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Biomedical subjects

T E Fritz

Publications and source records attributed to T E Fritz.

At least 19 recordsLinked to original sources
PubMed2002

Hematopoietic responses under protracted exposures to low daily dose gamma irradiation.

In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d-1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d-1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (>1 yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d-1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d-1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation.

Animals↗
PubMed1996

Biological effects of 137CsCl injected in beagle dogs of different ages.

The toxicity of 137Cs in the beagle dog was investigated at the Inhalation Toxicology Research Institute (ITRI) and Argonne National Laboratory (ANL) as part of programs to evaluate the biological effects of both radionuclides in atomic bomb fallout and internally deposited fission-product radionuclides. In the ITRI study, young adult dogs were exposed once by intravenous injection to a range of 137Cs concentrations; the results have recently been published (Nikula et al., Radiat. Res. 142, 347-361, 1995). The purpose of the present report is to summarize the ANL study and to compare the results of the two studies. At ANL, 63 dogs in three age groups (15 juveniles, 142-151 days old; 38 young adults, 388-427 days old; and 10 middle-aged dogs, 1387-2060 days old) were given 137Cs intravenously at levels (61-162 MBq/kg) near those expected to be lethal within 30 days after injection. There were 17 control dogs from the same colony. Twenty-three of the dogs injected with 137Cs, including all middle-aged dogs, died within 52 days after injection due to hematopoietic cell damage resulting in severe pancytopenia that led to fatal hemorrhage and/or septicemia. The other significant early effect was damage to the germinal epithelium of the seminiferous tubules of all male dogs. These early effects are the same as those reported for the dogs injected with 137Cs at ITRI. In addition, the design of the ANL study revealed an age- and gender-related differential radiosensitivity for early effects: The middle-aged dogs died significantly earlier due to complications of hematological dyscrasia compared to the juvenile and young adult dogs, and the middle-aged females died significantly earlier than the middle-aged males. The most significant non-neoplastic late effects in the 137Cs-injected dogs from ANL and ITRI were atrophy of the germinal epithelium of seminiferous tubules with azoospermia, and a significant dose-dependent decrease in survival. However, the survival of the ANL dogs was decreased more than that of the ITRI dogs at similar radiation doses from 137Cs. Numerous neoplasms occurred at many different sites in the dogs injected with 137Cs at ANL and ITRI. Two differences in the findings of the two studies were that (1) there was an increased risk for malignant thyroid neoplasms in the ANL male dogs injected with 137Cs, but not the ITRI dogs of either gender, and (2) there was an increased relative risk for benign neoplasms excluding mammary neoplasms in the ITRI dogs injected with 137Cs, but not the ANL dogs. In both groups, there were dose-related increased incidences of malignant neoplasms, malignant neoplasms excluding mammary neoplasms, all sarcomas considered as a group, all non-mammary carcinomas considered as a group and malignant liver neoplasms. In summary, the similarity of the findings between the two studies and the dose-response relationships for survival and for large groupings of neoplasms suggests that these results are consistent findings in 137Cs-injected dogs and might be dose-related late effects in humans exposed to sufficient amounts of internally deposited 137Cs.

Age Factors↗
PubMed1995

Response of hemopoiesis in dogs to continuous low dose rate total body irradiation.

Among the cytotoxic agents which particularly cause damage to cell renewal systems, ionizing radiation is one of the most effective ones since it leads to inactivation of all types of proliferating cells including resting stem cells. It is the aim of this paper to present the effects of continuous low dose rate total body irradiation (TBI) on hemopoiesis in dogs. The animals were exposed to gamma-rays from a 60-Co source, receiving a daily radiation dose of 0.0188 Gy for indefinite times. Sequential hematological studies performed included determinations of peripheral blood cell counts and of total cell numbers in standardized bone marrow samples, assessments of progenitor cells GM-CFC in the blood and bone marrow, and of colony-stimulating activity (CSA) in the serum. The lymphocytes, the thrombocytes and neutrophilic granulocytes uniformly showed early decreases within the first 200 to 500 days corresponding to cumulative radiation doses in the range up to 3.8 to 9 Gy, but remained stable at subnormal levels in the period up to 1,700 days of exposure. The GM-CFC numbers in bone marrow samples from the rib clearly showed a strong decrease within the first 150 days of exposure preceding the changes in the blood granulocyte concentration. A transient partial recovery of the GM-CFC was observed at later times between 700 and 1,200 days of exposure, followed by another decrease to extremely low values at cumulative doses in the range of 32 Gy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Continuous irradiation of beagles with gamma rays.

The effects of exposure to 60Co gamma rays for the duration of life on mortality patterns in beagles were investigated. Doses of 3, 7.5, 18.8, 37.5, 75, 127.5, 262.5, 375, or 540 mGy were delivered over a 22-h day 7 days a week. Hazard models with time-dependent covariates were used to identify radiation-related trends in mortality. Hematopoietic failure occurring early in life was positively associated with the accumulated dose and the rate at which the dose was delivered. The risk of death from causes other than cancer that occurred later in the life span also depended on accumulating dose and dose rate but was lower than the cancer risk. Once an animal survived long enough to die from cancer, failure times depended only on the accumulating dose. The slope 1 and slope 2 boundary in a Gompertz plot historically used to identify the transition between dose rate and total dose effects was also found to distinguish between late-occurring deaths associated with tumor or nontumor events.

Animals↗
PubMed1991

Responses of the beagle to protracted irradiation. I. Effect of total dose and dose rate.

The effects of protracted exposure to 60Co gamma rays on survival and tumor induction in the beagle were investigated. Total accumulated doses of 450, 1050, 1500, and 3000 cGy were given at rates of 3.8, 7.5, 12.8, and 26.3 cGy/day. Hazard models were used to identify trends in mortality associated with radiation exposure. The probability of an acute death (related to hematopoietic aplasia) was positively associated with the total dose received and the rate at which the dose was delivered. Once an animal survived the initial hematopoietic effects of radiation exposure, the risk of death from causes other than cancer, while elevated, was far less responsive than the neoplastic end points. No relationship between tumor or chronic nontumor deaths and dose rate could be identified. However, survival curves for tumor mortality did separate into a pattern clearly dependent on the accumulated dose.

Animals↗
PubMed1989

Blood responses under chronic low daily dose gamma irradiation: I. Differential preclinical responses of irradiated male dogs in progression to either aplastic anemia or myeloproliferative disease.

Male beagles chronically exposed to low daily doses of 60Co gamma rays (7.5 cGy/22h/day) show one of three hematopoietic patterns, which reflect three different distinctly responding subgroups: (1) low radioresistance with progressing aplastic anemia and shortened survival (-S-AA subgroup); (2) high radioresistance with a complex of progressing myeloproliferative disorders (+R-MPD group); or (3) high radioresistance with other nonMPD syndromes (+R-nonMPD group). Blood cell levels (granulocytes, monocytes, erythrocytes, lymphocytes, and platelets) were assessed and fitted to a flexible polynomial spline model, thus defining the (a) initial suppressive and (b) subsequent recovery phases for the subgroups. Results showed that relative to the overall magnitude of blood cell loss as well as to the maximum rate of suppression during the initial phase, the subgroups were generally ranked -S-AA much greater than +R-MPD greater than +R-nonMPD. Relative to the overall strength of the recovery response, the subgroups were generally ranked +R-MPD greater than +R-nonMPD much much greater than -S-AA. In terms of overall maintenance levels of circulating blood cells during the recovery phase, however, the +R-nonMPD subgroup consistently exhibited stronger responses than the +R-MPD subgroup. These results tend to support our contention that selected subgroups of dogs have strong propensities to specific hematopathologies (i.e. aplastic anemia and myeloid leukemia) under chronic irradiation and that these pathology-prone animals exhibit a series of marked differential hematopoietic responses during early preclinical phases, which serve effectively to prognosticate subsequent pathological progression.

Adaptation, Physiological↗
PubMed1987

Chronic radiation leukemogenesis: postnatal hematopathologic effects resulting from in-utero irradiation.

Previous studies have shown that continuous whole-body exposure to low daily doses of gamma radiation is highly leukemogenic for beagles initially exposed during either young adulthood or fetal development. In contrast, terminated radiation-exposure regimens (continuous exposure terminated after accumulation of preset total radiation doses) markedly reduce leukemogenic potential. In this study, we examined leukemic incidences and postnatal hematopoietic function in three groups of dogs; continuously irradiated (7.5 cGy/day) during both fetal life and after birth, continuously irradiated during fetal life only, and nonirradiated. Results were compared to results from studies with similarly irradiated and nonirradiated groups of young adult dogs initially tested at 400 days of age. Hematopoietic function was assessed in terms of both circulating blood levels of red cells, platelets, granulocytes, and monocytes, and marrow concentrations and radiosensitivities of hematopoietic progenitors. Results indicated that under continuous fetal/postnatal irradiation, i.e. the high leukemogenic exposure regimen, a marked, progressive suppression in hematopoietic function occurred following birth. This suppression continued to 100-150 days of age and was followed by partial hematopoietic recovery that was associated with an acquired radioresistance by hematopoietic progenitors. In contrast, neonates that had been continuously irradiated during fetal life, but not postnatally, i.e. the low leukemogenic regimen, exhibited a similar initial suppression of hematopoietic function followed by partial recovery. However, no temporally linked acquisition of radioresistance by hematopoietic progenitors was demonstrated. These results support the hypothesis, developed from earlier studies with adult dogs, that the processes of acquired radioresistance and recovery in numbers of transformable hematopoietic progenitors are causally linked to early stages of the leukemogenic process under continuous ionizing irradiation.

Animals↗
PubMed1983

Increased incidence of malignant tumors in dogs after total body irradiation and marrow transplantation.

One hundred fifty-three dogs were given 6.1-21.3 Gy total body irradiation at 0.02-0.2 Gy/minute delivered from two opposing cobalt sources followed by allogeneic (131 dogs) or autologous (22 dogs) marrow grafts and observed for 6-127 (median 33) months. The incidence of malignant tumors in radiation chimeras was compared to that in 242 untreated dogs observed for 6-188 (median 81) months. Thirteen malignancies were observed in 11 radiation chimeras. These tumors included two leiomyosarcomas of the mesentery, four adenocarcinomas of the breast, prostate and ovary, two mastocytomas, one hypernephroma, perianal gland carcinoma, seminoma, Brenner tumor, and an oligodendroglioma. Fifty-four malignancies were seen in 44 control dogs. These included 12 mammary carcinomas, 12 thyroid carcinomas, six lymphomas, two malignant melanomas, and a number of other solid tumors. On the basis of time-dependent Cox regression analysis, radiation chimeras had an estimated relative risk of developing a malignancy that was 5-fold higher than in control dogs (p less than 0.001). No tumor has yet been observed in a group of 15 chimeras conditioned by cyclophosphamide or dimethyl busulfan and followed for 6-97 (median 24) months. The increased risk of cancer among canine radiation chimeras suggests that high-dose total body irradiation may increase the risk of developing a malignancy and should be avoided whenever possible in the conditioning for marrow transplantation of human patients with nonmalignant diseases.

Animals↗
PubMed1982

Radiosensitivity and life span of dog peripheral blood lymphocytes.

Observations made after 48 h of cultivation show that 52% of dog lymphocytes are already in M2 and 17% in M3 at that fixation time. Evidently, the large discrepancy observed between man and dog with respect to the yield of dicentric chromosomes induced by an exposure to 200 rad of X-rays and observed after a culture time of 48 h does not correspond to a difference in chromosomal radiosensitivity. There is, indeed, no statistically significant difference between the yield of dicentrics observed in M1 human lymphocytes (32.0 per 100 cells) and that in dog lymphocytes after correction of the values obtained at 48 h (28.6 per 100 cells). From the observations performed on whole-body irradiated dogs one can estimate that the half-time of dog lymphocytes carrying chromosome aberrations is less than 30 days.

Animals↗
PubMed1982

Aberrant megakaryocytopoiesis preceding radiation-induced leukemia in the dog.

Six of nine decedent beagles exposed continuously to 2.5 R*/22 hour day of whole-body 60Co gamma-radiation died with myeloproliferative diseases: three cases of myelogenous leukemia and one each of monocytic leukemia, erythroleukemia, and erythremic myelosis. The three dogs that died with myelogenous leukemia had micromegakaryocytes and megakaryoblasts in the peripheral blood during the preleukemic phase when myeloblasts were not observed in the peripheral blood or in increased numbers in the bone marrow. In this study we have examined the megakaryocytes during the preleukemic period by a combination of light, transmission, and scanning electron microscopy. Morphologic abnormalities seen by light microscopy included mononucleated and binucleated forms, many with cytoplasmic blebs. The small mononuclear forms in the bone marrow tended to form clusters. Ultrastructural features included a paucity of both specific alpha granules and dense granules. The micromegakaryocytes showed dysgenesis of the demarcation membrane system. This membrane system appeared disorganized with a few dilated round, oval, or rarely, elongated vesicles and showed no evidence of platelet formation. The cells also had a paucity of endoplasmic reticulum, few mitochrondria, and sparse glycogen accumulations. The scarcity of cytoplasmic organelles gave a pale immature appearance to the cytoplasm. By scanning electron microscopy, the sponge-like surface of large mature megakaryocytes from unirradiated marrow contrasted with the characteristically smooth, topographically featureless surfaces of the micromegakaryocytes from preleukemic dogs.

Animals↗
PubMed1982

The ultrastructure of radiation-induced endosteal myelofibrosis in the dog.

A rapidly developing, progressive form of endosteal myelofibrosis (MF) (with myeloid metaplasia) has been shown to occur at low frequency (approximately 4%) in dogs exposed continuously to low daily doses (10 R/day) of whole-body gamma irradiation. We report in this study the morphological details of the endosteal surface during both preclinical and clinical phases of developing MF by combination light microscopy and scanning/transmission electron microscopy. Pronounced alterations of the endosteum were observed and included: (1) during the early preclinical phases, a progressive time-dependent transition of the endosteal surface from predominantly resting to actively formative and resorptive states; and (2) during the late preclinical phase, aberrant autonomous osteogenic process(es) characterized by a marked reduction in the resorptive, osteoclast-associated endosteal areas occurring concomitantly with further increases in formative areas of the endosteum. Localized patches of overlapping, morphologically transformed endosteal cells (i.e., round-osteoblastic to branched-reticular shaped) were observed within the morphologically reactive, formative endosteum. Osteogenic-endosteal changes coincided with major restructuring of the hematopoietic parenchyma and supporting stromal network. We discuss the possibility that the early occurring endosteal changes are causally linked to normal reparative functions that operate during regenerative hematopoiesis following local and systemic injury. Based on morphological data collected during the late preclinical phase, we speculate that the mechanism of myelofibrosis induction involves the failure to terminate early osteogenic-dependent repair sequences.

Animals↗
PubMed1981

Viral antibody studies of laboratory dogs with diarrheal disease.

Viral antibody studies were done on laboratory dogs in an epizootic of gastrointestinal disease. Increased hemagglutination-inhibition antibody titers to a parvovirus (PV) antigenically related to feline panleukopenia virus were found in convalescent serum specimens of 78% (20/26) of the affected dogs and in 83% (5/6) of apparently healthy dogs. With one exception, all dogs tested had significant levels of hemagglutination-inhibition antibody to this PV. Similar increased antibody titers were found to feline panleukopenia virus. Also, neutralizing antibody responses were detected to the canine coronavirus in 24% (6/25) and canine herpesvirus in 45% (10/22) of the affected dogs. However, antibody titers did not increase to canine distemper virus, infectious canine hepatitis virus, canine parainfluenza virus, or minute virus of canines. Subsequent serotesting of the colony provided evidence that additional PV infections occurred in pups from each of 8 litters born 3 to 8 months after the epizootic. These findings indicated the continued presence of the PV for more than 1 year in the infected colony. Of 19 laboratory personnel who worked with the affected dogs, none, including 4 with a concurrent diarrheal disease, developed or had antibodies to the PV or canine coronavirus.

Animals↗
PubMed1980

Hemopathologic consequences of protracted gamma irradiation: alterations in granulocyte reserves and granutocyte mobilization.

Aplastic anemia and myelogenous leukemia are prominent pathologic effects in beagles exposed to continuous, daily, low-dose gamma irradiation. In the present work, granulocyte reserves and related mobilization functions have been sequentially assessed by the endotoxin stress assay during the preclinical and clinical phases of these hemopoietic disorders. Characteristic patterns of granulocyte reserve mobilization are described that reflect given stages of pathologic progression. For radiation-induced leukemia, a five stage pattern has been proposed. In contrast, a simple pattern of progressive, time-dependent contraction of granulocyte reserves and mobilization capacity was noted in the development of terminal aplastic anemia. Early preclinical phases of radiation-induced leukemia appear to involve an extensive depletion of the granulocyte reserves ((phase I) during the first approximately 200 days of exposure followed by a partial renewal of the reserves and associated mobilization functions approximately 200 and 400 days (phase II). Sustained, subnormal granulocyte mobilizations (phase III) following endotoxin stress typify the responses of dogs during the intermediate phase, whereas late preclinical, preleukemic stages (phase IV) are characterized by a further expansion of the reserves and in the mobilization capacities, particularly of the less mature granulocytes. Such late alterations in the pattern of granulocyte mobilization, together with other noted cellular aberrancies in the peripheral blood and marrow, appear to indicate leukemia (phase V) onset.

Anemia, Aplastic↗
PubMed1979

Acute monocytic leukemia in an irradiated Beagle.

A purebred female Beagle dog that had received 2,000 R of protracted wholebody gamma-irradiation from 60Co when 14 months old had hematologic changes consistent with a myeloproliferative disorder 3 years after the termination of radiation exposure. Peripheral blood and bone marrow findings during the 7-month period before death showed progressive anemia with increased numbers of platelets; immature granulocytes, monocytes and promonocytes. A period of partial remission occurred during which time the peripheral blood was aleukemic, although there was marked thrombocytosis and abnormal erythropoiesis which was evidenced by bizarre circulating nucleated red cells, anisocytosis, poikilocytosis and Howell-Jolly bodies. The dog had a terminal crisis with marked leukocytosis, most cells in the peripheral blood being bizarre monocytes and promonocytes. Tissues obtained at necropsy showed diffuse as well as focal infiltration of the spleen, liver, lymph nodes, heart, kidney and gastrointestinal wall with immature neoplastic cells resembling monocytes and monocytic precursors. The monocytic differentiation of the invasive cell population was confirmed by morphological, cytochemical, histological, ultrastructural and in vitro cell culture studies.

Animals↗