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Biomedical subjects

V P Bond

Publications and source records attributed to V P Bond.

At least 19 recordsLinked to original sources
PubMed1997

Evidence for an uncommon microsatellite instability on mouse chromosomes 2 and 4 and its possible role in radiation leukemogenesis.

Although microsatellite instability (MSI), usually detected by DNA length polymorphisms, has been implicated in the induction of solid tumors in both humans and animals, its role in leukemogenesis is unclear. The goal of this study was to investigate whether there is an association between MSI and radiation leukemogenesis in CBA/Ca mice. Microsatellite lengths at 55 loci, mapped to eight different mouse chromosomes, were examined in two groups of DNA samples: 1) 10 normal DNA samples collected from the bone marrow cells of control male CBA/Ca mice, and 2) 17 DNA samples isolated from the spleens of mice that developed myeloid leukemia (ML) after exposure to neutrons, or X rays, or gamma rays. Microsatellite markers were amplified using the non-radioisotopic multiplex-touchdown PCR protocols developed in our laboratory, and the sizes of amplicons were examined on 6% non-denaturing polyacrylamide gels. Although no correlation between microsatellite length polymorphisms and radiation leukemogenesis was observed at the 55 CBA/Ca mouse loci tested in this study, an uncommon MSI, manifested as the absence of DNA bands after PCR amplification at 2 loci (D2MIT140 and D4MIT104), was observed in both control and ML samples. However, the frequency of ML samples showing this type of MSI is statistically significant (p<0.05). Although there is no direct evidence that this type of MSI predisposes mice to the development of leukemia, the results suggests that genes flanking the D2MIT140 and D4MIT104 are susceptible to spontaneous mutation and perhaps to damage caused by ionizing radiation.

Animals↗
PubMed1997

Historical events associated with fallout from Bravo Shot--Operation Castle and 25 Y of medical findings.

The events prior to Bravo Shot-Operation Castle that led to a decision not to evacuate the Marshallese prior to testing the thermonuclear bombs are presented as are the actions taken after the fallout incident in evacuating the exposed Marshallese and the military personnel. The initial medical effects (findings during first 6 wk after exposure) are briefly described and are followed by description of long term effects, namely, induction of one case of fatal acute myeloid leukemia and a large number of thyroid tumors (benign and malignant) in addition to hypothyroidism in adults and children and two cases of cretinism. The hypothyroidism and cretinism responded well to administration of oral thyroxine. During the first 25 y, there was also much unrest and political agitation initiated by exposed and unexposed Marshallese who were very unhappy as a result of relocation and inability to return to their homelands and feeling that all illness and deaths were due to the mysterious radiation, which they understandably did not understand. The difficulties in part were ameliorated by financial aid from the U.S. Congress. In view of one of us (EPC), no one agency or person in the U.S. Government was willing to take the responsibility for care of the Marshallese and its financing. The exposed and nonexposed Marshallese had their lifestyle changed, some of their homelands made uninhabitable for several years and could aptly be called "nuclear nomads," an expression coined by others.

Blood Cell Count↗
PubMed1996

N-ras mutations in radiation-induced murine leukemic cells.

N-ras mutations were examined in DNA samples extracted from the spleen of CBA/Ca mice that developed myeloid leukemia (ML) following exposure to radiations of different qualities. A total of 17 ML cases, i.e. 5 cases of neutron-induced and 12 cases of photon- (3 gamma-ray and 9 x-ray) induced ML were included in the study along with 12 DNA samples from the bone marrow cells of control mice. Polymerase chain reaction-single strand conformational polymorphisms (PCR-SSCP) and the direct sequencing of PCR products were used to analyze three regions of the N-ras gene: (i) a 120 base-pair (bp) long portion of exon I (codons 2-37); (ii) a 103 bp long portion of exon II (codons 48-82); and (iii) a 107 bp long portion of exon III (codons 118-150). PCR-SSCP mobility shifts indicated mutations within only exon II of the N-ras gene. Such mutations were more prevalent in samples from mice exposed to fast neutrons. The exact type and location of these mutations were then determined by direct DNA sequencing. Silent point mutations, i.e. base transitions at the third base of codons 57 (GAC-->GAT), 62 (CAA-->CAC), or 70 (CAG-->CAA) were present only in mice that developed ML after exposure to fast neutrons. A base transversion at the third base of codon 61 (CAA-->CAC) was also observed in some ML cases. DNA sequencing demonstrated that ML samples contained normal as well as mutated DNA sequences. The higher frequency of N-ras mutations in neutron-induced ML suggested that fast neutrons are more effective in inducing genomic instability at the N-ras region of the genome. More importantly, N-ras mutations are not the initiating event in radiation leukemogenesis. This conclusion was supported by the finding that N-ras mutations were detected only in mice with an overt leukemic phenotype but not in mice with minimal tissue infiltration of leukemic cells, suggesting that the disease may be present prior to the presence of N-ras mutations. Alternatively, N-ras may be present in these mice but a large number of normal spleen cells in these mice interferes with the detection of mutation in a small population of leukemic cells.

Animals↗
PubMed1996

Relative biological effectiveness of ionizing radiations determined in tissue (RBE) fails in assessing comparative relative effectiveness in the tissue cells.

The value of the RBE of a test radiation is conventionally determined against a known standard radiation for a chosen response of a selected biological tissue and is expressed as the ratio of tissue absorbed doses at equal effect, or as ratio of magnitudes of the effect at equal absorbed dose. If such an effect is observable as a consequence of responses of individual elements of this tissue, namely the cells, such as induction of cancer that arises from a single cell, the relative biological effectiveness should be expressed as the ratio of the incidences of the effects at equal mean absorbed dose to the cells rather than at equal absorbed dose to tissue. This cell based relative biological effectiveness is here termed the relative local efficiency. Since tissue absorbed dose is a product of the number of energy deposition events in cells of that tissue (N(H)) and the mean absorbed dose to these cells in the exposed tissue (z(1)), per tissue mass equal tissue absorbed doses from different radiation qualities have different values of N(H) and z(1) As a result, for pink mutations in Tradescantia cells, the relative biological effectiveness of 0.43 MeV neutrons is 48 but the relative local efficiency in fact is 2.8.

Cells↗
PubMed1996

The use of cell-oriented factors and the hit size effectiveness function in radiation protection.

It has long been argued that ionizing radiation can be considered to interact with matter in discrete, randomly occurring energy transferring events ("hits") and that the resulting microscopically nonuniform pattern of energy deposition strongly influences the biological effect of a given exposure. Microdosimetric measurements combined with cellular biological response data in the form of a "hit size effectiveness function" (HSEF) suggest a possible cell-oriented alternative method of correlating exposure with effect at low levels of any radiation or mixture of radiations. The instrumentation required, the validity of the approach, and its practical usefulness in radiation protection are examined, and its application to space radiation exposure is proposed as a test case.

Aerospace Medicine↗
PubMed1996

Current misinterpretations of the linear no-threshold hypothesis.

Contrary to the "linear no-threshold hypothesis," which implies that "any amount, however small" of radiation energy is a serious cancer threat, it is shown here that only relatively quite large amounts of such energy can pose such a threat to a person or population. Key to doing this is to make a sharp distinction between the actual amount of the radiation agent imparted energy, epsilon, which must be expressed in units of joules, and the average concentration or density of energy, epsilon/m (i.e., absorbed dose), which is expressed in units of Gy. With any cellular system, e.g., in tissue culture, one can easily adjust the numbers of cells used at each dose point so that a clearly significant number of radiation-induced quantal responses (e.g., mutations, chromosome aberrations, malignant transformations, cell death), in the absorbed dose range of about 0.7 to 3 or more Gy, can be observed. However, if the number of cells is held constant as the absorbed dose is progressively reduced, a point is reached at which no significant excess is observable. This situation is frequently "remedied" by including more cells at that point, which, of course, can increase the number of malignant transformations sufficiently to render the excess statistically valid. However, because both axes are expressed in relative terms, the data point, despite having gained statistical significance, remains at the same location on the graph. This gives the false impression that no more of the agent energy was added or needed to achieve significance. However, if both coordinates are put in absolute terms, i.e., the actual number of quantal responses vs. imparted energy, and the same exercise of "improving the statistics" at low exposures is attempted, it then becomes evident that any point thus rendered significant must be relocated at a substantially higher energy point on the graph. This demonstrates unequivocally the fallacy in the proof of the "linear hypothesis" which is based on agent concentration response curves and not agent amount. It shows that the smaller the agent concentration (absorbed dose; epsilon/m), the larger the amount of radiation energy that must be added to the system in order to demonstrate a radiation-induced response. This suggests a minimum average energy requirement for production of a radiation-attributable cancer. It Ls concluded that the "linear hypothesis" should be abandoned as the cornerstone of radiation protection and practice.

Dose-Response Relationship, Radiation↗
PubMed1995

Hypermutability of mouse chromosome 2 during the development of x-ray-induced murine myeloid leukemia.

In an effort to identify the precise role of a deletion at regions D-E of mouse chromosome 2 [del2(D-E)] during the development of radiation-induced myeloid leukemia, we conducted a serial sacrifice study in which metaphase chromosomes were examined by the G-banding technique. Such metaphase cells were collected from x-irradiated mice during the period of transformation of some of the normal hematopoietic cells to the fully developed leukemic phenotype. A group of 250 CBA/Ca male mice (10-12 weeks old) were exposed to a single dose of 2 Gy of 250-kilovolt-peak x-rays; 42 age-matched male mice served as controls. Groups of randomly selected mice were sacrificed at 20 hr, 1 week, and then at intervals of 3 months up to 24 months after x-irradiation. Slides for cytogenetic, hematological, and histological examination were prepared for each animal at each sacrifice time. An expansion of cells with lesions on one copy of chromosome 2 was evident in 20-25% of treated mice at each sacrifice time. The majority of such lesions were translocations at 2F or 2H, strongly suggesting hypermutability of these sites on mouse chromosome 2. No lesions were found in control mice. The finding leads to the possibility that genomic lesions close to 2D and 2E are aberrants associated with radiation leukemogenesis, whereas a single clone of cells with a del2(D-E) may lead directly to overt leukemia. The data also indicate that leukemic transformation arises from the cumulative effects of multiple genetic events on chromosome 2, reinforcing the thesis that multiple steps of mutation occur in the pathogenesis of cancer.

Animals↗
PubMed1995

Application of the HSEF to assessing radiation risks in the practice of radiation protection.

The primary risk coefficients upon which exposure limits for radiation protection purposes are currently based are derived almost exclusively from cancer-induction data obtained from human populations exposed to radiations of low linear energy transfer. The question of higher linear energy transfer radiations is handled by means of quality factors derived from values for relative biological effectiveness obtained from animal data. However, the advent of microdosimetry has made it possible to establish hit size effectiveness functions from single-cell systems, both in vitro and in vivo. This type of function can substitute completely for the concept of relative biological effectiveness, Q and equivalent dose. A common basis for risk coefficients and the hit size effectiveness function lies in the fact that human cancers are monoclonal and thus single cell in origin. The present communication utilizes this common base as a means of extending the present low-linear energy transfer based risk coefficients to include carcinogenic responses from exposure in radiation fields of any one or mixed qualities, extending from the smallest to the largest linear energy transfers of practical consequence. In doing so, risks from ionizing radiations of any linear energy transfer may be predicted more accurately than at present.

Biophysical Phenomena↗
PubMed1995

The meaning of linear dose-response relations, made evident by use of absorbed dose to the cell.

Experimental evidence shows that if the probability of biological response is plotted against the absorbed dose from ionizing radiation, and if both dose and response are determined at the same level of biological organization (e.g., cell or organ-organism) the result appears as a sigmoid, medical-toxicological type of "dose-response" function when plotted using linear coordinates. However, if the biological response expressed at the cellular level is similarly plotted against the average absorbed dose expressed at the organ-organism level, a linearly proportional, "non-threshold" function is obtained. To explain this marked difference in curve shape, the absorbed dose at the organ level in terms of its meaning at the cellular level was examined, and both dose and response were put on the latter level. The result is consistent with the conclusion that absorbed dose at the organ-organism level can be treated, at the cellular level, as the product of two quantities: 1) the mean energy concentration or dose in a cell from a deposition event, i.e., "hit size" (the frequency-averaged specific energy in a reference cell target), and 2) the number of deposition events, or "hits," on the exposed cells. When the mean hit size for a given radiation remains constant, and the number of hits is increased, the total number of responses follows a linearly proportional "hit number response function." However, if the hit number is held constant or normalized to a given value, and the hit size is varied, the resulting probability of cell response again plots as the apparently sigmoid curve mentioned above, which has been termed the "hit size effectiveness function." With decreasing hit size, the probability of a cellular response appears to decrease asymptotically, and become indistinguishable from zero before zero dose is reached. It follows from this inherent relationship between the two kinds of functions that a sufficiently extensive set of data on a population of cells permits either type of function to be produced at will. These findings bear on the interpretation of the "linear, non threshold" hypothesis.

Biophysical Phenomena↗
PubMed1995

Dose, effect severity, and imparted energy in assessing biological effects.

Because of the widespread efforts in cancer radioepidemiological studies to attach a value of absorbed dose to each exposed individual, the notion seems to have become prevalent that dose plays an essential role in the medical determination of the diagnosis and prognosis of the individual. This view is enhanced by the fact that, while the present quantities and units for radiological physics were developed in the context of the acute effects of large exposures to radiation, e.g., in radiotherapy where they still apply well, these same quantities and units have been used, without modification, to apply to cancer radioepidemiology in the context of low level irradiation. A principle purpose of the present communication is to show that, in medicine, dose plays a limited role even in the deterministic application of therapeutic agents, and that diagnosis and estimates of prognosis in medicine are based, not on dose, but on the severity of effect on, or damage to the organ or organs involved in a particular medical condition. Thus it is "going backward" to view estimates of the severity of effect, e.g., the fraction of cells with abnormalities, or killed, as a "biological dosimeter," rather than as a quantitative estimate of the severity of effect. The use of biological indicators is of maximum value in noncancerous disease or injury in which the severity of an effect causative for organ failure and a consequent quantal, e.g., a lethal response in the individual, can be measured with increasing accuracy by modern medical techniques.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Medical effects of exposure of human beings to fallout radiation from a thermonuclear explosion.

On March 1, 1954, after detonation of a thermonuclear device on Bikini atoll, an unexpected wind shift resulted in the deposition of radioactive fallout on inhabited atolls. The fallout radiation caused fleeting systemic effects, dose-dependent depression of hematopoiesis and skin burns primarily due to the beta ray component of the fission radionuclides. Within a few weeks, hematopoietic recovery was substantial but slight depression of blood counts was maintained for several years. One case of fatal acute myeloblastic leukemia developed in a boy receiving 1.9 Gy as an infant. Cretinism developed in two boys exposed as infants with estimated thyroidal dose in excess of 50 Gy. Chemical hypothyroidism was detected in several persons. Thyroid adenomas and cancer commenced appearance ten years after exposure and became a major long-term medical problem. There have been no late effects attributable to the beta burns 40 years after exposure. Internal contamination from ingestion and inhalation of radionuclides is detectable. The doses are comparable to background levels in the U.S. There is no detectible decrease in longevity of the exposed Marshallese compared to an unexposed Marshallese population.

Adolescent↗
PubMed1995

Cellular mechanisms of protection and repair induced by radiation exposure and their consequences for cell system responses.

The complex biological systems that constitute living organisms operate at various levels of organization, from the atomic-molecular to the cellular to the organ-organism level. The response of an organism to disturbances that are detrimental to structure and function generally begin at the level of organization where the primary injury has occurred. Detriment that occurs from simultaneous or sequential, or single or multiple interactions at a relatively low level of organization tends to be transferred to higher levels. However, at each level of organization there is a given probability of such detriment being removed according to the tolerance to injury that is peculiar to that level. There is thus a direct relationship between the frequency of injurious events at a lower level of organization, and the degree of structural complexity of the system at the high level at which such detriment is eventually manifested. The extent of structural disruption at any given level determines the degree of functional failure at that level. In the exposure of tissue to ionization radiation, the primary injury begins with energy deposition events (tracks or hits) consisting of many ionizations and excitations in localized clusters of submicroscopic dimensions at the atomic-molecular level of organization within the cell, and the cell is affected as a whole. The cell is the elementary unit of life and the sum of the individual cell responses determines the response of the tissue and the organism. Individual cell responses are nevertheless found to differ in type and degree depending on the absorbed dose. With decreasing values of absorbed dose to the tissue, the probability of a cell being hit by an energy deposition event decreases linearly. At very low values of absorbed dose to tissue, only a fraction of the total cell population experiences single hits and these are of different sizes. The size distribution or spectrum of these hits is invariant, independent of their total number over a considerable range at low-dose levels and is determined only by the type and quality of the given radiation. The probability that a hit cell will suffer a given detriment such as a chromosomal aberration, gene mutation or death has been shown to increase in a sigmoid fashion with increasing hit size.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Survival of spleen colony-forming units (CFU-S) of irradiated bone marrow cells in mice: evidence for the existence of a radioresistant subfraction.

Because of increasing evidence of heterogeneity in the hematopoietic stem cell compartments, the radiosensitivity of spleen colony-forming units (CFU-S) was reevaluated to ascertain whether the classical single exponential curve for a graded dose of radiation is applicable at higher doses of radiation, 400-600 cGy. Bone marrow cells (BMC) removed from mice immediately after death under anesthesia were irradiated in vitro. Great care was taken to exclude anoxic effects during irradiation and to avoid any possible effects in the recipient mice from injection of excessive numbers of BMC. By estimating the number of cells to be injected to produce numbers of colonies within the evaluation range of the assay, we obtained a radiation survival curve that appeared to have a multiphasic concave shape; the D0 value for the 400-600 cGy range was estimated to be about 275 cGy, whereas the D0 for the lower doses was 95 cGy, the same value as previously reported. The reason a single exponential survival curve was previously obtained after graded doses of radiation is discussed, and a comparison of those results with the present data from in vitro radiation is made. Lacking experimental evidence, we speculate that the major factor that determines the slope of the survival curve is the degree to which the stem cells are in their normal hematopoietic environment during the irradiation. The probable existence of a fraction surviving after an exposure to 600 cGy, estimated by the limiting dilution assay, was about 1 per 2 x 10(6) BMC. Such radio-insensitive CFU-S appear to be primitive CFU-S, which can contribute materially to the long-term survival of lethally irradiated bone marrow recipients.

Animals↗
PubMed1995

The equal effectiveness ratio: a quantitative approach to the evaluation of compounds for boron neutron capture therapy.

The resurgence of interest in boron neutron capture therapy (BNCT) as a potential treatment for glioblastomas and melanomas has resulted in a quest to identify and synthesize candidate compounds which can physiologically target the 10B atoms to tumor cells. Numerous boron-carrying compounds are now available and awaiting evaluation. Because the products of the boron neutron capture (BNC) reaction generally contribute greater than 50% of the dose in BNCT, the evaluation of the efficacy of boron compounds would be more precise if it were possible to remove, quantitatively, the dose contributed by the external reactor radiations. The purpose of this study is to report a method which does just that, i.e., leaves for precise evaluation the biological effect that is ascribable to the BNC products only. The evaluation involves a series of separately quantifiable factors, the product of which provides an overall "figure of merit" for the compound.

Animals↗
PubMed1993

A specific chromosomal deletion in murine leukemic cells induced by radiation with different qualities.

G-banded metaphase chromosomes prepared from 14 male CBA/Ca mice with histologically confirmed myeloid leukemia (ML) were studied in an effort to identify specific chromosomal changes associated with radiation leukemogenesis. The chromosome studies were undertaken as part of a larger investigation of radiation carcinogenesis, in which mice were exposed to radiation of several different qualities, i.e., x-rays, gamma-rays and "monoenergetic" fast neutrons of 5 mean energies ranging from 0.2 to 14 MeV. The 14 ML cases showed no histologically phenotypic differences and they were transplantable in syngeneic mice. We detected a specific chromosomal deletion in 1 copy of mouse chromosome 2 at regions D-E in all radiation-induced ML cells, regardless of radiation quality. Our results strongly implicate the involvement of genes within or close to regions D-E of chromosome 2 in radiation leukemogenesis. In addition to the specific deletion in chromosome 2, loss or gain of the Y chromosome was also detected in some cells from 6 ML cases. Because this hypo- or hyperploidy occurred in only a small fraction of leukemic cells, a causative role in radiation leukemogenesis appears unlikely.

Animals↗
PubMed1991

A different perception of the linear, nonthreshold hypothesis for low-dose irradiation.

Two equally useful dosimetric quantities, both of which are called dose, are used in toxicology. With radiation measurement, only one--the energy per unit mass D--is called dose. The other--the total energy in the irradiated system--is here distinguished from D by assigning it the name collective energy, epsilon. The collective energy is a more complete statement of dose because it is the product of the energy concentration D and the mass irradiated m. Especially in radioepidemiology, in which epsilon is the total energy imparted to all persons irradiated, the quantity m must be specified because it is situation specific and thus highly variable. At present, radioepidemiological dose-response curves are given only in terms of the toxicological model--i.e., the fraction (probability) of radiation-attributable cancers occurring as a function of D. Because this relation does not involve the number of persons at each value of D, it fosters the illusion that any dose, no matter how small, can result in cancer. However, we show that if the dose-response relationship is expressed in terms of the absolute number of attributable cancers as a function of epsilon, cancer occurs, on average, only if the collective energy exceeds a relatively large minimum value, the magnitude of which will be estimated. Therefore, we conclude that the nonthreshold aspect of the linear hypothesis is misleading and quite probably invalid. For example, in or around a facility in which exposure of humans to relatively low values of D occurs, attributable cancers are most unlikely to appear unless the epsilon to the irradiated population exceeds this minimum value.

Dose-Response Relationship, Radiation↗
PubMed1991

Severity of organ injury as a predictor of acute mortality for disparate patterns of absorbed dose distribution.

Nonuniform distribution of absorbed dose is frequently encountered in the irradiated mammal; the degree of nonuniform distribution is generally more severe as the size of the animal increases and the energy or penetrating power of the radiation decreases. However, acute mortality under these conditions, e.g., from the hematopoietic syndrome, appears not to be consistently predictable from the dose at any given location or locations within the animal. It is thus reasonable to seek a biological quantity that may be adequate for this purpose. Accordingly, it was postulated that, in animals dying from the bone marrow syndrome, survival is determined by the total number of viable stem cells remaining in the entire body, independent of their distribution. To test this hypothesis, the LD50/30 value for mice exposed to nonuniform irradiation of varying degrees of severity was obtained, as was that for mice receiving uniform total-body irradiation. The distribution of bone marrow in transverse segments of tissue along the spinal axis was determined, as was the dose to each of the segments. The data were analyzed by multiplying, for each segment, the fraction of stem cells in the fraction of cells surviving, as determined from the dose and a survival curve for stem cells determined separately. The sum of these products yielded the surviving number of stem cells in the total mouse, for both the uniformly and nonuniformly exposed animals. The surviving fraction was found to differ by no more than 20%; this was taken to be reasonable evidence that, based on the number of surviving stem cells, it is possible to predict the mortality rate for both uniform and markedly nonuniform irradiation.

Animals↗