1. 10:20am Oct 5, 2011Geog 34321 Toxicology and Human Health (Moeller Chapter 2) Geography 361a Environment and Health Context What is toxicology? Toxins in the body Toxicity of chemicals Tests for toxicity Outcomes measured Establishing exposure limits

2. 10:20am Oct 5, 2011Geog 34322 Context Chemicals in the Environment Outline some of the challenges the table below represents. How can we (society) address those challenges? AuthorChemicals in Existence New Chemicals/Year Moeller (2003)70,000200-1000 Philp (1995)64,000700

3. 10:20am Oct 5, 2011Geog 34323 Toxicology: Definition “The discipline that integrates all scientific information to help preserve and protect the health and the environment from the hazards presented by chemical and physical agents “(Society of Toxicology as cited in Moeller 2005, 28) (see models of health/causality from last day)

4. 10:20am Oct 5, 2011Geog 34324 Environmental Toxicology: Definition The study of the harmful effects of (combinations of) chemicals on the health of entire ecosystems. Used as the basis for chemical management (e.g., safe limits, priorities for cleanup) See Health Canada’s Chemical Substances PortalChemical Substances Portal (useful for assignment 1 too)

5. 10:20am Oct 5, 2011Geog 34325 Toxins into the Body lungs, gastrointestinal tract, skin most toxins enter how? respiratory system GI tract

6. 10:20am Oct 5, 2011Geog 34326 Toxins in the Body biological transformation metabolic process that transforms substance so moves from one organ or tissue to another chemical conversion to new compound typically less absorbable (excreted) bioactivation –biological transformation that forms a compound that is more toxic than the original substance inhaled/ingested/absorbed

7. 10:20am Oct 5, 2011Geog 34327 Toxins removed from the Body excretion urination – main form of excretion lungs GI tract, sweat glands – least important liver and kidneys health of these systems can effect body’s ability to withstand toxic “insults”

8. 10:20am Oct 5, 2011Geog 34328 Toxins in the Body Other biological factors influencing response age – young and old most vulnerable sex – particularly reproductive impacts disease – esp. liver disease (re: excretion)

9. 10:20am Oct 5, 2011Geog 34329 Toxins in the Body Environmental factors influencing response ambient temperature (e.g. ↑ temp + dinitrophenol herbicide = ↑ toxicity) humidity – ↑ typically = worse light – diurnal pattern ↑ light typically = worse social – lab animals housed singly or in groups

10. 10:20am Oct 5, 2011Geog 343210 Toxicity of Chemicals “What is it that is not poison? All things are poison and nothing is without poison. It is the dose only that makes a thing not a poison.” (Paracelsus, 16 th C, emphasis added)

11. 10:20am Oct 5, 2011Geog 343211 Toxicity of Chemicals

12. 10:20am Oct 5, 2011Geog 343212 Toxicity of Chemicals qualitative ranking of toxicity of chemicals ethanol sodium chloride, aspirin Examples caffeine, phenol arsenic, strychnine dioxin, botulinum

13. 10:20am Oct 5, 2011Geog 343213 Toxins in the Environment biomagnification up the food chain typically accumulate in fat heavy metals (e.g.,lead, mercury) organochlorine pesticides (e.g., DDT) PCBs

14. 10:20am Oct 5, 2011Geog 343214 Tests for Toxicity: Exercise Suggest ways that the toxicity of substances might be tested scientifically. What problems are involved?

15. 10:20am Oct 5, 2011Geog 343215 Tests for Toxicity laboratory – highly controlled, randomization animals – rats or mice typically ethical issues

16. 10:20am Oct 5, 2011Geog 343216 Tests for Toxicity: Types of Studies acute toxicity single or multiple doses (high) short period of time short-term (subacute, subchronic) repeated (daily) doses period = 10% of animal lifespan (e.g, rat = 3mo) long-term (chronic) entire lifespan of animal

17. 10:20am Oct 5, 2011Geog 343217 Tests for Toxicity: Outcomes change in body weight growth of tumours change in body size death (typically) (see LD 50 ) MTD maximum tolerable dose highest dose below which cancer does not occur debated whether high doses exaggerate carcinogenicity (but see precautionary principle)

18. 10:20am Oct 5, 2011Geog 343218 Acute Toxicity Studies some animals are more susceptible, some more resistant

19. 10:20am Oct 5, 2011Geog 343219 Acute Toxicity Studies LD 50 using cumulative % curves Which substance is more toxic: (A) or (B)?

20. 10:20am Oct 5, 2011Geog 343220 Example LD50 Values dichlorvos, an insecticide commonly used in household pesticide strips Oral LD50 (rat): 56 mg/kg Dermal LD50 (rat): 75 mg/kg Injected to abdomen LD50: (rat) 15 mg/kg Inhalation LC50 (rat): 1.7 ppm (15 mg/m3); 4-hour Oral LD50 (rabbit) 10 mg/kg Oral LD50 (pigeon:): 23.7 mg/kg Oral LD50 (mouse): 61 mg/kg Oral LD50 (dog): 100 mg/kg Oral LD50 (pig): 157 mg/kg

21. 10:20am Oct 5, 2011Geog 343221 Acute Toxicity Studies: Summary Benefits death is easily measured autopsies = info on probable target organs determine doses to be used in longer-term studies Drawbacks death is only one of many possible outcomes humans rarely exposed at such high levels

22. 10:20am Oct 5, 2011Geog 343222 Short and Long-Term Toxicity Studies typically 2 or more species (rat + dog) animal to biotransform chemical much like human would in real world three dose ranges – high(won’t kill) medium low(no expected effects)

23. 10:20am Oct 5, 2011Geog 343223 Longer Term Toxicity Studies: Summary Benefits biotransformation measured assess acceptable intake values NOEL – no observed effect level Drawbacks $$ biotransformation assumptions – different species

24. 10:20am Oct 5, 2011Geog 343224 Outcomes Measured carcinogenesis –staged: initiation, promotion, progression –some chemicals do one, two or all three Ames Test –in vitro test of mutagenicity to bacteria –very inexpensive –assumes mutatagenicity similar to carcinogenicity

25. 10:20am Oct 5, 2011Geog 343225 Outcomes Measured reproductive toxicity both to parents and offspring e.g. mother during or prior to gestation e.g. lead or PBC – menstrual disorders developmental toxicity (teratogenesis) congenital effects e.g. growth retardation, malformations e.g. thalidomide

26. 10:20am Oct 5, 2011Geog 343226 Outcomes Measured Neurotoxicity cognitive, sensory, motor often wide variation between rat/dog and human responses of this type 1000+ chemicals identified as neurotoxicants (only 10% - 7000 - tested though) e.g., trichloroethylene

27. 10:20am Oct 5, 2011Geog 343227 Outcomes Measured Immunotoxicity suppression of immune function host vulnerable to infection (incl. cancer) e.g., multiple chemical sensitivity syndrome – low dose exposure = AIDS-like response –very controversial at this point –emerging area of research e.g., pcb, ddt, asbestos, benzene

28. 10:20am Oct 5, 2011Geog 343228 Outcomes Measured Summary most chemicals (only 20% of chemicals in use today) assessed for carcinogenesis only being revisited under USA SARA legislation Agency for Toxic Substances and Disease Registry (ATSDR) data base growing (slowly) as a result (keep in mind 99% of all toxic human exposures from “natural” environment e.g., bacteria)

29. 10:20am Oct 5, 2011Geog 343229 Extrapolating from High Doses How can we know at what dose a substance is harmful or not? This video summarizes some of the key ideas in this entire lecture, but the main theme is extrapolating from high doses: http://www.youtube.com/watch?v=IKujq-TcJLM

30. 10:20am Oct 5, 2011Geog 343230 Extrapolating from Animals relative responsiveness small animals to large humans dose relatively high doses for short periods of time versus low doses over long periods of time creates highest uncertainty and highest controversy e.g., what is the shape of the dose-response below the minimum dose administered in toxicity experiments? – linear or threshold? – hormesis?

31. 10:20am Oct 5, 2011Geog 343231 Establishment of Exposure Limits Two Principles (order of importance): 1.use human data whenever possible 2.use surrogate species or surrogate chemicals if scientific basis for comparability with target population most frequently principle 1 not satisfied.

32. 10:20am Oct 5, 2011Geog 343232 Establishment of Exposure Limits Steps: establish range of effects for target or surrogate chemical – (chemical’s database) establish dose-response relationship in target species or surrogate species establish exposure limit by adding in safety factor

33. 10:20am Oct 5, 2011Geog 343233 Dose/Response Curves many acute effects are threshold effects many chronic/cancer effects are non-threshold effects

34. 10:20am Oct 5, 2011Geog 343234 Dose/Response Curves most animal studies involve medium or high doses that must be extrapolated backwards if “C” is limit set = “safe” according to extrapolation “B” but unsafe according to extrapolations “D” and especially, “E”

35. 10:20am Oct 5, 2011Geog 343235 Establishment of Exposure Limits Safety Factor (or Uncertainty Factor – UF) of: 10 (account for most sensitive human) i.e., 10 * NOEL or threshold level valid chronic human exposure data 100 (account for interspecies extrapolation) i.e. 100 * NOEL or threshold level no human data satisfactory chronic exposure data in other species 1000 (account for interspecies extrapolation) i.e. 1000 * NOEL or threshold level chronic exposure data incomplete for other species

36. 10:20am Oct 5, 2011Geog 343236 “Conservative” Estimates precautionary principle