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 3432

2. ContextChemicals in the Environment • Outline some of the challenges the table below represents. • How can we (society) address those challenges? Geog 3432

3. 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) Geog 3432

4. 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 Portal (useful for assignment 1 too) Geog 3432

5. Toxins into the Body • lungs, gastrointestinal tract, skin • most toxins enter how? respiratory system GI tract Geog 3432

6. 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 Geog 3432

7. 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” Geog 3432

8. 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) Geog 3432

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 3432

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 3432

11. Toxicity of Chemicals Geog 3432

12. Toxicity of Chemicals • qualitative ranking of toxicity of chemicals Examples ethanol sodium chloride, aspirin caffeine, phenol arsenic, strychnine dioxin, botulinum Geog 3432

13. 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 Geog 3432

14. Tests for Toxicity: Exercise • Suggest ways that the toxicity of substances might be tested scientifically. • What problems are involved? Geog 3432

15. Tests for Toxicity • laboratory – highly controlled, randomization • animals – rats or mice typically • ethical issues Geog 3432

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 3432

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 3432

18. Acute Toxicity Studies • some animals are more susceptible, some more resistant Geog 3432

19. Acute Toxicity Studies • LD50 using cumulative % curves • Which substance is more toxic: (A) or (B)? Geog 3432

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 3432

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 3432

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 3432

23. Longer Term Toxicity Studies: Summary Benefits • biotransformation measured • assess acceptable intake values • NOEL – no observed effect level Drawbacks • $$ • biotransformation assumptions – different species Geog 3432

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 3432

25. 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 Geog 3432

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) • e.g., trichloroethylene Geog 3432

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 • e.g., pcb, ddt, asbestos, benzene Geog 3432

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 3432

29. 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 Geog 3432

30. 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? Geog 3432

31. 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 3432

32. 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 3432

33. Dose/Response Curves • many acute effects are threshold effects • many chronic/cancer effects are non-threshold effects Geog 3432

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 3432

35. 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 3432

36. “Conservative” Estimates • precautionary principle Geog 3432