Chemical Disposition - Toxicology Slide 2

Taught by Dr. Ramez Labib; 1.5 hr lecture

Toxicodynamics

Refers to the actions and interactions of the toxicant within the organism and describes processes at organ, cellular and molecular levels; what chemical does to body

Toxikenetics

Refers to the process of absorption, distribution, elimination and metabolism of a toxicant; what the body does to chemical

absorption

Process by which toxicants cross the epithelial cell barrier/membrane

why is it that normally, exposure to toxins isn’t that big of an issue?

Normally they are condiments and safety measures that prevent the toxin from being exposed to the person directly or being absorbed

Why are natural catastrophes such a problem when it comes to exposure and absorption of a toxin?

regulatory confinements and regulations for chemical and toxins absorption are removed

what form (ionized or non-ionized) does a chemical have to be in to move through the cell membrane using passive diffusion?

non-ionized form

What are all the methods of cellular absorption?

• Diffusion

  • Requires concentration gradient

  • Fick’s Law

• Facilitated diffusion

  • Membrane surface carrier proteins

  • glucose transport

• Active transport

  • Requires cellular energy (ATP)

  • Endo/exo-cytosis

  • Phago/pino-cytosis

what form of cellular absorption requires a concentration gradient?

Diffusion 

Examples of cellular absorption that requires a concentration gradient?

Fick’s law

what form of cellular absorption uses membrane surface carrier proteins?

Facilitated diffusion

Examples of cellular absorption that uses membrane surface carrier proteins?

Glucose transport

what form of cellular absorption requires cellular energy?

Active Transport

Examples of cellular absorption that requires cellular energy?

• Endo/Exo-cytosis

• Phago/Pino-cytosis

Routes of Absorption

• Gastrointestinal Tract (GI)

• Reparatory

• Skin (Percutaneous)

There are also special routes as well

what are all the parts in the Digestive system route?

1. Mouth

2. Oral cavity

3. esophagus

4. stomach

5. small intestine

6. rectum

7. anus

what can residence time help you determine?

the site of toxicant entry/injury

Examples of residence times

• mouth - short residence time

• small intestine - long residence time

why does a lot of absorption happen in the digestive system route?

This is because many tissue structures in the digestion system are specially designed for absorption

what is the primary site of absoption?

Small intestine

what are all the different tissues in the small intestine?

• mucosa

• submucosa

• muscularis (movement)

• serosa (casing)

information about mucosa layer in install intestines

• Avascular

• s. Squamous or columnar epithelium

• some regions contain villi and microvilli structures which aid in absorption by increasing surface area

information about submucosal layer in install intestines

• contains blood

• contains lymph system interface

what does this diagram tell u?

it shows how in different environments(pHs) compounds will change in ionization allowing them to be more or less able to be absorbed

in lower pH which compound will be better to be absorbed?

Benzoic acid

in higher pH which compound will be better to be absorbed?

Aniline

What is the respiratory system composed of?

• squamous epithelium

• ciliated columnar

• cuboidal epithelium

  • (for all points) non-keratinized but ciliated tissues and mucus secreting cell provide  '“mucociliary escalator”

what is the role of mucociliary escalators

secretes mucus that will help expel chemicals that are trapped in the nasopharyngeal region in ciliated tissues

different parts of respiratory system route

1. nasopharyngeal

2. Tracheobronchial

3. Pulmonary

nasopharyngeal

upper portion of respiratory track (nose-mouth)

The nasopharyngeal contains the 

• Nostrils

• nasopharynx

• oropharynx

• laryngopharynx

The nasopharyngeal contains hairs and mucus that traps particles of what size?

>5 µm

Tracheobronchial

middle, trachea to bronchi

the Tracheobronchial contains the

• trachea

• bronchi

• bronchioles

• cillial action

The Tracheobronchial contains luminal mucus that traps partials of what size?

2-5µm particles and H20 soluble aerosols and gas

Pulmonary

deep into lung

the Pulmonary contain the

alveoli

alveoli

high surface area gas exchnage with cardiovascular system

substances of what size and enter the alveoli

substances smaller then >1µm are able to enter

solubility ratio

At equilibrium the ratio of the concentration of a chemical in the blood and chemical in the gas phase is constant

perfusion limited

Low solubility ratio, rate of absoption is dependent on perfusion

perfusion

process by which blood flows through an organ or tissue, delivering oxygen and nutrients and removing waste products

ventilation limited

High solubility ratio, the rate of transfer is primarily a function of the rate and depth of reparation

Ventilation

breathing in and out

what does this diagram tell you?

It shows how the mucociliary escalators can take the trapped partials and bring them up to the previous regions to be excreted and sometimes helps them get ingested and taken into the GI tract

what does this diagram show you?

It shows the pathway of the respiratory system, the regions, sizes that can path and names of mechanisms while also displaying how abrupt direction can change due to air moving in each region

Inertial impaction

particles that are in the process of being excreted

T/F a particle that is 10µm can reach the bronchiolar region

False, they can only reach the nasopharyngeal region

T/F a particle that is 3µm can reach the alveolar region and get absorbed into the pulmonary

False, particles that size would only be able to reach the bronchiolar region 

T/F a particle that is 1µm can reach the alveolar region and get absorbed into the pulmonary

true, but can be mechanically removed through phagocytosis or through lymphatics

Integumentary system route

skin, hair, nails, mammary glands

what are the different parts of the integumentary system?

• Epidermis

• Dermis

• Hypodermis

Epidermis

• avascular

• keratinized stratum corneum

• 15-20 cells thick

• provides most toxicant protection

Dermis

• Highly vascularized

• nerve endings

• hair follicles

• sweat and oil glands

Hypodermis

Connective and adipose tissue

where does absorption take place in the integumentary system?

it has to reach the dermis; passing the stratum corneum and epidermis

what are special routes of absorption?

• intravenous

• intraperitoneal

• subcutaneous

• intramuscular 

what is interesting about these special routes

these special routes tend to bypass protection mechanism, the most special is intravenous since it completely bypasses absorption and is directly in the blood stream

Distribution

if a chemical is absorbed through the skin, lungs or intestinal tissue it will go on a passage into the interstitial fluid which will enter the lymph or blood supply and can mobilize into other parts of the body entering local tissue cells

what are the 2 different types of distribution>

• lymphatic system

  • slow

  • draining system; drains fluid from systems

• cardiovascular system

  • fast

  • major distribution

lymphatic system contains

• lymph capillaries

• nodes

• tonsils

• spleen

• thymus

• lymphocytes

cardiovascular system contains

• heart

• arterial and venous vessels

• capillaries

• blood

what effects the toxicity of the toxin?

from where it enter the blood stream

first pass metabolism effect

what happens when a toxin enters the blood stream through the digestive system?

the portal vein carries the toxin to the liver which is a major site for detoxication; this is called first pass metabolism effect/hepatic circulation 

what happens when a toxin enters the blood stream through the respiratory system?

it goes directly into pulmonary circulation, particulates can slowly migrate through lymph system

what happens when a toxin enters the blood stream through the percutaneous system?

enters the peripheral blood supply and can impact tissues far away

Factors affecting distribution

• physical or chemical properties of the toxicant

  • chemical - lipophilic or no

  • physical - volatile?

• cardiac output to the specific tissue

  • bc kidneys have high high cardiac input they will receive the toxin and could harm them

• Detoxication reactions

  • proteins that can bind to the toxin, which can reduce the concentration that can react

• tissue sensitivity to the toxicant

  • e.g. if the substance is lipophilic, might bind to and be stored with adipose tissue

  • another e.g is bones that can store metals

  • if they get released from storage the concentration in the blood stream can be very high and cause toxicity 

• barriers that inhibit migration

  • blood-brain and placental

plasma protein binding

toxicants can bind to plasma proteins, e.g albumin, which can reduce the half life and distribution of the toxin

what are indicators for plasma protein binding

plasma concentration and apparent value of distribution (V_D)

apparent value of distribution (V_D)

total volume of body fluids in which a toxicant is distributed

hepatic circulation

mechanism that works to reduce the toxicity of chemicals by sending chemicals from the GI tract to and from the liver 

what does hepatic circulation result in>

First pass metabolism

first pass metabolism

it is a detoxification reaction for chemicals 

Enterohepatic recirculation allows for what?

recycled exposure 

Enterohepatic recirculation path

Blood—> liver—> bile ducts—> intestine—> portal vein—> blood (repeat) 

what are examples of storage effecting distribution?

• accumulation of toxicants in specific tissues

• Binding to plasma proteins

• storage in bones

• storage in liver

• storage in the kidneys

• storage in fat

what rate of exposure would have greater systemic effects?

Skin and respiratory, slower metabolism

How can rate of metabolism impact systemic effects?

slow metabolism will allow wider distribution

Disposition models

different models that display chemicals traveling through different tissue compartments or staying in one tissue compartment; they display the concentration of the chemical over time

Disposition model 1

stays in the one tissue compartment, not as complex

Disposition model 2

travels to and from different compartments, e.g. blood and liver; typically more complex

blood-brain barrier

brain has specialized cells, astrocytes, which limit passage of water soluble molecules from the capillary endothelium and the neurons of the brain

placental barrier

consists of several cell layers between the maternal and fetal circulatory vessels in the placenta

structural barrier block toxicants in what way?

chemically/structurally

metabolism summarized

biotransformation; sum of biochemical reactions occurring to a molecule within the body; anabolism -build up, catabolism - break down

where does metabolism take place?

occurs in the cytoplasm or at specific organelles within the cell 

biotransformation

changing a substance from hydrophobic to hydrophilic to aid in elimination

why is biotransformation important and useful?

hydrophilic molecules cant cross cellular membranes , makes it more filterable, decrease half life, and helps be eliminated in feces and urine

59:00

59:00