An Introduction to the Principles of Toxicology

1
An Introduction to the Principles of Toxicology
A Small Dose of Toxicology
Steven G.Gilbert, PhD,DABT A Small Dose of
Toxicology www.asmalldoseof.org
2
Child Health
3
Toxicology Definitions
The study of poisons or the adverse effects of
chemical and physical agents on living organisms.
4
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.
5
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
6
Environmental Health
Conditions that ensure that all living things
have the best opportunity to reach and maintain
their full genetic potential. Steven G.
Gilbert, 1999
7
What do these have in common?

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

8
Who are these white guys?
9
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)
10
What Is This?
O
CH3
CH3
N
N
7
1
3
N
O
N
CH3
11
Key Words
Dose / Response

• Risk
• Hazard X Exposure

Individual Sensitivity
12
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)
13
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)
14
Superman
15
Neuron
16
What Is This?
(CH3-CH2-OH)
17
Effects of Prenatal Alcohol
18
FAS Child
19
Mouse Scanning EM
20
A Small Dose of Lead
21
Lead In Homes
22
Lead History
Lead Makes the Mind Give Way

• Greek 2nd BC

23
Lead in Families
24
Recycling Lead
25
CDC Blood Lead Levels
26
A Small Dose of Mercury
27
Polluting with HG
Discharge in Minamata Bay
28
Fetal Effects of MeHg
29
Life-Long Effects of MeHg
30
The Mercury Cycle
31
Key Words
Dose / Response

• Risk
• Hazard X Exposure

Individual Sensitivity
32
Effects of Amount on Response
33
Effects of Size on Response
34
Glasses of Wine - Dose Response
All Effected
100
75
Difficulty Walking
50
Amount half are effected
25
NO Effect
0
0
1
2
3
4
5
6
7
8
Glasses of Wine
35
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
36
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 ??
37
Exposure Absorption
Route of exposure
1) Skin (dermal) 2) Lung (inhalation)
3) Oral (gut)
38
Frequency Of Exposure
Number of Times
Time Between
4 Beers in an hour or 4 Beers in 4 Days
39
Duration Of Exposure
Acute Exposure
Sub-chronic Exposure
Chronic Exposure
40
Distribution
Where It Goes
(body water, fat, bone)
Where It Accumulates
41
Metabolism
How The Body Breaks It Down
What It Turns Into
How Fast It Does It
42
Caffeine - 1,3,7 Trimethylxanthine
O
CH3
CH3
N
N
7
1
3
N
O
N
CH3
43
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)
44
Susceptibility Variability

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

45
What Is This?
CH3
N
N
46
The Potential of Children
47
Principles of Toxicology
48
Additional Information

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

49
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
50
Normal Receptor-Ligand Interaction
1
Ligand
Outside Cell
Receptor
Cell Membrane
2
Inside Cell
Ligand binds to receptor
3
Signal Protein
Positive Response
51
Inactivation of Receptor by Toxicant
1
Toxicant
2
Toxicant inactivates receptor
3
No Response
52
Competition For Receptor
Ligand
1
Toxicant
2
Toxicant out competes normal ligand
Ligand cannot bind receptor
3
No Response
53
Susceptibility of Children

• Dose Response Issues
• Higher metabolic rate
• Different nutritional requirements
• Rapidly dividing migrating cells
• Immature organs

54
Sequence of Human Development
Red - most sensitive, Gray - Less
55
Ancient Awareness

• Many ancient cultures had fertility goddess
• Many ancient documentation of malformations
• Malformations rich aspect of mythology
• 6500 BC Turkey - figurine of conjoined twins
• 4000-5000 BC Australia drawings of twins
• 2000 BC - Tablet of Nineveh describes 62
  malformations and predicts the future

56
Historical Awareness

• 15th-16th centuries malformations caused by the
  devil, mother and child killed
• 1830s - Etienne Geoffroy Saint-Hilaire
  experimented with chicken eggs
• 1900s began acceptance of malformations related
  to genetics
• 1940s - Josef Warkany environmental factors
  affect rat development

57
Historical Events

• 1941 Human malformations linked to rubella
  virus
• 1960s Thalidomide (a sedative and anti-nausea
  drug) found to cause human malformations
• 1950s Methylmercury recognized as
  developmental toxicant
• 1970s Alcohol related to developmental effects
  Fetal Alcohol Syndrome (FAS)

58
Structure of PBDEs
PolyBrominated Diphenyl Ether
X Y are number of Bromine atoms Common Penta,
Octa, and Deca
59
PBDEs in House Dust (ppb)
From EWG - Toxic Fire Retardants Contaminate
American Homes - http//www.ewg.org/reports/inthed
ust/summary.php
60
PBDEs in Breast Milk (ppb)
From EWG - Toxic Fire Retardants in Breast Milk
from American Mothers - http//www.ewg.org/reports
/mothersmilk/es.php
61
PBDEs California Status

• Legislation to ban - Penta and Octa-PBDE
• Did not ban Deca-PBDE
• Must report amount of electronic waste and toxic
  chemicals in waste such as PBDEs, metals

62
Ethical, Legal, and Social Issues Related to DART
ELSI Children Toxicology
Reproductive Developmental Toxicology
Pharmaceutical, Environmental, and Legal
Considerations Northern and Southern California
Chapters of the Society of Toxicology - Fall 2004
Meeting Sept 30 Oct 1, 2004 Steven G.Gilbert,
PhD, DABT
63
Child Health
64
Convergence of Issues

• Vision of Child Health
• Knowledge of Reproductive and Developmental
  Toxicology
• Policy Approach within an ethical framework
• Social responsibilities
• No technical solutions
• Restriction of freedoms
• Precautionary Principle

65
WHO Vision for Child Health

• A World Fit for Children
• Promoting healthy lives
• Providing quality education
• Protecting against abuse, exploitation and
  violence
• Combating HIV/AIDS.

http//www.unicef.org/why/why_worldgoals.html
66
CDC Vision for Child Health
Environmental Health at CDC strives to promote
health and quality of life by preventing or
controlling those diseases or deaths that result
from interactions between people and their
environment.
http//www.cdc.gov/node.do?id0900f3ec8000e044
67
American Academy of Pediatrics
Mission and vision To attain optimal physical,
mental and social health and well-being for all
infants, children, adolescents and young adults.
http//www.aap.org/member/memcore.htm
68
American Academy of Pediatrics
The APA goes on to state To this purpose, the
AAP and its members dedicate their efforts and
resources. The vision 1) to advocate for
infants, children, adolescents, and young adults
and provide for their care 2) to collaborate
with others to assure child health and .
http//www.aap.org/member/memcore.htm
69
Vision for Child Health
Children can develop and mature in an
environment that allows them to reach and
maintain their full potential.
70
Vision of Environmental Health
Conditions that ensure that all living things
have the best opportunity to reach and maintain
their full genetic potential.
71
Susceptibility of Children

• Dose Response Issues
• Higher metabolic rate
• Different nutritional requirements
• Rapidly dividing migrating cells
• Immature organs

72
Sequence of Human Development
Red - most sensitive, Gray - Less
73
Ancient Awareness

• Many ancient cultures had fertility goddess
• Many ancient documentation of malformations
• Malformations rich aspect of mythology
• 6500 BC Turkey - figurine of conjoined twins
• 4000-5000 BC Australia drawings of twins
• 2000 BC - Tablet of Nineveh describes 62
  malformations and predicts the future

74
Historical Awareness

• 15th-16th centuries malformations caused by the
  devil, mother and child killed
• 1830s - Etienne Geoffroy Saint-Hilaire
  experimented with chicken eggs
• 1900s began acceptance of malformations related
  to genetics
• 1940s - Josef Warkany environmental factors
  affect rat development

75
Historical Events

• 1941 Human malformations linked to rubella
  virus
• 1960s Thalidomide (a sedative and anti-nausea
  drug) found to cause human malformations
• 1950s Methylmercury recognized as
  developmental toxicant
• 1970s Alcohol related to developmental effects
  Fetal Alcohol Syndrome (FAS)

76
Case Studies

• Thalidomide
• Methylmercury
• Lead
• Ethanol (Alcohol)
• PBDEs

77
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

78
Fetal Effects of MeHg
79
The Mercury Cycle
80
WA State Advisory
Limit the amount of canned tuna you eat, based on
your bodyweight. Guidelines are Women of
childbearing age should limit the amount of
canned tuna they eat to about one can per week
(six ounces.) A woman who weighs less than 135
pounds should eat less than one can of tuna per
week. Children under six should eat less than
one half a can of tuna (three ounces) per week.
Specific weekly limits for children under six
range from one ounce for a twenty pound child, to
three ounces for a child weighing about sixty
pounds.
http//www.doh.wa.gov/fish/FishAdvMercury.htm
81
San Francisco Hg TMDL
San Francisco Bay Regional Water Quality Control
Board. San Francisco Bay Mercury Total Maximum
Daily Load (TMDL) Numeric targets for mercury
concentrations in suspended sediment, fish
tissue, and bird eggs
http//www.swrcb.ca.gov/rwqcb2/sfbaymercurytmdl.ht
m
82
Alcohol
(CH3-CH2-OH)
83
FAS Child
84
FAS FAE
Most common preventable cause of adverse CNS
development Fetal Alcohol Syndrome
(FAS) 4,000-12,000 infants per year in US Fetal
Alcohol Effect (FAE) 7,000-36,000 infants per
year in US 1 to 3 infants per 1,000 world wide??
85
Policy Approaches

• 1981 - U.S. Surgeon General first advised that
  women should not drink alcoholic beverages during
  pregnancy.
• 1988 - U.S. requires warning labels on all
  alcoholic beverages sold in the United States.
• 1990 - U.S. Dietary Guidelines state that women
  who are pregnant or planning to become pregnant
  should not drink alcohol.
• 1998 - 19 states require the posting of alcohol
  health warning signs where alcoholic beverages
  are sold

86
Structure of PBDEs
PolyBrominated Diphenyl Ether
X Y are number of Bromine atoms Common Penta,
Octa, and Deca
87
PBDEs in House Dust (ppb)
From EWG - Toxic Fire Retardants Contaminate
American Homes - http//www.ewg.org/reports/inthed
ust/summary.php
88
PBDEs in Breast Milk (ppb)
From EWG - Toxic Fire Retardants in Breast Milk
from American Mothers - http//www.ewg.org/reports
/mothersmilk/es.php
89
PBDEs California Status

• Legislation to ban - Penta and Octa-PBDE
• Did not ban Deca-PBDE
• Must report amount of electronic waste and toxic
  chemicals in waste such as PBDEs, metals

90
Scientific Process
Variability Uncertainty
91
Types of Uncertainty

• Statistical
• Model
• Fundamental

92
Statistical Uncertainty
Reducing Variability

• Easiest to examine reduce
• Not knowing the exact value of a variable (inter
  and intra subject variance)
• Sample size

93
Model or System Uncertainty

• Not fully understanding the relations between
  variables (mechanism of action)
• Which variables are most important (high dose vs
  low dose)

94
Fundamental Uncertainty

• Not knowing the right questions to ask
• Most sensitive end point
• we dont know what we dont know

95
Sir Austin Bradford Hill
"All scientific work is incomplete - whether it
be observational or experimental. All scientific
work is liable to be upset or modified by
advancing knowledge. That does not confer upon us
a freedom to ignore the knowledge we already have
or postpone the action that it appears to demand
at a given time. " Sir Austin Bradford Hill
(1965)
96
Determining Causation

• Strength of association
• Consistency of findings
• Biological gradient
• Temporal sequence
• Biologic or theoretical plausibility
• Coherence with established knowledge
• Specificity of association
• Sir Austin Bradford Hill (1965)

97
Socially responsible white guys?
98
The Commons
The Tragedy of the Commons By Garrett Hardin,
Science, 1968
99
Technical Solutions
It is our considered professional judgment that
this dilemma has no technical solution. The
Tragedy of the Commons By Garrett Hardin,
Science, 1968
100
Problems Solutions?

• Lead and kids
• Fetal alcohol syndrome
• Nuclear disarmament
• Bioterrorism
• Ocean Fisheries
• Persistent chemicals
• The Commons

101
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.
102
Safety Efficacy vs Harm

• FDA regulations of Drugs (1938)
• FDA regulations of Dietary Supplements (Dietary
  Supplement Health and Education Act of 1994
  (DSHEA))
• Ephedra present an unreasonable risk of illness
  or injury (Dec, 2003)

103
Central components

• 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.

104
Values of the precautionary principle
1) Respect - for the needs and rights of this and
future generations as well as others who cannot
speak for themselves 2) Humility - towards the
natural world and our ability to understand it
through science 3) Democracy - giving people a
voice in matters that affect their lives 4)
Responsibility - governments public trust
responsibility to manage the commonwealth for
this and future generations. - Individuals
including industry, obligation to take
responsibility for their actions in the world.
105
Seattle Initiative

• City Comprehensive Plans
• Every citizen of Seattle has an equal right to a
  healthy and safe environment.
• Seattle sees the Precautionary Principle approach
  as its policy framework to develop laws for a
  healthier and more just Seattle.

106
Knowledge - Responsibility

• 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

107
Citizen Toxicologist
Socially Responsible Toxicologist
The citizen toxicologist is a thoughtful advocate
for human and environmental health, who strives
to share their scientific knowledge with the
public, speaking to public interests rather than
private or special interests.
108
Socially Responsible Actions

• Testifying
• Writing review papers
• K-12 class room teaching
• Adding expertise to community groups
• Education
• Mentoring
• Speakers Bureau

109
SOT - ESLI Specialty Section

• Forum in which to discuss the ethical
  implications of results from our science as well
  as the resulting legal and social implications.
• 2005 SOT meeting workshop on Conflict of
  Interest

http//www.toxicology.org/memberservices/specsecti
on/specsection.html
110
Lead In Homes
111
Lead History

• 6500 BC. - Lead discovered in Turkey, first mine.
  
• 500 BC-300 AD.- Roman lead smelting produces
  dangerous emissions.
• 100 BC. - Greek physicians give clinical
  description of lead poisoning. Lead makes the
  mind give way.
• 1904 - Child lead poisoning linked to lead-based
  paints.
• 1922 - League of Nations bans white-lead interior
  paint U.S. declines to adopt
• 1923 - Leaded gasoline goes on sale in selected
  markets
• 1971- U.S. Lead-Based Paint Poisoning Prevention
  Act passed
• 1923 - Leaded gasoline goes on sale in selected
  markets
• 1986 - Primary phase out of leaded gas in US
  completed

112
Lead Out of Gasoline
1990 lead removed from Gasoline Between 1976
and 1994, the mean blood lead concentration in
children dropped from 13.7 mcg/dL to 3.2
mcg/dL One of the major public health triumphs
of the 20th century
113
Workplace Lead
Health of lead exposure on workers in London -
Steel dust, stone dust, clay dust, alkali dust,
fluff dust, fiber dust- all these things kill,
and they are more deadly than machine-guns and
pom-poms. Worst of all is the lead dust in the
white lead trades. 1903 book The People of
the Abyss Jack London
114
Agency Blood Lead Levels
115
Lead - Absorption
Orally Consumed Lead Absorbed In Place of
Calcium CHILDREN 30-50 OF LEAD ADULTS 5-10
OF LEAD Increased During Pregnancy
116
Lead - Nutrition
NUTRITIONAL DEFICIENCIES INCREASE ABSORPTION
(high fat diets, iron, calcium) VITAMIN D (from
sun) INCREASES
117
Half-life Of Lead
25 DAYS -- BLOOD 40 DAYS -- SOFT TISSUE 20
YEARS -- BONE
118
Children Vulnerability
CHILDREN are more vulnerable exposure than
ADULTS Size Consume More Food Inhale More
Air Developing Nervous System Increased need for
Calcium
119
Needleman, NEJM, 1979
120
CHILDREN ADULTS
Blood Lead
(ug Pb/dl)
150
Death
Encephalopathy
100
Encephalopathy
Frank Anemia
Nephropathy
Frank Anemia
Decreased Longevity
Colic
Hemoglobin Synthesis
50
Peripheral Neuropathies
Infertility (MEN)
40
Hemoglobin Synthesis
Nephropathy
Systolic Blood Pressure (MEN)
30
Vitamin D Metabolism
Hearing Acuity
20
Nerve Conduction Velocity
Erythrocyte Protoporphyrin
Erythrocyte Protoporphyrin
(Women)
Vitamin D Metabolism(?)
DEVELOPMENTAL TOXICITY
10
Hypertension (?)
IQ
HEARING
Transplacental Transfer
GROWTH
- Low birth weight
- Miscarriages, Stillbirth
- Premature birth
121
Reproductive Effects Of Lead

• WOMEN
• lead crosses the placenta
• low infant birth weight
• retarded mental development
• miscarriages
• premature birth
• stillbirth
• MEN
• decreased sex drive
• impotence
• sterility
• altered sperm-birth defects

122
Childhood Lead Exposure
-- LONG TERM PROBLEMS --
LOW GRADES ABSENTEEISM READING
DISABILITY HIGH SCHOOL DROP OUT
123
Academic Social Costs Of Lead Exposure

• Increased risk of not graduating from high school
  (rr 4.8)
• Poorer reading scores
• Increased evidence of depression
• Higher rate of hard drug use
• Increased risk for attention deficit disorder
• Increased risk for antisocial behavior

124
Children Affected
16 of all American children Children with blood
leads above 15 UG/DL 7 of economically favored
white children 55 of African American children
in poverty source The nature and extent of
lead poisoning in children in the US a report
to Congress - ATSDR
125
Mechanisms Of Lead Toxicity

• Lead-Calcium Interactions
• Lead-Protein Interactions
• Lead-Dopamine Systems Interactions
• Lead-Opioid Systems Interactions

126
Lead Chelating

• EDTA, Bal, Succimer
• EDTA In Use For 48 Years
• Little Knowledge Of Benefits Or Hazards Of These
  Drugs
• The Treatment Is Removing The Source Of Lead

127
Lead In Ethnic Remedies
128
Recycling Lead
129
Truth and Lead
How long a useful truth may be known and exist,
befort it is generally receivd and practisd
on Benjamin Franklin
130
Animals Killed Annually in the U.S.
400 Million Motorists
200 Million Hunters
20 Million Dogs Cats Abandoned
5 Billion Food Livestock Poultry
18 Million Rats Mice Research
2 Million Other Species Research
131
Additional Information

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

132
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