A review of job-exposure matrix methodology for application to workers exposed to radiation from internally deposited plutonium or other radioactive materials

The potential radiotoxicity of the long-lived alpha-particle-emitting isotopes of plutonium was recognised soon after its discovery [1]. Plutonium-239, with a half-life (t_½) of 24 100 years, is normally produced by the neutron bombardment of uranium-238 in a nuclear reactor, and is usually the isotope of principal interest [2]. The longer the uranium fuel is kept in a reactor (i.e. the higher the fuel 'burnup') the greater the proportions of other plutonium isotopes produced. Plutonium exposure may occur to workers engaged in plutonium production, nuclear fuel reprocessing, decommissioning and clean-up operations [3, 4] or to the general public as a result of atmospheric testing of nuclear weapons, nuclear accidents, or discharges and waste disposal from nuclear facilities [5].

Alpha-particle radiation is the main risk posed by exposure to plutonium, although low-energy x-rays and gamma-rays are also emitted during alpha-particle decay, as are neutrons from spontaneous fission [6]. Plutonium-241 (t_½  =  14 years) emits beta-particles but decays to americium-241 (t_½  =  433 years) which is also an alpha-particle emitter and can produce significant doses of radiation [6]. Since the alpha-particles emitted by plutonium possess high energies but only travel short distances (approximately 50 μm in tissue, i.e. the typical length of one adult human liver cell), the greatest concern regarding health effects of exposure is the biological damage that may occur once plutonium has been taken into the body via inhalation, ingestion or puncture wounds [7]. In most exposure scenarios, alpha-particle radiation from sources external to the body does not penetrate the topmost dead layer of skin and hence generally poses little health risk [8]. Once plutonium radioisotopes are taken into the body they can be retained for decades [9, 10]. Primary retention sites are the liver and skeleton, with the lung being important for inhalation exposures, which is the primary route for most occupational exposures [9, 10]. The long physical and biological half-lives of plutonium mean that exposed tissues accumulate doses of alpha-particle radiation over many years even if exposure was of short duration.

Evidence for increased cancer and non-cancer risks from plutonium exposures has been reported for workers at the Mayak Production Association in the Russian Federation [11–14]. Mayak was used to produce plutonium for nuclear weapons and exposures, in the early years of operation, are known to be significantly higher than similar facilities elsewhere [13, 15]. In contrast to the findings from Russia, studies of plutonium workers in other countries have been inconclusive, which is likely the result of much lower tissue doses [16–22]. Remaining scientific uncertainty regarding the overall health effects of occupational exposure to plutonium, particularly at lower levels, suggests that further epidemiological studies are important [23, 24]. It is clear that the reliability of these types of studies is directly related to the availability and accuracy of plutonium and other radionuclide exposure assessments for occupational intakes [23, 25]. Also of interest to epidemiological studies of plutonium workers are any doses due to occupational exposures to external sources of penetrating radiation (for plutonium workers, these are predominantly gamma radiation and neutrons), and other workplace exposures (e.g. asbestos), as such exposures can also affect health outcomes [4].

The absorbed dose of ionising radiation is defined as the energy deposited per unit mass, and has the SI unit of the gray (Gy), which is one joule per kilogram [26]. Some types of radiation, such as alpha-particles, are more densely ionising than others (e.g. gamma-rays) and more effective at causing biological damage at the cellular level [27]. This difference in effect is called the Relative Biological Effectiveness (RBE) and for the purposes of radiological protection the RBE is taken into account through the radiation weighting factor (w_R). Under the International Commission on Radiological Protection (ICRP) system, the absorbed dose (in gray) multiplied by w_R gives the equivalent dose for an organ/tissue which is expressed in sieverts (Sv) [26]. The w_R for gamma-rays is one, so one gray is equal to one sievert, while for densely ionising alpha-particles w_R is 20, so that one gray is equal to 20 Sv [26]. For doses from internally deposited radionuclides that are heterogeneously distributed among body tissues, the dose recorded for radiation protection purposes is often the effective dose, which is the sum of all the organ/tissue equivalent doses each weighted by the ICRP tissue weighting factor (w_T). The tissue weighting factor takes into account the radiosensitivity of the organ/tissue, mainly with respect to the risk of cancer induction but also including hereditary risks from gonadal doses [26]. The effective dose is also measured in sieverts. For epidemiological analyses the absorbed dose in gray is generally preferred because one of the purposes of epidemiological research is to determine the magnitude of any differences in health outcomes due to doses received from different types of radiation.

It is practically and technically straightforward to measure exposures to penetrating radiation and express it as a whole-body dose (at least for gamma-rays and x-rays, but not necessarily for neutrons) [28]. Exposure to external sources of penetrating radiation is usually measured directly using individual monitoring based on personal dosemeters such as film badges and thermo-luminescent dosemeters (TLDs), worn on the worker's outer clothing [26]. Because the radiation involved is penetrating, an easy simplifying assumption, for protection purposes, is that doses to all organs and tissues are the same (i.e. a whole-body dose), even though in practice some organs and tissues tend to be at least partially shielded by others, meaning doses to the shielded organs are actually lower. In epidemiological studies of nuclear workers with external exposures the doses used are, typically, annual whole-body doses, which can be summed to give the cumulative dose within any period of interest (used in, for example, [14, 21, 22]).

When the primary purpose of an epidemiological study is to investigate internal exposures, however, it is necessary to use organ/tissue-specific doses because internally deposited radionuclides often distribute heterogeneously within the body and doses tend to differ significantly by organ/tissue, hence it is the cumulative doses received by specific organs/tissues that are of interest.

Occupational doses from plutonium and other alpha/beta-particle-emitting radionuclides are mainly assessed indirectly using biological samples provided by workers considered to be potentially exposed to them. This is because the low penetration radiation they emit is difficult to detect directly when the source is located within the body, and the limit of detection for such in vivo monitoring can equate to a dose that substantially exceeds the annual limit. For plutonium, urine samples are generally used as the basis for most internal dose assessments, as urine is relatively easy to collect in the required volumes, and plutonium continues to be excreted in urine long after intake has ceased [29]. Faecal sampling is principally used only for the assessment of acute exposures, because clearance through this route decreases rapidly following cessation of intake and also because there are more issues with sample collection [29]. Body tissues collected at autopsies have also been used to assess exposures within some populations (e.g. [21, 30, 31]).

As well as bioassay measurements (e.g. urinalysis), assessments of plutonium organ/tissue doses also rely on knowledge of the nature of the plutonium intake [29] and the way it is metabolised in the body. The absorption, distribution, retention, and excretion of plutonium depends on many factors including the initial chemical composition (material solubility affects absorption in the lung, gut and wound tissues), aerosol particle parameters (e.g. size, density) for inhalation exposures, organ/tissue residence times, and mode of exposure [10, 32–35]. Calculating intakes of, and organ/tissue-specific doses from, plutonium is therefore difficult and complex [29], and can be a labour-intensive and costly exercise [4]. Metabolic (biokinetic) models which relate urine concentrations to initial intake(s) and tissue burdens have changed over time as more information has become available [9, 10, 36, 37]. This improving knowledge of plutonium metabolism means that assessed intakes and doses, based on the same bioassay results, will change over time. This can lead to a situation in which epidemiological studies of plutonium workers are not directly comparable due to differences in dosimetry methodologies.

Dosimetry information that would provide quantitative estimates of exposures from plutonium and other radionuclides may also be unreliable, missing or unusable for other reasons. Examples of this include adventitious contamination of biological samples, lack of person specific data as a consequence of administrative decisions on the monitoring of individuals, or changes in analytical methods, detection thresholds, and recording practices over time. These problems exist among the world's most important cohorts for assessing plutonium workers' exposure risks [18, 31, 38, 39]. For example, Wing et al [18] observed that the majority of workers in the US Hanford Site cohort had no bioassay monitoring in most years of employment, and Khokhryakov et al [31] reported that only 32% of the Russian Mayak workers had at least one urine bioassay sample. Riddell et al [39] noted that, due to the high reporting limit associated with some early urine samples, the historical monitoring data available for several hundred early UK Sellafield workers cannot provide the accurate and unbiased exposure assessments needed for risk analyses.

Another issue is that the internal monitoring of workers that has been undertaken was to meet regulatory requirements and for operational protection purposes, rather than for epidemiological research purposes [40, 41]. Because of the conservative approach encouraged in the systems used for such purposes, recorded doses have tended to be systematically overestimated.

All these problems pose a challenge to obtaining accurate, reliable and unbiased doses—from internally deposited plutonium and other radionuclides—for use in studies of the potential risks of occupational exposures. The primary purpose of this paper is to conduct a substantial review of the job-exposure matrix (JEM) approach as an alternative method of evaluating internal exposures (from plutonium and other radionuclides), particularly for epidemiological studies of nuclear workers where quantitative dosimetry data based on urine monitoring for the cohort (or parts thereof) are unreliable, cannot be obtained at all, or are missing, for the reasons discussed above. The motivation for this review was in the first instance to inform a JEM assessment of exposures to plutonium for early workers at the Sellafield nuclear complex in Cumbria, north-west England, but the paucity of summary information on this approach will make the review of relevance to most, if not all, nuclear worker cohorts.

In general, the problem of missing doses will reduce the statistical power of epidemiological studies due to subjects with missing doses. This is a particularly significant issue because the ability of an epidemiological study to detect any adverse health effects is usually directly related to the size of the study population and this has to be large when potential risks are small [42]. Occupational exposures to radiation are typically low dose and low dose-rate and are therefore associated with small increases in risk [43, 44]. Consequently, epidemiological studies of plutonium workers are hampered by the lack of exposure assessment data of the required quality (e.g. [16, 19, 22]). This is reflected in the limited number of studies of nuclear workers that have specifically examined exposures from internally deposited plutonium and other radionuclides, especially in terms of organ/tissue-specific doses [4, 45].

It should be noted that the missing data problem is not restricted to analyses of plutonium workers, but in reality affects nearly all epidemiological cohort studies. In the statistical literature, methods of multiple imputation [46], full information maximum likelihood [47] and mean imputation [48] are used to impute missing data, either for data missing completely at random and/or missing at random [49]. The review of the problems leading to missing doses in the preceding section indicates that missing historical dose data are not missing at random. Moreover, if historical exposure data from a whole time period are missing the imputed doses following these statistical imputation methods are likely to be flawed. Both of these issues have important implications for epidemiological analyses of plutonium workers indicating that a different framework for imputing missing data is needed. This framework should enable the building of exposure estimation methods, based upon available information on determinants that model exposure across time periods and jobs, so that missing combinations can be imputed from overall trends. Within the occupational epidemiology literature, the most common approach to retrospective exposure assessment is to use occupation (job title) and industry as an exposure proxy [50–52].

In lieu of direct information, principal among those retrospective exposure estimation techniques are the job-exposure matrices (JEMs), exposures self-reported by study subjects, and exposures assessed by experts [50–52]. In occupational epidemiology, cohort and case-control studies have long used the JEM approach where occupations and/or industries represent one axis, exposure agents the other (many studies have a third axis representing time periods/work durations for assessment of time trends), and the cells of the matrix indicate the likely presence, intensity, frequency, and/or probability of exposure to a specific agent in a specific job [52–54]. The approach is based on the observation that study subjects' job histories within a company can serve as a basis for assigning exposures [52–54], assuming that people with the same job, in the same time period, get approximately the same exposure.

The PubMed and MEDLINE databases for the period 1 January 1980–31 May 2015 were searched to identify relevant studies of workers who are potentially exposed to radioactive materials. Various combinations of the following search terms were used: epidemiology, nuclear workers, health risk, mortality, cancer, radiation exposure, internal exposure, internal contaminations, plutonium, plutonium isotopes, radioactive materials, radionuclides, internal emitters, alpha emitters, intakes, bioassay measurements, occupational doses, internal doses, and organ/tissue doses. References in identified papers were reviewed for additional sources. Only studies published in peer-reviewed journals were considered. Papers published in the English language, which examined the health risk of occupational exposures to radiation from internally deposited plutonium and other radionuclides and used JEM techniques as alternative methods of evaluating internal exposures in the absence of quantitative dosimetry data based on urine monitoring, were selected for this present review. Specific review of the selected studies is provided in the next section, followed by an overall discussion on the quality of these JEMs in radiation epidemiology in section 5.

Nine studies of nuclear worker cohorts in France, Russia, the USA and the UK that had incorporated JEMs in their exposure assessments were selected and reviewed in depth. Table 1 summarises these studies: four assessed internal exposure to plutonium and other radionuclides [18, 55–57]; three assessed internal exposure to uranium [58–60]; one assessed internal exposure to thorium and its decay products [61]; one assessed internal exposure to tritium [62].

Specific reviews of these studies follow.

4.1. Studies of workers at the Oak Ridge site [55, 59, 60]

4.2. The Liu et al 1992 study of thorium-processing workers [61]

4.3. The Rooney et al 1993 study of UKAEA employees [56]

4.4. The Wing et al 2004 study of Hanford Site workers [18]

4.5. Studies of plutonium workers at the Mayak Production Association in the Russian Federation

4.6. The tritium JEM for employees at the Savannah River Site [62]

4.7. The JEM for the main uranium conversion plant in France [58]

4.8. Other studies

The JEMs reviewed in this paper have typically been constructed in the absence of sufficient quantitative data. The JEM techniques reviewed are used to deal with missing historical exposure data that are not missing at random [49]. They are based upon available information on determinants that model exposure across time periods, jobs and work locations (activities) so that missing combinations can be imputed from overall trends. This approach is generally considered better than the generalised standard methods of imputation for dealing with data missing completely at random and missing at random [49].

These JEMs have typically constructed the job dimension of the matrix on the basis of detailed information on employment and job history, including: job title, job duty and work area, plus one extra axis with consistent dates of hire and termination, and dates of job title, job duty and work area changes. Such detailed information was then typically used to assign values for the exposure dimension of the job-exposure matrix based on expert knowledge of where and when an exposure was likely to occur and/or on existing exposure monitoring data.

This present review reveals that the overall trend in the development and use of JEMs in nuclear industry studies has been toward increased complexity and sophistication in the detail of the qualitative information on subjects' employment, occupation (job title and job duty) and work area/process (activities and materials used at the workplace), and also the techniques of deciding the levels of potential exposure over time. For example, earlier studies (i.e. [55, 56, 59, 61]) tended to use the JEM to derive levels of potential exposure, which were then directly used to stratify the risk assessment analyses. The later studies either combined task- and time-dependent weighting factors with duration of employment to derive exposure indices to be used in the risk assessment [18, 57, 58] or combined known dosimetry data to impute exposure dose values to be used in the risk assessment [60, 62].

The JEMs reviewed are, by their nature, study-specific or cohort-specific JEMs. In comparison, 'generic' JEMs have been developed to describe exposures across the range of jobs and industries that might be relevant to the general population [82–84]. Validation studies have indicated that generic JEMs have relatively poor sensitivity [85–87] and fail to account for heterogeneity in exposure levels within jobs [88]. A significant advantage of these specific JEMs is that exposures are assigned to a very detailed list of jobs identified within the study or cohort in question, therefore leading to improved sensitivity [52, 85, 89]. A remaining limitation is that even specific JEMs are unable to fully account for variability in exposures within a job—whether across different plants or departments or in the same area between different individuals with varying degrees of interaction with the agent in question [52]. Task-exposure matrices (TEMs) have been developed to address this (e.g. [90]), but the detailed information required to build them is hardly ever available, especially not retrospectively. A further limitation of their study-specific development is that they cannot be used for any other cohort, thus making direct comparisons of results across studies difficult.

In general, the JEM approach is based on the observation that study subjects' job histories within a company can usually serve as the basis for assigning exposures [52–54]). The majority of the studies [18, 55–57, 59–61] provided insufficient information or discussion as to how the JEMs used were validated. It is understandably difficult to validate JEMs because, by definition, they are developed for parts of the study where exposure data are missing (so there are often no data available to validate against). These JEMs were constructed and used on the basis of the assumption that workers undertaking similar job tasks at similar work areas/processes over the same period of time would have received the same or similar level of exposures from sources of ionising radiation. Accordingly, assessment of exposure levels was based upon the similarity of exposures in the industrial process combined with expert knowledge and judgement (e.g. from occupational health and safety personnel, as well as the workers under study). Given that comparisons of groups of workers involved in the same work often show similar urinary excretion of radionuclides over an extended period [43], the validity of a JEM approach based upon this assumption has some support. In other industries, some validation has been attempted by, for example, setting aside part of the data prior to JEM development and then using the JEM to estimate the withheld data [91].

Two of the studies [58, 62] provided sufficient information on their procedures for validating the JEM and the evaluation results were reported and discussed. The evaluation results indicate that the JEM method generates acceptable estimates of exposure. The validation procedures reported in these two papers provide valuable insights for the development of future JEMs.

Some of the JEMs were built upon purely qualitative information [18, 55, 56, 58]; others were a mix of qualitative and quantitative data [57, 59–62]. When quantitative dosimetry data are not available at all, qualitative JEMs become essential as they are built using only experts' knowledge and experience. Such an approach is, however, difficult to validate as it does depend on the subjective judgement of experts [92] and therefore it cannot provide the objective estimates that can be achieved by a quantitative approach. JEMs built upon a mix of qualitative and quantitative data (the 'hybrid method' [62]) seem desirable since they combine the best aspects and mitigate the problems, of each approach.

Two examples of the hybrid method were the studies by Dupree et al 1995 [60] and Hamra et al 2008 [62] (also see [28]). These two studies contained detailed information on work history, but this was not used to assign the exposure level in terms of exposure categories or exposure indices, as was typically used in the other JEMs reviewed in this paper. Instead, detailed qualitative information was combined, with area uranium in air monitoring results in Dupree et al [60] and with recorded dosimetry data in Hamra et al [62], to impute quantitative dose values. Dupree et al [60] identified possible dose misclassification as an issue; and organ/tissue-specific doses from tritium exposure [62], which distributes relatively homogeneously throughout body tissues, are comparatively simple to calculate given adequate urinalysis results [4]. However, the techniques [60, 62] used are promising for future research in this area. The hybrid method employed by Hamra et al [62], using a JEM in conjunction with known quantitative dose data and regression modelling, has been successfully applied in epidemiological studies in various industries; including, for example, the rubber industry [93]. One remaining methodological concern with the hybrid method is that it is difficult to weight the input from each type of information (qualitative, quantitative and expert judgement) if they do not agree. Nonetheless, a transparent hybrid JEM should be adaptable to, or facilitate benchmarking of, exposure data for other cohorts, thereby enabling direct comparison or even pooling of different nuclear workers' cohorts and allow whole cohorts, rather than just those with complete monitoring data, to be included.

With respect to epidemiological analyses, there are limitations in occupational radiation monitoring data, particularly for internally deposited radionuclides, such as plutonium, in the early years of operation of the nuclear industry. A methodology to better estimate levels of exposure for the purposes of epidemiological studies is required. One such approach is the job-exposure matrix and studies that have used this JEM approach have been reviewed here. The JEM approach becomes essential when measurement data are missing, limited or unreliable. Previous validation results suggest that the JEM method can generate acceptable estimates of exposure. It is important that future JEMs in radiation epidemiology use a systematic approach to validating the JEM techniques employed, and they should also report on this validation approach and the results of it in any description of the JEM analysis or its results.

This paper is independent research commissioned and funded by the Department of Health Policy Research Programme (091/0204). The views expressed in this publication are those of the authors and not necessarily those of the Department of Health (England).