Exposure assessment and other challenges in non-ionizing radiation studies of childhood leukaemia

Studies of electromagnetic fields (EMF) and the development of childhood leukaemia face unique difficulties. EMF are imperceptible, ubiquitous, have multiple sources, and can vary greatly over time and distances. Childhood leukaemia and high average exposures to magnetic fields are both quite rare. Thus, a major challenge in EMF epidemiology is the small number of highly exposed cases and the necessity for retrospective assessment of exposure. Only studies designed to minimize bias while maximizing our ability to detect an association, should one exist, would have a potential to contribute to our understanding. New approaches are needed; the most promising in the extremely low-frequency range involves a study of a highly exposed cohort of children who have lived in apartments next to built-in transformers or electrical equipment rooms. Another promising avenue is an investigation of possible joint effects of environmental exposures and genetic co-factors. An exposure assessment methodology for residential radiofrequency fields is still in its infancy. Rapid changes in technology and exponential increases in its use make exposure assessment more difficult and urgent.     

Exposure to infections through day-care attendance and risk of childhood leukaemia

There is growing evidence supporting a role for infections in the aetiology of childhood leukaemia. Hypotheses proposed by both Greaves and Kinlen describe childhood leukaemia to be a rare response to one or more common infections acquired through personal contacts. Previous epidemiological studies have used day-care attendance as an indicator of the increased likelihood of early and frequent exposure to infections. It is well-documented that in developed countries, exposures to common infections occur more frequently in this type of setting. Within the Northern California Childhood Leukaemia Study, the role of social contact has been assessed and a unique 'child-hours' summary measure incorporating information on the number of months attending a day-care, mean hours per week at this day-care and the number of children in the day-care setting was constructed. In this review, the previously reported day-care results have been described, showing that in non-Hispanic White children, children in the highest category of total child-hours of exposure had a reduced risk of acute lymphoblastic leukaemia (ALL), particularly common B-cell precursor ALL (c-ALL), compared with children without such exposures, with evidence of a dose-response effect. In addition, a literature review of relevant studies has been conducted, examining the relationship between day-care attendance and risk of childhood ALL. Overall, the 14 studies identified provided consistent support for this hypothesis, with the majority of studies reporting some evidence of a reduced risk. A meta-analysis is currently underway, which will provide a quantitative evaluation of the overall consistency and strength of the association between day-care attendance or social contact and risk of childhood ALL.     

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.     

Exposure assessment: implications for epidemiological studies of ionizing radiation

Quantitative estimates of ionizing radiation exposure are often available for use in epidemiological studies. However, depending on the context, the quality of the exposure estimates can vary. For example, the estimates may be specific to individuals in the study or generic values averaged over populations; unavailable for some of the potential study subjects or vary in their form between individuals; based on contemporary measurements or assessed retrospectively; based on measurements alone, on surrogate measures of exposure, or on an exposure assessment model; or, as is often the case, cover one source of radiation exposure rather than all of them. Various ways in which ionizing radiation exposures have been assessed are illustrated through reference to some studies of childhood leukaemia, concerning environmental, medical, natural and parental occupational exposures. Based on this, implications for the interpretation of radiation epidemiological studies are discussed.     

A Stochastic Model for the Analysis of Occupational Injuries on Jobs of Varying Physical Stresses

A stochastic model is used to analyze occupational injuries associated with heterogeneous job exposures, i.e., workers switch jobs with different physical stress. One problem encountered in modeling such cases is that the risk of injury while performing a low stress job may be affected by the length of previous exposure to a high stress job, and vice versa. A semi-Markov process is assumed for transition among heterogeneous jobs and subsequent injuries. The model is used to determine the significant factors related to major injury incidence for 1,251 workers in a southwestern industrial plant. Gender is found to be highly significant in predicting major injuries among workers exposed to high stress jobs. A worker's past minor injury experience also appears to be strongly associated with the likelihood of future major injury occurrence.     

Assessment of plutonium exposures for an epidemiological study of US nuclear workers

An ongoing case-control study evaluating the association between workplace external radiation exposures and leukaemia mortality required an assessment of internal plutonium exposures as a potential confounder. Of the study participants, 1,092 were employed at four Department of Energy sites where plutonium-bearing materials were processed or stored. Exposures were assessed by first categorising exposure potentials based on available bioassay data, then estimating doses for workers in the highest categories using recent recommendations of the International Commission on Radiological Protection. Given the aetiology of leukaemia, equivalent dose to active bone marrow was chosen as the exposure variable. There were 556 workers each with at least one plutonium bioassay result, assigned to one of three evaluation categories. Dose estimates were made for 115 workers resulting in a collective equivalent dose of 2.1 person-Sv for 2,822 exposure-years, compared with 29.8 person-Sv estimated from photon exposures. Modelling uncertainties were examined by comparison of results from independent analyses and by Monte Carlo simulation.     

Aetiology of childhood acute leukaemias: current status of knowledge

Acute leukaemia is a consequence of malignant transformation of a haematopoetic progenitor cell. Molecular studies have revealed a prenatal origin of many childhood leukaemias. According to current models, a preleukaemic stem cell clone is generated by a first mutation in utero which, in a minority of children, progresses to leukaemia after receiving further postnatal genetic hits. The nature of pre- and postnatal events involved in leukaemogenesis in children is not well understood. Although genetic predisposition and specific environmental exposures may account for individual cases, the bulk of childhood leukaemia cannot be explained by any of these factors. The higher incidence of the most common leukaemia subtype in affluent societies, as well as the age peak between 2-5 y, suggest a contributory role of socioeconomic factors. An abnormal immune response during delayed exposure to common infections provides a plausible mechanism for malignant progression of preleukaemic clones in a subgroup of children. As highlighted in this review, a common cause for all types and subtypes of childhood leukaemia is highly unlikely. Deeper insights into the pathogenesis of childhood leukaemia will rely on large-scale and combined epidemiological and biomolecular studies.     

The 'Kinderkrebs in der Umgebung von Kernkraftwerken' study: results put into perspective

A German case-control study on leukaemia in children below 5 y of age near nuclear installations showed a trend of increasing risk with decreasing distance of place of residence from the sites. The radiation exposure from the sites is considered as being too low by a factor of at least 1000 to explain the observed effect, but little is known about radiation effects from pre- or postnatal exposures on the leukaemia risk for ages up to 4 y. Within the study, it was shown that the observed trend in risk decreases over time. That could be indicative of some agent being involved for which the prevalence is reduced over time. Previous ecological studies showed increased risks among the youngest age groups in the closest vicinity of the sites, but no elevated risks for children of all ages (0-14). This could implicate a shift towards an earlier onset of the disease.     

Assessment of environmental exposures from agricultural pesticides in childhood leukaemia studies: challenges and opportunities

Pesticides are ubiquitous in environments of many rural communities due to drift from agricultural applications and home/garden use. Studies of childhood leukaemia predominantly relied on retrospective pesticide exposure assessment and parental recall of use or proximity to fields or pesticide applications. Sample size requirements mostly preclude the collection of individual-level exposure information, biomarkers or environmental measurements of pesticides prospectively in cohorts. Yet such measures can be used in nested case-control approaches or for validating exposure models that can be applied to large populations. Recently developed models incorporate geographic information system technology and environmental databases of pesticide and/or crop data to assess exposure. Models developed in California to estimate residential exposures are presented by linking addresses to agricultural pesticide application data and land-use maps. Results from exposure validation and simulation studies and exposure measurement error issues are discussed.     

Bias and uncertainty of penetrating photon dose measured by film dosemeters in an epidemiological study of US nuclear workers

A retrospective exposure assessment of 1269 study subjects was completed for use in a multi-site case-control study of the relationship between protracted workplace external radiation exposure and leukaemia mortality. The majority of exposure data result from film badge monitoring programmes at the four US weapons production facilities and a US Naval shipyard. Bias and uncertainty in reported exposures among study facilities and across time were as result of differences in incident photon energy, exposure geometry, dosemeter type and dosimetry methods. These sources of measurement uncertainty were examined by facility and time to derive bias factors (B) for normalising exposures. In conjunction with facility reported results, the bias factors provide a means to estimate the equivalent dose, penetrating to a depth of 10 mm [H(p)(10)] and the equivalent dose to the active bone marrow for use in the epidemiological study. Uncertainty was expressed as the constructed 95% confidence interval (i.e. the 2.5th-97.5th% range) of the estimated parameter. The bias factors indicate that recorded exposures provide a reasonable estimate of H(p)(10) (bias factor near unity) and overestimate equivalent dose to active bone marrow (H(T)) by a factor between 1.2 and 1.7. On average, dosemeter-response uncertainties estimated using Monte Carlo simulation were approximately +/-19 and +/-33% for H(p)(10) and H(T), respectively.     

Health Canada's approach to manage risks to populations at risk during a radiological emergency

The approach that Health Canada uses to manage risks to individuals and to populations who might be exposed to ionising radiation is based upon the risk management paradigm. The paradigm differs little between an emergency and a non-emergency situations. In both events, technical experts assess the risk by determining the exposure to the source of radiation. They usually calculate the radiation dose and then assess the potential for any health effects. The initial technical assessments often use scoping calculations. The calculations for children recognise that they are smaller and have different metabolic rates and different behaviour from adults. However, most rigorous quantitative models for dosimetry do not differentiate between children and adults. The risk assessments that were conducted to evaluate the contamination of Canadians who were in London during the Litvenenko poisoning are a good example to illustrate this general approach. The scoping risk assessment concluded that the risks to children and adults were low. No Canadian children were exposed to polonium during this event and, to date, there have been no radiation emergencies in Canada where children have been exposed to a significant source of radiation. Therefore, the comparisons between theory and practice are very limited and conclusions are drawn from international experience and other incidents or sources of radiation exposure such as radon and medical exposures.     

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.     

Residential exposures to pesticides and childhood leukaemia

Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case-control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of approximately 600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene-environment interaction studies.     

Implications of the space radiation environment for human exploration in deep space

Human exploration of the solar system beyond Earth's orbit will entail many risks for the crew on these deep space missions. One of the most significant health risks is exposure to the harsh space radiation environment beyond the protection provided by the Earth's intrinsic magnetic field. Crew on exploration missions will be exposed to a complex mixture of very energetic particles. Chronic exposures to the ever-present background galactic cosmic ray (GCR) spectrum consisting of all naturally occurring chemical elements are combined with sporadic, possibly acute exposures to large fluxes of solar energetic particles, mainly protons and alpha particles. The background GCR environment is mainly a matter of concern for stochastic effects, such as the induction of cancer with subsequent mortality in many cases, and late deterministic effects, such as cataracts and possible damage to the central nervous system. Unfortunately, the actual risks of cancer induction and mortality owing to the very important high-energy heavy ion component of the GCR spectrum are essentially unknown. The sporadic occurrence of extremely large solar energetic particle events (SPE), usually associated with intense solar activity, is also a major concern for the possible manifestation of acute effects from the accompanying high doses of such radiations, especially acute radiation syndrome effects such as nausea, emesis, haemorrhaging or, possibly, even death. In this presentation, an overview of the space radiation environment, estimates of the associated body organ doses and equivalent doses and the potential biological effects on crew in deep space are presented. Possible methods of mitigating these radiations, thereby reducing the associated risks to crew are also described.     

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.     

The time variation pattern of mechanical exposure and the reporting of low back pain

Creating mechanical exposure profiles for multi-component jobs for use in epidemiological studies of work-related musculoskeletal disorders is challenging but becoming more common. Once time-varying mechanical exposure profiles are created, some form of exposure index must be derived. Available techniques typically provide information about the relative amount of time exposed to different levels and durations of stressors. Little or no information concerning the sequence or history of exposure delivery is maintained. The current paper examines an approach to the processing of time varying exposures for epidemiological studies. Shift-long exposure data of 68 production operators (34 cases; 34 controls) from a large epidemiological study of low back pain reporting were used to create individual shift-long internal mechanical exposure profiles. These were processed through a first-order system with varying time constants to generate a range of modelled responses from which two exposure indices were then created. The utility of these mechanical exposure indices was evaluated using low back pain reporting as the health outcome from the same epidemiological study. The modelled response using the first-order system appeared to provide additional exposure information, perhaps time-history sensitive exposure information that was not captured by the unprocessed exposure profiles. Risk estimates from the peak value exposure index derived from an internal exposure processed with a time constant of 2?s were almost doubled compared with the risk estimates of the unprocessed peak value, and the final value, taken from the internal exposure processed with a time constant of 5?000?s, generated higher risk estimates over the cumulative/average exposures. This study suggests a potential analysis approach for epidemiological studies of musculoskeletal disorders where long-duration mechanical exposure data is available.     

A case study on measuring inspection performance for inspection job design

In the quality control system, most of the information for decision making and problem solving can be obtained by inspection activities. Therefore, the inspection work should be organized to maximize meeting the quality objectives. It has already been publicized that data obtained from measurement of inspection performance will supply an effective basis for assessment and design of the inspection station and inspection job. This paper is intended to report on a case study of measurement of inspection performance conducted for the assessment and design of an inspection job in a manufacturing company. Quality control specialists selected three groups of items having representative deficiencies under routine inspection, inspected as inspection job samples. They had individual inspectors inspect each sample to obtain data consisting of the rate of defects detected out of all the defects, and the proportion of erroneous findings in the total number of findings by each inspector. Thus they identified many problems in the inspection job to be corrected to enhance the inspection accuracy. Appropriate action was taken to remedy the situation. In the first place, the inspection job was redesigned. In the second, the method of training inspectors was reviewed and modified. As a result, the probability of defects passing the inspection undetected was greatly reduced.     

Childhood leukaemia and socioeconomic status: what is the evidence?

The objectives of this systematic review are to summarise the current literature on socioeconomic status (SES) and the risk of childhood leukaemia, to highlight methodological problems and formulate recommendations for future research. Starting from the systematic review of Poole et al. (Socioeconomic status and childhood leukaemia: a review. Int. J. Epidemiol. 2006;35(2):370-384.), an electronic literature search was performed covering August 2002-April 2008. It showed that (1) the results are heterogeneous, with no clear evidence to support a relation between SES and childhood leukaemia; (2) a number of factors, most importantly selection bias, might explain inconsistencies between studies; (3) there is some support for an association between SES at birth (rather than later in childhood) and childhood leukaemia and (4) if there are any associations, these are weak, limited to the most extreme SES groups (the 10-20% most or least deprived). This makes it unlikely that they would act as strong confounders in research addressing associations between other exposures and childhood leukaemia. Future research should minimise case and control selection bias, distinguish between different SES measures and leukaemia subtypes and consider timing of exposures and cancer outcomes.     

Exposure to electromagnetic fields and the risk of childhood leukaemia: a review

Extremely low-frequency magnetic fields have been classified as possibly carcinogenic to humans, mainly based on epidemiological studies consistently showing an association between long-term average exposures to magnetic fields above 0.3/0.4 microT and the risk of childhood leukaemia. No mechanism to explain this finding has been established and no support for a causal link emerged from experimental studies. Chance or bias cannot be ruled out with reasonable confidence as an explanation for the observed association. If the association is causal, it explains only a small fraction of childhood leukaemia cases. There were some reports of childhood leukaemia clusters in the vicinity of high-power radio and television broadcast transmitters in studies in Australia and Italy. However, recent large-scale systematic studies in Korea and Germany show no association between exposure to radio frequency electromagnetic fields emitted from broadcast towers and childhood leukaemia risk. Studies on mobile phone use and leukaemia risk in adolescents and young adults may be indicated.     

Lung damage assessment from exposure to pulsed-wave ultrasound in the rabbit, mouse, and pig

The principal motivation of the study was to assess experimentally the question: "Is the MI (Mechanical Index) an equivalent or better indicator of nonthermal bioeffect risk than I(SPPA.3) (derated spatial peak, pulse average intensity)?" To evaluate this question, the experimental design consisted of a reproducible biological effect in order to provide a quantitative assessment of the effect. The specific biological effect used was lung damage and the species chosen was the rabbit. This work was initiated, in part, by a study in which lung hemorrhage was observed in 7-week old C3H mice for diagnostic-type, pulsed-wave ultrasound exposures, and, therefore, 6- to 7-week old C3H mice were used in this study as positive controls. Forty-seven adult New Zealand White male rabbits were exposed to a wide range of ultrasound amplitude conditions at center frequencies of 3 and 6 MHz with all temporal exposure variables held constant. A calibrated, commercial diagnostic ultrasound system was used as the ultrasound source with output levels exceeding, in some cases, permissible FDA levels. The MI was shown to be at least an equivalent, and in some cases, a better indicator of rabbit lung damage than either the I(SPPA.3) or p(r.3) (derated peak rarefactional pressure), thus answering the posed question positively. Further, in situ exposure conditions were estimated at the lung pleural surface (PS); the estimated in situ I(SPPA.PS) and p(r.PS) exposure conditions tracked lung damage no better than I(SPPA.3) and p(r.3), respectively, whereas the estimated in situ MI(PS) exposure condition was a slightly poorer predictor of lung damage than MI. Finally, the lungs of six adult crossbred pigs were exposed at the highest amplitude exposure levels permitted by a diagnostic ultrasound system (to prevent probe damage) at both frequencies; no lung damage was observed which suggests the possibility of a species dependency biological effect.