Bone marrow hematotoxicity

The main target organs for compound toxicity leading to either drug withdrawal or arrest of compound development as estimated in various studies [3], are classically pointing at liver, the cardiovascular system and bone marrow (hematotoxicity). Cardiovascular and hepatotoxicity were discussed in previous chapters and this chapter focuses on hematotoxicity. 

The model by Medinsky et al. (1995) considered the dosimetry of benzene and its metabolites in bone marrow in order to help explain their hematotoxic and myelotoxic effects. It is well known that none of the metabolites alone produces the effects seen with benzene exposure. Although it is not yet a fully developed PBPK model, this study lays the groundwork for further model development. 

Table 17.1 lists non-oncology compounds from diverse therapeutic, chemical, pharmacological areas and structures that induce clinical hematotoxicity. This demonstrates that bone marrow toxicity is not restricted to a small number of pharmacological or structural classes, thereby making it more difficult to understand specific mechanisms of toxicity. However, there are three classes of mechanisms of hematotoxicity, including antiproliferative, immune-mediated and other. Immune-mediated hematotoxicity and other indirect toxicities (e.g., a decrease of erythropoietin in kidney, leading to an impeded red cell production in the bone marrow) are not discussed in detail in this chapter as it requires involvement of the immune system or remote interactions and in vitro profiling assays have not been developed to detect these mechanisms. 

The AhR is expressed in bone marrow stromal cells [14] and human hematopoietic stem cells [15] and upon agonist binding the receptor translocates to the nucleus, resulting in altered transcriptional expression such as increased CYPlAl [16] and resulting in reactive oxygen species [17]. Nonpharmaceutical compounds such as TCDD, benzo(a)pyrene and benzene have been shown to induce hematotoxicity using this mechanism in vivo and in vitro [18, 19]. 

Figure 17.9 Rat in vivo hematotoxicity evaluated using flow cytometry (based on Saad et al. [59]). Gating strategy of flow cytometry evaluated rat bone marrow samples. N = at least 10000 cells. Results include absolute number nucleated cells, myeloid cells, nucleated erythroid cells and lymphoid cells.

More animal than human data are available from which to determine LOAEL or NOAEL values of benzene hematotoxicity. The data show that animal responses to benzene exposure are variable and may depend on factors such as species, strain, duration of exposure, and whether exposure is intermittent or continuous. Wide variations have also been observed in normal hematological parameters, complicating statistical evaluation. The studies show that benzene exerts toxic effects at all phases of the hematological system, from stem cell depression in the bone marrow, to pancytopenia, to histopathological changes in the bone marrow. The following studies demonstrate these adverse hematological effects in animals. Effects on leukocytes, lymphocytes, and bone marrow are also discussed in Section 2.2.1.3. 

The benzene metabolites hydroquinone and muconic dialdehyde can produce hematotoxic effects (Eastmond et al. 1987 Gad-El Karim et al. 1985 Latriano et al. 1986). The co-administration of phenol (75 mg/kg/day) and hydroquinone (25-75 mg/kg/day) twice daily for 12 days to B6C3Fj mice produced myelotoxicity similar to that induced by benzene (Eastmond et al. 1987). The proposed mechanism suggested that selective accumulation of hydroquinone occurred in the bone marrow after the initial hepatic conversion of benzene to phenol and hydroquinone. Additionally, phenol is thought to stimulate the enzymatic activity of myeloperoxidase, which uses phenol as an electron donor, thus producing phenoxy radicals. These radicals further react with hydroquinone to form 1,4-benzoquinone, a toxic intermediate that inhibits critical cellular processes (Eastmond et al. 1987). 

Ethanol can increase the severity of benzene-induced anemia, lymphocytopenia, and reduction in bone marrow cellularity, and produce transient increases in normoblasts in the peripheral blood and atypical cellular morphology (Baarson et al. 1982). The enhancement of the hematotoxic effects of benzene by ethanol is of particular concern for benzene-exposed workers who consume alcohol (Nakajima et al. 

Baarson K, Snyder CA, Green J, et al. 1982. The hematotoxic effects of inhaled benzene on peripheral blood, bone marrow, and spleen cells are increased by ingested ethanol. Toxicol Appl Pharmacol 64 393-404. 

Zhu H, Li Y, Trush MA. 1995. Differences in xenobiotic detoxifying activities between bone marrow stromal cells from mice and rats implications for benzene-induced hematotoxicity. J Toxicol Environ Health 46 (2) 183-201.The reference list is being compiled and printed from a database. It will be converted to WordPerfect in a later draft. A reference list is attached. 

Bone marrow suppression is a recognized toxic effect of flucytosine anemia, leukopenia, and thrombocytopenia occur in about 5% of cases. The hematological effects are dose-related and occur after prolonged high blood concentrations of flucytosine (over 100 pg/ml). Hematotoxicity is seen more often in the presence of renal insufficiency and hence during the use of flucytosine in combination with amphotericin. If bone marrow reserve has already been depleted by underlying disease or by medications, the risk of hematotoxicity increases. 

Chronic exposure to benzene is markedly hematotoxic. Injury to bone marrow cells is characteristic of this aromatic hydrocarbon. Benzene has also been identified as a possible leuke-mogenic agent. The answer is (B). 

Hi. Biological Applications. Copper(II) bis(dithiocarbamate) complexes have a number of potential biological applications. For example, while dithio-carbamate salts (R = Me, Ft) are potent inhibitors of a clonogenic response in human C34 bone marrow cells, addition of copper sulfate greatly potentiates the hematotoxicity, suggesting a more general role for copper in dithiocarba-mate-induced hematotoxicity (1779). 

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