Toxicology and Human Health (Moeller Chapter 2)

1. Geography 361aEnvironment and Health Toxicology and Human Health(Moeller Chapter 2) • Context • What is toxicology? • Toxins in the body • Toxicity of chemicals • Tests for toxicity • Outcomes measured • Establishing exposure limits Geog 361b

2. ContextChemicals in the Environment • Outline some of the challenges this table represents. • How can we (society) address those challenges? Geog 361b

3. Toxicology: Definition • The study of the harmful effects of chemicals on the health of organisms (ultimately, humans). • (see models of health/causality from last day) Geog 361b

4. Environmental Toxicology: Definition • The study of the harmful effects of (combinations of) chemicals on the health of entire ecosystems. • See Health Canada’s Chemical Substances Portal (useful for assignment 1 too) Geog 361b

5. Toxins into the Body • lungs, gastrointestinal tract, skin • most toxins enter how? respiratory system GI tract Geog 361b

6. Toxins in the Body biological transformation • transformation 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 substance inhaled/ingested/absorbed Geog 361b

7. Toxins removed from the Body excretion • urination – main form of excretion • lungs • GI tract – least important • organs: liver and kidneys • health of these systems can effect body’s ability to withstand toxic “insults” Geog 361b

8. Toxins in the Body Other factors influencing response • age – young and old most vulnerable • sex – particularly reproductive impacts Geog 361b

9. 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 Geog 361b

10. 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, 16thC, emphasis added) Geog 361b

11. Toxicity of Chemicals Geog 361b

12. Toxicity of Chemicals • qualitative ranking of toxicity of chemicals Geog 361b

13. Toxins in the Environment biomagnification • up the food chain • typically fat soluble toxins Geog 361b

14. Tests for Toxicity: Exercise • Suggest ways that the toxicity of substances might be tested scientifically. • What problems are involved? Geog 361b

15. Tests for Toxicity • laboratory – highly controlled, randomization • animals – rats or mice typically • ethical issues Geog 361b

16. 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 Geog 361b

17. Tests for Toxicity: Outcomes • change in body weight • growth of tumours • change in body size • death (typically) (see LD50) MTD • maximum tolerable dose • highest dose below which cancer does not occur • debated whether high doses exaggerate carcinogenicity (but see precautionary principle) Geog 361b

18. Acute Toxicity Studies • some animals are more susceptible, some more resistant Geog 361b

19. Acute Toxicity Studies • LD50 using cumulative % curves Geog 361b

20. 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 Geog 361b

21. 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 Geog 361b

22. 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) Geog 361b

23. Longer Term Toxicity Studies: Summary Benefits • biotransformation measured • assess acceptable intake values • NOEL – no observed effect level Drawbacks • $$ • biotransformation assumptions – different species Geog 361b

24. 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 Geog 361b

25. Outcomes Measured reproductive toxicity • both parents and offspring • e.g. mother during or prior to gestation developmental toxicity (teratogenesis) • congential effects • e.g. growth retardation, malformations • e.g. thalidomide Geog 361b

26. 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) Geog 361b

27. 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 Geog 361b

28. 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) Geog 361b

29. 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 • this type creates highest uncertainty and highest controversy • e.g., what is the shape of the dose-response below the minimum does administered in toxicity experiments? – linear or threshold? Geog 361b

30. Establishment of Exposure Limits Two Principles (order of importance): • use human data whenever possible • use surrogate species or surrogate chemicals if scientific basis for comparability with target population • most frequently principle 1 not satisfied. Geog 361b

31. 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 Geog 361b

32. 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 Geog 361b

33. Dose/Response Curves • many acute effects are threshold effects • many chronic/cancer effects are non-threshold effects Geog 361b

34. 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” Geog 361b

35. “Conservative” Estimates • precautionary principle • see tutorial slides from Rachel Geog 361b

36. Assignment 1 Geog 361b

37. Assignment 1 Geog 361b