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Biomedical subjects

H E Wichmann

Publications and source records attributed to H E Wichmann.

At least 19 recordsLinked to original sources
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↗
PubMed1992

Occupational and environmental hazards associated with lung cancer.

In a hospital-based case-control study 194 lung cancer cases, 194 hospital controls, and 194 population controls were interviewed for their smoking, occupational, and residential history by trained interviewers, using a standardized questionnaire. In order to include many different environmental exposures, case ascertainment took place in seven different hospitals with catchment areas ranging from rural to highly industrialized. Lung cancer risk strongly increases with cumulative cigarette dose, reaching an odds ratio (OR) of 16.19 (95% confidence limits (CL): 5.10, 51.33) for male smokers of more than 40 pack-years and an OR of 19.99 (95% CL: 4.98, 80.24) for female smokers of more than 20 pack-years. For the quantification of occupational exposure to known carcinogens of the lung a novel approach was developed which accumulates exposure information obtained by supplemental questionnaires through an automatic procedure. The OR for the highest exposure group in males was 2.7 (95% CL: 1.23, 5.78). Significantly increased risks were observed in the metal industry, particularly in smelter and foundry workers (OR 4.8, 95% CL: 1.15, 20.16) and in turners (OR 2.2, 95% CL: 1.05, 4.75). In the construction industry the risks were particularly high in road construction workers (OR 3.7, 95% CL: 1.06, 13.20) and in unskilled construction workers (OR 2.7, 95% CL: 1.24, 5.76). The risks in these occupational groups increased with duration and with latency. Quantification of air pollution was done on a county basis by time period. An index based on emission data for sulphur dioxide was compared to a semiquantitative index, which included additional information on ambient air pollution. After adjustment for smoking and occupational exposures an OR of 1.01 (95% CL: 0.53, 1.91) for an emission index and of 1.16 (95% CL: 0.64, 2.13) for a semiquantitative index was obtained.

Adult↗
PubMed1991

Smoking cessation and nonsmoking intervals: effect of different smoking patterns on lung cancer risk.

A case-control study of lung cancer was conducted in northwestern Germany in 1985-86. The study included 194 lung cancer cases and the same number of hospital controls and population controls who were matched to the cases by sex and age. Personal interviews were conducted by trained interviewers. We report here the effect of different smoking patterns--such as nonsmoking intervals, and time since quitting smoking--on lung cancer risk. Both quitting smoking and having a nonsmoking interval are seen to reduce lung cancer risk significantly. For a nonsmoking interval of three years or more, relative risk (RR) = 0.21, 95 percent confidence interval (CI) = 0.08-0.52; for quitting smoking for 10 years or more, RR = 0.23, CI = 0.11-0.48). A dose-response relationship was estimated for cigarette dose, length of nonsmoking interval, and time since stopped smoking.

Adult↗
PubMed1991

Air pollution and acute respiratory illness in five German communities.

To assess the impact of short-term exposure to air pollution on respiratory illness in children we recruited pediatricians and hospitals in five German cities to report daily counts of children's visits for croup symptoms and obstructive bronchitis. Data were collected for at least 2 years in each location. These symptoms are predominantly found in very young children, with the croup reporting peaking at 2 years of age and obstructive bronchitis at 1 year. Attacks of croup and obstructive bronchitis were relatively rare events: the mean number of cases of croup per day in each city ranged from 0.5 to 3, and obstructive bronchitis was even less frequent. A total of 6330 cases of croup and 4755 cases of obstructive bronchitis were observed during the study. The distributions of these events were quite skewed and were modeled as a Poisson process. To focus the analysis on short-term correlations and avoid seasonal confounding, biannual, annual (seasonal), and six shorter term cycles were controlled for in the regression models. After controlling for short-term weather factors, total suspended particulate matter (TSP) and nitrogen dioxide (NO2) were associated with croup cases. An increase in TSP levels from 10 micrograms/m3 to 70 micrograms/m3 was associated with a 27% increase in cases of croup; the same increase in NO2 levels resulted in a 28% increase in cases. No pollutant was associated with daily cases of obstructive bronchitis.

Air Pollution↗
PubMed1991

[Croup and air pollutants: results of a two-year prospective longitudinal study].

The Reutlingen/Tübingen/Rottenburg region in Baden-Württemberg is characterized by medium and small sized towns and rural areas. In 1986/87 875 cases of croup were registered there by the treating physicians during a 24-months period. In consideration of meteorological and virological "disturbing variables" the influence of the measured air pollution by SO2, NO, NO2, CO, ozone and dust on croup frequency was computed by means of statistical regression methods. For the months September till March, the main manifestation period of croup, weak but statistically significant influences of the daily means of NO and NO2 were found, for the whole year influences of NO, NO2, and CO. During the winter months temperature correlates positively and velocity of wind negatively, both statistically with significance, to croup frequency. The essential conditions of croup are individual and familiar disposition on the one hand, virus infections on the other. Air pollution of a concentration like given in the investigated region was found to be a weak additional factor that favours the manifestation of croup.

Air Pollutants↗
PubMed1990

A mathematical model of erythropoiesis in mice and rats. Part 4: Differences between bone marrow and spleen.

In a preceding analysis we hypothesized that the most important parameter controlled by erythropoietic regulation in vivo is the degree of amplification (number of cell divisions) in the CFU-E and erythroblast cell stages. It was concluded that erythropoietic amplification in vivo is controlled according to a sigmoidal dose-response relationship with respect to the control parameter which is the haematocrit (or haemoglobin concentration). Here, this hypothesis is extended to include the differences in murine bone marrow and splenic erythropoiesis that are described and quantified by different dose-response relationships. Comparing several sets of experimental data with mathematical model simulations, this approach leads to the following conclusions: (i) in the unperturbed normal steady state at least one extra erythropoietic cell division takes place in the spleen compared with the bone marrow; (ii) a strong erythropoietic stimulus, such as severe bleeding or hypoxia, can induce five to six additional cell divisions in the spleen but only two to three additional divisions in the bone marrow; this results in a considerable increase in the spleen's contribution to erythropoiesis from about 10% in normal animals to over 40% during strong stimulation; (iii) under erythropoietic suppression, such as red cell transfusion, a similar number of cell divisions is skipped in both organs and the splenic contribution to erythropoiesis remains unchanged. In conclusion, the concept that bone marrow and spleen microenvironments differ in the dose-response relationship for erythropoietic regulation provides an explanation for the changing contribution of splenic murine erythropoiesis following a variety of experimental treatments.

Animals↗
PubMed1990

Synchrony of bone marrow proliferation and maturation as the origin of cyclic haemopoiesis.

Cyclic haemopoiesis in Grey Collie dogs is characterized by stable oscillations in all haemopoietic lineages. It is proposed that in these animals, in contrast to normal animals, the maturation process of haemopoietic (in particular granuloid) cells from the primitive progenitors to the functional cells is characterized by an abnormally strong synchrony. It is conjectured that the marrow maturation time has a very small variance compared with non-cyclic normal dogs. With a mathematical model of haemopoiesis it is shown that small fluctuations are amplified via regular feedback processes such that stable granuloid oscillations are established. Erythroid oscillations are induced indirectly by granuloid feedback to the stem cell pool. The model calculations further show that the synchrony hypothesis of bone marrow maturation can quantitatively explain the following experimental results: (1) the maintenance of stable cycles of granuloid and erythroid bone marrow and blood cells with a period of approximately 14 d; (2) the disappearance of granuloid and erythroid cycles during the administration of the colony stimulating factor rhG-CSF; (3) the reappearance of oscillations when the administration of CSF is discontinued; (4) the cessation of cycles during endotoxin application; and (5) the persistence of cycles during erythroid manipulations (bleeding anaemia, hypoxia, hypertransfusion). We therefore conclude that cyclic haemopoiesis is not caused by a defect in the regulatory control system but by an unusual maturation process.

Animals↗
PubMed1990

[Supplementary comments on the health effects of the 1985 smog period].

This paper discusses the objections made by Hompesch (1989) in this journal against our analysis of the smog episode 1985. We consider these claims and show that the complete data from the analysis of the smog episode are widely consistent internally and with external findings. Overall as before we conclude that during the smog episode small influences of air pollution on respiratory and cardiovascular diseases and mortality have been shown.

Cardiovascular Diseases↗
PubMed1990

[Results of the histology of bronchial carcinoma form an epidemiological study in North Rhine-Westphalia and northern Germany].

In a case-control study to examine the risk factors for bronchial carcinoma, 194 histologically confirmed cases of lung cancer and twice the number of controls (194 hospital controls, 194 population controls) were covered. In addition, the histological material obtained from 139 patients was assessed by a reference pathologist. In 107 cases (77%) the data coincided with the findings by the hospital pathologists. In women, young patients and persons with better general job qualifications adenocarcinomas and other bronchial carcinomas were seen more often and small-cell carcinomas as well as squamous cell carcinomas were rarer. Smoking did not entail any significant difference in respect of bronchial carcinoma risk. There was a significant risk increase among persons occupationally exposed to polycyclic aromatic hydrocarbons, arsenic, chromium, nickel and radionuclides in respect of squamous cell and small-cell carcinomas but not of adenocarcinomas and other histological types of carcinoma.

Adenocarcinoma↗
PubMed1989

A mathematical model of erythropoiesis in mice and rats. Part 1: Structure of the model.

A mathematical model has been developed which describes the regulation of erythropoiesis in mice and rats. The main model assumptions are: (1) Regulation is mediated by erythropoietin (EPO). (2) The production of EPO depends exponentially on the tissue oxygen pressure (e.g. in the renal production sites). (3) There are sigmoidal dose-response curves relating the EPO concentration in the plasma to the mitotic activity of CFU-E and proliferative erythropoietic precursors. For maximum stimulation two to four additional mitoses may occur, while for an absent stimulus three to five mitoses may be omitted. (4) The normal precursor transit time of three to four days may be shortened by more than 50% during maximum stimulation. (5) The erythrocytes have a normal lifespan of 42-56 days, which may be reduced to 15-20 days under erythropoietic stimulation. Among these assumptions, the dose-response relationships between EPO and the mitotic activity of CFU-E and the proliferative erythropoietic precursors are the most important hypotheses of the model. This is the first of a series of three papers and gives a description of the mathematical formalism and the parameters used. In the subsequent papers computer simulations on erythropoietic stimulation and suppression are presented.

Animals↗
PubMed1989

A mathematical model of erythropoiesis in mice and rats. Part 2: Stimulated erythropoiesis.

A mathematical model of erythropoietic cell production and its regulation process has been proposed in a preceding paper. It is primarily based on the assumption that the number of cell divisions taking place in the CFU-E and erythropoietic precursor stages is regulated depending on the oxygen supply of the tissue. Quantitative dose-response relationships for in vivo erythropoiesis are suggested. Here, we demonstrate that this model adequately reproduces data obtained in situations of stimulated erythropoiesis in mice and rats. In detail, this implies a quantitative description of the following processes: (1) Changes in tissue oxygen tension (Pto2) following removal of red cells (bleeding, haemolytic anaemia) or increase in plasma volume (dilution anaemia) or decrease in atmospheric oxygen pressure (hypoxia). (2) Pto2 dependent erythropoietin (EPO) production. (3) Dose-response of EPO on erythropoietic amplification (up to two to four additional mitoses). (4) The changes of the marrow transit time. Model simulations are compared with experimental data for changes of erythropoiesis during hypoxia, EPO-injection, and different forms of anaemia. A satisfactory agreement suggests that the model adequately describes and correlates different direct and indirect ways to stimulate erythropoiesis. It quantifies the role and relative contribution of the haematocrit, haemoglobin concentration, atmospheric oxygen pressure, tissue oxygen pressure, and plasma volume as triggers in erythropoietic stimulation under various conditions. Furthermore, the model may allow to optimize the scheme of EPO-administration and to find the maximum increase of erythropoiesis for a given amount of erythropoietin.

Anemia↗
PubMed1989

A mathematical model of erythropoiesis in mice and rats. Part 3: Suppressed erythropoiesis.

A mathematical model of erythropoietic cell production and its regulation process has been proposed in a preceding paper. It is primarily based on the assumption that the number of cell divisions taking place in the CFU-E and erythropoietic precursor stages can be regulated depending on the oxygen supply to the tissue. Here we provide evidence that this model adequately describes situations of suppressed erythropoiesis. In detail this implies a quantitative description of the following processes: (1) changes in tissue oxygen tension (Pto2) due to increase in red cell numbers (red cell transfusion, posthypoxia), decrease in plasma volume (dehydration) or increase in atmospheric oxygen pressure (hyperoxia), (2) Pto2 dependent reduction of erythropoietin (EPO) production, (3) dose-response of reduced EPO-levels on erythropoietic amplification (omission of three to five mitoses). Model simulations are compared to experimental data obtained from red cell transfusion, posthypoxia, hyperoxia and dehydration. A satisfactory agreement suggests that the model adequately describes and correlates different ways to suppress erythropoiesis. It quantifies the role and relative contribution of the haematocrit, haemoglobin concentration, atmospheric oxygen pressure, tissue oxygen pressure and plasma volume as triggers in erythropoietic suppression under various conditions. In conjunction with the preceding two papers it could be shown that one unique set of model parameters is sufficient to describe erythropoiesis in steady state, stimulation and suppression. Limitations of the model are discussed and experiments for a more detailed investigation of the feedback mechanisms are proposed.

Animals↗
PubMed1989

Health effects during a smog episode in West Germany in 1985.

In January 1985 a smog period occurred for 5 days in parts of West Germany, including the Rhur District. Mortality (24,000 death certificates), morbidity in hospitals (13,000 hospital admissions, 5400 outpatients, 1500 ambulance transports) and consultations in doctors' offices (1,250,000 contacts) were studied for a 6-week period including the smog episode and a time interval before and thereafter. The study region was the State of North Rhine-Westfalia (16 million inhabitants), but the analysis is restricted to the comparison of the polluted area and a control area (6 million inhabitants each). During the smog period, mortality and morbidity in hospitals increased in the polluted area, but there was no substantial increase in the control area. The increases were for the total number of deaths 8 vs. 2% (polluted area vs. control area), for hospital admissions 15 vs. 3%, for outpatients 12 vs. 5% and for deliveries by ambulance to hospitals 28% in the polluted area (not investigated in the control area). The effects were more pronounced for cardiovascular diseases than for respiratory diseases. The consultations in doctors' offices show a slight decrease (-2 vs. -4%). Regression analysis shows a moderate influence of temperature, but a strong influence of ambient air pollution. The maxima of the ambient concentrations are more important on the same day, whereas the influence of the daily averages is more pronounced after a delay of 2 days. The results are discussed considering other possible confounders such as indoor pollution and psychogenic influences of the alarm situation. In total, the study suggests moderate health effects due to increased air pollution during the smog episode.

Acid Rain↗
PubMed1988

[Measurement of respiratory resistance in healthy persons in the winter of 1985/86 and in January/February 1987].

From November to May 1986 oscillatory resistance Ros was measured 6 times in 72 healthy persons in Cologne. Every person was examined at a fixed time of day, respiratory symptoms and bronchopulmonary diseases were considered. Seasonal fluctuations of resistance were found, with slightly elevated values in autumn and spring compared to the winter. Regression analysis showed a decrease of the mean and range of resistance with increasing height and a slight increase in smokers. There was no relation between the seasonal pattern of resistance and the air pollutants, as expected due to relatively low ambient concentrations. When in January 1987 ambient pollution increased, the investigation was repeated on Jan 21, 1987, the day with the highest concentration (daily average of SO2: 256 micrograms/m3). In February control investigations were performed. The resistance was significantly elevated in January 1987 compared to February 87 or to January 86. These results agree with those of other authors, who found a slight impairment of lung function in healthy persons when daily averages of SO2 concentrations exceeded 250 micrograms/m3. However, changes of the same or a greater extent may be caused by meteorological factors.

Adult↗
PubMed1988

[Lung function and carboxyhemoglobin during the smog episode of January 1987].

During a phase of elevated ambient air pollution in January 1987 the alert level of the smog alarm recommendation in Northrhine Westfalia (FRG) was reached. The average concentrations during examinations were 0.255 mg/m3 SO2 and 3.2 mg/m3 CO at the closest station. In 111 healthy persons in Cologne and Düsseldorf, resistance measured by oscillatory method was elevated during this period compared to control examinations. In 59 patients with moderate airway-obstruction from different parts of West Germany lung function showed further deterioration during the smog phase: Airway resistance measured by body-plethysmography was higher than during a control period, FVC, FEV1, PEF and MEF75 were decreased. Finally levels of carboxyhemoglobin in blood also were increased in 46 healthy nonsmokers. The investigation shows, that even in moderate smog episodes (compared to earlier years) small, but consistent changes of lung function parameter can be measured.

Adolescent↗