a small dose of toxicologyprinciples of toxicology – 01/07/10 an introduction to the principles of...

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 Principles of Toxicology – 01/07/10

A Small Dose of Toxicology

See: www.asmalldoseof.org -- smdose

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

Small Dose of Toxicology

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

Milestones of Toxicology

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

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

The World Library of Toxicology

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

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

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.

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

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.

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

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

Child Health

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

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

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

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

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

“The Commons”

The Tragedy of the CommonsBy Garrett Hardin, Science, 1968

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

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

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

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

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

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

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?

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

Who are these white guys?

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

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

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

Key Words

Risk =

Hazard X Exposure

Dose / Response

Individual Sensitivity

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

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

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

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

Neuron

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

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

What Is This?

CH

H

H

OHC

H

H

(CH3-CH2-OH)

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

Effects of Prenatal Alcohol

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

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

Mouse – Scanning EM

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

A Small Dose of Lead

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

Lead In Homes

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

Lead History

Greek 2nd BC

Lead Makes the Mind Give Way

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

Recycling Lead

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

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

A Small Dose of Mercury

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

Hg – Like Water

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

Discharge in Minamata Bay

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

Fetal Effects of MeHg

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

Life-Long Effects of MeHg

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

The Mercury Cycle

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

Pesticide Application

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)

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

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)

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

Key Words

Risk =

Hazard X Exposure

Dose / Response

Individual Sensitivity

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

Effects of Amount on Response

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

Effects of Size on Response

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

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

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)

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

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

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

Acute Exposure

Sub-chronic Exposure

Chronic Exposure

Duration Of Exposure

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

Where It Goes

(body water, fat, bone)

Where It Accumulates

Distribution

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

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

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

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

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

N

CH3N

What Is This?

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

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

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

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)

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

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

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

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

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

The Potential of Children

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

Principles of Toxicology

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

Additional Information

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

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

Authorship Information

For Additional Information ContactSteven G. Gilbert, PhD, DABT

E-mail: smdose@asmalldoseof.orgWeb: www.asmalldoseof.org

This presentation is supplement to “A Small Dose of Toxicology”

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

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

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