PRINCIPLES OF TOXICOLOGY

204 IMMUNOTOXICITY: TOXIC EFFECTS ON THE IMMUNE SYSTEM
sitivity syndrome, and, more recently, idiopathic environmental intolerances. There is no defined
symptomology for this condition; in fact, physical diagnostic and laboratory findings are typically
normal. Complaints are almost always subjective, including fatigue, headache, nausea, irritability, and
loss of concentration and memory. It appears almost exclusively in adults, primarily in women.
Offending substances are commonly identified by odor, although symptoms can also be ascribed to
substances in food, to drugs, and to electromagnetic fields. While sensitivity is thought to arise from
a single initial exposure, perhaps to a single agent, it is visualized as progressing to eventually involve
an expanded array of substances; hence the term multiple-chemical sensitivity. Diagnosis is made
principally on the basis of history—the patient indicates intolerance to a variety of substances in the
environment. The symptoms are triggered by exposure to these substances at levels generally well
tolerated by the vast majority of the population. Improvement in symptoms is attributed to avoidance
of these substances.
Tests are sometimes performed on these patients, including a provocation–neutralization test and
a panel of immunologic tests. In the provocation–neutralization test, reaction to various substances is
tested by administering small doses sublingually, intracutaneously, or subcutaneously. The test agents
are not necessarily those thought to be causing the patient’s illness, and the battery of agents tested
can vary from practitioner to practitioner. After administration of the test substance, the patient records
any symptoms that occur over the next 10 minutes. There is no standard for what constitutes a symptom
in this testing. If no symptoms are recorded, the dose is increased until a positive response is obtained.
Increased or diminished doses are then given until the symptom(s) abate. This becomes the “neutralization”
dose that may be recommended to the patient for subsequent treatment of the condition.
Immunologic tests usually consist of quantitation of serum immunoglobulins, complement components,
lymphocyte counts, autoantibodies, and immune complexes.
The status of multiple-chemical sensitivity as a legitimate disease entity has been controversial.
Mainstream medical organizations do not recognize it as a defined disease for several reasons: (1) there
are no objective physical signs or symptoms, or clinical laboratory observations that characterize the
disease; (2) there are no clearly defined diagnostic criteria—the provocation-neutralization test
described above has no physiologic basis, and the diagnostic value of the immunologic tests typically
performed has not been validated; (3) although several mechanisms have been proposed to explain
symptoms in these patients, there are little data to support any of these, and many explanations are
contrary to current understanding of immunology and toxicology; (4) objective evidence of any
chemical agent as a specific cause of multiple chemical sensitivity is virtually nonexistent; and (5)
there are no treatments of proven efficacy.
Many theories have been proposed to explain multiple-chemical sensitivity, most involving the
immune system. Some have proposed that environmental chemicals may act as allergens or haptens,
and that an IgG (rather than IgE) response to these agents leads to an immune complex disease.
However, the symptoms of multiple-chemical sensitivity do not resemble serum sickness, and IgG
antibodies to the postulated array of triggering substances have not been demonstrated in these patients.
An autoimmune mechanism has also been proposed, but patients with multiple-chemical sensitivity
typically do not have demonstrably elevated autoantibody titers, nor do they have the usual clinical
manifestations of any of the autoimmune diseases. A more general concept of immune dysregulation
has also been advanced, commonly including the notion that T suppression has been impaired by
environmental chemical exposure. Compelling evidence that T suppression (or any other specific
immune abnormality) is a consistent feature of multiple chemical sensitivity is lacking, however, as is
an explanation as to how several different chemical substances, at low exposure levels, could produce
this effect. A high prevalence of psychiatric disorders has been observed in patients claiming to have
multiple chemical sensitivity. This suggests that somatization (i.e., symptoms of psychogenic origin)
may be involved, although proponents of multiple chemical sensitivity argue that this is a manifestation,
rather than a cause, of the disease. Credibility for multiple-chemical sensitivity within the medical and
scientific community has also been impaired somewhat by the significant percentage of individuals
with this condition using it as a basis for workers’ compensation claims or other litigation.