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M Loeffler

Publications and source records attributed to M Loeffler.

At least 73 records · Page 4Linked to original sources
PubMed1996

Rationale for dose escalation of first line conventional chemotherapy in advanced Hodgkin's disease. German Hodgkin's Lymphoma Study Group.

Which strategy is more promising to improve the outcome of primary conventional chemotherapy in advanced Hodgkin's disease (HD): a moderate dose escalation or treatment intensification by shortening cycles? The answer generally depends on two factors: the tumour growth velocity and the chemosensitivity of the tumour. A simple mathematical model of tumour growth and chemotherapy effects was developed to quantify this dependency. The model allows to estimate the distribution of latency times (i.e., the time a tumour requires to grow from one cell to clinical detection) and the distribution of chemosensitivity in a patient population on the base of clinical data on tumour control and treatment given. The model was fitted to the data of 705 stage IIIB/IV HD patients of the German Hodgkin's Lymphoma Study Group (GHSG). The model reveals considerable heterogeneity in chemosensitivity and a significantly positive slope of the dose-response relationship at the standard treatment dose level. The model can be used to simulate the effect of various treatment escalation and intensification strategies. On the basis of such simulations we predict only small benefits (about 3% in 5-year tumour control rates) with shortening cycle intervals from 4 to 3 weeks. In contrast, we predict that a moderate dose escalation by 30% of a standard chemotherapy will lead to a potential benefit in the order of 10% in tumour control at 5 years. The presently ongoing HD9 trial of the GHSG is designed to demonstrate this effect.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Autologous progenitor cell transplantation: prior exposure to stem cell-toxic drugs determines yield and engraftment of peripheral blood progenitor cell but not of bone marrow grafts.

Agents with stem cell-toxic potential are frequently used for salvage therapy of Hodgkin's disease (HD) and high-grade non-Hodgkin's lymphoma (NHL). Because many patients with relapsed or refractory lymphoma are candidates for autologous progenitor cell transplantation, possible toxic effects of salvage chemotherapy on progenitor cells must be taken into account. In a retrospective study, we have analyzed the influence of a salvage regimen containing the stem cell-toxic drugs BCNU and melphalan (Dexa-BEAM) on subsequently harvested bone marrow (BM)- and peripheral blood-derived progenitor cell grafts (PBPC) and compared it with other factors. Progenitor cells were collected from 96 patients with HD or high-grade NHL. Seventy-nine grafts were reinfused (35 PBPC and 44 BM) after high-dose chemotherapy. Compared with patients autografted with BM, hematopoietic recovery was significantly accelerated in recipients of PBPC. For PBPC, the number of Dexa-BEAM cycles ( > or = v > 1) was the predominate prognostic factor affecting colony-forming unit-granulocyte-macrophage (CFU-GM) yield (66 v 6.8 x 10(4)/kg, P = .0001), CD34+ cell yield (6.6 v 1.6 x 10(6)/kg, P = .0001), neutrophil recovery to > 0.5 x 10(9)/L (9 v. 11 days, P = .0086), platelet recovery to > 20 x 10(9)/L (10 v 15.5 days, P = .0002), and platelet count on day +100 after transplantation (190 v 107 x 10(9)/L, P = .031) using univariate analysis. Previous radiotherapy was associated with significantly lower CFU-GM and CD34+ cell yields but had no influence on engraftment. Patient age, patient sex, disease activity, or chemotherapy other than Dexa-BEAM did not have any prognostic impact. Multivariate analysis confirmed that Dexa-BEAM chemotherapy was the overriding factor adversely influencing CFU-GM yield (P < .0001), CD34+ cell yield (P < .0001), and platelet engraftment (P < .0001). BM grafts were not significantly affected by previous Dexa-BEAM chemotherapy or any other variable tested. However, prognostic factors favoring the use of BM instead of PBPC were not identified using joint regression models involving interaction terms between the graft type (PBPC or BM) and the explanatory variables investigated. We conclude that, in contrast to previous radiotherapy or other chemotherapy, exposure to salvage regimens containing stem cell-toxic drugs, such as BCNU and melphalan, is a critical factor adversely affecting yields and performance of PBPC grafts. Marrow progenitor cells appear to be less sensitive to stem cell-toxic chemotherapy. PBPC should be harvested before repeated courses of salvage chemotherapy involving stem cell-toxic drugs to preserve the favorable repopulation kinetics of PBPC in comparison with BM.

Adolescent↗
PubMed1995

The kinetics of murine hematopoietic stem cells in vivo in response to prolonged increased mature blood cell production induced by granulocyte colony-stimulating factor.

Because of the complexity of appropriate stem cell assays, little information on the in vivo regulation of murine stem cell biology or stemmatopoiesis is available. It is unknown whether and how in vivo the primitive hematopoietic stem cell compartment is affected during a continued increased production of mature blood cells. In this study, we present data showing that prolonged (3 weeks) administration of granulocyte colony-stimulating factor (G-CSF), which is a major regulator of mature granulocyte production, has a substantial impact on both the size and the location of various stem cell subset pools in mice. We have used the novel cobblestone area forming cell (CAFC) assay to assess the effects of G-CSF on the stem cell compartment (CAFC days 7, 14, 21, and 28). In marrow, in which normally 99% of the total number of stem cells can be found, G-CSF induced a severe depletion of particularly the most primitive stem cells to 5% to 10% of normal values. The response after 7 days of G-CSF treatment was an increased amplification between CAFC day 14 and 7. However, this response occurred at the expense of the number of CAFC day 14. It is likely that the resulting gap of CAFC day 14 cell numbers was subsequently replenished from the more primitive CAFC day 21 and 28 compartments, because these cell numbers remained low during the entire treatment period. In the spleen, the number of stem cells increased, likely caused by a migration from the marrow via the blood, leading to an accumulation in the spleen. The increased number of stem cells in the spleen overcompensated for the loss in the marrow. When total body (marrow and spleen) stem cell numbers were calculated, it appeared that a continued increased production of mature granulocytes resulted in the establishment of a higher, new steady state of the stem cell compartment; most committed stem cells (CAFC day 7) were increased threefold, CAFC day 14 were increased 2.3-fold, CAFC-day 21 were increased 1.8-fold, and the most primitive stem cells evaluated, CAFC day 28, were not different from normal, although now 95% of these cells were located in the spleen. Four weeks after discontinuation of the G-CSF treatment, the stem cell reserve in the spleen had returned to a normal level, whereas stem cell numbers in marrow had recovered to values above normal. This study shows that the primitive stem cell compartment is seriously perturbed during an increased stimulation of the production of mature blood cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Hemotoxicity by prolonged etoposide administration to mice can be prevented by simultaneous growth factor therapy.

In this study, we determined in vivo interactions between hemopoietic growth factors and etoposide (VP-16) to assess whether normal blood cell production could be maintained during chemotherapy if hemopoietic growth factors were simultaneously administered. Groups of mice were treated for 7 consecutive days with four different doses of VP-16 in combination with three different doses of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). In total, 12 combinations of VP-16 plus EPO and 12 combinations of VP-16 plus G-CSF were thus evaluated. Intricate dose-response surfaces of the effects of the different treatments on colony-forming units-erythroid, reticulocytes, hematocrit, colony-forming units-granulocyte/macrophage, and absolute neutrophil count were obtained, which revealed that: (a) simultaneous EPO administration was able to maintain reticulocyte production and to protect mice from VP-16 induced anemia; (b) simultaneous G-CSF administration was able to maintain granulocyte production and to protect mice from VP-16 induced neutropenia; (c) VP-16 dose escalation was feasible when EPO or G-CSF were simultaneously administered; and (d) no increased myelotoxicity on erythroid or granuloid progenitors was observed when EPO or G-CSF was simultaneously administered with VP-16. These results suggest that in vivo either individual hemopoietic progenitors can become resistant against VP-16-induced cell death by appropriate simultaneous growth factor administration or that the loss of overall cell amplification, induced by VP-16, can be compensated by extra amplification of surviving progenitors. Furthermore, these data indicate that a strict separation in time of cytostatic drug and growth factor treatment is not necessarily the optimal schedule with respect to the reduction of hemotoxicity.

Anemia↗
PubMed1995

Effects of continuous stem cell factor administration on normal and erythropoietin-stimulated murine hemopoiesis: experimental results and model analysis.

The aim of this study was to determine how stem cell factor (SCF) modifies hemopoietic cell production. First we determined the effects of a prolonged SCF administration on murine hemopoiesis and analyzed the results by a mathematical simulation model of hemopoiesis in order to explain the data. Subsequently we investigated the effects of simultaneous coadministration of SCF+erythropoietin (Epo), to see how effects of early and late cytokines superimpose. SCF administration during 14 days induced a proliferative wave through the hemopoietic system; colony forming units-granulocyte macrophage (CFU-GM), burst forming units-erythroid (BFU-E) and colony forming units erythroid (CFU-E) were the first to be augmented, followed by their respective progeny, ultimately leading to increased blood cell numbers. Despite continued treatment most cell numbers returned to normal values in 14 days, colony forming units-spleen (CFU-S), however, remained elevated. This wave pattern could be explained within the framework of a previously established mathematical model of hemopoiesis, if it was assumed that SCF affected the cycling status of primitive cells and if regulatory feedback loops of erythroid and myeloid progenitors on these cells were also allowed. Simultaneous SCF and Epo administration led to synergistic effects on CFU-E numbers and hematocrit values at moderate Epo doses. At high Epo doses, however, this was less pronounced. We conclude that SCF increases the input into committed hemopoietic lineages, where late acting cytokines can induce further amplification.

Animals↗
PubMed1995

Is stem length important in uncemented endoprostheses?

In an uncemented total hip replacement where the femoral stem is thinner than the medullary canal it may be hypothesized that the distal portion of the stem has no mechanical function. In this study an uncemented total hip replacement has been modelled mathematically using finite element analysis and mechanical tests of a similar system have been carried out loading implants in cadaveric proximal femora. Two implants have been tested mechanically; one with a full length stem and the second with the stem shortened, but three implants have been modelled with an additional intermediate length stem analysed. Additionally the finite element analysis has been done with a high neck resection and a standard level resection. The finite element model showed that the full length stem produced lower interface contact stress levels under the proximal neck, particularly when the nec was resected, and this was borne out by the mechanical testing.

Biomechanical Phenomena↗
PubMed1995

Further chemotherapy versus low-dose involved-field radiotherapy as consolidation of complete remission after six cycles of alternating chemotherapy in patients with advance Hodgkin's disease. German Hodgkins' Study Group (GHSG).

OBJECTIVE: It was the aim of this prospective randomized multicenter study to compare chemotherapy and radiotherapy as consolidation treatments in patients achieving complete remission (CR) after 6 cycles of doxorubicin-containing chemotherapy in advanced-stage Hodgkin's disease (HD). METHODS: A total of 288 previously untreated patients aged 18-60 years with stage IIIB or IV HD received induction chemotherapy with 3 X (COPP + ABVD). Patients achieving CR were eligible for randomisation to either 20 Gy radiotherapy to initially involved fields (RT-arm) or to an additional 1 X (Copp + ABVD) (CT-arm ). Patients with nodal PR were allocated to more intense radiotherapy (IRT-arm: 20 Gy IF, 40 Gy to persisting tumor). Four patients with persisting organ involvement after induction received salvage chemotherapy. RESULTS: Of 288 patients, 171 (59%) achieved CR after induction chemotherapy. Of these, 100 patients were successfully randomized to RT or CT. In the CT arm relapses were observed on 10 of 49 patients compared with 13 of 51 patients in the RT arm (p = n.s.). Fifty patients refused randomisation and for them a treatment was chosen, and 21 patients refused any further treatment. Of these 21 patients with no consolidation therapy, 9 relapsed, indicating an approximately 3-fold increased relapse risk compared with those receiving either of the consolidation therapies. No relapse was observed in initially involved lung or liver sites. Adverse prognostic factors for freedom from treatment failure and survival were low hemoglobin and large mediastinal mass at initial presentation. CONCLUSIONS: No statistically significant differences in treatment efficacy were detected between 20 Gy IF radiotherapy and 1X (COPP + ABVD) chemotherapy following CR after six cycles of alternating chemotherapy in patients with advanced-stage HD. However, limited observations in a non-randomized cohort indicate that patients without consolidation treatment of CR after 6 cycles of chemotherapy may have an elevated risk of relapse.

Adolescent↗
PubMed1995

In vivo effects of interleukin-11 and stem cell factor in combination with erythropoietin in the regulation of erythropoiesis.

In this study we evaluated the in vivo effects of interleukin-11 (IL-11) and stem cell factor (SCF), in combination with erythropoietin (EPO) on murine erythropoiesis. Mice were treated for 7 d with IL-11. SCF and EPO, each at three dose levels. In total, 27 different dose combinations were tested. IL-11 as well as SCF could only marginally stimulate erythroid progenitor cell numbers, but IL-11 in combination with SCF was able to increase BFU-E and CFU-E numbers 4-fold, in the absence of exogenous EPO. This resulted in an increased reticulocyte count. In contrast with the stimulatory effect on immature erythroid cell stages, IL-11 treatment induced a mild anaemia, which probably resulted from a plasma volume expansion. The additional treatment with EPO resulted in strong synergistic effects on CFU-E numbers. The combination of high-dose IL-11 and high-dose SCF was able to increase the overall efficiency of EPO-induced erythroid amplification, which was reflected by a left-shift of the in vivo EPO dose-response curve. The stimulating effects of IL-11 and SCF were further demonstrated when the effects on the reticulocyte count of a single high-dose EPO injection were assessed in normal and SCF+IL-11 treated mice. Whereas a single EPO dose increased the reticulocyte count by a factor of 3, IL-11 + SCF pretreatment increased this to a factor of 7. This study shows that in vivo SCF and IL-11 are important modulators of red blood cell production. First, these factors probably increase the input from the stem cell compartment into the erythroid lineage, where subsequently EPO is required for further amplification. Additionally, however, IL-11 and SCF increase the overall efficiency of EPO-induced amplification, probably due to a stimulatory effect on late-stage erythroid cells and to a redistribution of cells from marrow to spleen.

Animals↗
PubMed1994

Mutual inhibition of murine erythropoiesis and granulopoiesis during combined erythropoietin, granulocyte colony-stimulating factor, and stem cell factor administration: in vivo interactions and dose-response surfaces.

We investigated the in vivo effects of erythropoietin (EPO) on granulopoiesis and, conversely, the effect of granulocyte colony-stimulating factor (G-CSF) treatment on erythropoiesis. Recombinant human EPO at four different doses in combination with recombinant human G-CSF also at four different doses was simultaneously administered for 7 days to splenectomized mice. In total, 16 different combinations of growth factors were thus tested. G-CSF administration increased granulocyte production as expected, whereas immature colony-forming unit granulocyte-macrophage numbers were decreased. EPO analogously increased late erythroid cell numbers. Both EPO and G-CSF dose-dependently inhibited late cell stages of the opposite lineage, with EPO abrogating G-CSF-stimulated granulopoiesis and, conversely, G-CSF inhibiting EPO-stimulated erythropoiesis. In a subsequent experiment, we tested whether these lineage-competitive effects could be prevented by coadministering stem cell factor (SCF). In these three factor-treated mice, all granuloid and erythroid cell stages increased, thereby reducing the effect of the mutual inhibition. We conclude that EPO-stimulated erythropoiesis and G-CSF-stimulated granulopoiesis inhibited each other at a late level. Simultaneous SCF administration increased the input into both the erythroid and granuloid compartment and thereby compensated the mutual inhibition. This study shows that intricate dose-response relationships exist between various growth factors that should be carefully analyzed before combinations of these factors are used in humans.

Animals↗
PubMed1994

The crypt cycle in mouse small intestinal epithelium.

We have used a mutation-induced marker system in the intestine of mice heterozygous at the Dlb-1 locus, which determines the expression of binding sites for the lectin Dolichos biflorus agglutinin, and the frequency of clustering of mutated crypts with time as a means of investigating the frequency of the crypt fission process and the crypt cycle. Whole-mount preparations from heterozygous Dlb-1b/Dlb-1a mice were stained with a peroxidase conjugate of Dolichos biflorus agglutinin. Mutations at the Dlb-1b locus in crypt stem cells result in loss of DBA-Px binding in these cells and subsequently their progeny, which eventually results in a rare isolated single, unstained crypt. The subsequent development of pairs, triplets and clusters of negative staining crypts has been assumed to be the result of crypt fission. The frequency of these fission events has been measured in control untreated mice. These negative crypts are the result of spontaneous mutations. We have also looked at mutated crypts after treatment with N-nitroso-N-ethylurea or N-methyl-N'-nitro-N-nitrosoguanidine of young adult mice, which elevates the number of mutations. Our results suggest that the crypt cycle in control animals is very long, 187 +/- 44 weeks (3.6 years, i.e. essentially the life of a laboratory mouse). This implies that about a third of the crypts may divide once in the life of a mouse. After sufficient time for conversion of mixed crypts to monophenotypic crypts after mutagen treatment several clusters of negative crypts were seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Somatic mutation, monoclonality and stochastic models of stem cell organization in the intestinal crypt.

Among highly proliferating tissues the intestinal tissue is of particular interest. Techniques are available that permit an insight into how intestinal crypts as the basic macroscopic tissue unit are regenerated from a small population of self-maintaining stem cells. However, neither the precise number of these stem cells nor their properties are known. We have recently suggested a model of stem cell organization which explains the life cycle of murine intestinal crypts, their birth (by crypt fission) and extinction rates, as well as their size distribution on a quantitative basis (Loeffler & Grossman, 1991). The model assumptions involve two stochastic branching processes, one for the growth of several independent indistinguishable stem cells and a second for a threshold dependent crypt fission process. New data have now become available challenging the above concept. They relate to the conversion of crypts to monoclonal phenotypic expression after mutagenic events, presumably taking place in single stem cells. A detailed analysis of these data is shown here utilizing a more elaborate version of the above model. The new data are consistent with this model within the range of parameters predicted previously. We conclude that the cellular regeneration of intestinal crypts can be explained on the basis of several indistinguishable stem cells which can replace each other.

Animals↗
PubMed1993

Microenvironmentally dependent effects on murine haemopoiesis by a prolonged interleukin-1 treatment.

We administered recombinant human IL-1 beta (400 ng/d, s.c.) for 10 d to normal C57B1 mice and determined daily granuloid and erythroid parameters in marrow, spleen and blood. In the marrow CFU-GM numbers were not affected but later granuloid cell stages were moderately enhanced (170%). In the spleen, however, CFU-GM numbers were sharply increased (1600%), whereas the granuloid precursors only doubled. Blood granulocytes increased transiently to 275% on day 5. In the marrow all erythroid parameters were severely reduced. This reduction was partially compensated by the spleen where initially only BFU-E and with some delay also more mature erythroid cells accumulated. At the end of the treatment mice were slightly anaemic. When mice were treated with IL-1 and erythropoietin (10 U/d) simultaneously, the inhibitory effects on erythropoiesis were less severe. In agreement with in vivo results, IL-1 inhibited in vitro colony growth of CFU-E from normal bone marrow and spleen but spleen CFU-E from 5 d IL-1 treated mice were insensitive. We conclude that IL-1 can induce stimulation or inhibition of haemopoietic progenitor cells depending on their microenvironment.

Animals↗
PubMed1993

The differentiation and lineage development of goblet cells in the murine small intestinal crypt: experimental and modelling studies.

The objective of this study was to provide a new insight into the origin and lineage development of mucus-producing cells in the small intestinal crypt. For this, new experimental data were obtained from both crypt sections and whole mounts. Model simulation studies were undertaken to investigate which rules are most likely to govern the dynamic cellular development and goblet cell pedigree. We have measured the frequency of mucus-secreting goblet cells (using alcian blue and periodic acid Schiff's stains) at each cell position in the ileal murine crypt. These measurements, made on sections, overestimate the number of goblet cells because of the size and centripetal position of the stained cytoplasm. The correction factor for this overscoring has been measured to be 0.25 by two independent methods. The data suggest that there are about 12 functional goblet cells per crypt many of which retain an ability to divide. We have also determined the labelling index of the crypt goblet cells at each cell position. Spatially, goblet cells exhibit a small degree of clustering in the crypt and show a good mixture with columnar cells. We have adapted our earlier dynamic matrix-based computer stimulation model to take into account goblet cell differentiation. The modelling suggested the following conclusions: firstly, goblet cells do not have their own stem cells but share a common stem cell with the columnar cells; secondly, the goblet lineage differentiates from the transit population two to three generations before the end of the lineage; and thirdly, the decision to switch on goblet properties is stochastic at a specific step in the development of columnar cells.

Animals↗
PubMed1993

Visually controlled trocar insertion by means of the "optical scalpel".

The importance of a safer approach to the abdominal cavity has led to several developments in the field of trocars, cannulae and puncture techniques. Examples are the insertion of a needle scope into a Veress needle, complex access cannulae and our new principle of using an "optical scalpel". In our view, direct optical visualization and actively controllable penetration of the abdominal wall are mandatory. First experimental and clinical applications indicate the newly developed "optical scalpel" (Olympus Winter & Ibe, Hamburg, Germany) as a reliable and useful instrument for a safe approach to the endoscopic operative field. This instrument was successfully used in 10 endoscopic operations and is currently undergoing further clinical testing.

Abdomen↗
PubMed1993

Optimal erythroid cell production during erythropoietin treatment of mice occurs by exploiting the splenic microenvironment.

In this study, quantitative effects on erythroid cell production by a prolonged recombinant human erythropoietin (rhEpo) treatment of mice are presented. Epo treatments, given subcutaneously (s.c.) twice per day in doses of 0.5 to 500 U per day, were performed under steady-state production conditions. We found striking differences between the behavior of the different erythroid cell compartments (burst-forming unit erythroid [BFU-E], colony-forming unit erythroid [CFU-E] and erythroid precursors), as well as between the microenvironments of bone marrow and spleen. Whereas the total-body BFU-E was not changed by Epo, a redistribution of BFU-E from marrow to spleen occurred, resulting in decreasing marrow and increasing splenic BFU-E numbers. Splenic BFU-E produced CFU-E as much as 8 times more efficiently than marrow BFU-E at 50 U of Epo. At low Epo doses (to 1 U/day) no difference was found. The CFU-E in the spleen produced erythroblasts at a higher efficiency at all Epo doses (1.5 to 5 times). It seems as if this efficiency was higher at low Epo doses. Because of the migration phenomenon and the excellent microenvironment in the spleen, at the highest Epo concentrations nearly 70% of all erythroid cells reside in the spleen. Even at the highest Epo doses, granuloid cell production was not affected. Similar to the BFU-E, total-body granuloid cells remained constant (despite a shift of granulocyte-macrophage progenitors [CFU-GM]) from marrow to spleen; however, these cells did not flourish in the spleen. Under these conditions, 90% of the granuloid precursors were still localized in the marrow. Erythropoietin did not change the transit time of erythroid cells at high Epo doses.

Animals↗
PubMed1992

A mathematical approach to benzo[a]pyrene-induced hematotoxicity.

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.

Administration, Oral↗
PubMed1992

Hematotoxic effects of benzene analyzed by mathematical modeling.

The hematopoietic cell response to benzene intoxication in mice (during and after long-term inhalation) was analyzed by a mathematical model of murine hematopoiesis. Two complementary methods, Time-Curve and Steady-State Analysis, were developed to identify target cells for benzene toxicity and to quantify the extent of damage in different stages of development of these target cells. We found that (i) erythropoietic cells were the most sensitive; (ii) granulopoietic cells were about half as sensitive as erythropoietic and (iii) hematopoietic stem cells exhibited a sensitivity that ranged between that of erythropoietic and granulopoietic cells. A dose-response relationship between benzene levels and damage in target cells (valid from 1 to more than 900 ppm) was derived that was linear for doses up to 300 ppm and plateaued thereafter. This relationship indicated that benzene-induced hematotoxicity is subject to a saturable process. Recovery of hematopoiesis following chronic benzene intoxication was simulated for different doses and preceding exposure periods. The impaired recovery following exposure periods greater than 8 weeks could be explained by a severe reduction in the maximum self-maintenance of stem cells. This study indicates that the present mathematical model represents a useful approach to investigate alternate hypotheses for the action of hematotoxic agents.

Animals↗