Dose-effect Models Research Articles

Dose-effect models for risk – relationship to cell survival parameters

There is an increased interest in estimating the induction of cancers following radiotherapy as the patients have nowadays a much longer life expectancy following the treatment. Clinical investigations have shown that the dose response relationship for cancer induction following radiotherapy has either of two main characteristics: an increase of the risk with dose to a maximum effect followed by a decrease or an increase followed by a levelling-off of the risk. While these behaviours have been described qualitatively, there is no mathematical model that can explain both of them on mechanistic terms. This paper investigates the relationship between the shape of the dose-effect curve and the cell survival parameters of a single risk model. Dose response relationships were described with a competition model which takes into account the probability to induce DNA mutations and the probability of cell survival after irradiation. The shape of the curves was analysed in relation to the parameters that have been used to obtain them. It was found that the two main appearances of clinical data for the induction of secondary cancer following radiotherapy could be the manifestations of the particular sets of parameters that describe the induction of mutations and cell kill for fractionated irradiations. Thus, the levelling off appearance of the dose response curve could be either a sign of moderate to high inducible repair effect in cell survival (but weak for DNA mutations) or the effect of heterogeneity, or both. The bell-shaped appearance encompasses all the other cases. The results also stress the importance of taking into account the details of the clinical delivery of dose in radiotherapy, mainly the fractionated character, as the findings of our study did not appear for single dose models. The results thus indicate that the shapes of clinically observed dose response curves for the induction of secondary cancers can be described by using one single competition model. It was also found that data for cancer induction may be linked to in vivo cell survival parameters that may be used for other modelling applications.

Comparison of health and environmental impacts from electricity generation systems

Health and environmental impacts from fossil, renewable and nuclear electricity generation are estimated following a detailed bottom-up impact pathway analysis. By using a set of harmonised air quality and dose-effect models, a methodological framework has been established and consistently applied across different fuel chains, including the analysis of consequences from beyond design nuclear accidents. As far as possible, welfare losses resulting from environmental impacts are transferred into monetary terms to make results comparable on an aggregated level, and to indicate the costs to society resulting from health and environmental damage related to electricity generation.

Estimate of the number of observations required to check the adequacy of dose-effect models

Estimate of the number of observations required to check the adequacy of dose-effect models

Prediction of the yield of stochastic effects of low-dose irradiation for nonlinear dose-effect models

Prediction of the yield of stochastic effects of low-dose irradiation for nonlinear dose-effect models

Dose-effect models for ozone

Short-term ozone exposure causes lung function decrements, increased airway reactivity, airway inflammation, increased respiratory symptoms and hospital admissions. Exposure to long-term elevated ozone levels seems to be associated with reduced lung function (aging), increase of respiratory symptoms, exacerbation of asthma, and airway cell and tissue changes. Health risk caused by exposure to ozone has been evaluated mainly in a qualitative way by comparing ozone air quality data with health-based guidelines or standards. A preliminary approach to quantifying health risk from short-term exposure to oxidant air pollution has been taken by expert judgement, describing known or expected effects at specific levels of ozone. For quantitative assessment of the health impact of distinct ozone exposure conditions (acute, repeated daily, chronic) specific exposure-dose-response models are being developed which can be linked to human exposure data. Exposure-(dose-)response models using data from epidemiological, human-clinical and animal toxicity studies are presented.

Effects of sonic booms on animals: Past history and future directions

Models developed to describe and mitigate damage to human hearing after sonic-boom exposure can be applied to a wide range of species. If humans and laboratory animals are poor models for a species of concern, or if intense focused sonic booms are anticipated, experimental assessments will be needed. Although attenuation across interfaces (air–water and air–soil) will protect many aquatic and fossorial species, attenuation may not protect individuals near the interface if boundary phenomena like evanescent energy are found to be important. Panic reactions are a likelier hazard for animals, at least in air. Damage in panics is predicted best by species-typical avoidance behaviors (e.g., panic flight), sound exposure level (after appropriate weighting), and previous experience with impulsive man-made noise. Dose-effect models have not been developed because controlled experimental studies with booms at levels up to 150 dB (peak flat SPL) have failed to elicit panics. However, widespread concern continues because there are circumstantial accounts of catastrophic damages, notably the ‘‘Sooty Tern Incident.’’ Controlled studies of habituation using initially naive animals are needed to develop dose-effect models for damaging responses. Effects of impulse-induced frights on (1) gametogenesis, conception, and early embryonic development, (2) parental care, (3) activity, and (4) habitat use should be investigated as well.

Radiological Effects After Inhalation of Highly Radioactive Fuel Particles Produced by the Chernobyl Accident

A short review is presented of the results of long-standing research into the hot particles released into the environment after the Chernobyl accident, and their radiobiological significance. Due to the lack of direct measurements of hot particles in the lung, a conceptual method has been developed to estimate integral lung intake from measurements of soil contamination. The significance of the beta component of the radiation from hot particles has been reconsidered because this component may give rise to preconditions for oncogenic effects. A modification factor F has been introduced, which is defined as the ratio of average risks for different conditions of irradiation. It is shown that linear dose effect models give the same results for uniform and point irradiation. Over the dose range 0.1 to 2 Gy it was found that a hot particle gives a higher risk of oncogenic detriment than the corresponding uniform dose distribution (F>1). The corresponding modification factor shows a maximum value of 5 at (0.6 Gy.

A unified approach to dose-effect relationships in radiotherapy. II: Inhomogeneous dose distributions

Conventional dose-effect relationships, such as those based upon the NSD or linear-quadratic concepts, do not account for dose inhomogeneities. Only a single “dose” value can be used in these equations and this can give rise to significant errors in the estimation of the “tolerance” dose in situations where dose distributions are inhomogeneous. This paper presents a method of “integrating” the biologically effective dose over the entire volume of each organ or tissue irradiated. Integral forms of the variable-exponent TDF and linear quadratic factor (LQF) models (ITDF and ILQF, respectively) can be used to determine whether or not any organ or tissue in an irradiated volume has exceeded tolerance, regardless of dose distribution non-uniformity. Several examples are given with comparisons to solutions obtained by conventional dose-effect models.

Methodologies for Predicting the Expected Combined Stochastic Radiobiological Effects of Different Ionizing Radiations and Some Applications

A methodology for predicting the expected combined stochastic radiobiological effects of sequential exposure to different ionizing radiations is used to arrive at a methodology for predicting the radiobiological effects of simultaneous exposure. Both methodologies require developing additive-damage dose-effect models. Additive-damage dose-effect models are derived assuming (a) each radiation comprised by the combined exposure produces initial damage called critical damage that could lead to the radiobiological effect of interest; (b) doses of different radiations that lead to the same level of radiobiological effect (or risk) can be viewed as producing the same amount of critical damage and being indistinguishable as far as the effects of subsequently administered radiation. Derived dose-effect functions that describe the risk per individual, conditional on radiation dose, are called risk functions. The methodologies allow the use of known radiation-specific risk functions to derive risk functions for combined effects of different radiations. The risk functions for combined exposure to different radiations are called global risk functions. For sequential exposures to different ionizing radiations, the global risk functions derived depend on how individual radiation doses are ordered. Global risk functions can also differ for sequential and simultaneous exposure. The methodologies are used to account for some previously unexplained radiobiological effects of combined exposure to high and low linear-energy-transfer radiations.

Lung tumor induction in Syrian hamsters with internally deposited particulate Pu: a synthesis based on microscopic dose distribution.

Syrian hamsters inhaled a monodisperse aerosol of 238PuO2 and were serially sacrificed to study the microscopic distribution of particles, tissue at risk and dose as a function of time after exposure. The distribution of dose and tissue at risk around single particles in lung and the changes in distribution of particles with time have been reported previously. In the present paper, these measurements are applied to the computation of tissue-at-risk and radiation-dose-rate distributions within the lungs of Syrian hamsters. Based on these results, airway epithelium is irradiated at the same levels as other lung tissue and does not require separate consideration on the basis of dose to tissue. Incorporation of the measured microscopic radiation dose distribution into existing dose-effect models allowed data on lung tumor induction in Syrian hamsters from several laboratories to be adequately described by a model fit to data from a single laboratory.

Theoretical models for estimating dose-effect relationships after combined exposure to cytotoxicants.

Two classes of dose-effect models for cell killing (additive damage and independent effects) are developed under alternative hypotheses about the damage that leads to cell death. Generalized models, along with specific models for cell killing after exposure to a specific cytotoxicant, are used to make predictions about the effects of sequential or simultaneous exposure to different cytotoxicants. It is demonstrated that with the additive damage models developed one can adequately account for the combined effects of the cytotoxicants considered. Theoretical results are presented which suggest that after simultaneous exposure of cells to low total doses (<0.1 Gy) of different ionizing radiations, use of the conventional relative biological effectiveness approach to predict cell killing risks is unnecessary; cell killing risks can adequately be determined by assuming the effects of the different radiations to be independent. Also, for simultaneous exposure of cells to total doses of different radiations much larger than 0.1 Gy, use of the conventional RBE approach to arrive at cell killing risk could lead to overestimation of the risk.

Cytogenetic effects of strontium-90 on the bone marrow of the Chinese hamster.

NUMEROUS studies have been made with the ultimate goal of establishing dose effect models that will enable quantitative assessments of the damage inflicted by various types of radiation exposures. In most, the animals were exposed to whole body gamma or X-irradiation delivered at high dose rates. The number of chromosome aberrations changes as a function of total radiation dose, radiation dose rate and time after exposure1–3, so it is not clear how these criteria apply in interpreting aberrations produced by internally deposited radionuclides which give low, continuous and non-uniform radiation dose rate exposures. Several workers have used in vivo or in vitro exposure to internal emitters and in vitro cell sampling to determine radiation damage4–7. These are relatively indirect, so we have tried to evaluate the influence of an internally deposited radionuclide on the frequency of chromosome aberrations produced and sampled in vivo. We selected 90Sr (in equilibrium with its daughter 90Y) because it exists in abundance in a number of nuclear processes, and localizes selectively in osseous tissues, resulting in beta irradiation of both bone and bone marrow. Aberrations in bone marrow cells are readily studied in vivo and may also be significant in the development of haematopoietic tissue neoplasms. We took two time periods, 2 and 14 days after injection, because differences in the aberration frequency which may be observed as a function of the total radiation dose and dose rate change with time.