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Environment and cancer—How can the ecological study help us?
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Preventive Medicine 45 (2007) 325 – 326 www.elsevier.com/locate/ypmed
Editorial
Environment and cancer—How can the ecological study help us? The recognition that more than 80% of cancers are caused by factors external to mankind has often led to confusion, as many have interpreted such statements as an attribution to manmade factors in “the environment”, that is carcinogenic contaminants in air, water, and soil, that may either affect us directly, or through our food supply. The appreciation that exposure to the majority of the causal factors for cancer is attributable to our lifestyle, what we smoke, eat, drink, how much we exercise, and with what we work, has still not completely satisfied many, who feel that “they”, i.e. others exemplified by government and industry, are poisoning our environment, and if catastrophe is not already with us, it is not far around the corner. Estimates of the proportion of cancers that are due to such factors have usually been very small, however; recently an estimate of 1-4% for the world as a whole was made (IARC, 2003). The trouble for epidemiologists in conducting the research necessary to refine such estimates is that when exposure is uniform, the classical observational analytic methods, case– control, and cohort, cannot work well because they depend on a contrast of measured or estimated exposures. Sometimes we can utilize a quantitative measure of exposure of an individual's environment, such as the use of meters of magnetic and sometimes also electrical fields, when investigating the possibility that such fields increase the risk of cancers in the occupational and general environment. However, even when the same or similar meters were used, this did not prevent the emergence of discrepant results in similar studies, possibly because of differences in the way the exposure measurements were made (Green et al., 1999). Similarly, even when it was possible to use an estimate of the extent to which a contaminant accumulated in the body, such as the presence of organochlorines in body fat, which are measures of the extent that such substances accumulate from environmental contamination, differences between studies in the associations found still arose (Woolcott et al., 2001). An ecological study is defined as “A study in which the units of analysis are populations or groups of people, rather than individuals.” (Last, 1995). The problem with such studies is of course the ecological fallacy, defined as “The bias that may occur because an association observed between variables on an aggregate level does not necessarily represent the association that exists at an individual level” (Last, 1995). When the National Research Council's Committee on Environmental Epidemiology considered the studies available on exposure to 0091-7435/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2007.06.020
hazardous waste sites, we included ecological studies among those that might help to clarify some of the issues (Committee on Environmental Epidemiology, 1991). However, for nearly all ecological studies that we reviewed, we noted that it was impossible to adequately consider potential confounders. In this issue of Preventive Medicine, we have another example of such a study by Mohr et al. (2007), raising the hypothesis (one can consider the findings no more convincing than that) that exposure to high levels of ultraviolet light is associated with a reduced risk of endometrial cancer, at first sight an improbable hypothesis, but as the authors indicate, one with some theoretical justification. The study of Mohr et al. is one of a series of studies which Garland and Grant and their colleagues have conducted over many years, essentially all with the same basic hypothesis, that ultra violet flux (or more precisely ultraviolet light B–UVB– irradiance) is associated with the occurrence of a number of cancers. One concern has to be that of publication bias: are we seeing just the results of those associations that by chance prove to be significant? Without a clear statement by the authors that this is not so, and that they have submitted for publication the null associations they have found, and some confirmation that editors and reviewers have accepted such reports with the same facility that they accept reports of significant associations, we cannot be sure. Therefore we are in an area where there has to be some doubt over the validity of the findings. We also need to consider the ecological fallacy for this particular study in some detail. Most of us will be comfortable with the findings associating the incidence of endometrial cancer with high intake of energy from animal sources and proportion of population overweight, as such associations have frequently been found before using other epidemiologic designs. Indeed, even if they had not been found, we still would have had good reason to doubt the validity of all the findings of Mohr et al.. Similarly for per capita health expenditure, probably an index for gross national product, found to be associated with the incidence and mortality of many cancers in the classic ecological study of Armstrong and Doll (1975). But what about UVB irradiance? Considerable care appears to have been taken by Mohr et al to obtain a precise estimate of exposure for each country, adjusted for cloud cover, and applied to the “population centroid” of the country concerned. Although no lag time was included, the estimates
326
Editorial
for animal food consumption were backdated to 1980 to account for the time period for cancer induction, but not for UVB, it being assumed that this was constant. However, it could be argued that recent UVB exposure has increased because of the reduction in the ozone layer, especially at higher latitudes. Thus, ignoring such an the effect is more likely to have minimized the possibility of finding an association than to have increased it, which is not the same level of concern as whether these group estimates apply to the relevant individuals. In fact the measurements of UVB irradiance employed probably have little relationship to individual exposures except in a broad geographic sense. It is entirely possible that those who live in an area of high UVB irradiance who are susceptible to its effects protect themselves from such exposure to a greater extent than those who live further North. Thus the validity of the data for UV exposure at the individual level is suspect. Adjustment for pigmentation was also performed at the country level, but this cannot adjust for individual susceptibility to the effects of skin exposure which must be associated with the degree that individuals use protective measures such as seeking shade and wearing clothing covering most of the skin, the latter possibility being acknowledged by the authors in discussing the study's limitations. The authors propose that further studies are needed of the effect of prediagnostic serum 25 hydroxyvitamin D levels (a circulating vitamin D metabolite) and oral intake of vitamin D on endometrial cancer risk. They point out that the association found in this study is similar to a previous ecologic study they performed on mortality from endometrial cancer and that the association is stronger than they found for breast cancer. These observations do not remove the potential effects of the ecological fallacy, however. There is a wider issue concerning this study and others like it that we must not overlook. The possibility that sun exposure, and therefore endogenous production of vitamin D, may be protective for some important cancers has led to suggestions that we should relax our advice with regard to protection against sun exposure, such protection having been urged repeatedly in
the last few decades to reduce the risk of skin cancer, and especially melanoma of the skin, one of the few cancers increasing in incidence (endometrial cancer not being one of them). In my view we have to be cautious pending further evidence. We cannot risk being led astray by ecological studies of this type. If that means further research, so be it, but let us attempt to perform this research without too much diversion from other potentially more important issues. It does suggest, however, that those in charge of the biobanks for some of the large cohort studies that encompass populations at different latitudes might consider evaluating whether they can assess serum 25 hydroxyvitamin D levels in relation to the incidence of endometrial cancer. References Armstrong, B., Doll, R., 1975. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int. J. Cancer 15, 617–631. Committee on Environmental Epidemiology, 1991. Environmental Epidemiology. Public Health and Hazardous Wastes. National Research Council. Washington DC, National Academy Press. Green, L.M., Miller, A.B., Agnew, D.A., et al., 1999. Childhood leukemia and personal monitoring of residential exposures to electric and magnetic fields in Ontario Canada. Cancer Causes and Control, vol. 10, pp. 233–243. International Agency for Research on Cancer, 2003. World cancer report. In: Stewart, B.W., Kleihues, P. (Eds.), IARC Press, Lyon. Last, J.M. (Ed.), 1995. A Dictionary of Epidemiology, 3rd edition. New York, Oxford University Press. Mohr, S.B., Garland, C.F., Gorham, E.D., Grant, W.B., Garland, F.C., 2007. Is ultraviolet irradiance associated with incidence rates of endometrial cancer: an ecological study of 107 countries. Prev. Med. 45, 327–331. Woolcott, C.G., Aronson, K.J., Hanna, W.M., et al., 2001. Organochlorines and breast cancer risk by receptor status, tumor size and grade (Canada). Cancer Causes and Control, vol. 12, pp. 395–404.
Anthony B. Miller Department of Public Health Sciences, University of Toronto, Canada E-mail address: [email protected].
Preventive Medicine 45 (2007) 325 – 326 www.elsevier.com/locate/ypmed
Editorial
Environment and cancer—How can the ecological study help us? The recognition that more than 80% of cancers are caused by factors external to mankind has often led to confusion, as many have interpreted such statements as an attribution to manmade factors in “the environment”, that is carcinogenic contaminants in air, water, and soil, that may either affect us directly, or through our food supply. The appreciation that exposure to the majority of the causal factors for cancer is attributable to our lifestyle, what we smoke, eat, drink, how much we exercise, and with what we work, has still not completely satisfied many, who feel that “they”, i.e. others exemplified by government and industry, are poisoning our environment, and if catastrophe is not already with us, it is not far around the corner. Estimates of the proportion of cancers that are due to such factors have usually been very small, however; recently an estimate of 1-4% for the world as a whole was made (IARC, 2003). The trouble for epidemiologists in conducting the research necessary to refine such estimates is that when exposure is uniform, the classical observational analytic methods, case– control, and cohort, cannot work well because they depend on a contrast of measured or estimated exposures. Sometimes we can utilize a quantitative measure of exposure of an individual's environment, such as the use of meters of magnetic and sometimes also electrical fields, when investigating the possibility that such fields increase the risk of cancers in the occupational and general environment. However, even when the same or similar meters were used, this did not prevent the emergence of discrepant results in similar studies, possibly because of differences in the way the exposure measurements were made (Green et al., 1999). Similarly, even when it was possible to use an estimate of the extent to which a contaminant accumulated in the body, such as the presence of organochlorines in body fat, which are measures of the extent that such substances accumulate from environmental contamination, differences between studies in the associations found still arose (Woolcott et al., 2001). An ecological study is defined as “A study in which the units of analysis are populations or groups of people, rather than individuals.” (Last, 1995). The problem with such studies is of course the ecological fallacy, defined as “The bias that may occur because an association observed between variables on an aggregate level does not necessarily represent the association that exists at an individual level” (Last, 1995). When the National Research Council's Committee on Environmental Epidemiology considered the studies available on exposure to 0091-7435/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2007.06.020
hazardous waste sites, we included ecological studies among those that might help to clarify some of the issues (Committee on Environmental Epidemiology, 1991). However, for nearly all ecological studies that we reviewed, we noted that it was impossible to adequately consider potential confounders. In this issue of Preventive Medicine, we have another example of such a study by Mohr et al. (2007), raising the hypothesis (one can consider the findings no more convincing than that) that exposure to high levels of ultraviolet light is associated with a reduced risk of endometrial cancer, at first sight an improbable hypothesis, but as the authors indicate, one with some theoretical justification. The study of Mohr et al. is one of a series of studies which Garland and Grant and their colleagues have conducted over many years, essentially all with the same basic hypothesis, that ultra violet flux (or more precisely ultraviolet light B–UVB– irradiance) is associated with the occurrence of a number of cancers. One concern has to be that of publication bias: are we seeing just the results of those associations that by chance prove to be significant? Without a clear statement by the authors that this is not so, and that they have submitted for publication the null associations they have found, and some confirmation that editors and reviewers have accepted such reports with the same facility that they accept reports of significant associations, we cannot be sure. Therefore we are in an area where there has to be some doubt over the validity of the findings. We also need to consider the ecological fallacy for this particular study in some detail. Most of us will be comfortable with the findings associating the incidence of endometrial cancer with high intake of energy from animal sources and proportion of population overweight, as such associations have frequently been found before using other epidemiologic designs. Indeed, even if they had not been found, we still would have had good reason to doubt the validity of all the findings of Mohr et al.. Similarly for per capita health expenditure, probably an index for gross national product, found to be associated with the incidence and mortality of many cancers in the classic ecological study of Armstrong and Doll (1975). But what about UVB irradiance? Considerable care appears to have been taken by Mohr et al to obtain a precise estimate of exposure for each country, adjusted for cloud cover, and applied to the “population centroid” of the country concerned. Although no lag time was included, the estimates
326
Editorial
for animal food consumption were backdated to 1980 to account for the time period for cancer induction, but not for UVB, it being assumed that this was constant. However, it could be argued that recent UVB exposure has increased because of the reduction in the ozone layer, especially at higher latitudes. Thus, ignoring such an the effect is more likely to have minimized the possibility of finding an association than to have increased it, which is not the same level of concern as whether these group estimates apply to the relevant individuals. In fact the measurements of UVB irradiance employed probably have little relationship to individual exposures except in a broad geographic sense. It is entirely possible that those who live in an area of high UVB irradiance who are susceptible to its effects protect themselves from such exposure to a greater extent than those who live further North. Thus the validity of the data for UV exposure at the individual level is suspect. Adjustment for pigmentation was also performed at the country level, but this cannot adjust for individual susceptibility to the effects of skin exposure which must be associated with the degree that individuals use protective measures such as seeking shade and wearing clothing covering most of the skin, the latter possibility being acknowledged by the authors in discussing the study's limitations. The authors propose that further studies are needed of the effect of prediagnostic serum 25 hydroxyvitamin D levels (a circulating vitamin D metabolite) and oral intake of vitamin D on endometrial cancer risk. They point out that the association found in this study is similar to a previous ecologic study they performed on mortality from endometrial cancer and that the association is stronger than they found for breast cancer. These observations do not remove the potential effects of the ecological fallacy, however. There is a wider issue concerning this study and others like it that we must not overlook. The possibility that sun exposure, and therefore endogenous production of vitamin D, may be protective for some important cancers has led to suggestions that we should relax our advice with regard to protection against sun exposure, such protection having been urged repeatedly in
the last few decades to reduce the risk of skin cancer, and especially melanoma of the skin, one of the few cancers increasing in incidence (endometrial cancer not being one of them). In my view we have to be cautious pending further evidence. We cannot risk being led astray by ecological studies of this type. If that means further research, so be it, but let us attempt to perform this research without too much diversion from other potentially more important issues. It does suggest, however, that those in charge of the biobanks for some of the large cohort studies that encompass populations at different latitudes might consider evaluating whether they can assess serum 25 hydroxyvitamin D levels in relation to the incidence of endometrial cancer. References Armstrong, B., Doll, R., 1975. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int. J. Cancer 15, 617–631. Committee on Environmental Epidemiology, 1991. Environmental Epidemiology. Public Health and Hazardous Wastes. National Research Council. Washington DC, National Academy Press. Green, L.M., Miller, A.B., Agnew, D.A., et al., 1999. Childhood leukemia and personal monitoring of residential exposures to electric and magnetic fields in Ontario Canada. Cancer Causes and Control, vol. 10, pp. 233–243. International Agency for Research on Cancer, 2003. World cancer report. In: Stewart, B.W., Kleihues, P. (Eds.), IARC Press, Lyon. Last, J.M. (Ed.), 1995. A Dictionary of Epidemiology, 3rd edition. New York, Oxford University Press. Mohr, S.B., Garland, C.F., Gorham, E.D., Grant, W.B., Garland, F.C., 2007. Is ultraviolet irradiance associated with incidence rates of endometrial cancer: an ecological study of 107 countries. Prev. Med. 45, 327–331. Woolcott, C.G., Aronson, K.J., Hanna, W.M., et al., 2001. Organochlorines and breast cancer risk by receptor status, tumor size and grade (Canada). Cancer Causes and Control, vol. 12, pp. 395–404.
Anthony B. Miller Department of Public Health Sciences, University of Toronto, Canada E-mail address: [email protected].