infection, as well as confounding the resulting immune response.

The study of human immunodeficiency disease syndromes reveals a clear association between the suppression or absence of an immunologic function and an increased incidence of infectious or neoplastic disease. Numerous examples of such deficiency diseases have been reported and are well characterized in humans (Table 5-1). A deficiency in one or more immunologic functions can lead to severe, recurrent infections throughout life. These infections can be bacterial, viral, fungal, or protozoan, and the predominant type of infection depends on the associated immunologic lesion. Some infections can be treated with antibiotics or gammaglobulin, and in some cases the immunologic defect can be restored by bone marrow transplantation. However, other immunodeficiency diseases are much more severe. For example, children born with reticular dysgenesis have no white blood cells and usually die from infectious disease in the first year of life; children born with ataxia telangiectasia rarely survive past puberty. These diseases of genetic deficiency are more severe than those caused by environmental toxicants, because they are the result of the absence of part of the immune system. They demonstrate well-characterized consequences of immunosuppression. These same diseases would be expected to be associated with specific immunosuppression, whether the cause were genetic or environmental.

There are more than 60 inbred hybrid and mutant strains of rodents with well-defined immunodeficiencies (NRC, 1989c). Many of these animals have diseases that are comparable to the human immunodeficiency diseases listed in Table 5-1. An example is the beige mouse (the result of a recessive mutation on chromosome 13), which is a model for the human Chediak-Higashi disease syndrome. This defect results in reduced cell-mediated and natural killer immune function. Animal models have well-characterized, specific immunologic defects and known increased susceptibilities to infectious, neoplastic, and autoimmune diseases. Studies of human immunodeficiency diseases and the counterpart animal models emphasize the potentially serious consequences of immunosuppression, whether it occurs as a result of heredity, aging, or nutrition or is acquired as a result of exposure to xenobiotics.

For some time, immunosuppressive agents have been used in treating autoimmune diseases and as adjunctive therapy in organ transplantation procedures to prevent rejection by the recipient. Studies in this area have provided information on the potential clinical effects of chronic low-level immunosuppression. In addition, experimental studies with these compounds have provided comparative data between experimental animals and humans on immunosuppression that should have direct application to risk assessment.

Immunosuppressive treatments, such as x-irradiation, neonatal thymectomy, or the use of immunosuppressive drugs, result in an increased incidence of parasitic, viral, fungal, or bacterial infections. There is a well-established association between the therapeutic use of chemical immunosuppressants, such as those used in organ transplant therapy or in cancer chemotherapy, and an increased incidence of infections and neoplastic disease in humans (Ehrke and Mihich, 1985). For example, in a study of renal graft recipients undergoing immunosuppressive treatment, a 10-fold increased incidence of monoclonal gammopathies was observed (Radl et al., 1985). In another study, 50% of transplant patients developed cancer within 10 years after the operation (Penn, 1985). The tumors detected in these patients were heterogeneous and included skin and lip

Front Matter (R1-R18)

Summary (1-8)

1 Introduction (9-22)

2 The Structure and Function of the Immune System and Mechanisms of Immunotoxicology (23-32)

3 Biologic Markers for Immune-Mediated Disease (33-52)

4 Autoimmune Diseases (53-62)

5 The Capacity of Toxic Agents to Compromise the Immune System (Biologic Markers of Immunosuppression) (63-82)

6 Animal Models for Use in Detecting Immunotoxic Potential and Determining Mechanisms of Action (83-98)

7 Human Immune-System Biologic Markers of Immunotoxicity (99-112)

8 Application of Biologic Markers of Immunotoxicity in Epidemiology (113-126)

9 Use of Biologic Markers in Controversial Areas of Environmental Health (127-140)

10 Summary and Recommendations (141-148)

References (149-182)

Glossary (183-192)

Biographies (193-198)

Index (199-206)