10:20am Oct 5, 2011 Geog 3432 1 Toxicology and Human Health Toxicology and Human Health (Moeller Chapter 2) (Moeller Chapter 2) Geography 361a Geography 361a Environment and Health Environment and Health • Context • What is toxicology? • Toxins in the body • Toxicity of chemicals • Tests for toxicity • Outcomes measured • Establishing exposure limits
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10:20am Oct 5, 2011Geog 34321 Toxicology and Human Health (Moeller Chapter 2) Geography 361a Environment and Health Context What is toxicology? Toxins.
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10:20am Oct 5, 2011 Geog 3432 1
Toxicology and Human HealthToxicology and Human Health(Moeller Chapter 2)(Moeller Chapter 2)
Geography 361aGeography 361aEnvironment and HealthEnvironment and Health
• Context• What is toxicology?• Toxins in the body• Toxicity of chemicals• Tests for toxicity• Outcomes measured• Establishing exposure limits
10:20am Oct 5, 2011 Geog 3432 2
ContextContextChemicals in the EnvironmentChemicals in the Environment
• Outline some of the challenges the table below represents.
• How can we (society) address those challenges?
Author Chemicals in Existence
New Chemicals/Year
Moeller (2003) 70,000 200-1000
Philp (1995) 64,000 700
10:20am Oct 5, 2011 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)
10:20am Oct 5, 2011 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)
• lungs, gastrointestinal tract, skin• most toxins enter how?
respiratory system
GI tract
10:20am Oct 5, 2011 Geog 3432 6
Toxins in the Bodybiological 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
10:20am Oct 5, 2011 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”
10:20am Oct 5, 2011 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)
herbicide = ↑ toxicity)• humidity – ↑ typically = worse• light – diurnal pattern ↑ light typically = worse• social – lab animals housed singly or in groups
10:20am Oct 5, 2011 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)
10:20am Oct 5, 2011 Geog 3432 11
Toxicity of Chemicals
10:20am Oct 5, 2011 Geog 3432 12
Toxicity of Chemicals
• qualitative ranking of toxicity of chemicals
ethanol
sodium chloride, aspirin
Examples
caffeine, phenol
arsenic, strychnine
dioxin, botulinum
10:20am Oct 5, 2011 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
10:20am Oct 5, 2011 Geog 3432 14
Tests for Toxicity: Exercise
• Suggest ways that the toxicity of substances might be tested scientifically.
• What problems are involved?
10:20am Oct 5, 2011 Geog 3432 15
Tests for Toxicity
• laboratory – highly controlled, randomization
• animals – rats or mice typically• ethical issues
10:20am Oct 5, 2011 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
10:20am Oct 5, 2011 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)
10:20am Oct 5, 2011 Geog 3432 18
Acute Toxicity Studies• some animals are more susceptible, some more resistant
10:20am Oct 5, 2011 Geog 3432 19
Acute Toxicity Studies
• LD50 using cumulative % curves
• Which substance is more toxic: (A) or (B)?
10:20am Oct 5, 2011 Geog 3432 20
Example LD50 Values
• dichlorvos, an insecticide commonly used in household pesticide strips
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
10:20am Oct 5, 2011 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)
10:20am Oct 5, 2011 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
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?
10:20am Oct 5, 2011 Geog 3432 31
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.
10:20am Oct 5, 2011 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
10:20am Oct 5, 2011 Geog 3432 33
Dose/Response Curves
• many acute effects are threshold effects• many chronic/cancer effects are non-threshold
effects
10:20am Oct 5, 2011 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”
10:20am Oct 5, 2011 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 data100 (account for interspecies extrapolation)• i.e. 100 * NOEL or threshold level• no human data• satisfactory chronic exposure data in other species1000 (account for interspecies extrapolation)• i.e. 1000 * NOEL or threshold level• chronic exposure data incomplete for other species