Questions 2
1) Why might a chemical be less toxic when administered intraperitoneally as opposed to
intravenously?
Intravenous injection introduces toxicant directly into the bloodstream, thus eliminating the
process of absorption. Intraperitoneal injection results in rapid absorption of xenobiotics because
of the rich peritoneal and mesenteric blood supply and large surface area of the peritoneal cavity.
They are absorbed primarily through the portal circulation and must pass through the liver before
reach other organs
2) Although absorption of toxicants that are inhaled occurs mainly in the lungs, why is the
nose at risk for injury?
The nose is covered in a mucosa with a film of fluid and the gas molecules can be retained here
and not reach the lung
3) Discuss pH and pKa in terms of how these characteristics can affect membrane
transport and ultimately toxicity.
The pKa of exenobiotic is defined as the pH at which the xenobiotic exist as 50 percent ionized
and 50 percent non ionized. If pKa-pH=0, than 50 percent of xenobiotic is ionized and viceversa.
Ionized means water soluable, poor absorption. Weak acids and weak bases are non ionized in
instestine and will diffuse through the membrane. Weak acids are non ionized in the stomach and
will diffuse through membrane. Weak bases are highly ionized and will not be absorbed in the
stomach. Strong acids and Strong bases must be transported across the membrane by facilitative
or active transport
4) Describe how a toxicant is absorbed through: the skin, GI tract and lungs.
Skin: absorption through the epidermis and dermis (skin exposure)
GI Tract: Mixed with food and water, pharmaceuticals
Lungs: Inhalation, nasal or aerosol pharmaceuticals
5) Discuss different mechanisms of transport (e.g., active, simple diffusion, facilitated
diffusion)
Passive Transport: Simple diffusion- directly through cell membrane or channel; facilitated
diffusion-carrier mediated transport that is faster than simple diffusion
Active transport: xenobiotic transporters (ABC), facilitative transporters (solute carriers),
endocytosis (phago and pino)
6) Name the terms for “cell eating” and “cell drinking” and describe each.
- Phagocytosis (cell eating): large particles in the extracellular fluid are engulfed and transported
into cells or are destroyed within the cell
- Pinocytosis (cell drinking): liquids are engulfed; will also transport very small particles that are
in suspension with the extracellular fluid
7) Explain the blood-to-gas partition co-efficient, and how it affects the rate of absorption.
Blood-to-gas partition coefficient- solubility ratio of the concentration of chemical in the blood
to the concentration in the gas phase. Equilibrium between blood and the air is reached more
quickly for relatively insoluble gases than for soluble gases. At equilibrium, the ratio of the
concentration of chemical in the blood and chemical in the gas phase is constant. An increase in
blood flow increases the rate of uptake of a compound with a low solubility ratio because of
more rapid removal from the site of equilibrium. High blood gas partition, increase rate uptake
by increase respiration.
8) Describe three reasons why absorption of gases in the lungs differs from intestinal and
precutaneous absorption.
The disassociation of acids/bases and lipid solubility of molecules are less important factors in
pulmonary absorption because diffusion through cell membranes is not rate-limiting in the
pulmonary absorption of gases… 3 reasons:
1. Ionized molecules are of very low volatility, so that they do not achieve significant
concentrations in normal ambient air
2. The epithelial cells lining the aveoli are very thing and the capillaries are in contact with these
cells (type 1 pneumocytes) so that the distance for a chemical to diffuse is very short
3. Chemicals absorbed by the lungs are removed rapidly by the blood and blood moves very
quickly through the extensive capillary networks in the lungs
9) What is the rate determining step for chemicals passing through the skin, and how do
toxicants move across this barrier?
Passage through the stratum corneum is rate limiting step for passage of xenobiotics and is also
the most important. Toxicants move past this barrier by passive diffusion and lipophilic
compounds are absorbed more readily across the stratum corneum, whereas the penetration of
hydrophilic is more limited. Permeablilty also depends on the thickness of this layer.
10) The most common route of unintentional exposure to a toxicant is through what?
Accidental ingestion
11) List the four stages of disposition of a xenobiotic and describe each stage.
1. Absorption- how a substance enters the body, most crucial step of disposition
2. Distribution- how a substance moves from the site of entry to other tissues of the body
3. Biotransformation- the chemical modification of xenobiotic into a new chemical (metabolites)
4. Excretion- processes by which the xenobiotic or its metabolites leave the body
12) List the five factors that can influence the absorption of toxicants through the skin.
Integrity of the stratum corneum
The hydration state of the stratum corneum
Temperature
Solvents as carriers
Molecular size
13) Explain why regions of the body differ in their permeability of the skin to chemicals.
The human stratum corneum displays differences in structure and chemistry from one region to
another. Skin of the plantar regions are less permeable because there are made for weight bearing
and friction while no present hair follicles. The stratum corneum of the scrotum is thin and has a
high diffusivity per unit thickness.
14) Explain the process of “presystemic elimination” or “first-pass effect” and why higher
is better in regards to toxicants.
Toxicants with high first-pass effect will serve to limit exposure and typically minimize toxic
potential
Fill-in-the-blank, Multiple Choice, etc:
1) __skin____ is the largest organ and provides a relatively good barrier for separating
organs from the environment.
2) Enteral administration involves intravenous, intraperitoneal, intramuscular and
subcutaneous routes. False- involves, sublingual, oral, and rectal
3) Carried mediated transport not requiring the input of energy is referred to as _facilitated
transport__.
4) The phenomenon of the removal of chemicals before entrance into systemic circulation is
referred to as _presystemic elimination or first-pass effect__________.
*5) During absorption, xenobiotics penetrate through membranes by different processes
than do biologically essential substances such as oxygen, food stuffs, and other nutrients.
True or False.
6) List the 3 major groups of toxicants that can be absorbed by the lungs.
1. gases
2. Vapors of volatile or volatilizable liquids
3. aerosols
7) For acidic drugs, when the pH > pKa, the drug is ________________. When the pH <
pKa, the drug is ______________________.
8) If a toxicant is a weak organic acid or base, it tends to not be absorbed by simple
diffusion as part of the GI tract. False- it is absorbed by the G.I. tract where it exists in most
lipid soluble (nonionized) form