PRINCIPLES OF TOXICOLOGY

certain situations immunosuppression is intentionally induced via drug therapy to prevent rejection of
transplants. Agents employed for this purpose are diverse, and several potential mechanisms are
involved, including inhibition of cytokine production (e.g., corticosteroids, cyclosporin) and lymphocyte
proliferation (e.g., azothioprine). Most of the evidence that environmental and occupational
chemicals suppress immune responses is derived from animal studies, and while the same principles
likely apply to humans as well, there are few clear examples in the clinical literature of immunosuppression
from chemical exposure other than that from intentional treatment with immunosuppressive
drugs.
The opposite reaction, immunological enhancement, is also possible, and several natural and
synthetic agents have been shown to increase immune responsiveness under experimental conditions.
Examples of agents that increase immune reactivity include the bacillus Calmette-Guerin (BCG), alum
(aluminum potassium sulfate or aluminum hydroxide), bacterial lipopolysaccharides and peptidoglycans,
a variety of synthetic polymers, and the antiparasitic drug Levamisole (phenylimidazolethioazole).
Difficulty in producing a controlled stimulation of the immune system and the enormous
potential for undesirable side effects limit the therapeutic use of these agents. To date, there are no
examples of environmental or occupational chemicals shown to produce immune stimulation in
humans, other than in the context of allergic reactions.
Autoimmunity
10.4 CLINICAL TESTS FOR DETECTING IMMUNOTOXICITY 195
Autoimmunity is defined as the induction and expression of antibodies to self-tissue, including nuclear
macromolecules. Studies of drug-related autoimmunity in humans have provided some of the best
examples of this type of reaction. Although there are many types of autoimmune disease, the most
common autoimmune syndrome produced by drugs is one resembling systemic lupus erythematosus
(SLE). Clinical signs and symptoms of so-called drug lupus are not identical to idiopathic SLE,
however. Both are characterized by arthralgia and the appearance of antinuclear antibodies in the blood,
but the pattern of antinuclear antibodies is somewhat different, and renal and CNS complications
dominate idiopathic SLE while these are typically absent in drug-lupus. Symptoms of drug lupus
generally subside after the drug is withdrawn. Demonstration of autoimmune responses from environmental
exposure to chemicals (other than drugs) has been difficult, in part because of problems
identifying etiologic agents in retrospective studies of patients developing autoimmune disease. One
concern is that some chemicals may exacerbate underlying autoimmune disease (e.g., SLE), rendering
symptomatic a patient with subclinical disease or increasing the duration or severity of symptoms in
those with active disease. Unfortunately, differentiating the effects of chemical exposure from
progression of the underlying disease is difficult or impossible in practice. Understanding of autoimmune
consequences of chemical exposure is further hampered by the general lack of satisfactory animal
models—the results obtained in laboratory animals seldom correspond exactly to observations in
humans.
10.4 CLINICAL TESTS FOR DETECTING IMMUNOTOXICITY
In the clinical setting, the use and proper interpretation of immunologic laboratory tests can be
important in establishing a differential diagnosis in a patient who has been exposed to an immunotoxic
agent. Immune system testing for diagnostic purposes can be challenging, however, because of the
complexity of the immune system and difficulty in establishing normal values for many of the tests.
When immune dysfunction from chemical exposure is suspected, it is important to be sure that the
patient is free from infectious disease and not taking medications that can influence immune function—obvious
confounders to interpretation of any immune tests. Also, it is important to recognize
that many immune parameters, such as lymphocyte subpopulation counts, can vary normally by age
and gender, making the use of appropriate controls essential for proper interpretation of results. Finally,