ETX 101 Midterm 1

What is toxicology?

branch of science that deals with poisons and their effects

Three elements of toxicology

toxic agent, biological system, & interaction between the toxic agent and the biological system

What needs to happen in order for there to be toxicity?

exposure

What does a toxicologist do?

studies the basic causes and mechanisms of toxic effects resulting from exposure to chemical agents, studies factors affecting fates, assess the hazard or safety, & predict the hazard to target population

What is environmental toxicology?

combination of toxicology and environmental chemistry

Why study chemicals and what do we know?

70% of chemicals with no available toxicology information

What is the environmental fate dependent on?

structure and properties of a chemical; does not matter if it's synthetic or natural

What is a point source?

pollution from a single source; easy to identify

Ex: specific agricultural field where a pesticide is applied

What is a nonpoint source?

Areas where the sources of the pollution cannot be identified and come from many sources.

Ex: automobiles

Pesticides

selective toxins that kill or control some undesired form of life (i.e. pests)

Are pesticides highly selective?

No, they can have off-target effects

Herbicides

weed killer

Fungicides

fungus killer

Insecticides

insect killer

Rodenticide

a toxic chemical that kills rodents

Piscicide

a chemical that is poisonous to fish

Nematocide

A chemical agent that is destructive to nematodes

Why use pesticides?

increase the yield of crops, used to eliminate vector-borne diseases, and decrease harvest loss

Why are insecticides important?

protection of plants (food crops), reductions in human disease, and control of urban pests

Risks of insecticide use

environmental contamination and adverse effects on the health of non-target species

Chlorinated hydrocarbons

- developed during WWII

- added chlorine to carbon-based molecules

- added chlorine instead of hydrogen

- can only make single bond to another atom

Environmental fate of human-made anthropogenic chemicals

they DO NOT recycle, last for decades, partitioned into fats and lipids, molecules passed around into different lifecycles of living organisms

DDT

two aromatic groups and two chlorines

Lindane

not an aromatic ring

MIREX

8 carbons and no hydrogens

Properties of a perfect insecticide

cheap, persistent, effective, and broad spectrum

Properties of a dangerous insecticide

cheap, persistent, effective, and broad spectrum

- plus resistant and bioconcentration/biomagnification

What leads to bioconcentration and biomagnification?

can start at a low level of the environment but concentrate up a food chain

- lipophilicity (high octanol/water partition (Kow))

- poor metabolism (metabolic stability)

Carbamates

- Close relatives of the organophosphate pesticides

- Dissipate quickly from the environment as a result of breaking down into other substances

- Some are approved for controlling garden pests (e.g., wasps, hornets, and snails).

- Not very toxic to wildlife

Organophosphates

Found in pesticides, can cause cholinergic overstimulation by inhibiting cholinesterase, Tx: atropine

- developed in 1930s-1940s as nerve gas agents

Use of organophosphates

- have high mammalian toxicity but are synthesized as a pro-toxicant to reduce their direct toxicity and inclusion of side groups that can be metabolized

- big post-harvest use to transport food

What dies it mean to have a small LD50?

more potent ; only needs a small amount to be effective

Pyrethroids

pesticide includes natural and synthetic insecticides

- discovered in chrysanthemum species

Natural plant products

- used to be called botanicals

- plants want to prtoect themselves from predators and they do so by thickening their skin and thorns

- we are exposed to high concentration of plant products

Allicin

antimicrobial sulfur compound found in garlic

Herbicide use

- used to genetically modify crops

- not very useful because of overlapping biological effects

Timing of application for herbicides

a. pre-planting

b. pre-emergence: applied to the soil before the usual time of appearance of the weeds

c. post-emergence: applied to the soil after germination of the crop or weeds

Mechanisms of herbicides

1. selective - toxic to some species

2. contact - toxic when in contact with plant foliage

3. translocated - absorbed from the soil or through the foliage into the plant xylem and phloem

Targets of translocated herbicides

1. Respiration: blocks cell respiration, phenolic chemicals are contact chemicals

2. Photosynthesis: blocks photosynthesis reactions

3. Growth: can cause increase in cell growth (elongation) and plant essentially overgrows itself to death

Transgenic crops

mix and match DNA sequences from one organism and move them to another organism

Fumigant/ sterilant

something that's not chemical itself but the environment transforms it into its activity

- parent compound is less toxic to start with and must be transformed into something highly reactive

ADME

Absorption, Distribution, Metabolism, and Excretion

3 Major Routes of Exposure

a. oral (including drinking, food ingestion) - G.I. tract

b. dermal (including skin injection, entry through wounds) - skin

c. inhalation (including particle, nasal intake) - lungs, gills

Time element of Exposure

acute - one time, simulating accident; ex: an overdose

chronic - simulating daily exposure

Absorption/ Penetration

- general scheme of xenobiotic absorption (not naturally found in human being), distribution, and excretion

- how chemicals are absorbed in the body: physiochemical properties greatly affect the rate of absorption

How to find concentration of a chemical in your body?

dose received divided by body mass

physiochemical properties

- the ability of a chemical to move across membranes

- the ability of a chemical to across membrane will govern its fate in the body

What are membranes made up of?

Lipid bilayer

- they amphipathic since they contain both polar & non-polar components

partition coefficient

An experimentally-derived measure of a drug's lipid solubility used to predict its relative rate of movement across cell membranes.

- a measure of lipid solubility

A compound that readily moves across a biological membrane would be:

lipophilic, hydrophobic, nonpolar and nonionized

Kow

octanol-water partition coefficient

The higher the partition coefficient ...

the greater the lipophilicity of the compound

What increases water solubility?

- ionizable - has the ability to have a charge

- polarity

If a chemical is a weak acid or base containing ionizable groups,

the ability to pass across membranes cane be markedly at different pHs

Low water solubility means

high permeabilty

high water solubility means

low permeability

carboxylic acid

can lose a proton and pick up.a negative charge

Amines

can gain a proton and pick up a positive charge

Henderson-Hasselbalch equation

pKa is the pH point where 50% of the test compound is ionized and 50% is unionized

Most proton donors are

carboxylic acids

Most acceptors are

amines (weak base)

At lower pHs,

BASES are charged, acids are uncharged

At higher pHs,

ACIDS are charged, bases are uncharged

Passive Transport (Diffusion)

A process that requires no energy to move molecules down their concentration gradient(from high to low concentration)

- ionized compounds do not readily move by diffusion due to low lipid solubility

Rate of diffusion of a compound is

a. proportional to the surface area of the membrane

b. dependent on its physiochemical properties: water solubility, Kow, ionization, pKa, acids and bases

c. proportional to concentration gradienr

Movement through membrane pores - Filtration

most membranes have pores that allow lower molecular weight compounds(

Endocytosis - Phagocytosis (solids) - Pinocytosis (liquids)

specialized transport processes in the can engulf a foreign particle or toxicant

Carrier-mediated transport mechanisms

- aka active transport

- a membrane carrier protein that binds to the toxicant on one side of the membrane, ferries it across the membrane, and the chemical dissociates from the carrier on other side of membrane

Characteristics of active transport

- transport against a concentration gradient

- require expenditure of energy, ATP

- can be competitively inhibited - they can be blocked but could be problematic leading to a toxic response to a chemical

Toxicants that are absorbed this way (active transport) use endogenous transport systems

- lead is actively absorbed from the gut via the calcium transport system

- the toxic substance paraquat is actively absorbed into the lungs

Where are the vulnerable sites for the absorption of chemicals?

Skin, Respiratory Tract, G.I. tract, Excretion

What 3 layers make up the skin?

epidermis (outermost), dermis (innermost), & subcutaneous layer

Skin layer important for absorption of chemicals

epidermis

- can vary from 0.1 - 0.8mm so different parts of the body show differences in their ability to allow passage of toxicants

What does skin act as?

- first pass organ

- metabolizes toxicants before entry into the systemic circulation

Respiratory tract

- vulnerable to airborne substances

- rate of entry of vapor-phase toxicants is controlled by alveolar ventilation rate

journey of airborne toxicant

-once it enters and reaches the alveolar region, the barrier to penetration from the alveoli is very THIN (1-2 μm) --> allowing for rapid absorption - primarily passive diffusion

Why is the alveolar surface large?

- 50-80 m3

- the lung receives large cardiac output from the heart

Toxicants can be delivered to the lung in two forms:

1. Compounds subject to gas laws

2. particles, including aerosols

Rate of absorption is dependent on

the blood

- gas solubility

Low solubilty

rate of absorption is dependent on blood flow through the lung (perfusion limited)

High solubility

dependent on the rate and depth of ventilation (ventilation limited)

Site of particle deposition in the respiratory tract is determined by:

physical forces and lung anatomy

Deposition site is important for

1. severity of the consequences of tissue damage

2. degree of absorption

3. clearance mechanisms for removal

Larger particles

are deposited higher in the respiratory tract by inertial impaction

Medium-sized particles

in the bronchiolar region by sedimentation

Smallest particles

in the alveolar region by diffusion

Optimal retention in the alveolar region is

~ 6 μm

Asbestos fiber

phagocytosed in the lungs by the macrophages and remain there indefinitely (cannot be degraded) - fibrosis and possibly lung tumors

G.I. tract

- large surface area for absorption due to microvilli

- distance from outer membrane to vasculature is 40 μm

- absorption of toxicants from the stomach (pH 1-2) or intestine (pH 5-6) and can be favored whether compound is a weak acid or base

"First pass" metabolism in the liver

major factor influencing how the compound reaches systematic circulation after absorption from the GI tract

Function of portal vein

materials absorbed from the stomach or intestine are carried via the portal vein

directly to the liver where they undergo extensive metabolism

- portal vein = metabolic gate

Other factors important for absorption

1. solubility of the chemical in the content of the gut

2. GI tract bacterial metabolism

3. Acid stability of compound

4. Presence of chelating compound - inorganic substances (metals)

5. Presence of food

6. Intestinal motility - how fast the GI tract works

Acid & Base characteristics in G.I. tract

- weak acids absorbed fairly well

- strong acids not absorbed

- highly ionized compounds (paraquat) are absorbed

- some large molecules (polystyrene 22 mM and botulinum toxin (200,000-400,000 MW))

When does distribution start?

starts the instant a chemical is absorbed

Chemicals are distributed over our entire mass; what is mass?

mass is proportional to the amount of water in our body

Journey of distribution throughout the body

- after the chemical is absorbed and enters the plasma, it's available for distribution throughout the body

- race of distribution is rapid & determined by blood flow and the ease with which the chemical crosses the biological membrane

- rate of movement between body compartments varies depending on blood flow, accessibility of the compartment and physiochemical characteristics of the compound

- EX: blood-brain barrier --> stops distribution of chemicals to our nervous system; only permeable to lipophilic compounds

Distribution of chemicals into various tissues is dependent on:

1. capacity to bind to plasma and cellular proteins - decrease the concentration of whatever substance

2. uptake via active transport mechanisms

3. lipid solubility and state of ionization (storage in fat (DDT, dioxin, PCBs), bone (lead))

Chemicals that are lipid soluble can be

stored in fat for long periods of time

Sequestration of Chemicals

- an important determinant of toxicological activity

If a chemical is sequestered (by plasma protein bonding, storage in fat or bone) it cannot:

1. produce an effect

2. be metabolized

3. be readily excreted