PRINCIPLES OF TOXICOLOGY - Biology East Borneo

88 HEMATOTOXICITY: CHEMICALLY INDUCED TOXICITY OF THE BLOOD(hemolytic anemia, which reduces the oxygen transport capacity of blood), and hydrogen sulfide.Exposure to hydrogen sulfide can be a significant industrial hygiene concern in the refining ofpetroleum products and the biological degradation of silage (fermented corn, grain, etc., used to feedlivestock) and sewage. As for the number of workers affected, benzene and hydrogen sulfide probablyconstitute the most significant risk factors for toxicity.Hematotoxicity is also an important concern in the administration of pharmaceuticals. For example,dapsone (used to treat leprosy) and primaquine (used to treat malaria) can produce a fatal hemolyticanemia in certain genetically predisposed individuals (those with a deficiency in glucose-6-phosphatedehydrogenase). Unfortunately, individuals most likely to require primaquine or dapsone therapy livein tropical areas of Africa, Asia, and the Mediterranean and are most likely to inherit a deficiency inglucose-6-phosphate dehydrogenase. Of widespread concern are the risks of bone marrow injury andsuppression caused by cancer chemotherapeutics, complications that can often limit the administrationof cancer-curing drugs. Another longstanding problem involves carbon monoxide poisoning, whichresults from exposure to improperly ventilated combustion products. Outside the workplace, the mostcommon occurrences of hematotoxicity involve carbon monoxide poisoning, due to faulty gas heating,and adverse hematologic effects due to prescription medications.Fortunately, hematotoxicity is rarely encountered due to the resiliency of bone marrow, theredundancy of various hematologic controls and functions, and the implementation of more conservativeoccupational hygiene standards. However, when it occurs it is often life threatening. Likewise,examples of hematotoxicity resulting from exposure to environmental chemicals are relatively rareand generally involve foods or medications. Although hematotoxicity is not prevalent, it is useful forindustrial hygienists, toxicologists, and occupational physicians to be aware of the chemicals that causehematotoxicity, relevant signs and symptoms, and any antidotes and treatments that are available.4.2 BASIC HEMATOPOIESIS: THE FORMATION OF BLOOD CELLS AND THEIRDIFFERENTIATIONAll blood cells originate from undifferentiated mesenchymal cells, which are located in the bonemarrow. The various stages of blood cell formation are depicted in Figure 4.1. From stem cells,clones of immature blood cells differentiate along one of two pathways: the myelogenous seriesor the lymphocytic series. The myeloid series gives rise to erythrocytes, macrophages, platelets,neutrophils, eosinophils, and basophils. The lymphoid series gives rise to T (thymus) and B(Bursa) lymphocytes.Bone marrow production of blood cells is highly dependent on, and controlled by, a number ofgrowth factors. Erythropoietin, a glycoprotein growth factor produced in the peritubular cells of thekidney, is essential for the differentiation and maturation of red blood cells. Under conditions ofhypoxia (low oxygen), such as that occurring at higher altitudes or during anemia (a reduction in redblood cells or hemoglobin content) affliction, the release of erythropoietin by the kidney is enhanced.Conversely, the release of erythropoietin is inhibited by polycythemia (the increased number ofcirculating red blood cells) or hyperoxia. Other important glycoproteins that act alone or in conjunctionwith erythropoietin to control red blood cell formation include interleukins such as IL3, IL1, and IL2;granulocyte-macrophage colony stimulating factor (GM-CSF); insulin-like growth factor; and granulocytecolony stimulating factor.White blood cell formation also depends upon stimulation and control by various growth factors.IL3 stimulates all of the myeloid series cells. GM-CSF stimulates the formation of granulocytes andmacrophages. Additionally, specific G-CSF and M-CSF proteins stimulate the granulocyte series orthe macrophage series, respectively. These growth factors, unlike erythropoietin, are produced byvarious cells including T lymphocytes, macrophages, fibroblasts, and endothelial cells. All the growthfactors work in concert to regulate different stages of myeloid and lymphoid differentiation andreplication.