Chemical toxicity of the granulocyte.

The effect of chemicals, including pharmacologic agents, on blood granulocytes, may be considered in terms of the effects on the function of mature cells as well as on their number. In turn, the number of cells can be influenced by chemicals which affect production, destruction or distribution within the blood. Neutrophil functions which can be inhibited by chemical agents include chemotaxis, phagocytosis, degranulation, the metabolic burst related to membrane perturbation and intracellular killing. Some drugs can influence multiple neutrophil functions. Neutrophil production may be inhibited by toxic chemicals with a predictable effect, such as cancer chemotherapeutic drugs, where the effects are dose related, or the process may be influenced in an unpredictable (idiosyncratic) fashion, occurring only in a small proportion of patients exposed. Ineffective granulopoiesis with intramedullary death may be seen as a result of exposure to some drugs, as may increased neutrophil destruction, sometimes via an immunologic mechanism. Predictable neutrophil production inhibition by anticancer agents depends on dose, schedule, route of administration, metabolic integrity of organ systems such as liver and kidney, and the proliferative state of the marrow. For a given drug, factors which determine neutrophil toxicity include its mechanism of action, cytotoxic concentration, pharmacokinetics, metabolic and excretory pathway and target cells in the marrow. The use of assays for clonogenic hematopoietic precursor cells is allowing correlation with more traditional toxicologic methods and may be helpful in predicting specific hematologic toxicity in man, prior to actual clinical trials. The agar diffusion chamber assay for neutrophil-macrophage committed colony-forming cells is particularly useful since it allows in vivo exposure of the target cells to the agents being studied.