Chapter 11_ Toxic Responses of the Blood

Blood as a Target Organ

• Hematotoxicology: Study of adverse effects of chemicals on blood and blood-forming tissues.

• The hematopoietic system is unique due to:

  • Vital functions of blood cells.

  • High susceptibility to intoxication, ranking hematotoxicity alongside liver and kidney toxicity in risk assessment.

• Blood Composition:

  • Represents approximately 7% of body weight (4.7 to 5.5 L in adults).

  • Essential functions include:

    • Oxygen delivery to tissues.

    • Maintenance of vascular integrity.

    • Support for immune functions.

• Hematopoietic Tissue:

  • High proliferative and regenerative capacity.

  • Blood cells produced at rates of 1-3 million per second; increased in conditions like hemolytic anemia or inflammation.

Hematopoiesis: Formation of Blood Cellular Components

• Hematopoiesis is regulated proliferation and differentiation of blood cell precursors.

• Main sites of hematopoiesis include:

  • Bone Marrow: The primary site, dominant post-birth.

  • Lung: Identified as a major site with blood stem cells capable of repopulating the bone marrow.

  • Spleen: Primarily involved in the clearance of defective cells.

• In fetuses, hematopoiesis occurs in:

  • Liver, spleen, bone marrow, thymus, lymph nodes.

  • Shifts mainly to bone marrow in late gestation.

• Marrow Changes with Age:

  • Active bone marrow transforms in adults to yellow or fatty marrow, especially in the distal long bones, with hematopoiesis limited to axial skeleton and proximal long bones.

Hematotoxicity: Direct and Secondary Effects

• Primary Hematotoxicity: Directly affects blood components; common serious effects from drugs.

• Secondary Hematotoxicity: Results from other tissue injuries or systemic disturbances affecting blood cells.

  • Can often react or compensate and provides tools for monitoring in toxicologic assessments.

Toxicology of the Erythron

• Erythrocytes (Red Blood Cells): Constitute about 40–45% of blood volume; principal function includes:

  • Oxygen transport and carbon dioxide removal from tissues.

  • Maintaining blood pH and regulating flow.

• Erythrocytes #increase oxidative stress due to oxygen delivery functions.

Erythrocyte Production and Toxicity Mechanisms

• Mechanisms Affecting Erythrocytes:

  • Decreased production or increased destruction leads to anemia.

  • Drugs (e.g., cobalt) can stimulate erythropoiesis or interfere with hemoglobin production.

  • Sideroblastic Anemia: Result of drug interference in heme synthesis (e.g., lead).

• Megaloblastic Anemia: Related to folate or vitamin B12 deficiency influenced by various drugs.

Neutrophil and Platelet Toxic Responses

• Neutrophils: Major leukocyte responding to inflammation; increased turnover in infection.

• Thrombocytopenia: Related to decreased production or increased destruction, often triggered by drugs or chemicals.

Thrombotic and Hemostasis Mechanisms

• Hemostasis: Involves platelets and various plasma proteins;

  • Breakdown and clearance affected by xenobiotic exposure.

• Hemostasis Disruption Mechanisms: Immune-mediated responses leading to destruction or dysfunction (e.g., HIT).

Assessing Hematotoxicity

• Model for predicting hematotoxic effects through animal testing and in vitro assays focusing on blood parameters, morphological features, and suppression insights.

• Continuous development of in vitro models seeks to replicate complexities of bone marrow interactions to evaluate toxic responses better.

Leukemogenesis

• All leukemias stem from a clonal proliferation of an HSC/HPC that alters differentiation due to genetic and ecological factors.

• Mechanisms: involve chromosomal aberrations or genetic mutations that disrupt normal hematopoiesis.

Environmental Influence on Leukaemia

• Chemicals like benzene classified as known human leukemogens, with specific mutations and chromosome changes commonly observed in cases.

Cytotoxic Chemotherapeutic Agents

• Threats from chemotherapy: Risk of therapy-related leukemia* linked to various therapeutic agents post-cancer treatment.

  • Types include alkylating agents and topoisomerase inhibitors that present risks of MDS and AML.

Conclusion

• Understanding the toxic responses involving blood components provides vital insights that inform safety assessments for drugs and environmental exposures.