TOXICOLOGY 1159
metabolism or at concentrations related to pollutant or toxi-
cant exposure.
Some chemicals are able to actually increase or stimulate
the biotransformation of other compounds. This is known as
“induction.” Induction can occur for a variety of compounds.
As previously mentioned, biotransformation is generally
divided into two categories, Phase I and Phase II. Phase I
reactions involve oxidation, reduction, and hydrolysis, which
prepare the compound to undergo a Phase II reaction. Phase II
involves conjugation. Commonly the most toxic products of
a chemical are those from Phase I. If the system becomes
saturated, Phase I compounds will seek alternative routes of
metabolism, and this may result in more toxic intermediates.
If this occurs, it is said that the metabolic system has become
saturated.MIXTURE TOXICITYMost toxicology studies involve the use of a single com-
pound; however, rarely in the real world does exposure occur
to only a single substance. Although single-exposure events
do occur, they generally result in acute toxicity, while mul-
tiple exposures are more frequently associated with chronic
events. Certainly there are numerous exceptions to this rule,
like asbestos and mesothelioma, but even with asbestos there
are mixtures associated with this substance. One of the best
illustrations for a mixture is asbestos and smoking in the case
of lung cancer. Here smoking magnifies the potential effect of
inhaled asbestos, resulting in a higher-than-expected rate of
lung cancer than would occur for either alone. Most exposures
in the industrial environmental focus on a single predominant
toxicant associated with that activity, or at the most the top
two or three chemicals, and generally concerns are identified
with acute events. Both PEL and TLV are established with
nonexposure time periods between exposures and often have
an emphasis on acute occurrences. In environmental toxicol-
ogy this is not always the case, since most regulatory stan-
dards have been established to protect against chronic events,
considering most organisms spend their entire life in a single
media. This is also true for humans as related to air and water
pollution.
Mixture toxicity or interaction studies can be generally
categorized by several terms (Table 6). Additivity is when two
chemicals together exhibit equal toxicity with each having the
same additive response. So if chemicals A and B were mixed
and have an effect of ten, by adding five units of each, thanadding ten units of A alone or B alone would have the effect
of ten as well. Synergism is where the combination of the two
chemicals magnify the outcome, as in asbestos and smoking.
Asbestos may cause 1 cancer in 1000 and smoking 200 cases
in 1000, but when together this may rise to 700 cases out of- Antagonism is when one chemical reduces the effect
caused when combined with another. Potentiation is when one
chemical allows another to have its full toxic potential. This
can be illustrated when the barrier of the skin is disrupted, as
with DMSO, and a chemical that would not previously pass
through the skin now enters easily. Generally, most chemical
combinations exhibit additivity.
Unfortunately, little information exists on chemical com-
binations (Lange and Thomulka, 1997). The lack of informa-
tion is often due to the complexity and costs associated with
these studies. However, recent advances in using bacterial
systems (Lange and Thomulka, 1997) for evaluating mix-
tures does provide a more cost-effective and convenient way
of testing more than one chemical.
There have been a number of methods published, exclud-
ing statistical comparisons, for evaluating two chemicals in
combination. One of the early methods was a graphic repre-
sentation of the two chemicals together, called an “isobole
plot” (Lange and Thomulka, 1997). Here chemical combina-
tions at some set value (like each chemical’s LD 50 ) are plot-
ted. Usually combinations of 100% of A, 80(A)20(B)%,
60 40%, 2080%, and 100% of B are used in making the
plot. When this graph is represented in proportions, it is
called an isobologram (Lange et al., 1997).
Another method that employs a formula is called the
additive index (AI) (Lange and Thomulka, 1997). Here two
chemicals using the same endpoint value (like LD 50 ) are
evaluated, and these results are incorporated into the formula
to obtain the AI. The AI is shown below:
S A m A i B m B i^S is sum of activity
A and B are chemicals
i is individual chemical and m is mixture of toxicities
(LD 50 )for S 1.0, the AI 1 S 1.0
for S 1.0, the AI S (1) 1For the AI, a negative number (sum of activity, S ) suggests
that the chemicals are less than additive (antagonistic), with
zero being additive and a positive value synergistic. Certainly
in these calculations the numbers are not exact, so confidence
intervals (CIs) are often incorporated to reflect the range of
these mixture interactions. In using CI values, at 95%, the
upper and lower CIs are used to determine the range. If the
CI range includes zero, then this mixture is considered to be
additive.
Mixture toxicity is a commonly discussed topic, but as
mentioned, it is not well understood. One basis for syner-
gism is related to inhibition of detoxification pathways;
however, as noted, most chemical mixtures are additive,TABLE 6
Terms used for identifying mixture interactionsTerm Example by Numerical Value
Additivity 5 5 10
Synergism 5 5 40
Antagonism 5 5 7
Potentiation 1 5 12C020_003_r03.indd 1159C020_003_r03.indd 1159 11/18/2005 11:09:30 AM11/18/2005 11:09:30 AM