1156 TOXICOLOGY
Dose-response curves are often used to provide informa-
tion on a chemical as well as comparison to other chemicals.
Potency is one factor that can be derived from the dose-
response. This term refers to the concentrations that result in
an increasing response to the chemical. Two chemicals can
have the same slope on a dose-response curve, but have dif-
ferent potencies. Thus, various information can be extracted
from dose-response curves.EXPOSUREExposure can be considered to be at the heart of toxicology.
Just because you are exposed does not mean that there will
be an effect or even that the chemical will be taken up by the
organism. There are a number of factors that influence the
cause and effect, including absorption, distribution, excre-
tion, and biotransformation. To understand exposure, a brief
discussion of each will be presented.
A toxicant is often called a xenobiotic, which means a
foreign substance, and these terms are often used interchange-
ably in texts. In some cases, a xenobiotic may not be foreign
to the organism (e.g., selenium), but exist in a higher or lower
concentration that results in a disease state. Of importance
to environmental and occupational toxicology is that a lower
concentration may also result in disease or an undesired event,
which for the purposes of this chapter will be considered a
toxic action. In some unusual cases increased occupational
exposure has been reported to result in beneficial effects.
This has been illustrated by the exposure of organic dust that
appears to reduce lung cancer (Lange, 2000; Lange et al.,
2003). However, it needs to be noted that exposure to organic
dust (like cotton dust, in the textile industry) also results in
severe respiratory diseases (e.g., bysinosis), which outweigh
any benefits of reduced lung cancer, as in this case.AbsorptionAbsorption is the process where a xenobiotic crosses a mem-
brane or barrier (skin) and enters the organism, most com-
monly into the blood. As previously mentioned, the major
routes of absorption are ingestion (the gastrointestinal [GI]
system), inhalation (lungs), and dermal (skin). Oral intake
is not a common route of occupational exposure, but one of
major importance environmentally. Transport across barriers
occur as passive transport, active transport, facilitated dif-
fusion, or specialized transport. Transport can occur in the
uptake and excretion of chemicals. Passive transport, which
is simple diffusion, follows Frick’s Law and does not require
energy. Here a concentration gradient exists, and molecules
move from the higher to the lower concentration. As a rule,
for biological systems, the more nonionized the form of a
molecule, the better it is transported across lipid membranes.
The membranes of cells are composed of a lipid bilayer, thus
favoring nonionized compounds. Active transport involves
the movement of a chemical against a gradient and requires
the use of energy. This requires a transporter molecule to
facilitate the movement and would be subject to saturationof the system. Facilitated transport is similar to active trans-
port, except it does not work against a gradient and does not
require energy. There are other specialized forms of transport,
such as phagocytosis by macrophages. These various transport
mechanisms are also used to bring essential substances and
xenobiotics into the organisms.
Absorption in the GI tract can occur anywhere from the
mouth to the rectum, although there are some generalizations
that can be made. If the chemical is an organic acid or base,
it will most likely be absorbed in locations where it exists
in its most lipid-soluble form. The Henderson-Hasselbalch
equation can be used to determine at what pH a chemical
exists as lipid-soluble (nonionized) as compared to ionized.
As a general rule, ionized forms of a chemical are not easily
absorbed across biological membranes.
For the lungs, gases, vapors, and particles can be
absorbed. In the lungs, ionization of a chemical is not as
important as it is for the GI tract. This is due to the rapid
absorption of chemicals and the thinness of the separation
of alveolar cells (air in the lungs and blood system) with
the body fluids (blood). Ionized molecules are also generally
nonvolatile and are therefore usually not in high concentra-
tion in the air. Particles are separated as they travel the pul-
monary system. The larger ones (say, greater than 10 m in
size) are removed early in the pulmonary system, like in the
nasal area, whereas the smaller ones (say, 1 m) enter the
alveolar region. As a general rule, it can be said that particles
around 5 to 10 m are deposited in the nasopharyngeal area,
those 2 to 5 m in the tracheobronchial area, and those less
than 1 to 2 m in the alveolar region. The alveolar region
is where air is exchanged with the blood system, oxygen is
taken up, and waste gases (carbon dioxide) are returned to
the atmosphere. Particles that are deposited into the alveolar
region have been termed “respirable dust” (Reist, 1993).
Distribution of particles described is not exact, but provides
a generalization of particle distribution for lungs. Some
chemicals, like those that are highly water-soluble (e.g.,
formaldehyde), can be scrubbed out at various locations of
the respiratory tract. Here, formaldehyde is removed by the
nose, and in general this is a site of its toxic action, irritation,
and nasal cancer (Hansen and Olsen, 1995).
Skin is generally not highly penetrable and is a good
overall protective barrier. This protection is a result of the
multiple layers of tissue associated with the skin. However,
the primary layer of protection is the stratum corneum. This
is the top layer of cells on the skin; it is dead and can vary in
thickness. On the hands and feet this cell layer can be 400 to
600 m thick, while on the legs it can be 8 to 15 m. Some
chemicals can disrupt the skin’s protection and allow chemi-
cals to pass more easily. An example of this is dimethyl sulf-
oxide (DMSO), which can de-fat the skin and allow better
penetration of chemicals.DistributionAfter a chemical enters the organism, it is usually distributed
rapidly. This distribution is commonly achieved by the blood
system. Many chemicals have locations in the organism whereC020_003_r03.indd 1156C020_003_r03.indd 1156 11/18/2005 11:09:29 AM11/18/2005 11:09:29 AM