a small dose of toxicologyprinciples of toxicology – 01/07/10 an introduction to the principles of...
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
An Introduction to the Principles of Toxicology
A Small Dose of Toxicology
Steven G. Gilbert, PhD, DABTwww.asmalldoseof.org
www.toxipedia.org
ENV H 472 A - ENVIRONMENTAL RISK AND SOCIETY
Class 2
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
A Small Dose of Toxicology
See: www.asmalldoseof.org -- smdose
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Small Dose of Toxicology
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Milestones of Toxicology
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
www.toxipedia.org
A free toxicology encyclopedia and resource center that anyone can edit. Toxipedia provides comprehensive, accurate, and scientifically based information on the hazards and risks of chemical and physical agents, with the goal of advancing human and environmental health. Toxipedia
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
The World Library of Toxicology
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Toxipedia suite of sites
www.ipmopedia.org
www.healthyworldtheater.orgwww.wanmec.org
www.toxipedia.org
www.wltox.org
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
LDDI Consensus Statement
Scientific Consensus Statement on Environmental Agents Associated with
Neurodevelopmental DisordersDeveloped by the Collaborative on
Health and the Environment’s Learning and Developmental Disabilities
InitiativeNovember 7, 2007
http://www.iceh.org/LDDI.html
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
LDDI Consensus Statement
http://www.iceh.org/LDDI.html
Given the established knowledge, protecting children from neurotoxic environmental exposures from the earliest stages of fetal development clearly is an essential public health measure if we are to help prevent learning and developmental disorders and create an environment in which children can reach and maintain their full potential.
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
NW Public Health
See: http://healthlinks.washington.edu/nwcphp/nph/
nwph
Public Health and the Precautionary
Principle
By Steven G. Gilbert
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Precautionary Principle
“When an activity raises threats of harm to human health or the environment,
precautionary measures should be take even if some cause and effect relationships are not
fully established scientifically.”
Wingspread Conference, 1998.
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
• Setting goals (Health indicators)• Taking preventive action in the face of
uncertainty• Shifting the burden of responsibility to the
proponents of an activity (Who benefits?)• Exploring a wide range of alternatives to
possibly harmful actions (Is it necessary?)• Increasing public participation in decision
making (transparency of information & environmental justice)
Central components
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Child Health
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
So Many Chemicals so Little Data
2863 above 1 Million pounds
78.2% no data
21.4% some data
12 or 0.4% good data
www.preventingharm.org
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Nearly 12 million children (17%) under age 18 in the US suffer from one or more developmental disabilities
Learning disabilities – 5-10% of kids in public school
ADHD – 3-6% of all school kids, maybe higher
The Consequences
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
"A thing is right when it tends to preserve the integrity, stability, and beauty of the biotic community. It is wrong when it tends otherwise." -
Aldo Leopold, 1949, A Sand County Almanac
The First Bioethicist
---------- 1887 - 1948 ----------
Aldo Leopold
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
“An ethic, ecologically, is a limitation on freedom of action in the struggle for
existence”Aldo Leopold
Limits on Freedom
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
“The Commons”
The Tragedy of the CommonsBy Garrett Hardin, Science, 1968
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Technical Solutions
“It is our considered professional judgment that
this dilemma has no technical solution.”
The Tragedy of the CommonsBy Garrett Hardin, Science, 1968
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Problems – Solutions?
Lead and kids Fetal alcohol syndrome Nuclear disarmament Bioterrorism Ocean Fisheries Persistent chemicals The Commons
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
The study of poisonsor
the adverse effects of chemical and physical agents on living
organisms.
Toxicology Definitions
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
399 BC Death of Socrates by HemlockSocrates 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.
Ancient Awareness
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
From Romeo and Juliet - act 5Come bitter pilot, now at once run on
The dashing rocks thy seasick weary bark!
Here’s to my love! O true apothecary!
Thy drugs are quick. Thus with a kiss I die.
Shakespeare (1564-1616)
Historical Awareness
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
“Conditions that ensure that all living things have the best opportunity to reach and maintain their full genetic potential.”
Steven G. Gilbert, 1999
Human & Environmental Health
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
• Hong Kong
• Princess Diana
• Ambassador to Mexico
• Coeur d’Alene, Silver Valley, ID
• Tacoma
• $100 Billion, $65 Billion
• Food, noise, dust
• 11,000 to 689,000 Children
What do these have in common?
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Who are these white guys?
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
“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)
Power To Discover The Truth
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
What Is This?
N
NN
N
CH3
CH3
CH3
O
O
1
3
7
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Key Words
Risk =
Hazard X Exposure
Dose / Response
Individual Sensitivity
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
“All substances are poisons; there is none which is not a
poison. The right dose differentiates
a poison from a remedy.”
Paracelsus (1493-1541)
Paracelsus
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
“The sensitivity of the individual differentiates a poison from a remedy.
The fundamental principle of toxicology is the individual’s response to a dose.”
S. G. Gilbert (1997)
An Individual View
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10Superman
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Neuron
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
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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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
What Is This?
CH
H
H
OHC
H
H
(CH3-CH2-OH)
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Effects of Prenatal Alcohol
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10FAS Child
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Mouse – Scanning EM
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
A Small Dose of Lead
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Lead In Homes
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Lead History
Greek 2nd BC
Lead Makes the Mind Give Way
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Recycling Lead
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Agency Blood Lead Levels
60
40
3025
2015
10
20
10
20
30
40
50
60
Blo
od
Lea
d (
ug
/dl)
CDC1960
CDC1973
CDC1975
CDC1985
WHO1986
EPA1986
CDC1990
CDC2006?
Agency and Year
Acceptable Childhood Blood Lead Levels
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
A Small Dose of Mercury
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Hg – Like Water
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10Polluting with HG
Discharge in Minamata Bay
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Fetal Effects of MeHg
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Life-Long Effects of MeHg
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
The Mercury Cycle
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Pesticide Application
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Classes Of Pesticides
Insecticides (kill insects)• Organochlorines• Organophosphates• Carbamates• Synthetic Pyrethroids
Herbicides (kill plants) Rodenticides (kill rodents) Fungicides (kill fungus) Fumigants (kill whatever)
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Other Exposure
Dietary exposure• Pesticide residues on crops, dust –
hand to mouth
Community exposure• Airborne drift from commercial app
Contaminated drinking water• Leaching from soils to ground water
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
• Focus – long-term prevention of pest problems
• Reduce or eliminate chemical pest control methods
• Monitor for the presence of pests before treating
• Nonchemical strategies (make habitat less attractive, physical controls)
• Learn about your pests
Integrated Pest Management (IPM)
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Key Words
Risk =
Hazard X Exposure
Dose / Response
Individual Sensitivity
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Effects of Amount on Response
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Effects of Size on Response
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Glasses of Wine - Dose Response
0
25
50
75
100
0 1 2 3 4 5 6 7 8
Glasses of Wine
% D
iffi
cult
y W
alki
ng
All Effected
NO Effect
Amount half are effected
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Dose (mg/kg body weight)Increasing dose
Dose Response Function
0
25
50
75
100
0 10 20 30 40 50 60 70 80 90 100
% R
esp
on
se
NO Effect
All Effected
Half Effected
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Ethyl alcohol 10,000Salt (sodium chloride) 4,000Iron (Ferrous sulfate) 1,500Morphine 900Mothballs 500 (paradichlorobenzene)Aspirin 250DDT 250Cyanide 10Nicotine 1Tetrodotoxin (from fish) 0.01Dioxin (TCDD) 0.001Botulinum Toxin 0.00001Bee Venom ??
Agent LD-50 (mg/kg)
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
1) Skin (dermal)
2) Lung (inhalation)
3) Oral (gut)
Route of exposure
Exposure & Absorption
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Number of Times
Time Between
4 Beers in an hour or4 Beers in 4 Days
Frequency Of Exposure
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Acute Exposure
Sub-chronic Exposure
Chronic Exposure
Duration Of Exposure
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Where It Goes
(body water, fat, bone)
Where It Accumulates
Distribution
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
How The Body Breaks It Down
What It Turns Into
How Fast It Does It
Metabolism
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
N
NN
N
CH3
CH3
CH3
O
O
1
3
7
Caffeine - 1,3,7 Trimethylxanthine
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Co
nce
ntr
atio
n (
µg
/ml)
Time (hrs)
How Long It Takes To Go
Half-life
02
46
810
1214
0 1 2 3 4 5 6 7 8 9 10 11
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
• Young or Old
• Male or Female
• Individual Variability
• Genetics Differences
• Species Differences
Susceptibility & Variability
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
N
CH3N
What Is This?
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Structure of PBDEs
X & Y are number of Bromine atomsCommon Penta, Octa, and Deca
PolyBrominated Diphenyl Ether
O
BrxBry
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
PBDEs in House Dust (ppb)
From EWG - Toxic Fire Retardants Contaminate American Homes - http://www.ewg.org/reports/inthedust/summary.php
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
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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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Estimated Costs - National
Best Estimate
Low Estimate High Estimate
Lead Poisoning $43.4 $43.4 $43.4
Asthma $2.0 $0.7 $2.3
Cancer $0.3 $0.2 $0.7
Neurobehavioral Disorders
$9.2 $4.6 $18.4
TOTAL $54.9 $48.8 $64.8
Estimated Costs of Pediatric Disease of Environmental Origin, United States,1997 (billions)
(From “Environmental Pollutants and Disease in American Children,” Landrigan, Schechter, et.al., 2002)
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Estimated Costs - Washington
Diseases and disabilities (asthma, cancer, lead exposure, birth defects, and neurobehavioral effects) attributable to environmental contaminants.
Best Estimate
Direct Costs
Indirect Costs
Range
Childhood $1,875 $310.6 $1,565
$1,600-$2,200
Adult & child $2,734 $782.1 $1,953
$2,800-$3,500
Disease/Disability (2004 $ million)
Kate Davies Economic costs of diseases and disabilities attributable to environmental contaminants in Washington State. Antioch University Seattle 2005. http://washington.chenw.org/pdfs/EnvironmentalCosts.pdf
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
“When an activity raises threats of harm to human health or the environment,
precautionary measures should be take even if some cause and effect relationships are not
fully established scientifically.”
Wingspread Conference, 1998.
Precautionary Principle
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
• Taking preventive action in the face of uncertainty
• Shifting the burden of proof/responsibility to the proponents of an activity
• Exploring a wide range of alternatives to possibly harmful actions
• Increasing public participation in decision making
Wingspread Conference, 1998.
Central components
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
• Children have a right to a safe, fair and healthy environment
• Ethical Responsibility to share and use of knowledge
• Duty to promote health and well being of children
• Thoughtful public health advocate
Knowledge - Responsibility
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
The Potential of Children
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Principles of Toxicology
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Additional Information
• A Small Dose of Toxicology• www.asmalldoseof.org
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Authorship Information
For Additional Information ContactSteven G. Gilbert, PhD, DABT
E-mail: [email protected]: www.asmalldoseof.org
This presentation is supplement to “A Small Dose of Toxicology”
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
ReceptorReceptor
LigandLigand
Cell MembraneCell Membrane
Signal ProteinSignal Protein
Positive ResponsePositive Response
Outside CellOutside Cell
Inside CellInside Cell
Ligand binds to receptorLigand binds to receptor
11
33
22
Normal Receptor-Ligand Interaction
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
ToxicantToxicant11
Toxicantinactivates
receptor
Toxicantinactivates
receptor
No ResponseNo Response
3322
Inactivation of Receptor by Toxicant
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A Small Dose of Toxicology Principles of Toxicology – 01/07/10
Toxicant1
No Response
32
Ligand
Toxicant out competes normal ligand
Ligand cannot bind receptor
Competition For Receptor