Role of molecular biology in radiation biology.
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Animals↗
Biomedical subjects
K H Chadwick
Publications and source records attributed to K H Chadwick.
On the linearity of the dose-effect relationship of DNA double strand breaks.
Most radiation biologists believe that DNA double-strand breaks are induced linearly with radiation dose for all types of radiation. Since 1985, with the advent of elution and gel electrophoresis techniques which permit the measurement of DNA double-strand breaks induced in mammalian cells at doses having radiobiological relevance, the true nature of the dose-effect relationship has been brought into some doubt. Many investigators measured curvilinear dose-effect relationships and a few found good correlations between the induction of the DNA double-strand breaks and cell survival. We approach the problem pragmatically by assuming that the induction of DNA double-strand breaks by 125I Auger electron emitters incorporated into the DNA of the cells is a linear function of the number of 125I decays, and by comparing the dose-effect relationship for sparsely ionizing radiation against this standard. The conclusion drawn in that the curvilinear dose-effect relationships and the correlations with survival are real. The problem of why the dose-effect relationship is curvilinear when microdosimetric considerations predict that even for sparsely ionizing radiation energy deposition in and close to the Watson-Crick double helix should give a linear dose-effect relationship remains.
DNA↗
Response to the paper 'Biological low-dose radiation effects'.
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Animals↗
Animal models in radiation carcinogenesis--biophysical considerations.
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Disease Models, Animal↗
The molecular basis of stochastic and nonstochastic effects.
Stochastic effects have been defined as those for which the probability increases with dose, without a threshold. Nonstochastic effects are those for which incidence and severity depends on dose, but for which there is a threshold dose. These definitions suggest that the two types of effects are not related. In this paper it will be shown that at least some of the nonstochastic effects are the consequence of accumulated stochastic effects and that both types of effect can be related to a common cellular damage. It is proposed that, at the cellular level, effects such as mutation induction and cell reproductive death are related to DNA double-strand breaks caused by radiation. Further, we propose that stochastic effects depend on a mutational event induced in a critical cell of a target organ. Nonstochastic effects are considered to arise because the function of a substantial proportion of critical cells is impaired. In some cases the predominant effect is comparable to cell reproductive death. Animal mortality, for instance, may occur because a substantial proportion of bone marrow cells is killed. Using this concept, mathematical formulas can be derived for the various effects. Modification of the irradiation conditions (e.g., low dose rate or density ionizing radiation) leads to changes in the initial molecular lesions and, consequently, to changes in the dose effect relationships of stochastic and nonstochastic effects. Experimental support will be discussed, using animal mortality as an endpoint. The implications of this approach will be discussed with emphasis on its application to radiological protection.
Animals↗
Dosimetry concepts and measurements in food irradiation processing.
The associations between the dosimetry concepts, Minimum absorbed dose (D min), maximum absorbed dose (D max), and average dose and median dose are investigated for the case of a large cobalt-60 plaque source irradiating homogeneous bulk product in a two-pass, two-sided irradiation. It is assumed that to a first approximation the intensity of radiation decreases exponentially with the depth, t, in the product. A series of mathematical relationships is derived for the average dose, the maximum and minimum dose, the median dose [defined as (D max/D min)/2], and the uniformity ratio (defined as U.R. = (D max/D min). The relationships are derived in terms of a constant D0 (the dose on the surface of the product in the pass close to the source) and the relaxation length (mu t) of the radiation in the product. Since the uniformity ratio and other dose parameters can be calculated for certain chosen values of mu t, the individual values of mu (the energy absorption coefficient) and t do not need to be known. By dividing the dose range from D min to D max into 10 equal fractions, the amount of product irradiated to each of the fractions is calculated, and it is shown that, independent of the value of U.R., about a third of the product receives a dose in the first fraction above D min. It is also shown that for a given median dose, the average dose decreases as U.R. increases. The calculated dose relationships are confirmed by measurements in homogeneous dummy product, using the lyoluminescence of glutamine to measure dose. The implications of these results for the regulation of the food irradiation process and for the design of irradiation facilities are discussed.
Cobalt Radioisotopes↗
The combined effect of DBE and X-rays on the induction of somatic mutations in Tradescantia.
The induction of somatic mutations in the stamen hair cells of Tradescantia KU 9 has been used to investigate the effects of combined exposure to 1,2-dibromoethane (DBE) and X-rays. At low radiation doses a synergistic interaction has been found between the two agents for both DBE exposure followed by acute X-rays and chronic simultaneous exposures. The synergism is discussed in terms of an interaction of single strand lesions in the DNA. It is concluded that although this type of interaction should not be too important for radiological protection, it could be of significance in evaluating the effects of chemicals at low exposure rates.
Dose-Response Relationship, Drug↗
A quantitative analysis of the cytotoxic action of chemical mutagens.
A quantitative hypothesis is developed to explain the cytotoxic action of chemical mutagens on eukaryotic cells. The hypothesis forms an extrapolation of previously developed concepts used to explain the effect of ionizing radiation and the cytotoxic action of UV light. The crucial potentially lethal lesion is assumed to be a DNA double-strand lesion which may be an interstrand cross-link or a pair of DNA single-strand alkylations, for example. The effect of repair processes is included in the analytical equation derived to describe cell survival. The analysis of several sets of cell survival data for different chemical mutagens is used to demonstrate the applicability of the hypothesis. The logical extension of the hypothesis permits a division of chemical mutagens into 4 separate classes on the basis of the mechanisms proposed for the cytotoxic activity, and the relative importance of the risk associated with low-level exposure to each class is discussed. The hypothesis is amenable to further experimental verification.
Animals↗
A quantitative analysis of UV-induced cell killing.
A quantitative hypothesis is developed, analogous to a previously developed model for ionising radiation, to describe the induction of eukaryotic cell killing by ultraviolet light. The hypothesis makes use of a recent proposal which suggests that pairs of dimers close to, and on either side of, a replication termination site provide long-lived blocks to replication, by suggesting that these 'paired dimer' lesions are potentially lethal. The hypothesis contains two crucial elements: (i) two dimers form the crucial lesion, and (ii) the paired dimer lesion is only recognised at the DNA-replication subsequent to exposure. Cell survival is predicted to be related to the square of the UV exposure and several sets of data are shown to be in good agreement with this prediction for surviving fractions down to 5% at least. It is shown that making use of a known molecular repair process, excision repair, the hypothesis gives a logical explanation for the unusual effects of UV fractionation reported previously for both exponentially growing cells and also for stationary cells. The hypothesis is amenable to further experimental verification.
Cell Survival↗
The influence of time between cutting and irradiation on the sensitivity of Tradescantia stamen hairs to mutation induction.
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Mutagenicity Tests↗
An analytical approach to the induction of translocations in the spermatogonia of the mouse.
An analysis of a series of data providing a comprehensive impression of the effect of radiation on the induction of translocations in the spermatogonia of the mouse is presented. It is assumed that the spermatogonial stem-cell population is made up of a sensitive and resistant compartment, that the same type of basic lesion can lead to either translocation induction or cell inactivation, and that the basic lesion has a linear-quadratic dose relationship. The same set of parameter values is used to provide a quantitative description of the acute dose--response relationship and the effects of dose-rate and short-term, 24-h and long-term fractionation. The unusual effect of 24-h fractionation can be explained by proposing that the first dose blocks the progression of sensitive cells into the resistant compartment whilst the progression of the resistant cells into the sensitive compartment is unaffected. The analysis indicates that (1) the majority of the spermatogonial stem cells in the mouse are in the sensitive compartment; (2) that the yield of translocations is proportional to accumulated dose for chronic radiation schedules; (3) the biology of spermatogenesis should be taken into account when extrapolations are made from one animal species to another.
Animals↗
Synergism between EMS and X-rays for the induction of somatic mutations in Tradescantia.
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Ethyl Methanesulfonate↗
The repair of sub-lethal damage and the stimulated repair of potentially lethal damage in Saintpaulia.
The repair of sublethal and potentially lethal damage in stationary resting epidermal cells of Saintpaulia has been investigated. Fractionation experiments reveal an efficient repair of sublethal damage with a half-life of 1.9 hours. No repair of potentially lethal damage was noted when cultivation of the leaves was delayed for 24 hours after irradiation. At delay times of 2, 3 and 4 days some repair of potentially lethal damage has been found. A small pre-dose given 24 hours before a challenging dose improved the cells' chance to regenerate and the improvement has been shown to be compatible with an improved repair of potentially lethal damage induced by X-rays and fast neutrons. It hs been shown that the stimulated repair process takes 12 to 24 hours to develop, is dependent on the size of the pre-dose, has single-hit dose kinetics, and an r.b.e. of 1 for neutrons. With delayed cultivation of 2 days the stimulated repair process leads to an alteration in the shape of the regeneration (survival)-dose relationship which increases the low dose r.b.e. for neutrons from 10 to 35.
DNA Repair↗
An analysis of the interaction between two nitrosourea compounds and X-radiation in rat brain tumour cells.
Experimental measurements have shown that both BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] and CCNU [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] are toxic in rat 9L brain tumour cells and also sensitize these cells to the action of ionizing radiation. The interaction of BCNU and CCNU with radiation has been interpreted using a recently developed extension of the molecular theory of cell survival. The experimental results are shown to be compatible with the mathematical equations predicted by the model and the analysis indicates that the sensitizing effect is caused by a synergistic interaction between sublethal damage caused by the nitrosourea compound and the radiation at the molecular level. The analysis of the dependence of the interaction on the time between nitrosourea treatment and radiation indicates that the optimal interaction occurs with a 5 hour interval.
Animals↗
The regeneration of epidermal cells of Saintpaulia leaves as a new plant-tissue system for cellular radiation biology.
Investigation of the nucleus of epidermal cells of the petioles of Saintpaulia leaves by cytofluorimetry revealed that all cells are in a non-cycling pre DNA synthesis phase. Cultivation of dissected leaves results in a synchronous regeneration process of a defined number of cells. Five days after onset of cultivation the cells reach the first mitosis. The nuclear development during the regeneration process is described. Irradiation of the leaves results in a directly visible inhibition of this regenerating capability which is used to quantify cell survival in a tissue. The data show that the radiation response has a similar shape to that of the survival of single cells in culture. This response can be observed before the first mitosis of the cells and its application as a new plant tissue system for cellular radiation research is discussed.
Cell Cycle↗
An analysis of radiation-induced malignancy based on somatic mutation.
If, as has been proposed, the factor which controls the malignant nature of a cell behaves as a recessive genetic character, a somatic mutation in the normal dominant homologous gene of a diploid cell, which carries the malignant factor, may allow the expression of the recessive malignant character. Using this proposal together with the molecular theory of cell survival, a mathematical equation is derived to provide a general description of the dose response for radiation-induced malignancy which is non-linear and peaked. The equation is based on the assumption that a radiation-induced DNA double-strand break can cause a somatic mutation or a chromosome aberration which may leave the cell in a precancerous state. The equation is used to analyse data on the radiation-induced transformation of diploid cells and extended logically to analyse data on the transformation of tetraploid cells.
Cell Transformation, Neoplastic↗
The rejoining of DNA double-strand breaks and a model for the formation of chromosomal rearrangements.
The recombination type of process, which has been proposed by Resnick to explain the rejoining of radiation-induced DNA double-strand breaks, is combined with the molecular theory of radiation action to provide a description of the formation of chromosomal rearrangments. It is shown that the majority of chromosomal aberration types found at the first mitosis after radiation can be explained on the basis of one radiation-induced DNA double-strand break in the backbone of the unineme chromatid, followed by the enzymatically controlled recombinational process for the rejoining of the double-strand break. The recombinogenic process for the repair of DNA double-strand breaks relies on the close association between the broken DNA double helix and homologous DNA. The homologous nature of repeated DNA base pair sequences is used, in this model, to explain the occurrence of chromosomal exchanges between non-homologous chromosomes. The important role which repetitive DNA plays in the formation of chromosomal rearrangements and in the distribution of 'break-points' found in radiation experiments is discussed.
Base Sequence↗
An analysis of synergistic sensitization.
The molecular theory of cell survival predicts that a synergistic interaction on cell survival may be expected when DNA-damaging agents are used in combination with ionizing radiation. The synergism is expected to result from the interaction of DNA single-strand damage induced by the agent and single-stand breaks induced by the radiation. Mathematically this is expressed by an increase in the alpha coefficienty of the survival equation S = exp - (alpha D + beta D2), the beta coefficient remaining constant. Two examples of synergistic interaction with ionizing radiation are analysed, a chemical used in tumour therapy and ultra-violet light. The implication of this analysis for sensitization in radiation therapy are discussed.
Cell Survival↗