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INTRODUCTION

KEY POINTS

  • Hematotoxicology is the study of adverse effects of exogenous chemicals on blood and blood-forming tissues.

  • Direct or indirect damage to blood cells and their precursors includes tissue hypoxia, hemorrhage, and infection.

  • Xenobiotic-induced aplastic anemia is a life-threatening disorder characterized by peripheral blood pancytopenia, reticulocytopenia, and bone marrow hypoplasia.

  • Idiosyncratic xenobiotic-induced agranulocytosis may involve a sudden depletion of circulating neutrophils concomitant with exposure that persists as long as the agent or its metabolites are in the circulation.

  • Leukemias are proliferative disorders of hematopoietic tissue that originate from individual bone marrow cells.

  • Xenobiotic-induced thrombocytopenia may result from increased platelet destruction or decreased platelet production, which lead to decreased platelet aggregation and bleeding disorders.

  • Blood coagulation is a complex process involving a number of proteins whose synthesis and function can be altered by many xenobiotics.

BLOOD AS A TARGET ORGAN

Hematotoxicology is the study of adverse effects of chemicals on the blood and blood-forming tissues. The vital functions that blood cells perform, together with the susceptibility of this highly proliferative tissue to intoxication, make the hematopoietic system unique as a target organ.

The blood comprises around 7% of the body weight of a typical adult who has 4.7 to 5.5 L of blood. The delivery of oxygen to tissues throughout the body, maintenance of vascular integrity, and provision of the many affector and effector immune functions necessary for host defense require a prodigious proliferative and regenerative capacity. Each of the various blood cells (erythrocytes, granulocytes, and platelets) is produced at a rate of approximately 1 to 3 million/s in a healthy adult, making hematopoietic tissue particularly sensitive to cytoreductive or antimitotic drugs, such as those used to treat cancer, infection, and immune-mediated disorders. Toxic chemicals may affect the supply of nutrients, such as iron; the clearance of toxicants and metabolites, such as urea; or the production of vital growth factors, such as erythropoietin and granulocyte colony-stimulating factor (G-CSF).

Hematotoxicity may be regarded as primary, where one or more blood components are directly affected, or secondary, where the toxic effect is a consequence of other tissue injury or systemic disturbances. Primary toxicity is regarded as among the more common serious effects of xenobiotics, particularly drugs. Secondary toxicity is exceedingly common, due to the propensity of blood cells to reflect a wide range of local and systemic effects of toxicants on other tissues.

HEMATOPOIESIS: THE FORMATION OF THE BLOOD CELLULAR COMPONENTS

The production of blood cells, or hematopoiesis, is a highly regulated sequence of events by which blood cell precursors proliferate and differentiate to meet the relentless needs of oxygen transport, host defense and repair, hemostasis, and other vital functions. The bone marrow is the principal site of hematopoiesis in humans and most laboratory and domestic animals. However, the lung harbors blood stem cells that can repopulate the bone marrow. In the human fetus, hematopoiesis ...

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