Proposal for a patient database on cardiac interventional exposures for epidemiological studies

Relatively high organ doses absorbed by patients in interventional cardiology suggest the opportunity to define these patients as a cohort to be followed forward in time in an epidemiological study of the cancer risks associated with exposure to low-dose ionising radiation. In this paper, the UNSCEAR 2000 Report risk estimates for the most exposed organs/tissues in cardiac interventional procedures are reviewed, as well as the critical features of such an epidemiological study that is anticipated to have an intrinsically low statistical power because of the low levels of risk and possible confounding factors. To overcome these limitations, data collected in different institutions can be combined provided that a common design and conduct are used for dose assessment. A minimum dataset to be collected on a patient basis is proposed that can be implemented routinely in most facilities. This data should be linked to the local patient information system in order to retrieve all the exposures of a given patient.     

Methodology issues in epidemiological assessment of health effects of low-dose ionising radiation

Epidemiological assessment of the health effects of exposure to low-dose ionising radiation is limited by the need for very large sample sizes and by various sources of bias that may generally affect epidemiological studies. Motivated by the present focus on low-dose effects, the following questions are examined: what are the strictly unavoidable limiting factors in the epidemiological methodology; what is its resolution limit in terms of effect size and what can be done to obtain further supportive evidence from the data?     

Dosimetric characteristics of Li2B4O7:Cu,Ag,P solid TL detectors

A two-mutation carcinogenesis (TMC) model is used as a bridge between cellular radiation biological effects and the incidence of cancer. This model has been applied to several sets of experimental animal and epidemiological data. In this paper the advantage of the model and the implications for radiation risks at low doses are discussed with respect to the age and dose dependence of cancer incidence and the effect of age at exposure on radiation risk; the link between the radiation effect and background cancer incidence and the transfer of radiation risk across different population groups; the implications of acute and protracted radiation exposures for risks at low doses and the dose-effect relationship for radium induced bone cancer.     

Health risks of low photon energy imaging

The major health risk associated with low photon energy imaging is thought to be the induction of cancer as a consequence of the radiation exposure and this is the focus of this paper. Low photon energy imaging typically involves exposure to a low dose (<50 mGy) of low linear energy transfer (LET) radiation delivered at high dose-rate. Since epidemiologic data cannot provide an accurate assessment of risk at the doses used in imaging, risk estimates are currently made by fitting a linear response to intermediate and high dose data for cancer induction in radiation-exposed human populations. This method assumes a linear no-threshold (LNT) response and implies that no dose of radiation is safe. This assumption is not borne out by many laboratory studies of cancer-related endpoints that would suggest that the risk at low doses is much less than would be estimated from linear extrapolation from intermediate to high doses. It is also well recognised that the dose-response from many epidemiologic studies could equally well be fit by threshold models.Through the study of radiation-induced neoplastic transformation in vitro J-shaped dose-response curves for a variety of low LET radiations, including those used in low photon energy imaging, have been demonstrated. The relative risks calculated from this data compare remarkably well with those for breast cancer and leukemia incidence in radiation-exposed populations. From this it is concluded that the LNT hypothesis is likely to overestimate the risk of cancer induction by low photon energy imaging, at least for certain tumors.     

Dosimetric models used in the Alpha-Risk project to quantify exposure of uranium miners to radon gas and its progeny

The European project Alpha-Risk aims to quantify the cancer and non-cancer risks associated with multiple chronic radiation exposures by epidemiological studies, organ dose calculation and risk assessment. In the framework of this project, mathematical models have been applied to the organ dosimetry of uranium miners who are internally exposed to radon and its progeny as well as to long-lived radionuclides present in the uranium ore. This paper describes the methodology and the dosimetric models used to calculate the absorbed doses to specific organs arising from exposure to radon and its progeny in the uranium mines. The results of dose calculations are also presented.     

Improved confidence limits for low-dose carcinogenic risk assessment from animal data

An improved procedure is presented for estimating low-dose risks from dichotomous animal data. Based on the multistage model of cancer, the procedure gives a maximum likelihood fit to the experimental data. Because the model is approximately linear in the low-dose range, the procedure may be considered to be a generalized method for linear extrapolation which uses all of the data. The extrapolation procedure is different from an earlier procedure based upon the multistage model in that two improved methods are put forward for calculating statistical confidence limits. (One is a linearized approximation of the other.) A further innovation is a recommendation for the integration of several data sets in the calculation of risk levels.     

The use of biologically based cancer risk models in radiation epidemiology

Biologically based risk projection models for radiation carcinogenesis seek to describe the fundamental biological processes involved in neoplastic transformation of somatic cells into malignant cancer cells. A validated biologically based model, whose parameters have a direct biological interpretation, can also be used to extrapolate cancer risks to different exposure conditions with some confidence. In this article biologically based models for radiation carcinogenesis, including the two-stage clonal expansion (TSCE) model and its extensions, are reviewed. The biological and mathematical bases for such models are described, and the implications of key model parameters for cancer risk assessment examined. Specific applications of versions of the TSCE model to important epidemiological datasets are discussed, including the Colorado uranium miners' cohort; a cohort of Chinese tin miners; the lifespan cohort of atomic bomb survivors in Hiroshima and Nagasaki; and a cohort of over 200,000 workers included in the National Dose Registry (NDR) of Canada.     

EVALUATION OF THE CARCINOGENIC RISK OF BIOCHEMICALLY INERT INSOLUBLE PARTICLES BY THE EPA USING RAT INHALATION DATA

Regulations pertaining to inhalable particulate matter are promulgated primarily by three program offices of the U.S. Environmental Protection Agency (EPA): Pollution Prevention and Toxic Substances (OPPTS), Air Quality Planning and Standards (OAQPS), and Mobile Sources (OMS). Risk assessment for these agents are carried out either by the program offices or by the National Center for Environmental Assessment (NCEA), formerly the Office of Health and Environmental Assessment (OHEA). Particular matter pollutants within the regulatory domain of OAQPS for which either quantitative or qualitative assessment of cancer risk has been carried out include asbestos, beryllium, cadmium, nickel refinery dust, nickel subsulfide, and ambient particulate matter of less than 10 µm diameter (PM10). OPPTS has qualitatively evaluated manmade mineral fibers, titanium dioxide, and vermiculite. Asbestos is the only fiber for which cancer quantitation has been carried out. For several of these agents, risk is based upon human data with animal studies providing supporting data. Both qualitative and quantitative assessment of cancer risk from exposure to diesel engine emissions is under development by NCEA for OMS. Quantitative assessment of cancer risk from exposure to this agent is described as an example of EPA's approach to the use of rats for evaluation of cancer risk. The major uncertainties relating to this assessment include the appropriateness of rat data for assessing human risk and the selection of a low-dose extrapolation model.     

EVALUATION OF THE CARCINOGENIC RISK OF BIOCHEMICALLY INERT INSOLUBLE PARTICLES BY THE EPA USING RAT INHALATION DATA

Regulations pertaining to inhalable particulate matter are promulgated primarily by three program offices of the U.S. Environmental Protection Agency (EPA): Pollution Prevention and Toxic Substances (OPPTS), Air Quality Planning and Standards (OAQPS), and Mobile Sources (OMS). Risk assessment for these agents are carried out either by the program offices or by the National Center for Environmental Assessment (NCEA), formerly the Office of Health and Environmental Assessment (OHEA). Particular matter pollutants within the regulatory domain of OAQPS for which either quantitative or qualitative assessment of cancer risk has been carried out include asbestos, beryllium, cadmium, nickel refinery dust, nickel subsulfide, and ambient particulate matter of less than 10 µm diameter (PM10). OPPTS has qualitatively evaluated manmade mineral fibers, titanium dioxide, and vermiculite. Asbestos is the only fiber for which cancer quantitation has been carried out. For several of these agents, risk is based upon human data with animal studies providing supporting data. Both qualitative and quantitative assessment of cancer risk from exposure to diesel engine emissions is under development by NCEA for OMS. Quantitative assessment of cancer risk from exposure to this agent is described as an example of EPA's approach to the use of rats for evaluation of cancer risk. The major uncertainties relating to this assessment include the appropriateness of rat data for assessing human risk and the selection of a low-dose extrapolation model.     

Meta-analysis of second cancer risk after radiotherapy among childhood cancer survivors

Cancer risks among childhood cancer survivors following radiotherapy have not yet been well characterised in terms of radiation dose. A meta-analysis of studies on the excess relative risk per gray (ERR) of second cancer was conducted previously; unfortunately, the small number of eligible studies restricted quantitative evaluations. To solve this problem, a statistical method to calculate ERR estimates from other estimates was developed, and a meta-analysis was conducted again. The PubMed database was searched and 26 relevant studies were identified. ERR estimates were available in 15 studies, and for the other 11 studies, the regression-based model was used to calculate ERR estimates from other estimates. The overall ERR estimate was 0.40, which was much lower than that of atomic bomb survivors exposed as young children. Heterogeneity of the risk among studies was suggested, and a further study is needed to explore the heterogeneity among studies.     

Problems in the rational analysis of transportation safety

Analysis of air traffic control capacity shows the relation between traffic level and risk can be dealt with quantitatively only if units of risk are specified. Measuring risk in terms of fatalities per hour of exposure solves the major problem of how to compare the effects that many different kinds of risk have upon patterns of human activity, but leaves us with a number of unresolved secondary issues. Among these are : incommensurability of certain risks, failure of statistical independence, certain limitations of time-normalization, unequal distribution of costs and benefits, different weighting of voluntary and involuntary risks, liability, cost and value of uncertainty, positive value of some risks, acceptability of unequal risks, difficulty of estimating very small probabilities and threat of the unknown compared to threat of the known. Although these issues arose out of air traffic control studies, they are clearly relevant to risk analyses of many other systems.     

Prediction of the variation in risks from exposure to radon at home or at work

On the basis of a review of recent epidemiology, the ICRP recently issued a statement outlining a new approach to radon. The ICRP indicates that the Publication 65 dose conversion convention will be replaced using the dosimetric approach currently used for other radionuclides. Moreover, the ICRP indicates that the dose conversion factor is expected to increase by about a factor of 2. This paper independently examines the risks associated with exposure to radon and decay products through estimation of lifetime excess absolute risks per WLM for a variety of epidemiological risk projection models and baseline cancer and mortality rates. This paper suggests that current ICRP dosimetric models do not reflect the effect of smoking and suggest that basic risk estimates and dose conversion factors be based on risks to non-smoking populations with recognition that lifestyle choices, especially smoking, have a large effect on the risk from exposure to radon.     

Outdoor background ELF magnetic fields in an urban environment

Classification of 'exposed/non-exposed' subjects in epidemiological studies concerning the possible cancer risk associated with ELF magnetic field exposure is based on the a priori assumption of magnetic field value cut-off points that, often, are defined equal to minimum exposure levels typical of a population residing near high voltage facilities (0.1-4.2 microT), but in some cases an environmental magnetic field level not associated with transmission lines can exist. The results of an ELF magnetic field survey in an Italian urban area (about 1 million inhabitants) are presented: average field levels are correlated with population density of different districts. Exposure indexes are obtained, which are compared with those evaluated in studies regarding domestic exposure: background average levels result in comparable to cut-off points in epidemiological studies, but in some districts with high population density, they are much higher. This shows that knowledge of background magnetic field level in urban areas can assume a significant role in exposure assessment.     

Leukaemia following childhood radiation exposure in the Japanese atomic bomb survivors and in medically exposed groups

Incidence and mortality risks of radiation-associated leukaemia are surveyed in the Japanese atomic bomb (A-bomb) survivors exposed in early childhood and in utero. Leukaemia incidence and mortality risks are also surveyed in 16 other studies of persons who received appreciable doses of ionizing radiation in the course of treatment in childhood and for whom there is adequate dosimetry and cancer incidence or mortality follow-up. Relative risks tend to be lower in the medical series than in the Japanese A-bomb survivors. The relative risks in the medical studies tend to diminish with increasing average therapy dose. After taking account of cell sterilisation and dose fractionation, the apparent differences between the relative risks for leukaemia in the Japanese A-bomb survivors and in the medical series largely disappear. This suggests that cell sterilisation largely accounts for the discrepancy between the relative risks in the Japanese data and the medical studies. Excess absolute risk has also been assessed in four studies, and there is found to be more variability in this measure than in excess relative risk. In particular, there is a substantial difference between the absolute risk in the Japanese atomic bomb survivor data and those in three other (European) populations. In summary, the relative risks of leukaemia in studies of persons exposed to appreciable doses of ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions in childhood are generally less than those in the Japanese A-bomb survivor data. The effects of cell sterilisation can largely explain the discrepancy between the Japanese and the medical series.     

Does exposure to residential radon increase the risk of lung cancer?

In assessing the risks of exposure to ionising radiation, it is important to neither overstate nor understate the effects of the hazard. These requirements are often difficult to satisfy, especially since much of our knowledge about the effects of low levels of radiation is subject to rather large uncertainties. Our participants have given their opinions about the risk of lung cancer induction resulting from exposure to radon in residences. Each agrees that exposures to high concentrations of radon are hazardous. However, as with low level exposures to other types of ionising radiation, quantifying relatively small risks is quite difficult. The national and international standards setting bodies have recommended a fairly conservative approach that may overestimate the 'true' magnitude of deleterious effects and their dependence upon exposure, but this is to be expected given the uncertainties in the data and the need to avoid underestimates. A conservative approach can have both positive and negative consequences, and it is also important to neither overstate nor understate these consequences.     

Study of a selection of 10 historical types of dosemeter: variation of the response to Hp(10) with photon energy and geometry of exposure

An international collaborative study of cancer risk among workers in the nuclear industry is tinder way to estimate direetly the cancer risk following protracted low-dose exposure to ionising radiation. An essential aspect of this study is the characterisation and quantification of errors in available dose estimates. One major source of errors is dosemeter response in workplace exposure conditions. Little information is available on energy and geometry response for most of the 124 different dosemeters used historically in participating facilities. Experiments were therefore set up to assess this. using 10 dosemeter types representative of those used over time. Results show that the largest errors were associated with the response of early dosemeters to low-energy photon radiation. Good response was found with modern dosemeters. even at low energy. These results are being used to estimate errors in the response for each dosemeter type, used in the participating facilities, so that these can be taken into account in the estimates of cancer risk.     

Growth curve analysis of tumourigenesis using cellular level cancer model

It is known that carcinogenesis by low-dose radiation will start from DNA damage by ionising radiation. After the long time period, these very small effects will appear on a cellular scale by accumulation of various intracellular biological responses and finally grow to the tumour with clonal expansion of cancer cell. Thus, the biological radiation effects are phenomena with a very wide scale from DNA damage (10(-9) m, 10(-6) s) to the tumour (10(-3) m, 10(5) s); so the risk estimation of low-dose radiation is difficult to study by the experiments. To overcome these difficult situations at low-dose radiation effects' problems, it is good to study the process of carcinogenesis using a biologically based mathematical model. This study's cellular-scale mathematical model of tumourigenesis and some results of the statistical calculations about the tumour growth as presented in the work.     

Dosimetric and epidemiological approaches to assessing radon doses--can the differences be reconciled?

A significant problem in internal radiation dosimetry is the discrepancy between the radiation dose from exposure to radon inferred from epidemiological studies and the higher dose calculated using the Human Respiratory Tract Model (HRTM) adopted by the International Commission on Radiological Protection (ICRP). The difference is a factor of about 3. The agreement between these two assessments by radically different approaches is surprisingly good. Nevertheless, there has been concern to understand fully the reasons for this discrepancy and to attempt to reconcile the two approaches. This is of importance because radon contributes about half of the total effective dose from natural background radiation. Furthermore, the HRTM was developed with application to radon exposure in mind, yet at present it is not used for risk assessment purposes although ICRP does suggest that it is useful for comparative dosimetry.     

Assessing the effect of initial vapor-phase concentrations on inhalation risks of disinfection-by-products (DBP) in multi-use shower facilities

Inhalation during showering activities is a major pathway for exposure to volatile disinfection-by-products (DBPs). Disinfection-by-products such as trihalomethanes (THMs) and haloacetic acids (HAAs) have been shown to significantly increase cancer risks and can also pose other health hazards. In multi-family residences and common-shower facilities located in dormitories and gymnasiums, the time-lag between showers is likely to be short and the exposure to vapor-phase DBPs may be significantly increased due to residual concentrations from earlier showering activities. Current models do not consider the impacts of the initial vapor-phase concentration on health risks to be significant. The hypothesis that non-zero initial DBP vapor-phase concentrations lead to higher exposure and health risks was evaluated here using data from the City of Corpus Christi, TX at two levels of input parameter uncertainty. The inhalation risks and hazards were found to be over 1.5 times greater for subsequent showers compared to the initial shower of the day. For non-zero initial air concentrations and triangular distribution of input parameters, the model was found to be most sensitive to the initial air concentrations, highlighting the impact of initial conditions on cumulative daily intake (CDI) and subsequently on cancer risks and hazard indices. Increasing the time-gap between showers and improving ventilation are viable solutions to contend with the increased risk. It is recommended that the effects of initial air concentrations be incorporated in future risk assessments focusing on multi-family residences in older and poor neighborhoods where single shower dwellings are more common.     

A new view of radiation-induced cancer

Biologically motivated mathematical models are important for understanding the mechanisms of radiation-induced carcinogenesis. Existing models fall into two categories: (1) short-term formalisms, which focus on the processes taking place during and shortly after irradiation (effects of dose, radiation quality, dose rate and fractionation), and (2) long-term formalisms, which track background cancer risks throughout the entire lifetime (effects of age at exposure and time since exposure) but make relatively simplistic assumptions about radiation effects. Grafting long-term mechanisms on to short-term models is badly needed for modelling radiogenic cancer. A combined formalism was developed and applied to cancer risk data in atomic bomb survivors and radiotherapy patients and to background cancer incidence. The data for nine cancer types were described adequately with a set of biologically meaningful parameters for each cancer. These results suggest that the combined short-long-term approach is a potentially promising method for predicting radiogenic cancer risks and interpreting the underlying biological mechanisms.