13. Poisons/Toxins, Hazards chapter 20

1. 13. Poisons/Toxins, Hazards chapter 20

2. Are all chemicals toxic? • Yes……..but it depends on the dose!!! • Even pure water can kill you (Sacramento Cal. radio station contest Jan 2007) • Woman drank ~ 20 : 220mL bottles (ie 4.4 Liters) of pure water in ~ 3 hours , died from electrolyte imbalance • Lawsuits pending

3. A poison is a substance that can cause illness or death when it enters our bodies. A toxin is a harmful substance that has a biological origin. The effect of a toxic substance can be > immediate (acute toxicity) > prolonged (chronic toxicity)

4. Compounds that can counter- act the effects of a poison by destroying it or rendering it ineffective are called antidotes. eg.chelates for metals, thiosulfate('hypo') for cyanide

5. The lethal dose of a substance is the quantity that causes death. The LD50 of a chemical is the amount that kills exactly half of a large population of animals. as: mg(of substance) / Kg(of body weight) ie. Smaller = worse; Larger = better Problems: children have much lower LD50 values possible synergisms of mixtures can't extrapolate between species directly "Dosis sola facit venenum" - the dose makes the poison. (Paracelsus, 1493-1541)

6. Toxicity Classes Class supertoxic extremely very moderately slightly Water!! LD50(mg/kg) < 5 5 – 50 50 – 500 500 – 5000 5000 –15000 > 15g For 70kg male < 7 drops 7 dps – 1 tspn 1 tspn – 1 oz 1 oz – 1 lb 1 lb – 4 lb > 4 lb

7. LD50's for Several Chemicals LD50 (mg/kg, orally to rat) Chemical (*=natural) *Ethanol *Sodium chloride Aspirin *Caffeine *Heroin *Lead *Cocaine *Sodium cyanide *Nicotine *Strychnine 10000 3750 1750 200 150 20 17.5 10 2 0.8

8. LD50s of some of the Most Lethal Poisons LD50 (mg/kg, orally to rat) Substance (*=natural) *Botulinum toxin *Tetanus toxin *Diphtheria toxin 'Dioxin'(TCDD) *Muscarine(mushrooms) Sarin(nerve gas) *Tubocurarine(arrow poison) Parathion(insecticide) *Aflatoxin(peanut mold) *Solanine(greenspots on potatoes) 3 x 10-8 5 x 10-6 3 x 10-4 3 x 10-2 2 x 10-1 4 x 10-1 7 x 10-1 4 10 42

9. LD50 Values for Dioxin Species LD50 (mg/kg) Guinea pig Rat Monkey Rabbit Dog Mouse Hamster Bullfrog Human?(few deaths) 0.0006 0.04 0.07 0.12 0.15 0.20 3.5 >1.0 ~40kg/400km2 in Seveso, Italy,1976; Vietnam(agent orange)

10. Toxicity of Dioxin vs Botox • Botulinum toxin is 1 million times more toxic than Dioxin! • But we still use Botox for cosmetic purposes!! • Human vanity trumps safety concerns!!

11. Botox treatments • Botox injections are a diluted form of botulinum toxin (botulism) which are injected into facial (or other) muscles to paralyze or weaken the muscles that form wrinkles (nerve impulses are blocked) • 1.6 million done in USA in 2006 • Results last 3-4 months and require occasional touchups

12. Botox treatment cont’d • Approved for use by US FDA in 2002

13. Warnings! • Patient must remain upright and avoid alcohol for several hours after injection • Botulinum injections are also under study for possible treatment of migraines and juvenile cerebral palsy • *** The Dose is everything!!

14. US FDA Issues Botox Warning! • Feb 9, 2008 re: Botox, Botox Cosmetic and Myobloc products • Severe adverse reactions (including deaths) • May be related to overdosing • Toxin may spread from injection site • Symptoms: difficulty swallowing, talking breathing, general weakness

15. Most severe effects • In children with cerebral palsy, being treated for spasticity in limbs (not an FDA approved treatment) • No use permitted for ages<12.

16. Toxic doses can enter an organism by three means • inhalation • ingestion • skin contact Huge differences in LD50, eg. nicotine: orally(230mg) vs. intravenously(0.3mg) anthrax: inhalation vs. skin contact

17. Premature Death - What will Kill You? In NA an est. 1 million/yr die prematurely Chemical: in your food? - not too likely second-hand tobacco smoke ~3500 Sociological(ie. lifestyle): heart disease(obesity & smoking) ~500,000; cancer(>60% diet & smoking) ~200,000 Physical: murder ~22,000; car accidents? war? Biological: food poisoning ~10,000(~7 million ill) Geological: ? Radiation?? Worldwide: TB(3 million), measles(1.2 million), malaria(2 million), drinking contaminated water (3 million children under 5)

18. Socrates – a cup of Hemlock ‘Tea’ The Death of Socrates (Jacques Louis David – 1787)

19. Safety = the degree of acceptability of risk at either the individual or societal level. Eg. warning labels on products screw-cap bottle tops for aspirin nitrites/nitrates(carcinogens) in processed meats vs. botulinum smoking(individual 'rights' vs. public health safety & cost) tetrodotoxin(puffer fish) in Japan ( ~100 deaths/yr!)

20. The acceptable daily intake (ADI) of a food additive is 1% of the maximum daily amount of ' additive' that produces no observable effect* on laboratory animals (at least two and usually more). Any long-term hazards must also be considered. *no effect level = mg/kg of body wt for that animal (NB. much less than the LD50)

21. Toxic substances can be classified according to the way in which they disrupt body chemistry as: corrosive metabolic neurotoxic mutagenic teratogenic carcinogenic

22. Corrosive poisons destroy tissue which, if critically situated, can render the person(animal?) incapable of functioning. Corrosive poisons are usually: strong acids strong bases/alkalis oxidizing agents

23. Some Corrosive Poisons Strong acids: sulfuric acid(auto batteries) hydrochloric/muriatic acid(tile/concrete cleaner) Strong bases: sodium hydroxide(drain/oven cleaners-aerosols!) ammonia(window cleaners) Oxidizers: ozone(photocopiers/smog) hypochlorite/peroxide(bleach) chloramine/nitrosyl chloride gases(from mixing household ammonia + bleach!)

24. Metabolic Poisons A metabolic poison causes illness or death by interfering with a vital bio- chemical mechanism to such an extent that it ceases to function or is prevented from functioning efficiently. Two principal 'mechanisms of action' : > affect oxygen transport or oxidative processes in the cell > 'disable' certain proteins by reacting with -SH groups

25. Will it Kill me or just make me High? Does it contain ? 1) amatinin – a cyclic peptide(metabolic poison) from the amanita phalloides mushroom. 2) psylocibin – a seretonin analog(hallucinogen) from Teonancatal(psylocibe mexicana), the magic/ sacred mushroom.

26. The human body can usually accommodate small, repeated doses of many metabolic poisons because detoxification mechanisms (in liver) exist for them. However, over a long period of exposure, the build up of subacute doses of these cumulative poisons (which the body cannot efficiently eliminate) can lead to chronic effects. These usually result in a lessening of the efficiency of body functions, such as motor skills or cognitive ability. If these functional impairments are not recognized, damage becomes cumulative, with serious disabling or even lethal effects. Those having no warning properties are especially dangerous.

27. Jimson Weed seeds : a cheap and very dangerous high • Also known as fireweed, devil’s apple, stinkweed, Jamestown weed, angel’s trumpet, magical strawberries, thorn apple • 15 Cornwall teenagers hospitalized (Oct /07) • Attacks CNS, causes fever, racing heart, blurred vision, hallucinations • Seizures, coma and at least 2 deaths in Canada

28. Beautiful (but dangerous!)

29. Carbon Monoxide*- binds with Heme(Iron) Oxyhemoglobin (aq) + CO (g) Carboxyhemoglobin (aq) + O2(g)g If a person breathes air with a CO conc'n. higher than about 0.1%, formation of carboxyhemoglobin is favoured (60% conversion after 4hrs - and death!). When a victim is exposed to fresh air (pure O2) the equilibrium favours oxyhemoglobin. * from incomplete combustion, eg. kerosene heaters/BBQs/generators indoors, auto exhaust, cigarettes, smoldering leaves. ~250 million tons/yr generated in NA

30. Individuals differ in their tolerance of carbon monoxide, but generally those with anemia or other- wise low reserves of hemoglobin, eg. children are more susceptible to its effects. A pregnant woman who smokes can damage her fetus because carbon monoxide from the inhaled tobacco smoke can deprive the fetus of the oxygen it needs during critical developmental stages. Studies consistently show that low birth weight is closely related to the mother’s smoking habits.

31. Cyanide (HCN / NaCN) Irreversibly complexes to iron(Fe3+) of cytochrome oxidases (glucose oxidizing enzymes). Used to fumigate cargo ships/warehouses for insects & rodents. 50mg = death in seconds. Hydrogen cyanide(bp26o) Amygdalin Ar-HC(CN)-O-Sugars + 2H2O HCN + 2C6H12O6 + Ar-CHO Glucose Benzaldehyde Amygdalin(seeds of cherry/plum/peach/apple/apricot) = laetrile(contoversial anti-cancer 'drug')

32. Other Metabolic Poisons - Heavy Metals - Bind to various proteins, via -SH groups; thus changes structure(denaturation)  changes function. Kidney/liver damage, neurological effects, cancer >>>>>>>

33. Some Metal Poisons Arsenic - favourite homicidal poison, eg. Arsenic and Old Lace (Agatha Christie); present in - pressure treated wood (Cu/Cr/As), some insecticides, shrimp (~15ppm). Mercury - 'Mad Hatter's disease'(Alice in Wonderland); present in - thermometers, tooth amalgams, fluorescent lights, fungicides, mining & extraction (Minimata disease). Also: nickel, cadmium, chromium, copper/iron/zinc!

34. Lead - Environmentally Ubiquitous Lead often occurs in beverages (20-30 g/L), foods (100-300 g/kg), public water supplies (100g/L, from old lead- sealed pipes) and even air. Until the phase-out of lead in automobile fuels in the '80s, lead in air came primarily from automobile emissions. Today because so much lead was deposited from auto exhausts over the years, lead is still found in soil samples and even on city sidewalks and streets. Until the '80s most paints contained lead-based pigments. Even continuous handling of bullets, lead foil or toy soldiers can cause problems.

35. One of the major sources of lead is drinking water that has contacted lead-containing pipes, joints and plumbing fixtures. In 1993 the US EPA released a list of public water supplies that exceeded its maximum allowable level of 15 ppb lead. Hundreds of cities and towns were on the EPA list, some were as high as 484 ppb! We hope Canada isn't as bad.

36. On continuous exposure, lead can accumulate in the body, principally in the bones. The average person can excrete about 2 mg (2000 g)/day of lead; fortunately one’s daily intake is normally less than this. If intake exceeds this amount, accumulation and storage result. . In bones lead acts on the bone marrow (skeletal problems). . In soft tissues lead behaves like other heavy-metal poisons(metabolic problems). . Lead can also affect the central nervous system (neurological problems).

37. For adults in the workplace where lead exposure would be expected, the acceptable blood lead level is 40 g/dL. US estimates are ~500,000 miscarriages per year due to lead 'poisoning'.

38. Children are much more susceptible to lead poisoning: • for under six years of age 10 g/dL is the acceptable blood level. They do not 'store' lead in their bones. •many children (especially from low-income homes) chew old paint, play in city streets and are undernourished. In the US an estimated 1 in 6 are above this intervention level, ie. >10,000/yr with some mental retardation due to excess lead levels.

39. Effects of Lead(g/dL) in Children's Blood Blood levels Acute effectsChronic Effects ~5 none blood pressure ~10 none intelligence 15-20 none heme/vit D synthesis 25-40 none IQ, impaired CNS/ hearing/hemoglobin 40-80 CNS damage anemia >80 convulsions, mental retardation coma, death?

40. Lead in Montreal Water supply • March 2007 • Homes in Plateau Mont Royal,Villeray and Notre Dame de Grace districts still serviced by lead pipes! • 400,000 households • Children under 6 and pregnant women should only drink filtered water

41. Lead in Ontario School Drinking water: the law is an Ass! • November 2007; 5 minute flushing of pipes in all schools-no money for staff to do this .Waste of water. • Solution test for lead-easy to do. Restrictions to bottled water only in affected schools

42. Neurotoxins A type of metabolic poison limited to action on the nervous system. These include botulinumtoxin,strychnine, curare, atropine ('natural' alkaloids) and 'organophosphates' (nerve gases & insecticides).

43. A nerve impulse is transmitted along a nerve fiber by an electrical impulse carried by the movement of ions. Between one nerve fiber and the next is a gap called a synapse. The impulse / 'message' is carried across this gap by acetylcholine (a neurotransmitter) which then binds to a receptor on the adjacent nerve. The acetylcholine is then removed/recycled (by acetylcholinesterase) so the system can continue to function properly.

44. The CNS and a Nerve Synapse axon synapse

45. Acetylcholine – the Ubiquitous Neurotransmitter The human brain operates at ~25 W and can handle ~10 trillion bits of info’. The Central Nervous System (CNS) has 12 billion (109) neurons containing 1013(>10 trillion) synapses. Of more than 100 different neurotransmitters perhaps the most prevalent is acetylcholine: O CH3C-OCH2CH2-N+(CH3)3 For proper functioning the acetylcholine from I ‘synaptic firing’ must be ‘cleared’ within 2 milliseconds.

46. Neurotoxins affect the transmission of the nerve impulses by interfering with this neurotransmitter function in three ways. Block the synthesis of acetylcholine: no messenger = no impulses = paralysis(botulinum) Block the receptor site: no impulse received = rapid heart beat = death(atropine- also dilate pupils; curare - also muscle relaxant; local anesthetics) Inhibit the 'removal': neurotransmitter builds up = nerves 'fire' wildly = convulsions or death (organophosphates as nerve gases or insecticides)

47. Nerve Gases (LD50,mg/kg)Insecticides Sarin(0.55) Parathion(10) Tabun(3.7) Malathion(1000) Soman(0.8)

48. Teratogens Chemical agents that can cause birth defects are called teratogens. From the Greek 'terat' meaning 'monster'. In addition to chemicals, high-energy radiation and some viral agents are known teratogens. Birth defects occur in 2% to 3% of all births. About 25% of these occur from genetic causes, 5% to 10% are the result of known teratogens and the remaining ~60 % result from unknown causes..

49. In the development of the newborn, there are three periods during which the fetus is at risk. 1) For ~17 days between conception and implantation of the fertilized egg in the uterine wall, a chemical “insult” will result in cell death. If a 'lethal dose' is administered, death of the organism occurs, followed by spontaneous abortion or reabsorption. The so-called 'morning-after' pill, RU-486, (developed in France in 1988 ) works in this way.

50. The morning after pill • A modified steroid