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BLOOD AS A TARGET ORGAN

Hematotoxicology is the study of adverse effects of chemicals, including pharmaceutical drugs, 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. Accordingly, hematotoxicity ranks alongside toxicity to the liver and kidney as among the most important considerations in assessing risks to humans from pharmaceutical, occupational, and environmental chemical exposures.

The blood can be considered as a tissue in its own right, as it comprises around 7% of the body weight of a typical adult who has 4.7 to 5.5 L of blood. Some of the vital functions that the blood performs include 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. All of these functions 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 and several times that rate in conditions where demand for these cells is high, as in hemolytic anemia or suppurative inflammation (Kaushansky, 2006). As with intestinal mucosa and gonads, this characteristic makes hematopoietic tissue a particularly sensitive target for cytoreductive or antimitotic drugs, such as those used to treat cancer, infection, and immune-mediated disorders. This tissue is also susceptible to secondary effects of toxic chemicals that 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).

The consequences of direct or indirect damage to blood cells and their precursors are predictable and potentially life-threatening. They include hypoxia, hemorrhage, and infection. These effects may be subclinical and slowly progressive or acute and fulminant, with dramatic clinical presentations. In cancer treatment and other clinical settings, hematotoxicity is usually assessed in the context of risk versus benefit. It may be used to define dosage in treatment modalities in which these effects are limiting, such as those employing certain anticancer, antiviral, and antithrombotic drugs.

While limited hematotoxicity may be an unavoidable side effect of treatments for serious illnesses, it is unacceptable in treatments for less serious illnesses, such as mild hypertension or arthritis, or following exposure to contaminated foods or environmental contaminants. Risk-versus-benefit decisions involving hematotoxicity may be controversial, especially when the incidence of these effects is very low. Irrespective of whether the effect is linked to the pharmacologic action of the drug, as with cytoreductive or thrombolytic agents, or unrelated to its intended action, the right balance between risk and benefit is not always clear.

Hematotoxicity may be regarded as primary, where one or more blood components are directly affected, or secondary, where the toxic effect is ...

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