The conversion of exposures due to radon into the effective dose: the epidemiological approach

The risks and dose conversion coefficients for residential and occupational exposures due to radon were determined with applying the epidemiological risk models to ICRP representative populations. The dose conversion coefficient for residential radon was estimated with a value of 1.6 mSv year^?1 per 100 Bq m^?3 (3.6 mSv per WLM), which is significantly lower than the corresponding value derived from the biokinetic and dosimetric models. The dose conversion coefficient for occupational exposures with applying the risk models for miners was estimated with a value of 14 mSv per WLM, which is in good accordance with the results of the dosimetric models. To resolve the discrepancy regarding residential radon, the ICRP approaches for the determination of risks and doses were reviewed. It could be shown that ICRP overestimates the risk for lung cancer caused by residential radon. This can be attributed to a wrong population weighting of the radon-induced risks in its epidemiological approach. With the approach in this work, the average risks for lung cancer were determined, taking into account the age-specific risk contributions of all individuals in the population. As a result, a lower risk coefficient for residential radon was obtained. The results from the ICRP biokinetic and dosimetric models for both, the occupationally exposed working age population and the whole population exposed to residential radon, can be brought in better accordance with the corresponding results of the epidemiological approach, if the respective relative radiation detriments and a radiation-weighting factor for alpha particles of about ten are used.     

On the conversion of solid cancer excess relative risk into lifetime attributable risk

Risk coefficients representing the lifetime radiation-induced cancer mortality (or incidence) attributable to an exposure to ionizing radiation, have been published by major international scientific committees. The calculations involve observations in an exposed population and choices of a standard population (for risk transportation), of suitable numerical models, and of computational techniques. The present lack of a firm convention for these choices makes it difficult to inter-compare risk estimates presented by different scientific bodies. Some issues that relate to a necessary harmonization and standardization of risk estimates are explored here. Computational methods are discussed and, in line with the approach utilized by ICRP, conversion factors from excess relative risk (ERR) to lifetime attributable risk (LAR) are exemplified for exposures at all ages and for occupational exposures. A standard population is specified to illustrate the possibility of a simplified standard for risk transportation computations. It is suggested that a more realistic perception of lifetime risk could be gained by the use of coefficients scaled to the lifetime spontaneous cancer rates in the standard population. The resulting quantity lifetime fractional risk (LFR) is advantageous also because it depends much less on the choice of the reference population than the lifetime attributable risk (LAR). Received: 5 April 2001 / Accepted: 1 July 2001     

Epidemiological studies of cataract risk at low to moderate radiation doses: (not) seeing is believing

The prevailing belief for some decades has been that human radiation-related cataract occurs only after relatively high doses; for instance, the ICRP estimates that brief exposures of at least 0.5-2 Sv are required to cause detectable lens opacities and 5 Sv for vision-impairing cataracts. For protracted exposures, the ICRP estimates the corresponding dose thresholds as 5 Sv and 8 Sv, respectively. However, several studies, especially in the last decade, indicate that radiation-associated opacities occur at much lower doses. Several studies suggest that medical or environmental radiation exposure to the lens confers risk of opacities at doses well under 1 Sv. Among Japanese A-bomb survivors, risks for cataracts necessitating lens surgery were seen at doses under 1 Gy. The confidence interval on the A-bomb dose threshold for cataract surgery prevalence indicated that the data are compatible with a dose threshold ranging from none up to only 0.8 Gy, similar to the dose threshold for minor opacities seen among Chernobyl clean-up workers with primarily protracted exposures. Findings from various studies indicate that radiation risk estimates are probably not due to confounding by other cataract risk factors and that risk is seen after both childhood and adult exposures. The recent data are instigating reassessments of guidelines by various radiation protection bodies regarding permissible levels of radiation to the eye. Among the future epidemiological research directions, the most important research need is for adequate studies of vision-impairing cataract after protracted radiation exposure.     

Assessment of electrophoretic mobility changes of human erythrocytes by free flow electrophoresis after in vitro and in vivo irradiation

Single cell measurements of electrophoretic mobility showed a linear dose-response of human erythrocytes after exposure to ionizing radiation. To establish a biological indicator- or dosimeter-system for application to dose-estimations after accidental exposures, we tried to measure dose dependent EPM-changes by the free flow electrophoresis technique, a rapid and efficient method which supplies the capacity needed for application. The in vitro irradiated erythrocytes of most donors showed an oscillating dose-response but erythrocytes from several other individuals responded in a contradictory manner whereby the EPM of erythrocytes from radiotherapy patients increased linearly with the amount of administered dose. However, the wide interindividual EPM-range of unirradiated erythrocytes inhibits the application of this technique in biological dosimetry.     

Radiation protection: the NCRP guidelines and some considerations for the future.

The National Council on Radiation Protection and Measurements (NCRP) in the USA and the International Commission on Radiological Protection (ICRP), worldwide, were formed about 1928 and have since made recommendations on appropriate levels of protection from ionizing radiation for workers and for the public. These recommendations and much of the guidance provided by these organizations have usually been adopted by regulatory bodies around the world. In the case of the NCRP, the levels have fallen from 0.1 roentgen per day in 1934 to the current 5 rem per year (a factor of about 5). The present levels recommended by both the ICRP and the NCRP correspond to reasonable levels of risk where the risks of harm from ionizing radiation are compared with the hazards of other, commonly regarded, as safe, industries. Some considerations for the future in radiation protection include trends in exposure levels (generally downward for the average exposure to workers) and improvements in risk estimation; questions of lifetime limits, de minimis levels, and partial body exposures; plus problems of high LET radiations, acceptability of risk, synergisms, and risk systems for protection.     

Current status of biodosimetry based on standard cytogenetic methods

Knowledge about dose levels in radiation protection is an important step for risk assessment. However, in most cases of real or suspected accidental exposures to ionizing radiation (IR), physical dosimetry cannot be performed for retrospective estimates. In such situations, biological dosimetry has been proposed as an alternative for investigation. Briefly, biodosimetry can be defined as individual dose evaluation based on biological endpoints induced by IR (so-called biomarkers). The relationship between biological endpoints and absorbed dose is not always straightforward: nausea, vomiting and diarrhoea, for example, are the most well-known biological effects of individual irradiation, but a precise correlation between those symptoms and absorbed dose is hardly achieved. The scoring of unstable chromosomal-type aberrations (such as dicentrics and rings) and micronuclei in mitogen-stimulated peripheral blood, up till today, has been the most extensively biodosimetry assay employed for such purposes. Dicentric assay is the gold standard in biodosimetry, since its presence is generally considered to be specific to radiation exposure; scoring of micronuclei (a kind of by-product of chromosomal damages) is easier and faster than that of dicentrics for dose assessment. In this context, the aim of this work is to present an overview on biodosimetry based on standard cytogenetic methods, highlighting its advantages and limitations as tool in monitoring of radiation workers’ doses or investigation into accidental exposures. Recent advances and perspectives are also briefly presented.     

Molecular Biomarkers and Epidemiologic Risk Assessment

The use of molecular biomarkers in epidemiologic studies has been advancedas a way to improve risk assessments for occupational and environmental exposuresto toxic agents. We have used the detection of two cancer-related, molecular biomarkers of vinyl chloride exposure (mutant ras-p21 and mutant p53) to examine workers with equivalent cumulative exposures that would be above or below the current permissible workplace exposure limit for vinyl chloride for differences in the presence of these biomarkers. Workers with cumulative exposures above the current permissible exposure limit (equivalent of > 40 ppm-years) have a statistically significantly increased occurrence of both biomarkers in comparison to unexposed controls (p < 10^?3). Although workers with cumulative exposures of < 10 ppm-years, i.e., well below the current limit, do not have a statistically significantly increased occurrence of these biomarkers (p > 0.05), workers with cumulative exposures of 10 to 40 ppm-years, i.e., still below the current limit, are found to have a statistically significant increase (p < 0.05). This suggests that the current exposure limit may not be adequately protective and illustrates the potential utility of molecular biomarkers in the refinement of risk assessments for toxic exposures.     

Effective dose from radiation exposure in medicine: Past,present, and future

Effective dose (E) has been developed by the International Commission on Radiological Protection (ICRP) as a dose quantity with a link to risks of health detriment, mainly cancer. It is based on reference phantoms representing average individuals, but this is often forgotten in its application to medical exposures, for which its use sometimes goes beyond the intended purpose. There has been much debate about issues involved in the use of E in medicine and ICRP is preparing a publication with more information on this application. This article aims to describe the development of E and explain how it should be used in medicine. It discusses some of the issues that arise when E is applied to medical exposures and provides information on how its use might evolve in the future. The article concludes with responses to some frequently asked questions about uses of E that are in line with the forthcoming ICRP publication. The main use of E in medicine is in meaningful comparison of doses from different types of procedure not possible with measurable dose quantities. However, it can be used, with appropriate care, as a measure of possible cancer risks. When considering E to individual patients, it is important to note that the dose received will differ from that assessed for reference phantoms, and the risk per Sv is likely to be greater on average in children and less in older adults. Newer techniques allow the calculation of patient-specific E which should be distinguished from the reference quantity.     

Hereditary damage

Summary For the purposes of radiation protection, risk estimates should be based on effects of irradiation at low doses and low dose-rates. Although few genetic studies have been made on effects at low doses those carried out at low dose-rates suggest that the response is generally linear for induction of both gene mutations and chromosome aberrations. For obtaining an overall genetic risk assessment under these conditions a doubling dose of 100 rem (1 Sv) has been used by the ICRP and other bodies, with respect to radiation of low LET. In addition, it is necessary to know frequencies of human hereditary conditions, the extent to which these frequencies are maintained by recurrent mutation and the average number of generations the different categories of hereditary damage persist in the population. By the use of this information, as well as some data on translocation induction obtained directly from human exposures, an estimate of the risk of serious hereditary ill health in the first two generations after low-level radiation exposure was obtained for the Commission by one of its task groups. Thus the estimate of 10^–2 Sv^–1 used in ICRP 26 has a factual basis, although a number of far-reaching assumptions have still to be made when any risk estimation of this nature is attempted.Invited paper, presented at the 14th Annual Meeting of European Society of Radiation Biology, Jülich, Germany, October 8–14, 1978     

Biomarkers as Predictors in Health and Ecological Risk Assessment

Biomarkers are measurable biological parameters that change in response to xenobiotic exposure and other environmental or physiological stressors, and can be indices of toxicant exposure or effects. If the biomarkers are sufficiently specific and well characterized, they can have great utility in the risk assessment process by providing an indication of the degree of exposure of humans or animals in natural populations to a specific xenobiotic or class of xenobiotics. Most biomarkers are effective as indices of exposure, but adequate information is rarely available on the appropriate dose-response curves to have well-described biomarkers of effect that can be widely applicable to additional populations. Specific examples of acetylcholinest-erase inhibition following exposure to organophosphorus insecticides are cited from experiments in both mammals (rats) and fish. These experiments have indicated that the degree of inhibition can be readily influenced by endogenous (e.g., age) and exogenous (e.g., chemical exposures) factors, and that the degree of inhibition is not readily correlated with toxicological effects. Caution is urged, therefore, in an attempt to utilize biomarkers in the risk assessment process until more complete documentation is available on the specificity, sensitivity, and time course of changes, and on the impact of multiple exposures or the time of exposures.     

Tables of dose conversion coefficients for estimating internal and external radiation exposures to terrestrial and aquatic biota

Dose conversion coefficients (DCCs) for assessment of internal and external radiation exposures to terrestrial and aquatic biota are compiled for 75 radionuclides, for 14 terrestrial and 22 aquatic reference organisms. DCC values for internal exposure are calculated based on a homogeneous distribution of the radionuclides in both types of organisms. DCC values for external exposure of aquatic organisms are calculated for complete immersion in water. For external exposure of terrestrial organisms the soil is considered as a planar and homogenously contaminated volume source with a surface roughness of 3 mm and a thickness of 10 cm, respectively. For in-soil-organisms, DCC values for external exposure are given assuming that these organisms live in the middle of a uniformly contaminated 50 cm-thick soil layer. The tables can be used for assessment of exposures of animals and plants living in various habitats. The list of considered organisms covers the Reference Animals and Plants as adopted by the ICRP.     

Stochastic and Subjective Uncertainty in the Assessment of Radiation Exposure at the Waste Isolation Pilot Plant

The Waste Isolation Pilot Plant (WIPP) is under development by the U.S. Department of Energy as a geologic (i.e., deep underground) disposal facility for transuranic waste. An analysis is presented of possible radiation exposures associated with inadvertent drilling intrusions through the WIPP using future drilling rates obtained in accordance with requirements specified by the U.S. Environmental Protection Agency (EPA) in 40 CFR 194, Subpart B. The analysis attempts to maintain a separation between stochastic (i.e., aleatory) and subjective (i.e., epistemic) uncertainty as implied in the EPA regulations 40 CFR 191, Subpart B, and 40 CFR 194. The results of the analysis are presented as distributions of complementary cumulative distribution functions (CCDFs) for radiation exposure to oil field workers, where the individual CCDFs arise from stochastic uncertainty (i.e., many possible patterns of drill ing intrusions are possible over the 10,000?yr period specified in 40 CFR 191, Subpart B) and the distributions of CCDFs arise from subjective uncertainty (i.e., many inputs to the analysis have fixed, but poorly known, values). The projected radiation exposures during the 10,000?yr period following decommissioning of the WIPP in the year 2033 were found to be small (typically less than 0.001 person-Sv), with the dominant exposure pathway being the incidental ingestion of contaminated dirt by drilling crew members.     

Low‐dose linearity: The rule or the exception?

In 1976, Crump, Hoel, Langley, and Peto described how almost any dose‐response relationship for carcinogens becomes linear at low doses when background cancers are taken into account. This has been used, by the U.S. Environmental Protection Agency, USEPA, as partial justification for a regulatory posture that assumes low‐dose linearity, as is illustrated by a discussion of regulation of benzene as a carcinogen. The argument depends critically on the assumption that the pollutant and the background proceed by the same biological mechanism. In this paper we show that the same argument applies to noncancer end points also. We discuss the application to a number of situations: reduction in lung function and consequent increase in death rate due to (particulate) air pollution; reduction in IQ and hence (in extreme cases) mental deficiency due to radiation in utero; reduction of sperm count and hence increase in male infertility due to DBCP exposure. We conclude that, although the biological basis for the health effect response is different, in each case low‐dose linearity might arise from the same mathematical effect discussed by Crump et al. (1976). We then examine other situations and toxic end points where low‐dose linearity might apply by the same argument. We urge that biologists and chemists should concentrate efforts on comparing the biological and pharmacokinetic processes that apply to the pollutant and the background. Finally, we discuss some public policy implications of the possibility that low dose linearity may be the rule rather than the exception for environmental exposures.     

Multidisciplinary European Low Dose Initiative (MELODI): strategic research agenda for low dose radiation risk research

MELODI (Multidisciplinary European Low Dose Initiative) is a European radiation protection research platform with focus on research on health risks after exposure to low-dose ionising radiation. It was founded in 2010 and currently includes 44 members from 18 countries. A major activity of MELODI is the continuous development of a long-term European Strategic Research Agenda (SRA) on low-dose risk for radiation protection. The SRA is intended to identify priorities for national and European radiation protection research programs as a basis for the preparation of competitive calls at the European level. Among those key priorities is the improvement of health risk estimates for exposures close to the dose limits for workers and to reference levels for the population in emergency situations. Another activity of MELODI is to ensure the availability of European key infrastructures for research activities, and the long-term maintenance of competences in radiation research via an integrated European approach for training and education. The MELODI SRA identifies three key research topics in low dose or low dose-rate radiation risk research: (1) dose and dose rate dependence of cancer risk, (2) radiation-induced non-cancer effects and (3) individual radiation sensitivity. The research required to improve the evidence base for each of the three key topics relates to three research lines: (1) research to improve understanding of the mechanisms contributing to radiogenic diseases, (2) epidemiological research to improve health risk evaluation of radiation exposure and (3) research to address the effects and risks associated with internal exposures, differing radiation qualities and inhomogeneous exposures. The full SRA and associated documents can be downloaded from the MELODI website (http://www.melodi-online.eu/sra.html).     

Assessment of radiation exposure of murine rodents at the EURT territories

The study provides data on contemporary levels of radiation exposure of organs and tissues of murine rodents (several species of mice and voles) inhabiting the East-Ural Radioactive Trace. The estimation procedure involves the most advanced approach based on application of appropriate voxel phantom and biokinetic model. Input data for dose assessment are the results of measurements of skeletal ⁹⁰Sr activity concentration. Maximal internal dose to skeleton, accumulated during 45 days, is 303 mGy. Median internal dose rates on the last day before trapping were 0.83, 0.092 and 0.023 mGy/day for animals trapped at the sites with initial (1957) ⁹⁰Sr surface contamination >37 MBq/m², 18.5–37 MBq/m² and 0.074–18.5 MBq/m² respectively. Taking to account internal and external exposures, upper boundary of the ICRP Derived Consideration Reference Level (DCRL) is exceeded on the territory with maximal level of the initial ⁹⁰Sr surface contamination. On the territory with 18.5–37 MBq/m², whole body mean dose rates to murine rodents exceed the lower boundary of DCRL. On the areas with lower level of surface contamination, even the 90-th percentile of dose rate is below the DCRL.     

X-rays for medical imaging: Radiation protection,governance and ethics over 125 years

Starting from Röntgen's discovery and the first radiograph of his wife’s hand, the curtain was raised on a new technique with remarkable possibilities for contributing to human health. While growth in applications proceeded rapidly, it was accompanied by significant harms to those involved and by inappropriate opportunistic application. This paper places the attempts to deal with the harms and inappropriate activities side by side with the positive developments. It attempts a narrative on the development of medical radiation protection over the 125-year period and places it in the context of a commentary on governance and ethics. The substance of the narrative is based on the recommendations of ICRP as they developed and altered over time. The governance commentary is based on assessing the independence of ICRP and its attention to medical exposures. In terms of ethics, the recommendations at each stage are reviewed in the light of values that are deemed appropriate to both medical ethics and radiation protection. The paper, while celebrating Röntgen-125, also hopefully provides a perspective for discussion as ICRP’s centenary in 2028 approaches. This is an important part of ensuring continued acceptance and confident use of X-Rays, and helps underwrite the possibility of further developments in the area.     

Interactive effects of pesticide exposure and pathogen infection on bee health – a critical analysis

Bees are fundamentally important for pollination services and declines in populations could have significant economic and environmental implications. Pesticide exposure and pathogen infection are recognised as potential stressors impacting upon bee populations and recently there has been a surge in research on pesticide–disease interactions to reflect environmentally realistic scenarios better. We critically analyse the findings on pesticide–disease interactions, including effects on the survival, pathogen loads and immunity of bees, and assess the suitability of various endpoints to inform our mechanistic understanding of these interactions. We show that pesticide exposure and pathogen infection have not yet been found to interact to affect worker survival under field‐realistic scenarios. Colony‐level implications of pesticide effects on Nosema infections, viral loads and honey bee immunity remain unclear as these effects have been observed in a laboratory setting only using a small range of pesticide exposures, generally exceeding those likely to occur in the natural environment, and assessing a highly selected series of immune‐related endpoints. Future research priorities include the need for a better understanding of pesticide effects on the antimicrobial peptide (AMP) component of an individual's immune response and on social defence behaviours. Interactions between pesticide exposure and bacterial and fungal infections have yet to be addressed. The paucity of studies in non‐Apis bee species is a further major knowledge gap.     

Frequency-dependent alterations in enolase activity in Escherichia coli caused by exposure to electric and magnetic fields

Some neurochemical effects of low-intensity electric and magnetic fields have been shown to be nonlinear functions of exposure parameters. These effects occurred within narrow ranges of frequency and intensity. Previous studies on membrane-associated endpoints in cell culture preparations demonstrated changes in calcium efflux and in acetylcholinesterase activity following exposure to radiofrequency radiation, amplitude modulated (AM) at 16 and at 60 Hz, at a specific absorption rate of 0.05 W/kg. In this study, these modulation frequencies were tested for their influence on the activity of a cytoplasmic enzyme, enolase, which is being tested clinically for detection of neoplasia. Escherichia coli cultures containing a plasmid with a mammalian gene for enolase were exposed for 30 min, and cell extracts were assayed for enolase activity by measuring absorbance at 240 nm. The enolase activity in exposed cultures was compared to the activity in paired control cultures. Exposure to 147 MHz carrier waves at 0.05 W/kg, AM at 16 Hz showed enolase activity enhanced by 62%, and AM at 60 Hz showed enolase activity reduced by 28%. Similarly, exposure to 16 Hz fields alone, at 21.2 V/m_rms (electric) and 97 nT_rms (magnetic), showed enhancement in enolase activity by 59%, whereas exposure to 60 Hz fields alone, at 14.1 V/m_rms (electric) and 65 nT_rms (magnetic), showed reduction in activity by 24%. Sham exposures as well as exposure to continuous-wave 147 MHz radiation at 0.05 W/kg showed no change in enolase activity. Although the underlying basis for these field effects in the cytoplasmic compartment has not been established, differential sensitivities to 16 Hz and to 60 Hz signals provide a clear focus for additional research to determine the responsible mechanism. © 1994 Wiley-Liss, Inc.     

Methods for evaluating variability in human health dose–response characterization

Abstract

The Reference Dose (RfD) and Reference Concentration (RfC) are human health reference values (RfVs) representing exposure concentrations at or below which there is presumed to be little risk of adverse effects in the general human population. The 2009 National Research Council report Science and Decisions recommended redefining RfVs as “a risk-specific dose (for example, the dose associated with a 1 in 100,000 risk of a particular end point).” Distributions representing variability in human response to environmental contaminant exposures are critical for deriving risk-specific doses. Existing distributions estimating the extent of human toxicokinetic and toxicodynamic variability are based largely on controlled human exposure studies of pharmaceuticals. New data and methods have been developed that are designed to improve estimation of the quantitative variability in human response to environmental chemical exposures. Categories of research with potential to provide new data useful for developing updated human variability distributions include controlled human experiments, human epidemiology, animal models of genetic variability, in vitro estimates of toxicodynamic variability, and in vitro-based models of toxicokinetic variability. In vitro approaches, with further development including studies of different cell types and endpoints, and approaches to incorporate non-genetic sources of variability, appear to provide the greatest opportunity for substantial near-term advances.     

Long-Term Differential Changes in Mouse Intestinal Metabolomics after γ and Heavy Ion Radiation Exposure

Tissue consequences of radiation exposure are dependent on radiation quality and high linear energy transfer (high-LET) radiation, such as heavy ions in space is known to deposit higher energy in tissues and cause greater damage than low-LET γ radiation. While radiation exposure has been linked to intestinal pathologies, there are very few studies on long-term effects of radiation, fewer involved a therapeutically relevant γ radiation dose, and none explored persistent tissue metabolomic alterations after heavy ion space radiation exposure. Using a metabolomics approach, we report long-term metabolomic markers of radiation injury and perturbation of signaling pathways linked to metabolic alterations in mice after heavy ion or γ radiation exposure. Intestinal tissues (C57BL/6J, female, 6 to 8 wks) were analyzed using ultra performance liquid chromatography coupled with electrospray quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) two months after 2 Gy γ radiation and results were compared to an equitoxic ⁵⁶Fe (1.6 Gy) radiation dose. The biological relevance of the metabolites was determined using Ingenuity Pathway Analysis, immunoblots, and immunohistochemistry. Metabolic profile analysis showed radiation-type-dependent spatial separation of the groups. Decreased adenine and guanosine and increased inosine and uridine suggested perturbed nucleotide metabolism. While both the radiation types affected amino acid metabolism, the ⁵⁶Fe radiation preferentially altered dipeptide metabolism. Furthermore, ⁵⁶Fe radiation caused upregulation of ‘prostanoid biosynthesis’ and ‘eicosanoid signaling’, which are interlinked events related to cellular inflammation and have implications for nutrient absorption and inflammatory bowel disease during space missions and after radiotherapy. In conclusion, our data showed for the first time that metabolomics can not only be used to distinguish between heavy ion and γ radiation exposures, but also as a radiation-risk assessment tool for intestinal pathologies through identification of biomarkers persisting long after exposure.