An Introduction to the Principles of Toxicology

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An Introduction to the Principles of Toxicology
A Small Dose of Toxicology
Introduction to the Health Effects of
Chemicals BIS 411 Jan 9, 2006
Steven G. Gilbert, PhD, DABT www.asmalldoseof.org
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Child Health
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Toxicology Definitions
The study of poisons or the adverse effects of
chemical and physical agents on living organisms.
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Ancient Awareness
399 BC Death of Socrates by Hemlock Socrates was
charged with religious heresy and corrupting the
morals of local youth. The active chemical used
was the alkaloid coniine which, when ingested
causes paralysis, convulsions and potentially
death.
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Historical Awareness
From Romeo and Juliet - act 5 Come bitter pilot,
now at once run on The dashing rocks thy seasick
weary bark! Heres to my love! O true
apothecary! Thy drugs are quick. Thus with a
kiss I die. Shakespeare
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Environmental Human Health
Conditions that ensure that all living things
have the best opportunity to reach and maintain
their full genetic potential. Steven G.
Gilbert, 1999
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What do these have in common?

• Hong Kong
• Princess Diana
• Ambassador to Mexico
• Coeur dAlene, Silver Valley, ID
• Tacoma
• Seattle Schools
• 100 Billion, 65 Billion
• Food, noise, dust
• 11,000 to 689,000 Children

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Who are these white guys?
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Power To Discover The Truth
It is not the truth that makes you free. It is
your possession of the power to discover the
truth. Our dilemma is that we do not know how to
provide that power. Richard Lewontin (New York
Review of Books, Jan 7, 1997)
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What Is This?
O
CH3
CH3
N
N
7
1
3
N
O
N
CH3
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Key Words
Dose / Response

• Risk
• Hazard X Exposure

Individual Sensitivity
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Paracelsus
All substances are poisons there is none which
is not a poison. The right dose differentiates a
poison from a remedy. Paracelsus (1493-1541)
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An Individual View
The sensitivity of the individual differentiates
a poison from a remedy. The fundamental principle
of toxicology is the individuals response to a
dose. S. G. Gilbert (1997)
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Superman
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Neuron
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Thalidomide

• Introduced in 1956 as sedative (sleeping pill)
  and to reduce nausea and vomiting during
  pregnancy
• Withdrawn in 1961

• Discovered to be a human teratogen causing
  absence of limbs or limb malformations in
  newborns
• 5000 to 7000 infants effected
• Resulted in new drug testing rules

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What Is This?
(CH3-CH2-OH)
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Effects of Prenatal Alcohol
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FAS Child
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Mouse Scanning EM
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Fetal Alcohol Syndrome (FAS)
Most common preventable cause of adverse CNS
development 4,000-12,000 infants per year in
US Characteristics Growth retardation Facial
malformations Small head Greatly reduce
intelligence
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Fetal Alcohol Effect (FAE)
Milder form of FAS 7,000-36,000 infants per year
in US 1 to 3 infants per 1,000 world
wide?? Characteristics Growth deficiency Learning
dysfunction Nervous systems disabilities
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A Small Dose of Lead
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Lead In Homes
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Lead History
Lead Makes the Mind Give Way

• Greek 2nd BC

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Lead in Families
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Recycling Lead
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Agency Blood Lead Levels
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A Small Dose of Mercury
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Polluting with HG
Discharge in Minamata Bay
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Fetal Effects of MeHg
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Life-Long Effects of MeHg
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Structure of PBDEs
PolyBrominated Diphenyl Ether
X Y are number of Bromine atoms Common Penta,
Octa, and Deca
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PBDEs in House Dust (ppb)
From EWG - Toxic Fire Retardants Contaminate
American Homes - http//www.ewg.org/reports/inthed
ust/summary.php
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PBDEs in Breast Milk (ppb)
From EWG - Toxic Fire Retardants in Breast Milk
from American Mothers - http//www.ewg.org/reports
/mothersmilk/es.php
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Key Words
Dose / Response

• Risk
• Hazard X Exposure

Individual Sensitivity
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Effects of Amount on Response
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Effects of Size on Response
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Glasses of Wine - Dose Response
All Effected
100
75
Difficulty Walking
50
Amount half are effected
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NO Effect
0
0
1
2
3
4
5
6
7
8
Glasses of Wine
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Dose Response Function
All Effected
100
75
Response
50
Half Effected
25
NO Effect
0
0
10
20
30
40
50
60
70
80
90
100
Dose (mg/kg body weight)
Increasing dose
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Agent LD-50 (mg/kg)
Ethyl alcohol 10,000 Salt (sodium
chloride) 4,000 Iron (Ferrous sulfate) 1,500 Mor
phine 900 Mothballs 500
(paradichlorobenzene) Aspirin 250 DDT 250
Cyanide 10 Nicotine 1 Tetrodotoxin (from
fish) 0.01 Dioxin (TCDD) 0.001 Botulinum
Toxin 0.00001 Bee Venom ??
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Exposure Absorption
Route of exposure
1) Skin (dermal) 2) Lung (inhalation)
3) Oral (gut)
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Frequency Of Exposure
Number of Times
Time Between
4 Beers in an hour or 4 Beers in 4 Days
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Duration Of Exposure
Acute Exposure
Sub-chronic Exposure
Chronic Exposure
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Distribution
Where It Goes
(body water, fat, bone)
Where It Accumulates
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Metabolism
How The Body Breaks It Down
What It Turns Into
How Fast It Does It
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Caffeine - 1,3,7 Trimethylxanthine
O
CH3
CH3
N
N
7
1
3
N
O
N
CH3
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Half-life
How Long It Takes To Go
14
12
10
8
Concentration (µg/ml)
6
4
2
0
0
1
2
3
4
5
6
7
8
9
10
11
Time (hrs)
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Susceptibility Variability

• Young or Old
• Male or Female
• Individual Variability
• Genetics Differences
• Species Differences

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Risk Assessment
Process of estimating association between an
exposure and the incidence of some adverse outcome
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Risk Management
Policy developed to deal with hazards identified
through risk assessment Process of evaluating
alternative regulatory options and selecting
among them
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Asthma Diabetes
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Overweight Obese
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The Potential of Children
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Principles of Toxicology
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Additional Information

• A Small Dose of Toxicology
• www.asmalldoseof.org

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Authorship Information
This presentation is supplement to A Small
Dose of Toxicology
For Additional Information Contact Steven G.
Gilbert, PhD, DABT E-mail smdose_at_asmalldoseof.org
Web www.asmalldoseof.org