1 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
2 Department of Medicine, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden.
3 Division of Epidemiology, Stockholm Center of Public Health, Stockholm, Sweden.
Received for publication June 2, 2004; accepted for publication August 24, 2004.
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ABSTRACT |
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breast neoplasms; case-control studies; electromagnetic fields; female; receptors, estrogen
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INTRODUCTION |
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The epidemiologic data on occupational magnetic field exposure and breast cancer have indicated little or no overall effect (8, 9), but some studies have suggested an effect among premenopausal women, particularly for breast tumors that are rich in estrogen receptors (estrogen receptor positive), findings that fit the hypothesized biologic mechanism (1016). However, many of the early studies were not designed to specifically address the hypothesis and small numbers, crude exposure information, and lack of information on confounding factors are severe limitations in these studies. In more recent studies, some of these problems are addressed, and they all report somewhat increased risks of breast cancer, although with no consistent pattern of dose response or time for exposure (1217). One study reported elevated risks among postmenopausal women for exposures with a 10-year time lag and exposure before the age of 35 years (15), and another study found increased risks for premenopausal women exposed more closely to diagnosis (12).
A fundamental problem in the studies carried out so far is that little has been known about the magnetic field exposure in typically female occupations, because most studies involving measurements of occupational magnetic fields have been limited to men. In the recent epidemiologic studies, only one (14) was based on measurements actually performed among women. To improve the exposure assessment for women, we carried out a magnetic field measurement program in occupations common among women. Based on these measurements, a new job-exposure matrix was constructed, which covers a large proportion of the economically active women in Stockholm County and provides several different parameters to describe the exposure (18).
The purpose of this study was to apply this job-exposure matrix to a large case-control study by linking different Swedish population registers to obtain information about occupation, several important confounding factors, and estrogen receptor status for most cases in order to test the hypothesis that occupational magnetic field exposure increases the risk of female breast cancer.
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MATERIALS AND METHODS |
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Exposure assessment
The exposure assessment was based on information about occupation obtained from the censuses performed by Statistics Sweden in 1960, 1970, 1975, 1980, 1985, and 1990. Information about magnetic field exposure was assessed by linking a new job-exposure matrix developed from an electromagnetic field measurement program performed in Stockholm County between March 2001 and October 2002 to the occupational codes in the censuses (18). The new job-exposure matrix includes 49 of the most common occupations among women in Stockholm County and covers about 85 percent of the gainfully employed women according to the 1980 census. The measurements were made with personal magnetic field meters (Emdex Lite; Enertech Consultants, Campbell, California) that volunteer women in the different occupations carried on a belt by the hip for 24 hours. During the measurement periods, the subjects kept a diary of their whereabouts from which time spent at work could be abstracted. The number of measured subjects in each occupation varied between five and 24. The meter recorded the exposure every fourth second, and a number of parameters describing different aspects of the exposure were calculated. In this study, we evaluated the time-weighted average, maximum values, short-term variations (rate of change), and the proportion of the workday spent in levels exceeding 0.3 µT. The rate of change (RC), a measure of the short time variability of the exposure, was calculated as follows:
RC (µT/4 seconds) = ,
where M1 and M2 are successive magnetic field measurements registered every fourth second, and n is the number of measurements in a given time period (5). To reduce the influence of individual extreme values, we used the geometric mean and the median when summarizing the parameters over occupations.
Definitions of magnetic field exposure
The exposure described as the geometric mean of the time-weighted average was divided into four categories: <0.10 µT, 0.100.19 µT, 0.200.29 µT, and 0.30 µT. The cutpoints were chosen to enable comparison with previous studies. Based on the assumption that magnetic fields act as a tumor promoter (1), exposure at the last census providing information on occupation was investigated. To further evaluate different time windows for exposure and to compare with results from previous studies, we analyzed exposure at least 10 years before the referent year and exposure before the age of 35 years. The study period was split in two parts to evaluate exposure before and after 1985, assuming the measurements to be more accurate for the later period. The year 1985 was the census year that most closely splits the study period in half. Ever versus never being exposed was defined as ever holding an occupation with magnetic field levels at or above 0.30 µT compared with never having an occupation with more than 0.10 µT. Finally, we investigated the effect of being exposed to
0.30 µT in at least two, three, or four consecutive censuses prior to the referent year.
In a sensitivity analysis aimed at reducing potential misclassification of the exposure caused by variation in the exposure within an occupation, we performed analyses for a subset of the occupations using the following definition: An occupation was considered as having low exposure if the median of the measurements within the occupation was 0.10 µT or less and the third quartile was lower than 0.17 µT; we similarly defined an occupation as having high exposure if the median was 0.25 µT or more and the first quartile was higher than 0.17 µT. In this way, the exposure contrast between the occupations was increased. The rationale for these cutpoints was driven by the exposure distribution of the individual measurements on which the job-exposure matrix was based and chosen to refine the exposure to include only occupations that overlap as little as possible. The distribution of the occupations is described in detail elsewhere (18).
For the maximum values, we used the cutoff points 1.5 µT, 2 µT, and 3.5 µT, and for the rate of change, we used 0.05 µT/4 seconds, 0.07 µT/4 seconds, and 0.12 µT/4 seconds. These cutoff points followed the 10th, 50th, and 90th percentiles of the distribution among the controls. The proportion of time spent above 0.30 µT was analyzed with cutoff points following the 10th, 50th, 90th, and 95th percentiles (6, 10, 35, and 40 percent of the workday).
Confounders and effect modifiers
The confounding factors that we evaluated were socioeconomic status, age, referent year, number of children, and age at first birth. The information about socioeconomic status was obtained from the censuses and was categorized as shown in table 1. Both age and referent year influence the breast cancer risk and, since their distributions varied between categories of magnetic field levels, they were considered potential confounding factors. The socioeconomic status also varied between levels of electromagnetic field exposure but is more complicated as a confounder, since it is partly derived from the occupation and could be regarded as a step in the causal pathway and argued not to be controlled for (20, 21). There is, however, no reason to believe that the actual exposure (magnetic fields) in any way would affect the formation of the socioeconomic index and, since high socioeconomic status is a well-known risk factor for breast cancer, we found it relevant to evaluate socioeconomic status as a potential confounder.
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We performed age-specific analyses using the categories less than 50 years and 50 years or more as a crude categorization for menopause. Estrogen receptor status was available through the Regional Cancer Registry for about 64 percent of the cases. During the study period, all of the hormone receptor assays were done at one laboratory at the Karolinska Hospital, Stockholm. A case was considered estrogen receptor positive when the estrogen receptor content of the primary tumor was 0.05 fmol or more per µg of DNA (which corresponds to 23 fmol/mg of protein).
Statistical methods
To determine risk (odds ratio), we used logistic regression models in SAS version 8.2 software (SAS Institute, Inc., Cary, North Carolina). The random variation was assessed by 95 percent confidence intervals. The potential confounding variables were included one at a time for evaluation in the model, and the results are presented as both crude and adjusted odds ratios. Wherever possible, the variables were evaluated as both continuous and categorical. Since continuous variables in a logistic regression model assume an exponential relation between the variable and the outcome, the variables were first analyzed as categorized data and exponential trends were explored. No such trends were discovered and, since the large number of subjects allowed for many variables, the categorical approach was kept.
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RESULTS |
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Table 3 displays the results for magnetic field exposure for the last census providing information on occupation prior to the referent year. The average time to referent year was 7.6 years, with the interquartile distribution (quartile 1, median, and quartile 3) of 2, 5, and 11 years, respectively. The data were stratified according to age at referent year (<50 and 50 years) and estrogen receptor status (estrogen receptor positive and negative) and are presented in table 3 as both crude and adjusted odds ratios for the confounding factors that had an effect on the risk. In the crude analyses, the odds ratios were below unity for many subgroups but, in the adjusted model, the odds ratios were close to unity. In the highest exposure category (
0.30 µT), the adjusted odds ratio for postmenopausal women with estrogen receptor-positive breast cancer was 0.94 (95 percent confidence interval (CI): 0.72, 1.22). Of the potential confounding factors, age and socioeconomic status were more important than the referent year, although each contributed somewhat to the change in the risk estimates. For women without information on estrogen receptor status, the results were similar (not shown).
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DISCUSSION |
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The study has several strengths. It is population based, and the controls were selected at random from the population, minimizing the risk for selection bias. Exposure information was collected from census registries covering the total population, and therefore the participation of cases and controls was almost complete. The information in the Regional Cancer Registry is of high quality, and less than 2 percent of the breast cancer cases are not covered by the register (19). Estrogen receptor status was not available for 46 percent of the cases; however, the results did not differ between women with information on estrogen receptor status and those without. There were still 13,116 breast cancer cases with estrogen receptor status available for analyses, which is the largest number ever to be analyzed in relation to magnetic field exposure. Furthermore, all the estrogen receptor assays were done at only one laboratory, which increases the consistency over the study period. A considerable effort was made to improve the exposure assessment by development of a new job-exposure matrix that provided exposure information for a large proportion of the subjects. The matrix was based on actual measurements performed among women in a wide range of different occupations in Stockholm County. Several important confounding factors were investigated, of which socioeconomic status and age were found to be of some importance, whereas control for number of children and age at first child had no effect on the results.
The major concern in the study is exposure misclassification, even if exposure assessment has been improved compared with previous studies. There are a limited number of measurements within each occupation, and the measurements were performed later than the actual exposure. It is likely that magnetic field exposure may have changed over time in some occupations, but separate analyses of exposures occurring before and after 1985 did not indicate any major impact of exposure misclassification due to changes in the exposure over time. Furthermore, the information about occupation is based on census data every fifth year, and we have no information about occupation between the census years. Our results did not indicate that being exposed during up to four consecutive censuses was associated with any risk increase. Too few women were exposed during five or six censuses to allow meaningful analyses.
The exposure parameter that might be biologically relevant is unknown, but the most commonly used is the time-weighted average, which we evaluated in several analyses. Other suggested parameters are peak values, short-term variations in exposure magnitude, and time spent at different exposure levels. We investigated all of the discussed parameters but found no increased risks for any of them. Several different time windows for the exposure were also explored: exposure close in time prior to diagnosis, exposure with a 10-year time lag, and exposure before age 35 years. None of them showed any tendency for elevated risks.
We have evaluated and controlled for several important confounding factors, but we cannot exclude the possibility that some other occupational risk factors for breast cancer are more prevalent in occupations unexposed to magnetic fields, which could hide a possible association with magnetic field exposure. However, there are hitherto no established occupational risk factors for breast cancer that are likely to explain the lack of association.
In previous epidemiologic studies of magnetic field exposure and breast cancer, the exposure has been derived mainly from three different sources of magnetic fields: power lines near the residence, use of electric blankets, and occupational exposure. The studies performed before 1999 have been evaluated in two reviews (8, 9) and in an evaluation of the carcinogenicity of nonionizing radiation in the extremely low-frequency range by the International Agency for Research on Cancer (1). The majority of the studies on electric blankets have shown no effects and, for residential exposure, positive findings were restricted to subgroups where the number of exposed subjects was limited and where chance could be a possible explanation for the observed risk increase. Also, it is possible that findings in subgroups are reported more frequently if they are positive. More recent studies of residential exposure (2325) and use of electric blankets (26) have not reported increased risks.
The studies on occupational magnetic field exposure have showed more varying results, with several studies reporting elevated risks for industrial and electrical occupations, telephone installers, telegraph operators, and radio operators (8, 9). These types of occupations are, however, not very common among women (18), and the number of exposed cases is therefore generally low. Also, women and men with the same occupational title might not have the same exposure. The lack of data on occupational magnetic field exposure among women has raised concern in previous occupational studies. The crude and uncertain exposure assessment could have caused considerable exposure misclassification and a dilution of possible effects toward unity. If this were true, one would expect that improvements of the exposure assessment would give higher risk estimates. An attempt to improve the exposure assessment based on actual measurements was made by van Wijngaarden et al. (14). They found an increased risk for premenopausal women and estrogen receptor-positive breast cancer associated with long duration of high occupational exposure. However, despite the improvements, the highest exposure category was defined as "industrial workers," a broad occupational group, and the authors suggest that the association could be explained by some other risk factors for breast cancer among industrial workers.
In two other recent studies where elevated risks were found, the highest exposure category comprised textile workers (15, 17), an occupational group believed to be highly exposed to magnetic fields (27, 28). Seamstresses are included in the new job-exposure matrix but had an average exposure of 0.16 µT and were hence not included in the highest exposure category. In this study, the odds ratio of breast cancer for women having textile occupations compared with women in occupations with exposure of less than 0.10 µT was 1.37 (95 percent CI: 1.11, 1.68) and, compared with women in all other occupations (irrespective of magnetic field exposure), the odds ratio was 1.33 (95 percent CI: 1.10, 1.62). These results suggest that the increased risk for breast cancer in these occupations might be related to some exposure other than magnetic fields.
In our previous study of occupational magnetic fields and breast cancer (12), we based the exposure assessment on a job-exposure matrix developed from measurements performed on men (29). In that study, we found an increased risk of 1.5 (95 percent CI: 0.6, 3.5) in the group of highly exposed (0.25 µT) women aged less than 50 years and of 3.6 (95 percent CI: 0.7, 18.1) for young women with estrogen receptor-positive breast cancer. Both odds ratios are imprecise, because exposure information was missing for many of the occupations typically held by women, which limited the number of subjects available for analyses. With the new job-exposure matrix developed for this study, both the validity of the exposure assessment and the precision were greatly improved, and an equal or even higher odds ratio would have been expected if the previously found risk increase was real. Since no elevated risks were found in any subgroups in this study, it is most likely that the elevated risk in our earlier study was caused by random variation.
The study presented here is one of the largest studies ever on occupational electromagnetic field exposure and breast cancer risk, with an exposure assessment greatly improved compared with previous studies. This allowed us to estimate breast cancer risk with great precision also in subgroups where increased risks have been suggested in previous studies. The findings give no support to the hypothesis that magnetic field exposure increases the risk of female breast cancer.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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