A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 An Introduction to the Principles of Toxicology A Small Dose of Toxicology Steven G. Gilbert,

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


A Small Dose of Toxicology

See: www.asmalldoseof.org -- smdose


Small Dose of Toxicology


Milestones of Toxicology


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


The World Library of Toxicology


Toxipedia suite of sites

www.ipmopedia.org

www.healthyworldtheater.orgwww.wanmec.org

www.toxipedia.org

www.wltox.org


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


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.


NW Public Health

See: http://healthlinks.washington.edu/nwcphp/nph/

nwph

Public Health and the Precautionary

Principle

By Steven G. Gilbert


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.


• 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


Child Health


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


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


"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


“An ethic, ecologically, is a limitation on freedom of action in the struggle for

existence”Aldo Leopold

Limits on Freedom


“The Commons”

The Tragedy of the CommonsBy Garrett Hardin, Science, 1968


Technical Solutions

“It is our considered professional judgment that

this dilemma has no technical solution.”

The Tragedy of the CommonsBy Garrett Hardin, Science, 1968


Problems – Solutions?

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


The study of poisonsor

the adverse effects of chemical and physical agents on living

organisms.

Toxicology Definitions


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


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


“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


• 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?


Who are these white guys?


“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


What Is This?

N

NN

N

CH3

CH3

CH3

O

O

1

3

7


Key Words

Risk =

Hazard X Exposure

Dose / Response

Individual Sensitivity


“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


“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

A Small Dose of Toxicology Principles of Toxicology – 01/07/10Superman


Neuron


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


What Is This?

CH

H

H

OHC

H

H

(CH3-CH2-OH)


Effects of Prenatal Alcohol

A Small Dose of Toxicology Principles of Toxicology – 01/07/10FAS Child


Mouse – Scanning EM


A Small Dose of Lead


Lead In Homes


Lead History

Greek 2nd BC

Lead Makes the Mind Give Way


Recycling Lead


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


A Small Dose of Mercury


Hg – Like Water

A Small Dose of Toxicology Principles of Toxicology – 01/07/10Polluting with HG

Discharge in Minamata Bay


Fetal Effects of MeHg


Life-Long Effects of MeHg


The Mercury Cycle


Pesticide Application


Classes Of Pesticides

Insecticides (kill insects)• Organochlorines• Organophosphates• Carbamates• Synthetic Pyrethroids

Herbicides (kill plants) Rodenticides (kill rodents) Fungicides (kill fungus) Fumigants (kill whatever)


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


• 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)


Key Words

Risk =

Hazard X Exposure

Dose / Response

Individual Sensitivity


Effects of Amount on Response


Effects of Size on Response


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


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


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)


1) Skin (dermal)

2) Lung (inhalation)

3) Oral (gut)

Route of exposure

Exposure & Absorption


Number of Times

Time Between

4 Beers in an hour or4 Beers in 4 Days

Frequency Of Exposure


Acute Exposure

Sub-chronic Exposure

Chronic Exposure

Duration Of Exposure


Where It Goes

(body water, fat, bone)

Where It Accumulates

Distribution


How The Body Breaks It Down

What It Turns Into

How Fast It Does It

Metabolism


N

NN

N

CH3

CH3

CH3

O

O

1

3

7

Caffeine - 1,3,7 Trimethylxanthine


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


• Young or Old

• Male or Female

• Individual Variability

• Genetics Differences

• Species Differences

Susceptibility & Variability


N

CH3N

What Is This?


Structure of PBDEs

X & Y are number of Bromine atomsCommon Penta, Octa, and Deca

PolyBrominated Diphenyl Ether

O

BrxBry


PBDEs in House Dust (ppb)

From EWG - Toxic Fire Retardants Contaminate American Homes - http://www.ewg.org/reports/inthedust/summary.php


PBDEs in Breast Milk (ppb)

From EWG - Toxic Fire Retardants in Breast Milk from American Mothers - http://www.ewg.org/reports/mothersmilk/es.php


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)


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


“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.”


Precautionary Principle


• 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


Central components


• 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


The Potential of Children


Principles of Toxicology


Additional Information

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


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”


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


ToxicantToxicant11

Toxicantinactivates

receptor

Toxicantinactivates

receptor

No ResponseNo Response

3322

Inactivation of Receptor by Toxicant


Toxicant1

No Response

32

Ligand

Toxicant out competes normal ligand

Ligand cannot bind receptor

Competition For Receptor

Documents

A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 An Introduction to the Principles of Toxicology A Small Dose of Toxicology Steven G. Gilbert,