Transcript Geography 237 Geographic Research: Methods and Issues

Geography 361a
Environment 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
Jan 30, 2008, 12:06 am
Geog 361b
1
Context
Chemicals in the Environment
• Outline some of the challenges this table 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
Jan 30, 2008, 12:06 am
Geog 361b
2
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)
Jan 30, 2008, 12:06 am
Geog 361b
3
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)
Jan 30, 2008, 12:06 am
Geog 361b
4
Toxins into the Body
• lungs, gastrointestinal tract, skin
• most toxins enter how?
respiratory system
GI tract
Jan 30, 2008, 12:06 am
Geog 361b
5
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
Jan 30, 2008, 12:06 am
Geog 361b
6
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”
Jan 30, 2008, 12:06 am
Geog 361b
7
Toxins in the Body
Other factors influencing response
• age – young and old most vulnerable
• sex – particularly reproductive impacts
Jan 30, 2008, 12:06 am
Geog 361b
8
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
Jan 30, 2008, 12:06 am
Geog 361b
9
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)
Jan 30, 2008, 12:06 am
Geog 361b
10
Toxicity of Chemicals
Jan 30, 2008, 12:06 am
Geog 361b
11
Toxicity of Chemicals
• qualitative ranking of toxicity of chemicals
Jan 30, 2008, 12:06 am
Geog 361b
12
Toxins in the Environment
biomagnification
• up the food chain
• typically fat soluble toxins
Jan 30, 2008, 12:06 am
Geog 361b
13
Tests for Toxicity: Exercise
• Suggest ways that the toxicity of substances might
be tested scientifically.
• What problems are involved?
Jan 30, 2008, 12:06 am
Geog 361b
14
Tests for Toxicity
• laboratory – highly controlled, randomization
• animals – rats or mice typically
• ethical issues
Jan 30, 2008, 12:06 am
Geog 361b
15
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
Jan 30, 2008, 12:06 am
Geog 361b
16
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)
Jan 30, 2008, 12:06 am
Geog 361b
17
Acute Toxicity Studies
• some animals are more susceptible, some more resistant
Jan 30, 2008, 12:06 am
Geog 361b
18
Acute Toxicity Studies
• LD50 using cumulative % curves
Jan 30, 2008, 12:06 am
Geog 361b
19
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
Jan 30, 2008, 12:06 am
Geog 361b
20
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
Jan 30, 2008, 12:06 am
Geog 361b
21
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)
Jan 30, 2008, 12:06 am
Geog 361b
22
Longer Term Toxicity Studies: Summary
Benefits
• biotransformation measured
• assess acceptable intake values
• NOEL – no observed effect level
Drawbacks
• $$
• biotransformation assumptions – different species
Jan 30, 2008, 12:06 am
Geog 361b
23
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
Jan 30, 2008, 12:06 am
Geog 361b
24
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
Jan 30, 2008, 12:06 am
Geog 361b
25
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)
Jan 30, 2008, 12:06 am
Geog 361b
26
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
Jan 30, 2008, 12:06 am
Geog 361b
27
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)
Jan 30, 2008, 12:06 am
Geog 361b
28
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?
Jan 30, 2008, 12:06 am
Geog 361b
29
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.
Jan 30, 2008, 12:06 am
Geog 361b
30
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
Jan 30, 2008, 12:06 am
Geog 361b
31
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
Jan 30, 2008, 12:06 am
Geog 361b
32
Dose/Response Curves
• many acute effects are threshold effects
• many chronic/cancer effects are non-threshold
effects
Jan 30, 2008, 12:06 am
Geog 361b
33
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”
Jan 30, 2008, 12:06 am
Geog 361b
34
“Conservative” Estimates
• precautionary principle
• see tutorial slides from Rachel
Jan 30, 2008, 12:06 am
Geog 361b
35
Assignment 1
Jan 30, 2008, 12:06 am
Geog 361b
36
Assignment 1
Jan 30, 2008, 12:06 am
Geog 361b
37