Toxicology

Cancer-Can Anything Cause it? -History of Cancer; prehistoric times-notice acute effects cancer=a disease characterized by abnormal cells that grow and divide uncontrollably ultimately invading and destroying adjacent tissues Carcinogens=soot-scrotum-Pott-1775 first real solid pieces of evidence of chronic; pipe smoking-lipssommering; coal tar-skin-volkman, dye intermediates-bladder-rehn, x-rays-skin, tobacco juices-oral cavities; radioactive watch dial dyes-bono; sunlight-skin; tobacco (cigarrette smoking)-lung; asbestospleura; cadmium-prostate Atom bomb testing caused cancer after a one time event 20 years later to find what caused you cancer you need to negate everything in between that didn't prop 65 in gas pumps (benzene) and starbucks for krillimite is a carcinogen Causes of Human Cancer Deaths-tobacco-30% or 25 to 40%, alcohol 3%-2-4%; diet 35% 10-70%; reproductive and sexual behavior=7%-1-13%; food additives less than 1%; pollution-2%; industrial products-less than 1%, sunlight, uv-light other radiation-3%; medicine, medical procedures-1% old watches. Aluminous dials of watch be flurescent by painting radium on dials. Radium goes to bones and gets stuck there and radiates from inside which leads to bone cancer. Char-broiled food is in tobacco smoke and carcinogenic Mutation-damage by chemical or sunlight dna. Damage is usually lethal/natural selection Dna-oncogenes which are responsible for cell division. When go out of control a problem Carincogen-cheimcal that causes cancer by any means Genotoxic carcinogen-chemical that causes cancer by directly reacting w/ DNA to cause a change in its function Not all mutagens are carcinogens (part of natural selection) and not all carcinogens are mutagens (epigenetic carcinogen) Two types of carcinogens we deal with are genotoxic carcinogens and an epigenetic carcinogenchemical that causes cancer by non-genetic means (no direct interaction w/ DNA or attack) DNA-replication; transcription to RNA then translation to protein liver transfers chemical into chemical that causes cancer; most times it destroys (detoxification). DEFENSE MECHANISMS If it gets activated the liver can still destroy it. When in bloodstream it goes in portal vein and the first organ the chemical goes to is the liver to filter and destroy all toxic chemicals. Immune system attacks damaged cells (DNA repair). Can use surgery against cancer; metastasis-tumor spreads in bloodstream to other parts of body liver makes epoxide which is what attacks dna in benzopyrene body suffers 2million mutations a day. Repair efficiency is above 99% but decreases with age development of cancer following mutagenesis is very rare impaired repair mechanisms can lead to development of cancers at an early age benign tumors-tumors that contain cells like normal cells; don' invade or destroy adjacent tissues, just dangerous from getting too big malignant tumors-tumors different from normal cells; invade and destroy adjacent tissues sarcoma-cancer that arises from supporting or connective tissues (muscle) melanoma-cancer that arises from the pigmented cells of the skin (containing pigment melanin) Carcinoma-cancer that arises from epithelial cells (covering body or tissue surfaces) lymphoma- cancer that arises from the cells of the lymphatic system International Agency for Research on Cancer-a part of the WHO it classifies carcinogens based upon available scientific information. Classifications are regularly updated. Based on weight of scientific evidence with human evidence the most. 39 known human carcinogens classification-low 1 IARC=human carcinogen and EPA is A with sufficient human data; 4 and E is not carcinogen no human data. 2=possible human carcinogen

Industrial Chemicals Both synthetic and natural chemicals can be easily just as bad First person to identify chemicals in occupation are toxic was Greek historian named Stravo or Strabo with arsenic mining is toxic to miners Mercury-inorganic and organic forms. Used as drug no medicinal value but can be used in formulations for vaccines because antibiotic. Very toxic to anything. 1700S to 1800s for beaver hats who develop tremors (nerve damage) from hand exposure and become mental. Called hatters (mad hatter) types of industrial chemicals in house-solvent (alcohol), detergent, acids/bases, reagents, plasticizers, metals, salts. Chemicals in house is domestic usage. Organic Chemicals-Hydrocarbons-alkanes (commonly found in crude oil) CH4 methane in environment derivatives of alkanes are alkenes (double bonded carbon) which is ethylene-simplest one. uble bonded carbon) which is ethylene-fruit ripening. Alcohols. Hydrocarbons with OH on them. Symptoms of Methanol Intoxication is inebriation and drowsiness, dizziness, abdominal pain and vomiting, breathing difficulty, blurred vision and dilated pupuils, blindness. General solvent effect=drowsiness, dizziness, breathing difficulty any solvent does over time Solvent-Glycols. Ethanol-acetaldeayde-acetic acid (calories) Ethylene Glycol-oxacic acid (goes to kidney and brains and crystallizes (grow rocks in your brain!!)) PAH structures-aromatic hydrocarbons Major symptoms/ signs of methanol intoxication-inebriation and drowsiness (early onset), dizziness, abdominal pain and vomiting, breathing difficulty, blurred vision and dilated pupils, blindness, urinary formaldehyde odor Inorganic chemicals-positively charged ions like Lead, Mercury, Arsenic. Replace natural cations body uses for normal function like sodium, potassiu, calcium DNA has a negative charge to it so the metals can bond to DNA and serve as mutagents Lead-Roman empire fell in part due to severe lead poisonings Nickel and Cadmium in batteries when disposed of release the two in environment where they can get into groundwater and waterways and into drinking water Methyl mercury is fat soluble and accumulates in food webs Asbestos Fibers are toxic in lungs. Very tiny particles get to deepest parts of lungs and hang in tissues, leading immune system to kill tissue in lungs-asbestosis. Can get cancer-mesothelioma more than 99% pesticides humans exposed to are natural pesticides organic chemicals-neurotoxic to carcinogenic organic chemicals-neurotoxic to carcinogenic inorganic chemicals-neurotoxicity to liver and kidney damage HERP values-higher value the higher the human exposure is relative to the dose that gives tumors to rodents

Poisons Properties of ideal poison-undetectable by senses, soluble, delayed effect, easily obtained, not traceable, symptoms mimic actual disease, chemically stable, undetectable by instrumentation, potent advantages-silent, precise targeting, depersonalized, safe for attacker ethylene glycol-sweet odorless chemical in antifreeze can be put in foods like jello acrylamide-nervous system problems. In construction used acrylamide to seal tunnel but workers got affected and found in ground water potencies of poisons-botulinum toxin-.05 mg, ricin-.5mg, sodium cyanide-250mg a dime is 2300mg sources of poisons-commercial, laboratories, underground catalogs, antique drug collections, hobbies/natural sources like plants pesticide poisons of note-synthetic=organophosphates, carbamates, paraquat, fluoroacetate. synthetic=oleandar, poison hemlock, mushroom, ricin, atropine/belladonna, nicotine, cyanogenic glycosides top 5 homicidal poisons-arsenic 31%, cyanide 9, strychnine 6, morphine 3, chloroform 2 poison symptoms-constricted/dilated pupils (opiods, organophosphates), breath odor (arsenic-garlic), hair loss (thallium), convulsions (strychnine), paralysis (botulism), coma (depressants, hypnotics), skin color (co-cherry red; nitrites-blue), skin appearance (arsenic-hyperkeratosis, warts) (dioxin-chloracne) candies may include melamime autopsy samples-organs (brain, liver, kidney, muscle), blood (heart, peripheral), vitreous humor, bile (insoluble metabolites), urine (soluble), gastric contents (alkaloids), hair, bone, maggots motivation-love, money, power, random Environmental sources of poisonings-natural (arsenic in well water, marine toxins), accidents (pcb, pbb, mercury in iraq), adulteration (cooking oil), commercial activity (mercury, lead) Harmful algal blooms- thought increasing due to coastal pollution and ocean warming. Domoic acid -amnesic shellfish poison. Human effects-disorientation, loss of short term memory (moderate doses), fail at high doses PCB and PBB-mass poisonings from cooking oil concentration. Livestock die and cause bird beak to twist black market has lots of counterfeit pharmaceuticals

Plant Toxins Chemical warfare to avoid predation (can't run or hide) Plants use avoidance strategies like spines, irritant fuzz, thick tough surfaces, and chemicals (noxious forms, irritants and lethal) Witch Legend from Jimson weed (thornapple-atropine) put between legs and lead to hallucination feel like flying. sabbat=mental hiatus “Deadly” Nightshade Family-lot of toxic species Datura-jimson weed, thornapple Brugsmania-angel's trumpet (colorful insects on skin) Solanum-nightshades, potatoes (war gas-like toxins) Nicotiana-tobacco (stimulant insecticide) Nonpoisonous of nightshade family include tomatoes, pepper, eggplant Plant Toxin Alkaloid-nicotine Cyanide-hydrocyanic acid (bitter almonds) glycosides (sugars) esters (alochol) pencilbruhs lactones-cyclic esters (limes) phenols-alcohol form of benzene Food plants

Potato (solanine-nerve paralysis from green parts) Cacao bean/kola nut and coffee and tea(caffeine)-(nerve stimulants) Mango-causes skin rashes lime/celery-juice in sun will change to be skin irritant (phototoxic) lima bean/bitter almond (blocks cell metabolism) shut respiration down have cyanide Buttercup-protoanemonin (skin rash in milky sap) poison oak-laccol (allergic contact) stimulates immune system soap tecmu counters has petroleum and soap stinging nettle-histamine in needles when you grab its put into skin. skin rash bees or pollen also lead to histamine cells can release it too angel's trumpet-scopolamine-used for motion sickness (nerve paralysis) nightshade-solanine (nerve paralysis) oleandar-oleandrin (heart paralysis) clogged pipes and heart swells due to extra blood lupine-anagyrine (birth defects for livestock) dumbcane-oxalate effect to brain and kidney make slaves chew on it and make severe swelling of throat and tongue so couldn't speak philodendron-philodendrol milky sap cause allergic reaction with rash pencilbush-ester rash crown of throwns-skin rash tulip-allergic response plant poisonings-in California are 10,000 a year 90% are children under 5 top 5 poisonings-philodendron, dumbcane, oleandar, poison oak, ornamental chili pepper many if not all plants have many pesticides

Animal Toxins Passive-animals are poisonous following ingestion of poisons from their diet (mucus in skin when bit) defensive Active-animals that deliver venoms by specialized structures, such as fangs, stingers, spines, etc. (defensive or aggressive) Basic Actions of Venoms Hematoxic-destroy tissues by digesting proteins; either thinning or thickening the blood. (blood system/stream)-proteolytic (proteo=protein lytic=lysis(breakdown) Neurotoxic-act at neuromuscular junctions to cause skeletal muscle paralysis (shortout function of lungs, brain, etc.) Cardiotoxic-act to selectively paralyze the heart, causing heart failure Classes of Venomous Animals Marine Cnidarians Cnidarians-jellyfish, sea anenomes, portuguese men-of-war Stinging nematocysts within cnidoblast cells-used for defense predation, locomotion. On surface of skin and brushing against trigger stimulates nematocyst to shoot out and inject discharged thread into skin. responsible for sticky feeling of anemones box jelly fish has a cradiotoxic and necrotoxic venom (necrosis-tissue death) vinegar inactivates venom (weak acids).

molluscs-gastropods (conch); 85 species -cone snail is conch with harpoon-like tooth to spear fish with conotoxin -conotoxins cause nerve paralysis, nausea, speech difficulties -blue-ringed octopus venom kills in minutes via respiratory paralysis with tetrodotoxin (TTX)neurotoxin reptiles-snakes and lizards -45,000 ppl bitten in U.S. But 15 die yearly -antivenin-substances that counteract toxicity of venom -2 venomous lizards include Mexican bearded lizard and Gila Monster (grind venom into tissue) -snake families include elapidae-coral snakes (highly toxic with neurotoxic venom and red on black has no venom but red on yellow does), kraits and cobras (neurotoxic causes skeletal muscle paralysis) has bungarotoxins; viperidae-old world vipers; crotalidae-rattlesnakes (neurotoxic and proteolytic, has heat-sensing pits in head and have long hinged fangs) water moccasins, copperheads -Venoms are specialized saliva containing hundreds of proteins (subcutaneous=bite into skin, intravenous=right into vein; LD50 is lower for intravenous die more) -Ingestion-less toxic than if ingested in skin because of stomach acid. Proteins are digested and destroyed. Amphibians-frogs (bufonidae)-produce bufotenin which cause hypertension and hallucinations but dendrobatidae of frogs produce batrachotoxin and others which cause skeletal muscle paralysis) and toad venom is produced in skin glands it is cardiotoxic and causes pain and inflammation. fishes-700 species. Ichthyotoxism-ichthyosarcotoxic-fishes that contain toxins from ingestion (take from other organisms (boxfish/puffer fish) by eating plankton or bacteria they have tetrodotoxin, ; ichthyootoxic-fishes that produces toxins in gonads (eggs); ichthyohemotoxic-toxins in blood; ichthyocrinotoxic-fishes that secrete venoms from skin glands; ichthyovenomous fishes (defensive ones like scorpion fish and stonefish can cause intense pain, cardiac failure, limb paralysis) anthropods-spiders, scorpions, bees, etc. all 30,000 species of spiders venomous (200 deaths worldwide yearly) Hymenopterans (bees,wasps, hornets, yellow jackets, ants)-cause allergic reactions (anaphylactic shock). Venoms are mixtures of enzymes and histamine. Black widow-neurotoxic and one of most potent venoms known, dose too small to kill average healthy adult Brown recluse spider-necrotoxic (destroys tissues, blood vessels, blood cells) and painful lesions may take month or so to heal Sydney funnel web spider-large and aggressive with massive fangs that can pierce fingernails, firmly grip victim and bite repeatedly, atraxotoxin stimulates the nervous system causing painful muscle spasms, high blood pressure, and cardiac arrest, death results in 2 hours Scorpions-all species are poisonous, venoms contain neurotoxins, enzymes, and histamine. Cause intense pain swelling of face, high blood pressure, rapid heart rate and breathing and cardiac arrest Bees, wasps, yellow jackets-venom made of enzymes and histamine, responsible for most human deaths via anaphylactic shock-cardiac failure. Chemical Warfare Agents Chemical Warfare-any chemical used to kill, injure or incapacitate, also used to influence thoughts and actions. Common targets are humans, commerce, animals, crops, and physical materials Use them because simple and inexpensive to produce in large quantities, easy to disseminate to cause large casualty numbers, easy to produce fear and panic in an enemy -about 70 agents used in past century, used in colonial times by european powers to suppress rebellions (dumbcane)

-first used extensively in world war I by the german army to break trench warfare -minor casualties but psychological impact great -widespread military use avoided due to lack of effectiveness Chemical Agent Efficacy-many agents are gases, vapors, or aerosols (airbourne droplets), subject to environmental and weather conditions-pivotal factor, often effectiveness is difficult to control (can turn on you and air can make you run!) -Blister Agents-both sulfur and nitrogen mustards are blistering agents-target lungs, skin, eyes (mutate dna), as vesicants-they produce large blisters, caused largest proportion of casualties from chemical agents, stockpiled by Nazi Germany during WWII but not used, used by iraq against iran Arsenicals (lewisite)-synthesized prior to WWI named for Winford Lee Lewis who first attempted synthesis, stockpiled by US not actually used in either WW, familiar odor, relative of arsine gases used by industry today (clump of arsenic containing gas) vesicants -Blood-acting agents include arsine, hydrogen cyanide, cyanogen chloride; often spread as aerosols they work via ingestion or inhalation, prevent transport of oxygen by blood hemoglobin or oxygen's use by cells (respiration) ultimately cause asphyxiation; may have scent of almonds or garlic, fast acting, severe effects include convulsions, coma and death Pulmonary (choking) agents-via inhalation cause fluid build up in the lungs resulting in suffocation. Chlorine gas was first used via artilerry shells by British in the Crimean War and the Union in the Civil War (1850s and 60s), In WWI germans use against french in 1915 to stop trench warfare. Pale green gas reacts with water to form Hcl and hypochlorous acid. Replaced by phosgene in 1917 Phosgene-another choking agent, colorless heavier than air gas, causes massive fluid buildup in the lungs (edema), introduced by germans caused 80% of all deaths due to chemical agents in WWI, used by Japanese against Chinese during WWII, death in 12 hours, diphosgene developed which destroyed gas masks Nerve Agents-work to overstimulate nerves (severe contractions than paralysis). Include v, g, and gv series of agents. G series (tabun) accidentally discovered by IG Farben while working on insecticides. Spilled drop in lab and took 3 weeks to recover symptoms were dizziness, shortness of breath, pupil constriction. Farben discovered sarin and soman. All supertoxic G series include tabun, sarin (etc) low volatility; v series include VE, VX, and VG (low volatility); gv series include novichok gases (moderate volatility) Organophosphorous Insecticides-related to many nerve agents but much less toxic to mammals; need conversion to “oxon” to be toxic, include malathion parathion, and diazinon Nerve agents work by nerves conduct electrical signals in body and between nerves acetylcholine (transmitter chemical) transfers the signal. It is degraded by enzyme (acetylcholnesterase); agents block enzyme, causing overstimulation of nerve sarin used in iraq vs iran, iraq bombed Kurd city of Halabja. Religious group of aun shinrikyo released sarin in tokyo metro. Florine makes sarin toxic its so reactive Harassing Agents-chemicals used to control or subdue crowds, riots, or assailants; not meant to be toxic or lethal but sensory irritants (noxious); used by law enforcement and military, include agents that cause tearing, vomiting or unpleasant odors Some Harassing Agents-lachrymators cause tearing and irritate the mucus membranes-include capsaicin (pepper spray), chloracetophenone (mace), and tear gas capsaicinoids isolated in 1800s by peppers mace synthesized prior to Wwi, tear gas first discovered in 1920s Vomiting agents-include diphenycyanoarsine and diphenylchloroarsine they contain arsenic cause nausea vomiting and headaches malodorant-include skunk it is non-toxic (contains yeast and baking powder) others include virtually any sulfur-containing chemical like allicin from garlic most banned from international agreement but enforcement is difficult

Biological Warfare Agents -Motives of Terrorism is to influence thoughts or actions. Common targets are humans, commerce, animals, crops, physical materials. Use warfare agents because simple and inexpensive to produce in large quantities, easy to disseminate to cause large casualty numbers, easy to produce fear and panic. -History of Biological Warfare-500 BC Assyrians used fungi to poison enemy wells. 184 BC naval battle between Carthage led by Hannibal and King Eumenes of Perganum. Hurled vases of venomous snakes onto opposing ships Bacterium secrete toxins (large proteins made of amino acids) that illicit toxic effect on your cells. Middle Ages and the black death-throw cadavers of bubonic plague victims into cities by Mongols, Turks, and Russians. Most recent event in 1710 where Russians hurled corpses into Tallinn during war with Sweden. Plague consists of six toxic proteins. Smallpox in the New World-Francisco Pizarro gave indigenous people of South America smallpoxinfected clothing. 1500s. During French and Indian Wars (1754 to 1763) Sir Jerffrey Amherst gave native Americans loyal to the French smallpox-contaminated blankets World War I-1914 to 1918. Imperial Germany reportedly shipped livestock infected with anthrax and other pathogens to the U.S. And other Allies before entrance into war. 3 anthrax protein toxins. Absorbed by cells and cells make negative effect World War II-1939 to 1945. The Japanese biological weapons program (Unit 731) used over 3000 POWs for experiment. Over 1000 died from anthrax, botulism, cholera, gangrene infections and plague tetanus-overstimulation of muscles (tetany). Continuously contracted and won't relax. Caused by bacteria which secrete protein called tetanus toxin. 1000 died from anthra botulism, cholera, gangrene infections and plague japanese also planes scattered plague-contaminated rice over shusien, china, causing an outbreak of bubonic plague Diphtheria-shorts out nerves US established War Research Service with Merck Drug Company. Used info from Japanese unit 731. some 5000 anthrax bombs prepared but not used. General Mills engineered anthrax strain one gallon would kill every human o the planet. UK experimented with anthrax bombs in Scotland. US and UK planned to use anthrax on Germany if biological agents were used against them. Iraq in the first gulf war 1990 to 1991-iraq had 166 bombs-100 with botulinum toxin, 40 with anthrax and 16 with aflatoxin. Possessed 25 scud missiles-13 with botulinum toxin, 10 with anthrax and 2 with aflatoxin-released by fungus grown by peanuts underground (one of most potent human carcinogens). Possessed 122-mm rockets with all 3 toxins. Spray tanks fitted to aircraft to aerosolize agent. Tokyo Subway in 1995-Aum Shinrikyo released sarin (war gas) and resulted in 5500 health care visits and 12 deaths. Also tried anthrax and botulinum toxin but they weren't successful. Present Warfare Threats-In 1999 CDC developed categories of agents based on severity and communicability, weapon potential, need for vaccines, medication, detection, and ability to generate fear or terror in a target population Category A biological agents include smallpox (variola major), anthrax (bacillus anthracis), bubonic plague (yersinia pestis), botulism, tularemia, viral hemorrhagic fevers smallpox-responsible for about 100 million deaths in 20th century WHO declared eradicated in 1980 which ended vaccinations. No non-human reservoirs and no human carriers-strains remain in us and Russia. Treatment is supportive possibly cidofovir. Prevention is vaccination. Smallpox symptoms include fever, fatigue, headache, and severe rash. Lethality is moderate to high. If aerosolized 90% of virus matter will be inactivated or dissipated in about 24 hours. Anthrax-originates as a disease of herbivores. Infection via dermal, inhalation and oral routes. Spores can be delivered via wet or dry aerosol, and can disperse over a wide area. Found in envelopes sent via the US postal service. Symptoms include fever, ulcers, vomiting, respiratory distress and shock. Lethality is high and treated with antibiotics. Persistence is strong with very stable spores lasting for

over 40 years. Bubonic Plague-a bacterial disease with a rodent host and a flea vector (flea is not needed for human contagiousness). Bacillus is susceptible to UV light, heat, and drying. Former USSR created dry stable, antibiotic resistant form that could be aerosolized. Treatment include streptomycin and other antibiotics symptoms include fever, bloody cough, reduced circulations, buboes, gangrene. Lethality is high unless treated within 24 hours. Persistence up to 1 year in soil 270 days in culture. Botulism-most toxic substance known. Ld50 of .001 ug/kg. Spores found in soil but a poor weapon due to instability in water. Symptoms include drooping eyelids, double vision, paralysis and respiratory arrest. Treatment is respiratory support, antitoxins. Typhoidal Tularemia-disease common in rabbits and deer flies (rabbit fever). Contracted from tissues of infected animals, bites, inhalation. Weaponized by us in 1950 and 60s. Treatment is streptomycin and other antibiotics; resistance develops after recovery. Symptoms are fever, pneumonia, bloody cough, skin and mouth ulcers. Lethality is moderate if untreated. Persistence-months in moist soil. Viral Hemorrhagic Fevers-Animal reservoirs with arthropod vectors. Highly infectious by aerosol or infected tissues and blood. Cultures yield enough virus for an aerosolized weapon. Therapy-supportive only no treatment. Ebola and Marburg. Symptoms include fever, infection of connective tissue, loss of ability of blood to clot, lethality-moderate to high, persistence-relatively unstable, not a good weapon Category A represents biological agents Biological warfare for 2000 years Bruces Ames-1960s lotta new chemicals. Hard to test if safe or not. Ames made bacteria test instead of using mice. Ames salmonella assay-made his- salmonella (doesn't have ability to make amino acid histamine. Normal =his+ (backmutation) and radiates them so his- and see if chemicals can backmutate chemical back to normal (then chemical is mutagen) then use chemical that didn't act as mutagen and use for mice and test for chemical Pesticides-Designed Killers Pesticide is any substance used to prevent, destroy, repel, or mitigate any pesticides A pest is any harmful, destructive or nuisance organism Part of chemical warfare since beginning of time Types of pesticides include insecticides, herbicides, fungicides, bactericides, rodenticides,fumigants, nematicides In 1830, 58 hours of manpower for 1 acre of grain, now takes 2 hours. 1800S 98% US worked on farms now only 2% coffee pot sludge, blackened fish have carcinogens 1970s synthetic chemicals 50-50 1980s natural chemicals 50-50. hit rate of chemicals risk=exp/ld50 herp values for wine 4.0 poor carcinogen, root beer, apples, pear, parsnip, orange juice suppress vector-bourne diseases like tyhpus, west nile virus, yellow fever. Guarantees good harvest, prevent disease, eliminate pests like weeds 3 million cases of pesticide poisoning a year. 220,000 deaths from pesticides annually and worldwide criteria that make a good pesticide is specific for pest (targe species), readily degraded (not persistent), safe to use, relatively inexpensive (readily available) early history of pesticides-copper, sulfur, mercury, strychnine (from moonseed tree), nicotine ( from tobacco) DDT, Ld50=113mg/kg; aldrin ld50=55 mg/kg; lindane, ld50=88mg/kg organophosphorus insecticides. Malathion ld50=1375 mg/kg; diazinon ld50=100 mg/kg; parathion ld50=3 mg/kg lower ld50 is bad carbamate and pyrethroid insecticides-carbaryl, ld50=560 mg/kg. Esfenvalerate, ld50=451 mg/kg

pyrethroids-natural and otherwise. Pyrethrin I, ld50=1500 mg/kg. Bifenthrin. Lambda-cythalothrin chlorophenoxy herbicides. 2,4,5-trichlorophenoxy acetic acid production once produced dioxin in formulation of agent orange. No longer problem due to better synthesis best pesticides are highly selective and labile. Benefits include reduction of disease and starvation. Costs include impacts on non-target species. Never be perfect pesticide Chemical Sex Changes Genotypic sex-defined by X and Y chromosomes Phenotypic sex-physical expression of sexual characteristics Endocrine system-hormones which control many activities including development, reproduction and behavior Xenoestrogen-a foreign chemical with estrogenic properties Xenoandrogen-a foreign chemical with androgenic properties Steroid hormones are naturally synthesized from cholesterol and control female and male reproduction. Cholesterol. Hypothalamic-pituitary-gondal relationships control reproductive functions Endocrine disruption is an adverse effect of a foreign chemical that mimics or blocks the action of the natural hormone. hypothalamus out to pituitary which sends FSH and LH to testicle or ovary which go to sex accessory organs. Testicle sends testosterone back to pituitary and ovary sends estrogen and progesterone to pituitary for negative feedback loop to regulate. Agonist-works like natural hormone. The mimicry. Antagonist-blocks hormone. Opposite of what it would do Functions of Testosterone in Males-stimulates spermatogenesis in the testicles. Stimulate development of secondary sexual characteristics (muscle mass, hair growth, and deep voice). Stimulate development of support organs (prostate, seminal vesicles and cowpers glands), stimulate characteristic sexual behavior functions of estrogen in females. Control folliculogenesis, oogenesis, ovulation and the menstrual cycle. Stimulate development of secondary sexual characteristics (mammary glands, hair growth, and high voice), stimulate characteristic sexual behavior. Estrogen and progesterone are main factors in cycle. P and estrogen suppress ovulation like birth pills. Basic types of Endorcine Disruptors-Natural estrogens from human excretia. Excreted from sewers or from drugs Synthetic estrogens from contraceptives and hormone replacement therapy (menopause). (plants) Phytoestrogens such as isoflavonoids, coumestans, and soy proteins. Problem Endocrine Disruptors-Synthetic estrogens such as DES. PCBs. Highly persistent chemicals. Old-generation chlorinated insecticides like DDT, chlordane, aldrin, dieldrin, myrex Surfactants (detergents) such as nonylphenols TBT in Marine molluscs. Antifouling agent in paint for undersides of boats (hulls). Toxic pesticide to stop drag from nasty things sticking on hull. TBT would make female molluscs into males so it can't reproducve normally. Chlorinated Organic Chemicals and Birds. DDT cause eggshell thinning. Chlorinated organics bind to estrogen receptors to disrupt normal hormone actions. Bald and golden eagles, brown pelicans, peregrine falcons, kestrels, and herring gulls all drastically declined. DDT banned in 1972 allowing recovery of birds. DDT converted into DDE by liver or by soil microbes. Is actual endocrine disruptor that thins shells. DDT in western sea gulls. 1970S gulls of channel islands were impacted by a nearby DDT production plant (montrose chemical plant). The behavioral action-female-female pairing-resulted in the doubling of eggs per nest. Cause was thought due to a change in male gull behavior. Males get kicked out and eggs don't get incubated. Less gull babies! DDT in reptiles like Lake apopka with alligators that are impacted from accidental skills. DDE blocks

production of testosterone causing males to develop small penises and undeveloped testicles. Reduction in reproduction led to reduced populations in the 1990s. Nonylphenols and Fishes-nonylphenols have been used as detergents and pesticide solvents. They stimulate the estrogenic receptor causing production of the egg protein vitellogenin in genotypic males. First noticed in 1990s males become feminized and infertile. Also cause hermaphroditism. Impact halibut, flounder, white croaker, and rainbow trout Endocrine disruptors and humans. Average sperm count declined since 1940 from 113 million/mL to 66 million/ ML agents include lead, hydrocarbons and fumigants males are infertile when counts decline below 20 million/mL semen disruptors may block testosterone actions on spermatogenesis in females high estrogen levels late in the menstrual cycle inhibit ovulations-basis for the oral contraceptives Summary of Examples of Endocrine Disruption. Steroid hormones control reproductive processes. Endocrine disruptors can alter natural hormone levels and or actions. Many types of endocrine disruptors.

Module Readings Tobacco 160000 americans die yearly from lung cancer linear relationship between total smoke exposure and risk of cancer strong link with family history (susceptiblity genes or mutations making more vulnerable) women more vulnerable because of estrogen for chance of survival of years with lung cancer in stages look here Iressa and Tareeva work to hold tumors at bay Cancer smoking=30% of cancer deaths cancer is decreasing now except for blacks increase of cancer include high fat diet, obesity, lack of exercise. Lifestyle makes cancer more or less as well as bad genetics

to learn how cancer works and tumors form read here types of cancer and how to diagnose and treatment is here Industrial Chemicals Bruces Ames-Ames test-quick cheap way to identify industrial carcinogens. Uses mutated bacteria . Animals have defenses against a lot of plant defense chemicals by repairing DNA cells and get rid of damaged cells (surface cells disposed of new ones replace) HERP=daily human exposure dose/rodent potency dose, estimated daily dose of a chemical that will cause cancer in one half a group of animal and compare with estimated daily dose a human gets. Natural chemicals are just as dangerous Tobacco Study of effects of tobacco on health involves a wide range of important toxicological issues. These include the lung as a target and portal of entry to the rest of the body, the nature of evidence linking exposures to disease, multiple adverse effects of tobacco smoke, the biology of cancer in the lung and elsewhere, toxicity (especially cancer) testing in animals, and regulation of the largest cause of preventable death in the USA. Topics not covered in detail include chronic obstructive lung disease (chronic bronchitis, emphysema) and developmental effects (fetal growth retardation, childhood cancer and respiratory illness such as asthma and infections). I. Epidemiological Evidence - Note the criteria which the evidence satisfies: strength of the association (relative risk), dose/response relation, temporal relationship, consistency among different studies. A. Lung Cancer 1. Relation to tobacco consumption 2. Dose-response relations 3. Cigarette vs cigar and pipe smoking 4. Prevalence vs breast cancer in women B. Cardiovascular disease C. Mortality ratios 1. Dose-response relations 2. Effect of cessation D. Synergisms 1. Cancer - alcohol, radiation, asbestos 2. Cardiovascular - oral contraceptives E. Summaries 1. Balance of hazards 2. Males vs females II. Toxicological Evidence - Note how this strengthens the plausibility of the epidemiological evidence. A. Constituents 1. Gas phase (carcinogens, ciliatoxins) 2. Particulate phase (PAH, nitrosamines) B. Animal experiments III. Public Health Issues A. Lifestyle vs regulation 1. Blaming the victim (genetic polymorphisms) 2. Exemptions from toxic substance regulation B. Subsidies 1. Government (price supports, eliminating foreign trade barriers)

2. Insurance (life, health, fire, auto) C. Advertising 1. Recruitment - women, children, ethnic groups, third world as targets 2. Maintenance - portrayal as natural and desirable D. Nonsmokers’ rights 1. 10% of population is very sensitive to irritant effects 2. Driving force for smoking restrictions in public places 3. Tobacco industry response - to attempt preemption tobacco=most cause of preventable death and disability in usa. 10% of health care cost. Lung cancer kills 100,000 americans a year. 90% due to smoking most prevalent tobacco-related cause of death is cardiovascular disease which is 200,000 annually tobacco responsible for 350,000 deaths annually in usa