Lec 3B_Toxicol Chem2.pdf

TOXICOLOGICAL CHEMISTRY of CHEMICALS, Cont. Toxic Organic Compounds 1 Toxic Organic Compounds Synthetic chemicals Most are derived from petroleum or natural gas Types: Polycyclic aromatic hydrocarbons (PAHs) Organochlorine insecticides Organophosphate and carbamate insecticides Organic herbicides Dioxin contaminant of herbicides and wood preservatives 2 1 Polycyclic Aromatic Hydrocarbons (PAHs) 3 Polycyclic Aromatic Hydrocarbons (PAHs) PAHs consist of fused benzene rings Examples: 4 2 PAHs - Cont. Uses: Only naphthalene is made commercially - used as precursor to plasticizers, insecticides, surfactants, etc) Other PAHs don’t have uses Source: Incomplete combustion of C-based fuel (coal, wood, diesel) - Diesel engine exhaust recently labeled “probable human carcinogen” “Tar” of cigarette smoke Surface of charred or burnt food; Smoked food NOTE: PAHs constitute 0.1% (= 1000 ppm) of airborne particulate matter 5 PAHs (Cont.) Health effects: Carcinogenic to test animals Probable human carcinogen Most notorious is benzo[a]pyrene Level in several urban sites in the Great Lakes exceeds the current guidelines Bioaccumulates in the food chain => a worrisome pollutant 6 3 PAHs (Cont.) Baird, p. 365 7 PAHs (Cont.) Mechanism of PAH carcinogenity: Box 6-4, p. 363, Baird Research showed that PAHs themselves are not carcinogenic Their metabolic products are carcinogenic Chemical transformation: (1) oxidation into an epoxide ring (2) Subsequent hydration produces the active carcinogen + H2O Addition of H+ forms a stable cation that can bind to DNA, inducing mutations and cancer carcinogen 8 4 PAHs (Cont.) Environmental Chemistry of PAHs: Transport in the atmosphere ≤ 4 fused ring remain gaseous Form degradation products upon reaction with free radicals in the air > 4 fused ring have low vapor P Condense and adsorb onto surface of soot and ash They become respirable 9 PAHs - Environmental Chemistry (Cont.) Transport in the hydrosphere Creosote, a coal tar derivative used as wood preservative, contains PAHs Used in fishing docks (immersed in water) PAHs leach out Water pollution (Lobster, fatty tissues of fish, whales) Oil spills from tankers, refineries and off-shore drilling sites also cause pollution of water with PAHs 10 5 Organochlorine Insecticides 11 Organochlorine Insecticides NOTE: The following information were taken from Baird, C. “Environmental Chemistry, 2nd ed. (2003), pp. 297-. Characteristic properties Stable towards environmental degradation Low solubility in water Properties responsible for their High solubility in fatty materials bioaccumulation (hydrocarbon-like) in living matter Relatively high toxicity to insects Low toxicity to humans 12 6 Organochlorine Insecticides (Cont.) Example: HCB or hexachlorobenzene Used as fungicide for cereal crops after WWII Extremely persistent => Led to its widespread env’l contamination Toxicity effect: Carcinogenic to lab rodents Probable human carcinogen 13 Organochlorine Insecticides (Cont.) DDT or para-dichlorodiphenyltrichloroethane Historical perspective: 1939: Paul Müller (Swiss) discovered DDT as insecticide [He later received the 1948 Nobel Prize in medicine and physiology] 14 7 DDT – Cont. Historical perspective: (Cont.) During WWII DDT was used to combat insect-transmitted illnesses Malaria Transmitted by mosquitoes Yellow fever Typhus => transmitted by body lice Plague => carried by fleas W.H.O. estimated that > 5M lives have been saved by DDT 15 DDT – Cont. Historical perspective: (Cont.) After WWII, DDT became widely used as insecticide (accounted for 80 % of manuf. DDT) Fruit trees Vegetables Cotton 16 8 DDT – Cont. Desirable properties of DDT as insecticide Persistent chemical One spraying lasted for weeks or years (depending on method of application) Persistence due to its: Low vapor pressure (low volatility) Resisted Low reactivity to light and degradation; microorganisms transport Low solubility in water 17 DDT – Cont. Environmental effects of DDT Persisted in soil for several years Biomagnified in the food chain Some insect populations developed resistance Affected the reproductive abilities of birds Metabolic prod. interfered with a Ca-regulating enzyme Very thin shells; Baby bird unable to survive 1962: Rachel Carson (biologist) published the “Silent Spring” Env’l problems associated with DDT 1973: EPA banned all DDT uses (except those essential to public health) 18 9 Accumulation and fate of DDT 19 DDT – Cont. Accumulation and fate of DDT DDT levels accumulated in fatty tissues => higher levels in older trout 20 10 Accumulation and fate of DDT DDT in humans is slowly eliminated Stored in human fat mostly as its metabolic product DDE Source: Toxic Chemicals in the Great Lakes and Associated Effects, vol 1, part 2. 1991 Ottawa, Canada: Minister of Supply and Services. 21 Organochlorine Insecticides - Analogs to DDT DDT Analogs Same insecticidal properties as DDT Reasonably biodegradable No bioaccumulation Best known is methoxychlor (insecticide) Used domestically and in agriculture Controls flies; mosquitoes 22 11 Other Organochlorine Insecticides Lindane Contains one of 8 isomers of hexachlorocyclohexane Called gamma isomer = has insecticidal properties Same isomer in medical preparations for lice and scabies control Treatment of seeds and seedlings 23 Other Organochlorine Insecticides – Cont. Chlorinated cyclodienes Aldrin, Dieldrin, Chlordane, Heptachlor, etc. Used to control various pests: Fire ants; cockroaches; termites; locusts Undesirable properties Persistent chemicals; Bioaccum. due to solubility in fatty tissues Chlorinated Caused liver cancer in test animals cyclodienes Some are teratogenic Prohibited use in the U.S. 24 12 Modern Insecticides: Organophosphates and Carbamates 25 Organophosphate Insecticides - Esters, amides, or simple derivatives of phosphoric acid Nonpersistent Decompose within days or weeks Much more acutely toxic to humans and other mammals than are organochlorines Function as nerve poisons to insects Inhibit enzymes in the insects’ nervous system 13 Organophosphate (Cont.) Undesirable properties Exposure by inhalation, swallowing or absorption th/ the skin can lead to immediate health problems Clinical Signs (Organophospahe toxicity, http://www.michigan.gov/dnr/) Excess salivation, lacrimation, abdominal pain, vomiting, and diarrhea. Bronchoconstriction and an increase in bronchial secretions Involuntary irregular, violent muscle contractions and weakness of voluntary muscles. Death occurs as a result of respiratory failure. Concentrates in fatty tissues 27 Carbamate Insecticides Carbamates Nonpersistent Decompose upon reaction with water, forming nontoxic products Low dermal toxicity Examples: Carbaryl; Aldicarb; Carbofuran Lawn and garden insecticide Low toxicity to mammals Toxic to honeybees 28 14 Naturally-Occurring Pesticides 29 Natural Insecticides Manufactured by plants as defensive mechanism against insects Examples: Nicotine; Rotenone; Pheromones and Juvenile hormones Pyrethrins Obtained from crysanthemum (certain species) Have been used by humans for centuries Ex. Ground up dried flower heads used to control body lice during the Napoleonic times Paralyze insects (like organophosphates) 30 15 Pyrethrins (Cont.) Desirable properties Generally safe to use Mode of action: Cause paralysis on insects Undesirable properties Photodecomposition Synthetic pyrethrins = designed to withstand sunlight Outdoor application Names end in -thrin: Ex. Permethrin 31 Organic Herbicides 32 16 Herbicides Prior to use of organic pesticides: Inorganic compounds like sodium arsenate were used as weed-killers Toxic to humans; Persistent chemicals Organic pesticides now dominate the market High selectivity for certain plants Leave other plants unharmed 33 Organic Herbicides Triazines Alternating N & C atoms in a six-membered ring Useful triazine herbicides contain Cl and -NH2 or -NHR groups bonded to the ring carbon (next slide) 34 17 Triazines (Cont.) Best known is atrazine Atrazine Mode of action (as herbicide) Blocks photosynthesis Higher plants (e.g. corn) are not affected because they rapidly degrade atrazine 35 Atrazines (Cont.) Uses Kills grassy weeds in corn and soybean fields Undesirable properties Concentrations can build up in dry soil => No moisture to degrade it Can eradicate all plants High levels used to clear vegetation to create parking lots Widespread use can kill sensitive plants in water systems close to agricultural fields A possible human carcinogen (EPA list) 36 18 Other Organic Herbicides Phenoxy herbicides Introduced as weed-killers after WWII Prepared from phenol Examples: 2,4-D and 2,4,5-T 37 Phenoxy Herbicides (Cont.) 2,4-D & 2,4,5-T Uses 2,4-D: Control of broad-leaf weeds in lawns, golf course greens and agricultural fields 2,4,5-T: Clearing bush on roadsides and power line corridors Undesirable properties Increased incidence of the cancer non-Hodgkin’s lymphoma among farmers in the Midwest who applied large quantities of 2,4-D 38 19 Dioxin Contamination of Herbicides 39 Cause of Dioxin Contamination Synthesis of 2,4,5-T Do this on the board 40 20 Cause of Dioxin Contamination (Cont.) Trichlorophenol is a weak acid Ionizes to a small extent into trichlorophenoxy ion Self-reaction of phenoxy ion at high T produces “dioxin” High T and high [phenoxide] => higher levels of dioxin formed Structure of real dioxin 41 Dioxin Contamination: Historical Perspective Agent Orange A 1:1 mixture of 2,4-D and 2,4,5-T Used as defoliant during the Vietnam war Contains about 10 ppm dioxin as contaminant! HOW come? http://www.landscaper.net/agent.htm 42 21 Dioxin Nomenclature The three-ring unit is called dibenzo-p-dioxin Carbons shared between 2 rings (and thus are not bound to H) are not numbered --- can’t take any more substituent C #ing follows a clockwise pattern from C-1 43 Dioxin Congeners Congeners Members of a chemical family that differ only in the number and position of the same substituents There are 75 dioxin congeners 44 22 Dioxin: Health and Environmental Effects Health Effects One of the most toxic of all synthetic substances to some animals LD50 of 0.6 ug/Kg body mass in male guinea pigs The type and degree of its toxicity to humans is largely unknown Known to cause a severe skin condition called chloracne Environmental Effects A stable, persistent environmental pollutant Emission product from incineration of organochlorine compounds 45 Dioxins “Dioxin” is a general term for a group of hundreds of chemicals that are highly persistent in the environment. The most toxic compound is 2,3,7,8-tetrachlorodibenzo-p- dioxin or TCDD. TCDD structure. Image available at http://www.greener- industry.org/pages/chlorine/3chlorine_Issues. htm Reference: Dioxin Homepage at http://www.ejnet.org/dioxin/ 46 23 Dioxins Dioxin is formed as an unintentional by-product of many industrial processes involving chlorine, such as: Waste incineration, Chemical and chlorinated pesticide manufacturing, Production of polyvinyl chloride (PVC) plastics and Pulp and paper bleaching Dioxin was the primary toxic component of Agent Orange, was found at Love Canal in Niagara Falls, NY and was the basis for evacuations at Times Beach, MO and Seveso, Italy. Reference: Dioxin Homepage at http://www.ejnet.org/dioxin/ 47 In January 2001, the U.S. National Toxicology Program upgraded 2,3,7,8-TCDD from "Reasonably Anticipated to be a Human Carcinogen" to "Known to be a Human Carcinogen. Reference: Dioxin Homepage http://www.ejnet.org/dioxin/ 48 24 Levels of Dioxin in Food Supply (N. America) Image available at http://www.nrdc.org/breastmilk/diox.asp 49 Figure 7 shows that dioxin and furan levels in breast milk collected between 1996 and 1999 from women in the Aluoi Valley in central Vietnam were about six times higher than those in breast milk collected in 1988 in the city of Hanoi in northern Vietnam, where no Agent Orange was sprayed Image available at http://www.nrdc.org/breastmilk/diox.asp 50 25 Polychlorinated Biphenyls (PCBs) 51 Structure and Properties of PCBs Structure An example of a PCB molecule is: Ring C #ing similar to dioxins Properties High chemical, thermal and biological stability Low vapor pressure Insoluble in water; Soluble in fatty/oily substances Inexpensive, yet excellent electrical insulators 52 26 Uses of PCBs Coolant-insulation fluids in transformers and capacitors Plasticizers = agents used to make other materials more flexible Deinking solvent for recycling newsprints Heat-transfer fluid in machinery 53 Environmental Contamination of PCBs From PCB-containing discarded electrical equipment Incineration plants --- since PCBs escape as vapors Waste discharges from capacitor manufacturing plants Source of PCB contamination in the sediments of Hudson River Bioaccumulated in fish and other aquatic organisms 54 27 Environmental Contamination of PCBs 55 Environmental Contamination of PCBs 56 28 Aside: Toxic Alkaloids Alkaloids are naturally-occurring complex amines, usually isolated from plants Medical uses of alkaloids Stimulants – Ex. Caffeine, Nicotine Analgesic – Ex. Morphine, Codeine Tranquilizers Other properties Addictive Narcotics – Ex. Morphine; Heroin Some are toxic – Coniine (cup of hemlock); Nicotine 57 Alkaloids (Cont.) Some alkaloids from nature: The opium poppy “Incisions in the seed capsules of this plant yield a milky sap. When air-dried and kneaded, the sap forms a soft material known as opium, which contains opioids, a class of alkaloids known for their pain-killing and tranquilizing effects.” Source: J. Suchocki. “Conceptual Chemistry,” Addison Wesley, San Francisco: 2001. Chapter 14 opening photograph, p. 436 58 29

Lec 3B_Toxicol Chem2.pdf

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