The Role of Conventional Pathology and Toxicology in Evaluating the Immimotoxic Potential of Xenobiotics

Abstract

Investigating the immunotoxic potential of candidate drugs as part of a preclinical safety evaluation poses several problems. These include the need for practical, validated tests, the difficulty in establishing the toxicologic significance of positive findings, and a poor understanding of the predictive value such findings hold for drug effects in man. A key component of this investigation is the toxicologic profile generated through preclinical toxicity and safety studies. As this "routine" assessment becomes increasingly comprehensive and sophisticated, most toxicologically significant drug-associated effects are revealed. Such findings may serve as "triggers" for investigating possible immune mechanisms. Decisions to test specifically for immunotoxicity may also be influenced by the molecular structure and pharmacologic profile of the compound, as well as the intended use of the drug. Examples of such indications and follow-up studies are discussed in this review. We are presently poorly equipped to effectively screen drugs indiscriminately for an immunotoxic potential. We are better prepared, however, to investigate whether a drug-associated change is due to an adverse effect on the immune system. This problem-oriented approach to immunotoxicology challenges us as diagnosticians and immunopathologists, and requires a close working relationship among the toxicologic pathologist, the basic immunologist, the immunopharmacologist, and the clinician.

Endocrine Glands

“…This condition is characterized histologically by focal destructive alteration to thyroid acini with macrophage infiltration and fibrosis similar to de Quervain's thyroiditis except that granulomatous changes are absent. 314 Atrophy Although atrophy of the thyroid gland follows chronic inflammatory damage, trophic atrophy can be secondary to diminished secretion of thyroid stimulatory hormone or as a primary degenerative condition of follicular cells. 310À312 Although an immune mechanism may be important in some cases, the study by Smyrk and colleagues suggested that amiodarone therapy leads to thyroid follicular disruption and release of iodothyronines, with increased levels of thyroid hormones producing thyrotoxicosis, TSH suppression and consequent loss of activity in residual thyroid follicles.…”

Respiratory Tract

“…Although a seven-year toxicity study of auranofin in dogs showed evidence of an immune-mediated thrombocytopenia similar to that occurring in patients, pulmonary fibrosis was not reported. 196…”

Combination of fixation using PLP fixative and embedding in paraffin by the AMeX method is useful for histochemical studies in assessment of immunotoxicity.

“…Histopathological examination of major lymphoid organs such as spleen, thymus, bone marrow, lymph nodes and mucosa associated lymphoid tissue provides a reliable indication of the immunotoxic potential of a compound (Bloom et al, 1987;Schuurman et al, 1994;De Waal et al, 1995;Gopinath, 1996;The ICICIS Group Investigators, 1998). Lymphoid organs contain various types of cells, such as lymphocytes, macrophage lineage cells, eosinophils, basophils and epithelial cells.…”