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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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