toxbasics_tox435_10

7/29/2019 TOXBasics_TOX435_10

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Toxicology

TOX/BIO/FOR 435/535TOX/BIO/FOR 435/535Genes & Chemicals in Agriculture: Value &Genes & Chemicals in Agriculture: Value &

TOX/BIO/FOR 435/535TOX/BIO/FOR 435/535Genes & Chemicals in Agriculture: Value &Genes & Chemicals in Agriculture: Value &

as cs

Dave Stone, Ph.D.

Be able to identify the major exposure

Objectives:Objectives:

Understand characteristics/issues thatinfluence exposure levels

Understand the importance of thedose-response in toxicology and howinformation is obtained

BASICS OF

EXPOSURE

What is exposure?What is exposure?

Contact with a substance, typically by swallowing,breathin or touchin the skin or e es.

Is this exposure? What aboutthis?

How aboutnow?


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Complete Exposure PathwayComplete Exposure PathwayComplete Exposure PathwayComplete Exposure Pathway

B

A

E

Chemical Transport

Source ofChemical

Exposed Population

D

Exposure

Route

C

Point of

Exposure

Major Exposure Routes:Major Exposure Routes: Exposure Route & Toxicity:Exposure Route & Toxicity:

Depending on exposure route, some chemicals can havevery different toxicities. Why?

Paraquat ElementalMercury

Tetrodotoxin


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Absorption rate of chemicals varies by location of skin. Theeyelids and genitalia have the quickest absorption rates. Thesoles and palms tend to have the slowest absorption.

Skin (Dermal) Exposure:Skin (Dermal) Exposure:

Scalp/foreheadHIGH

Eyes/eyelidsVERY HIGH

Arms/legs/backMEDIUM

amsLOW

GenitaliaVERY HIGH

SolesLOW

Absorption of chemicalsthrough the skin is

Factors affecting sk in exposure:Factors affecting sk in exposure:

promoted by:

high lipid solubility

sweaty, hot skin

wrapping of skin

a ras on or nury

presence of solvents

Most absorption occurs in the

Ingestion:Ingestion:

.intestinal tract is only one cell thickand has an extremely large

surface area. Absorption canoccur throughout, including themouth and rectum. To limit toxiceffects from in estion, time isessential to limit absorption.

Inhalation:Inhalation:Adults breathe several cubic meters of air per day,depending on activity level. Fibers and small particles (


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The length of time that anorganism is exposed to a chemical

Duration of ExposureDuration of Exposure

.

Duration and frequencycontribute to dose. Both may altertoxic effects.

Acute Exposure = typicallyinvolves a single or shortexposure

Chronic Exposures =multipleexposures over time(frequency)

Vulnerable PopulationsVulnerable Populations

-Young-Elderly-Immunocomprimised-Organ Transplant-Pregnant/breast feeding-Enzymatic deficiency-Genetic makeup-Subsistence

-Soc o-economc status

BASICS OF DOSE &

RESPONSE

A key concept in toxicology is that auantifiablerelationshi exists

Paracelsus*Dose-Response

between a chemical concentrationand the magnitude of the toxic effect

(i.e. the Dose Makes the Poison).

In a given population, there will be a range ofsensitivities. There will also be an average sensitivityor dose in a population. These averages are importantto determine.

*a.k.a Areolus Phillipus Theophrastus Bombastus von Hohenheim


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Modify existing body functions

Toxicity expressedToxicity expressed

Change in cellular reactions

Reversible injury

Irreversible injury

Death

What are some examples of toxic effects?

Effects of Amount on ResponseEffects of Amount on Response

A Small Dose of Toxicology

Effects of Size on ResponseEffects of Size on Response

A Small Dose of Toxicology


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The magnitude of the toxic response isproportional to the concentration (how much)

DoseDose--Response RelationshipResponse Relationship

of the chemical at the target site.

The concentration of a chemical at the targetsite is proportional to the dose.

Fourimportant processes control the amountof a chemical that reaches the target site.

Abs or tion Tissue distribution

Metabolism

Excretion

Society of Toxicology 2008 (modified)

Effective Dose Lethal Dose

DoseDose--Response CurvesResponse Curves

ED50LD50

100

60

80

40

60

80

40

Phenobarbital (mg/kg) Log Scale

10 20 30 50 1001 2 3 5 7 10

Dose ResponseDose Response

100All Effected

25

50

75

Difficulty

Walking

NO Effect

Amount halfare effected

0

0 1 2 3 4 5 6 7 8

Glasses of Wine

A Small Dose of Toxicology, modified

Declining Safe Dose of LeadDeclining Safe Dose of Lead

60

Acceptable Childhood Blood Lead Levels

40

3025

2015

20

30

40

50

oodL

ead

(ug/dl)

20

10Bl

CDC

1960

CDC

1973

CDC

1975

CDC

1985

WHO

1986

EPA

1986

CDC

1990

CDC

2006?

Agency an d Year

A Small Dose of Toxicology, modified


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Many

ls

Exposure-Response

NumberofIndividua

Sensitive Individuals

Maximal

Effect

Resistant Individuals

Minimal

Effect

Majority of Individuals

Average Effect

Mild Extreme

Few

Response to SAME dose

Society of Toxicology 2008

Example of DoseExample of Dose--Response fo r Vitamin AResponse for Vitamin A

Too high: Anorexia,anemia, nose bleeds,muscle and joint pain

erseresponse

Threshold

Too low:Blindness,dry skin,increasedinfections

Dose

Ad

DoseDose--Response DataResponse Data

Traditionally, society has used animals to predicttoxicity in humans (primarily rodents). Anatomicaland h siolo icaldifferences can be dramatic.

Often, animals are exposed to high-doses over short

periods of time, with the health effects extrapolatedto humans.

A well-desi ned dose-res onse studwill include controls and multiple dosegroups consisting of several male andfemale animals. Good animalhusbandry practices are critical.

DoseDose--Response Data: the Future?Response Data: the Future?

Recently, a National Academies

entitled Toxicity Testing in the 21stCentury. This roadmap highlighted the

need to more away from animal testingand into models that are:

-based on in vitro models todetect chan es in biolo icalprocesses

-use human cell lines-molecular approaches &

advances-bioinformatics and

computational approaches


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