. Trace Organics: chemicals and their receptors

  40. Compound A Receptor for A e.g. AhR metabolised to B-like compound Inhibits? Enhance ? Receptor for B e.g. ER Compound B Q: Compare and contrast the structure and function of ER and AhR. Explain why some dioxin and PCBs are ligands of AhR, but could also be considered as an environmental estrogens.

  41. Adapted from: Ruegg et al., 2008. The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen β-selective co-activator, and its recruitment to alternative pathways mediates anti-estrogenic effects of dioxin.Mol. Endocrinol. 22:304-316. Adapted from: Matthews et al., 2005. Aryl hydrocarbon receptor-mediated transcription: ligand- dependent recruitment of estrogen receptor α to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters.Mol. Cell. Biol. 25:5317-5328.

  42. 4. Toxic effects and risk Assessment of trace organics • Dioxin has different toxicities on animals. • Sub-lethal effects are of major concern. • What mechanism of dioxins would take to cause their toxic effects? • How dioxins affect cell at the molecular level? • What component of cell can recognize dioxins? • It the most toxic compound known to human, what can we do to assess our risk to this compound?

  43. 4. Toxic effects and risk Assessment of trace organics Acute Toxicity of TCDD: species specificities Adapted from Tschirley et, 1986

  44. 4. Toxic effects and risk Assessment of trace organics DIOXINS & Chloracne • 1899, chloracne • Agent orange used in Vietnam war • Users and victims suffered from chloracne • PCBs and dioxins caused chloracne • Mechanisms not known, believed to be related to the halogens. • Causing dilations of the infundibular or suprafollicular area of the hair follicle with hyperkeratinization (accumulation of keratin and sebaceous gland secretion)

  45. 4. Toxic effects and risk Assessment of trace organics Chloracne is an occupational dermatosis with numerous acne form lesions located on the face and neck behind the ear. Follicular Hyperkeratosis: mouse skin treated with tetrachlorobiphenyl (Puhvel et al., 1982)

  46. 4. Toxic effects and risk Assessment of trace organics Ukraine President Yushchenko was suffering from a Dioxin intoxication during his election, high concentration of TCDD (100,000 picograms (10-12 μg) per L (so 100 ppb)) was found in his blood, normal person could only have a few ppt. photo taken on July 6 (left) and Dec 10, 2004 showed his face with symptoms of chloracne.

  47. 4. Toxic effects and risk Assessment of trace organics Other Dioxin Contamination Accidents Happened Worldwide • 1962-1970 Agent Orange used in Vietnam war • 1968 “Yusho”, Japan • 1976 Accident in Seveso, Italy • 1979 “Yucheng”, Taiwan Adapted from Schecter et al, 1999

  48. 4. Toxic effects and risk Assessment of trace organics The “Yucheng”(油症) Incident Adapted from Guo, Yu, Hsu & Rogan, 1999. Environmental Health Perspective 107:715-719. Background: • Central Taiwan in 1979, dioxins and PCBs mixture were used in rice oil processing. • About 2,000 people were found to be contaminated and mass poisoning occurred. • Symptoms included chloracne, hyperpigmentation, and peripheral neuropathy, and the illness was referred to as “Yucheng”(油症). • “Yucheng cohort” were estimated to have consumed about 1g of PCBs and 3.8 mg of PCDFs during that time! • They were interviewed and their clinical symptoms had been detected since then. • Women have higher prevalence of anemia, headache, goiter, gum pigmentation, chloracne.

  49. 4. Toxic effects and risk Assessment of trace organics Prevalence (%) of reported diseases ever diagnosed by a physician in Yucheng and control groups in Taiwan, 1993 Adapted from Guo, Yu, Hsu & Rogan, 1999. Environmental Health Perspective 107:715-719.

  50. 4. Toxic effects and risk Assessment of trace organics Basic Concepts of Toxic Equivalency Factor (TEF) • dioxin-like compounds exist in environmental and biological sample as complex mixtures of congeners. • compare toxicology of various dioxin-like compound. • simplify risk assessment and regulatory control. • Toxic Equivalency Factor (TEF) of 2,3,7,8-TCDD is 1 • Combine PCB and dioxins together : 4 x 10 –12 g TEQ per kg bw. (TEQ = Toxic Equivalency Quotient)

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