Objectives:

Toxicology B i Basics
TOX/BIO/FOR 435/535 Genes & Chemicals in Agriculture: Value & Risk

Be able to identify the major exposure routes and importance for toxicity Understand characteristics/issues that influence exposure levels Understand the importance of the dose-response in toxicology and how information is obtained

Dave Stone, Ph.D.

What is exposure?
Contact with a substance, typically by swallowing, breathing, or touching the skin or eyes.

BASICS OF EXPOSURE

Is this exposure?

How about now?

What about this?

Complete Exposure Pathway

A B E

Source of Chemical Chemical Transport Exposed Population

C
Point of Exposure

D
Exposure Route

Major Exposure Routes:

Exposure Route & Toxicity:

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

Tetrodotoxin

Paraquat

Elemental Mercury

Skin (Dermal) Exposure:

Absorption rate of chemicals varies by location of skin. The eyelids and genitalia have the quickest absorption rates. The soles and palms tend to have the slowest absorption.
Scalp/forehead HIGH Eyes/eyelids VERY HIGH Arms/legs/back MEDIUM Palms LOW Genitalia VERY HIGH Soles LOW

Factors affecting skin exposure:

Absorption of chemicals through the skin is promoted by: high lipid solubility sweaty, hot skin wrapping of skin abrasion abrasion or inj injury r presence of solvents

Ingestion:
Most absorption occurs in the small intestines intestines. The lining of the intestinal tract is only one cell thick and has an extremely large surface area. Absorption can occur throughout, including the mouth and rectum. To limit toxic effects from ingestion, g , time is essential to limit absorption.

Inhalation:
Adults breathe several cubic meters of air per day, depending on activity level. Fibers and small particles (< 1 micron) can be lodged in the lungs. Other gases can diffuse ff across the respiratory lining and enter the blood.

Duration of Exposure
The length of time that an organism is exposed to a chemical is critical to determine toxicity toxicity. Duration and frequency contribute to dose. Both may alter toxic effects. Acute Exposure = typically involves a single or short exposure Chronic Exposures = multiple exposures over time (frequency)

Vulnerable Populations
-Young -Elderly y -Immunocomprimised -Organ Transplant -Pregnant/breast feeding -Enzymatic deficiency -Genetic makeup -Subsistence -Socio-economic S i i status

Dose-Response
A key concept in toxicology is that a quantifiable relationship exists between a chemical concentration and the magnitude of the toxic effect (i.e. the Dose Makes the Poison).

Paracelsus*

BASICS OF DOSE & RESPONSE

In a g given p population, p , there will be a range g of sensitivities. There will also be an average sensitivity or dose in a population. These averages are important to determine.
*a.k.a Areolus Phillipus Theophrastus Bombastus von Hohenheim

Toxicity expressed
Modify y existing g body y functions Change in cellular reactions Reversible injury Irreversible injury Death

What are some examples of toxic effects?

Effects of Amount on Response

Effects of Size on Response

A Small Dose of Toxicology

A Small Dose of Toxicology

DoseDose -Response Relationship

The magnitude of the toxic response is proportional to the concentration (how much) of the chemical at the target site. The concentration of a chemical at the target site is proportional to the dose. Four important processes control the amount of a chemical that reaches the target site. Absorption Tissue distribution Metabolism Excretion
Society of Toxicology 2008 (modified)

DoseDose -Response Curves

Effective Dose 100 80 60 40 20 1 2 3 5 7 10 ED50 100 80 60 40 20 10 20 30 50 100 LD50 Lethal Dose

Phenobarbital (mg/kg) Log Scale

Dose Response
All Effected

Declining Safe Dose of Lead

Acceptable Childhood Blood Lead Levels

100

% Difficulty Walking

60

60

Blo ood Lead (ug/dl)

75 50 25
NO Effect Amount half are effected

50 40 30 20 10 0 CDC CDC 1960 1973 CDC CDC WHO EPA 1975 1985 1986 1986 Agency and Year CDC CDC 1990 2006? 40 30 25 20 15 10 2

0 0 1 2 3 4 5 6 7 8

Glasses of Wine

A Small Dose of Toxicology, modified

A Small Dose of Toxicology, modified

Exposure-Response
Many

Example of DoseDose-Response for Vitamin A

Number of Individuals

Majority of Individuals Average Effect Minimal Effect Maximal Effect

Adv verse response

Resistant Individuals

Sensitive Individuals

Too low: Blindness, dry skin, increased infections

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

Threshold

Few Mild Response to SAME dose Extreme

Dose
Society of Toxicology 2008

DoseDose -Response Data

Traditionally, society has used animals to predict toxicity in humans (primarily rodents). Anatomical and physiological differences can be dramatic. Often, animals are exposed to high-doses over short periods of time, with the health effects extrapolated to humans. A well-designed well designed dose-response dose response study will include controls and multiple dose groups consisting of several male and female animals. Good animal husbandry practices are critical.

DoseDose -Response Data: the Future?

Recently, a National Academies Workgroup proposed a road map entitled Toxicity Testing in the 21st Century. This roadmap highlighted the need to more away from animal testing and into models that are: -based on in vitro models to detect changes in biological processes -use human cell lines -molecular approaches & advances -bioinformatics and computational approaches

DISCUSSION DISCUSSION