Abstract
Benzo[a]pyrene (BaP) has been reported to exert a differential effect on murine hematopoiesis that is mouse strain specific. Interpretation of these results based solely on experimental data is restricted and leaves important questions unanswered. Therefore, a mathematical model of murine hematopoiesis was applied in order to: (1) identify the targets of BaP, (2) quantify the damage to target cells and (3) based on these results, interpret differences in strain susceptibility. Model analysis of the hematopoietic response of D2 and BDF1 mice to a daily oral administration of 125 mg/kg BaP showed that proliferating hematopoietic cells are the targets of BaP. Within this group it was found that: (a) erythropoietic cells were the most susceptible to BaP, (b) granulopoietic cells showed a susceptibility half that of erythropoietic cells and (c) the susceptibility of stem cells ranged between that of erythropoietic and granulopoietic cells. This damage pattern was the same for both strains, indicating that the difference between the strains was quantitative. As cell destruction rates were about 3-fold higher for D2 than BDF1 mice, it was concluded that D2 mice were about three times as susceptible to BaP as BDF1 mice. The study showed that the mathematical model, in addition to experimental methods, provided an efficient tool for the analysis of BaP hematotoxicity.
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References
Anselstetter V, Heimpel H (1986) Acute hematotoxicity of oral benzo[a]pyrene: the role of the Ah-locus. Acta Haematol 76: 217–223
Collins JF, Brown JP, Dawson SV, Marty MA (1991) Risk assessment for benzo[a]pyrene. Regul Toxicol Pharmacol 13 [2]: 170–84
International Agency for Research on Cancer (1983) IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Polynuclear aromatic compounds. Part I: Chemical, environmental, and experimental data, 32: 34–91
Legraverend C, Harrison DE, Ruscetti FW, Nebert DW (1983) Bone marrow toxicity induced by oral benzo(a)pyrene: protection resides at the level of the intestine and the liver. Toxicol Appl Pharmacol 70: 390–401
Loeffler M, Wichmann HE, Jarczyk AJ (1985) Chronic irradiation — a model analysis. In: Wichmann HE, Loeffler M (eds) Mathematical modeling of cell proliferation. Stem cell regulation in hemopoiesis, vol 1. CRC Press, Boca Raton, Fl, pp 139–146
Loeffler M, Pantel K, Wulff H, Wichmann HE (1989) A mathematical model of erythropoiesis in mice and rats. Part 1: Structure of the model. Cell Tissue Kinet 22: 13–20
Nebert DW (1989) The Ah locus: genetic differences in toxicity, cancer, mutation, and birth defects. CRC Crit Rev Toxicol 20 [3]: 153–74
Nebert DW (1991) Role of genetics and drug metabolism in human cancer risk. Mutat Res 247: 267–281
Nebert DW, Jensen NM (1979) Benzo(a)pyrene-initiated leukemia in mice. Association with allelic differences at the Ah-locus. Biochem Pharmacol 27: 149–151
Nebert DW, Levitt RC, Jensen NM, Hambert GH, Felton JS (1977) Birth defects and aplastic anemia: Differences in polycyclic hydrocarbon toxicity associated with the Ah-locus. Arch Toxicol 39: 109–132
Nebert DW, Jensen NM, Levitt RC, Felton JS (1980) Toxic chemical depression of the bone marrow and possible aplastic anemia explainable on a genetic basis. Clin Toxicol 16: 99–122
Scheding S, Loeffler M, Schmitz S, Seidel HJ, Wichmann HE (1992) Hematotoxic effects of benzene analyzed by methematical modeling. Toxicology (in press)
Schmitz S, Loeffler M, Jones JB, Lange RD, Wichmann HE (1990) Synchrony of bone marrow proliferation and maturation as the origin of cyclic haemopoiesis. Cell Tissue Kinet 23: 425–441
Twerdok LE, Mosebrook DR, Trush MA (1992) Comparison of oxidant-generation BP-diol activation by bone marrow cells from C57BI/6 and DBA/2 mice: implications for risk of bone marrow toxicity induced by polycyclic hydrocarbons. Toxicol Appl Pharmacol 112: 266–272
Wichmann HE, Loeffler M (1985) Mathematical modeling of cell proliferation. Stem cell regulation in hemopoiesis, vols 1 and 2. CRC Press, Boca Raton, FL
Wichmann HE, Loeffler M, Schmitz S (1988) A concept of hematopoietic regulation and its biomathematical realization. Blood Cells 14: 411–429
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Scheding, S., Loeffler, M., Anselstetter, V. et al. A mathematical approach to benzo[a]pyrene-induced hematotoxicity. Arch Toxicol 66, 546–550 (1992). https://doi.org/10.1007/BF01973384
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DOI: https://doi.org/10.1007/BF01973384