Epidemiology: allergy history, IgE, and cancer

Numerous epidemiological studies have investigated potential associations between allergy history and cancer risk with strong inverse associations reported in studies of pancreatic cancer, glioma, and childhood leukemia. Recently, there has been a rapid expansion of the epidemiological literature both of studies evaluating self-reported allergy history in relation to cancer risk and of studies evaluating biological indicators of allergy history and immune function including levels of immunoglobulin (Ig) E. However, there are several potential methodological limitations associated with prior studies, and further research is required to clarify associations observed. This paper summarizes the recent epidemiological literature examining associations between allergy history and cancer risk. From 2008, a total of 55 epidemiological studies were identified that examined some aspect of the association between allergy and cancer. Although the majority of studies examined self-reported allergy history in relation to cancer risk, there were also studies examining allergy diagnoses or discharges as captured in existing administrative databases, levels of IgE, polymorphisms of allergy, inflammatory- or allergy-related cytokine genes, and concentrations of immune regulatory proteins. The most frequently studied cancer sites included brain and lymphatic and hematopoietic cancers. Potential methodological sources of bias are discussed as well as recommendations for future work.     

Childhood cancer and malignancies other than lung cancer related to passive smoking

Biochemical intake markers show that the fetus and breastfeeding infant are exposed to compounds in tobacco smoke if the mother smokes or is exposed to environmental tobacco smoke (ETS). Experimental studies demonstrate that some compounds in tobacco smoke are transplacental carcinogens. The available epidemiological data provide no conclusive evidence of an effect of maternal smoking during pregnancy on the risk of cancer in children. Only a few studies have been performed on ETS and cancer risks in adults, except for lung cancer, and no firm conclusions can be based on the results. There is a need for further epidemiological studies on passive smoking and cancer, both in children and in adults.     

DNA adducts as markers of exposure and risk

Many carcinogens exert their biological effects through the formation of DNA adducts by metabolically activated intermediates. Detecting the presence of DNA adducts in human tissues is, therefore, a tool for molecular epidemiological studies of cancer. A large body of evidence demonstrates that DNA adducts are useful markers of carcinogen exposure, providing an integrated measurement of carcinogen intake, metabolic activation, and delivery to the target macromolecule in target tissues. Monitoring accessible surrogate tissues, such as white blood cells, also provides a means of investigating occupational or environmental exposure in healthy individuals. Such exposure to carcinogens, e.g. to polycyclic aromatic hydrocarbons, has been demonstrated in several industries and in defined populations, respectively, by the detection of higher levels of adducts. Adducts detected in many tissues of smokers are at levels significantly higher than in non-smokers, although the magnitude of the elevation does not predict the magnitude of the risk. While such associations do not demonstrate causality, they do, importantly, lend plausibility to observed associations between smoking and cancer. However, there is still resistance to the notion that such monitoring can inform, rather than merely confirm, epidemiological investigations of cancer causation. Interestingly, smoking was recently causally linked to cervical cancer after years of being considered a confounding factor; yet smoking-related adducts have been known to be present in cervical epithelium for some time. In the few prospective studies thus far, elevated adduct levels have been found in individuals who subsequently developed cancer compared with individuals who did not. The potential for biomarker measurements, such as DNA adducts, to provide answers to the origin of many cases of human cancer for which an environmental cause is suspected, needs to be exploited more fully in future epidemiological studies.     

Health effects of static magnetic fields--a review of the epidemiological evidence

Potential health effects of static magnetic fields have received far less attention than, for example, power frequency or radiofrequency fields. Static fields are found in certain occupational settings, e.g. in the aluminium and chloralkali industries, in arc-welding processes, and certain railways systems. Magnetic resonance imaging (MRI) for medical diagnosis is another source. This paper summarizes the epidemiological evidence of static magnetic field exposure and long-term health effects. There are only a few epidemiological studies available, and the majority of these have focused on cancer risks. There are some reports on reproductive outcomes, and sporadic studies of other outcomes. Overall, few occupational studies have focused specifically on effects of static magnetic field exposure, and exposure assessment have consequently been poor or non-existent. Results from studies that have estimated static magnetic field exposure have not indicated any increased cancer risks, but they are generally based on small numbers of cases and crude exposure assessment. Control of confounding has been limited, and it is likely that the “healthy worker” effect have influenced the results. A few studies have reported results on reproductive outcomes among aluminium workers and MRI operators, but limitations in study designs prevent conclusions. A problem in epidemiological studies of static magnetic fields is that workers in exposed occupations are also exposed to a wide variety of other potentially harmful agents, including some known carcinogens. In conclusion, the available evidence from epidemiological studies is not sufficient to draw any conclusions about potential health effects of static magnetic field exposure.     

Are pre- or postnatal diagnostic X-rays a risk factor for childhood cancer? A systematic review

The risk of cancer after diagnostic X-rays received as fetus or during early childhood has been investigated in many studies. The results of recent epidemiological studies are summarized in a present systematic review. The strategies for literature search, inclusion criteria, and items for study quality assessment were defined in the study protocol. All epidemiological case control and cohort studies published in English between 1990 and 2006 that reported at least the size of the study population and risk estimates were included. Results were summarized separately for pre- and postnatal exposure and for each cancer site. Nineteen case control studies and six cohort studies matched the inclusion criteria. No association of leukemia with prenatal exposures was observed in nine case control studies. Heterogeneous results were found for postnatal exposures and leukemia in four studies. No significant effect of pre- and postnatal X-ray exposure was observed for other cancer sites (non-Hodgkin lymphomas, solid tumors and brain tumors). Most studies have limitations in study design, study size, or exposure measurement, and involve very low exposures. These results thus do not contradict previous evidence accumulated since 1956 indicating risk increases associated with prenatal X-ray exposure. Computed tomography is not covered in the studies and needs to be investigated in the future.     

Facilitative mechanisms of lead as a carcinogen

The carcinogenicity of lead compounds has received renewed attention because of continuing environmental and occupational sources of exposure in many countries. The epidemiological evidence for an association between lead exposures and human cancer risk has been strengthened by recent studies, and new data on mechanisms of action provide biological plausibility for assessing lead as a human carcinogen. Both epidemiological and mechanistic data are consistent with a facilitative role for lead in carcinogenesis, that is, lead by itself may not be both necessary and sufficient for the induction of cancer, but at a cellular and molecular level lead may permit or enhance carcinogenic events involved in DNA damage, DNA repair, and regulation of tumor suppressor and promoter genes. Some of these events may also be relevant to understanding mechanisms of lead-induced reproductive toxicity.     

Cell phones and cancer: what is the evidence for a connection?

There have been allegations in the media and in the courts that cell phones and other types of hand-held transceivers are a cause of cancer. There have also been numerous public objections to the siting of TV, radio and cell phone transmission facilities because of a fear of cancer induction. A recent publication in Radiation Research by Repacholi et al. (147, 631-640, 1997) which suggests that exposure to radiofrequency (RF) radiation may increase lymphoma incidence in mice has contributed to this controversy. The goal of this review is to provide biomedical researchers a brief overview of the existing RF radiation-cancer studies. This article begins with a brief review of the physics and technology of cell phones. It then reviews the existing epidemiological studies of RF radiation, identifying gaps in our knowledge. Finally, the review discusses the cytogenetics literature on RF radiation and the whole-animal RF-radiation carcinogenesis studies. The epidemiological evidence for an association between RF radiation and cancer is found to be weak and inconsistent, the laboratory studies generally do not suggest that cell phone RF radiation has genotoxic or epigenetic activity, and a cell phone RF radiation-cancer connection is found to be physically implausible. Overall, the existing evidence for a causal relationship between RF radiation from cell phones and cancer is found to be weak to nonexistent.     

ELF magnetic fields: animal studies, mechanisms of action

Animal studies can contribute to addressing the issue of possible greater health risk for children exposed to 50–60 Hz extremely low frequency (ELF) magnetic fields (MFs), mostly in terms of teratological effects and cancer.Teratology has been extensively studied in animals exposed to ELF MFs but experiments have not established adverse developmental effects.Childhood leukaemia has been the only cancer consistently reported in epidemiological studies as associated with exposure to ELF MFs. This association has been the basis for the classification as “possibly carcinogenic to humans” by the International Agency for Research on Cancer in 2002. Animal experiments have provided only limited support for these epidemiological findings. However, none but one study used an animal model for acute lymphoblastic leukaemia (ALL), the main form of childhood leukaemia, and exposures to ELF MFs were not carried out over the whole pregnancy period, when the first hit of ALL is assumed to occur.Moreover, there are no generally accepted biophysical mechanisms that could explain carcinogenic effects of low-level MFs. The radical pair mechanism and related cryptochromes (CRY) molecules have recently been identified in birds and other non-mammalian species, as a sensor of the geomagnetic field, involved in navigation. The hypothesis has to be tested in mammalian models. CRY, which is part of the molecular circadian clock machinery, is a ubiquitous protein likely to be involved in cancer cell growth and DNA repair.In summary, we now have some clues to test for a better characterization of the interaction between ALL and ELF MFs exposure.     

Selenoproteins and human health: Insights from epidemiological data

Knowledge of the plasma selenium levels associated with optimised concentration or activity of specific selenoproteins can provide considerable insights from epidemiological data on the possible involvement of those selenoproteins in health, most notably with respect to cancer. For cohort studies, if selenoproteins such as glutathione peroxidase and selenoprotein P are relevant to cancer, one might only expect to see an effect on risk when the concentrations in the cohort range from below, to above, the level needed to optimise the activity or concentration of these enzymes. Similarly, trials would only show a beneficial effect of supplementation if selenium status were raised from below, to above, the optimal concentration for the selenoproteins likely to be implicated in cancer risk, as occurred in the NPC trial but not in SELECT. The most powerful evidence for the involvement of selenoproteins in human health comes from epidemiological studies that have related single nucleotide polymorphisms in selenoproteins to disease risk. The totality of the evidence currently implicates GPx1, GPx4, SEPS1, Sep15, SEPP1 and TXNRD1 in conditions such as cardiovascular disease, pre-eclampsia and cancer. Future studies therefore need to determine not only selenium status, but genotype, both in selenoproteins and related pathways, when investigating the relationship of selenium with disease risk.     

Uncertainty Distributions for Cancer Potency Factors: Combining Epidemiological Studies with Laboratory Bioassays—the Example of Acrylonitrile

For eight chemicals or chemical mixtures with clear positive epidemiological evidence of carcinogenicity by inhalation (acrylonitrile, arsenic, benzene, beryllium, cadmium, chromium VI, coke oven emissions, and nickel), the United States Environmental Protection Agency (USEPA) uses that evidence to obtain a single best estimate of cancer potency factor. The methods used have so far been ad hoc, because of the differences in published studies, although there are common factors. In every case, the uncertainties involved in the various stages of analysis are qualitatively acknowledged, and often quantitatively estimated, but no formal attempt has been made to propagate the uncertainties. I here provide a detailed case study for acrylonitrile that (a) incorporates all estimates of uncertainty mentioned by the US EPA in their analysis and propagates that uncertainty to produce an uncertainty distribution; (b) updates the USEPA analysis to incorporate more recent epidemiological data from the same study used in their analysis.

For most of the materials known to be carcinogenic to humans (through epidemiologic evidence), there are also available cancer bioassays performed on laboratory animals. If the procedures used for estimating human carcinogenic potencies from laboratory animal bioassays are to be believed in cases where there are no human epidemiological data, their evidence should also be used where there is epidemiological evidence. A consistent method of incorporating the results of both epidemiological studies and laboratory animal bioassays into a single probability distribution for a human cancer potency is here detailed, using acrylonitrile as an example for which there is positive epidemiological data. The methods are sufficiently general to allow the incorporation of any combinations of positive and negative bioassay and epidemiological data.     

Breast reduction surgery and breast cancer risk: does reduction mammaplasty have a role in primary prevention strategies for women at high risk of breast cancer?

Prophylactic bilateral mastectomy has been demonstrated to reduce breast cancer incidence in women with a high inherited susceptibility to breast cancer. For the majority of high-risk women, however, bilateral prophylactic mastectomy is not an acceptable option for primary prevention of breast cancer. Several epidemiological follow-up studies have indicated that there may be a substantial reduction in breast cancer risk among women who have undergone breast reduction surgery. The authors reviewed the evidence from these studies, with emphasis on the problems inherent in interpreting the results of nonexperimental studies of elective medical procedures. Although such observational studies cannot demonstrate definitively that reduction mammaplasty reduces the risk of breast cancer, the evidence from these studies is sufficiently strong to warrant the evaluation of breast reduction surgery as an option for primary prevention in clinical studies of women at increased risk of breast cancer. The availability of a more acceptable surgical option for primary prevention of breast cancer could increase the number of women willing to choose risk reduction surgery and thus may result in an overall reduction in breast cancer mortality among high-risk women.     

Acromegaly and cancer

In recent years, it has become increasingly recognized that acromegaly is associated with an increased prevalence of colorectal cancer and pre-malignant tubular adenomas. The aetiology of these tumours is unknown but is likely to reflect increased levels of both insulin-like growth factor I (IGF-I), which is implicated in the development of sporadic colorectal cancer, and environmental factors, such as the bile acid deoxycholic acid. There is also evidence to suggest that the prevalence of breast and perhaps haematological malignancies might be increased in acromegaly, although these associations have been based on mostly small epidemiological surveys and clarification will come in the future once large-scale epidemiological studies have been completed.     

Epidemiology, cancer genetics and microarrays: making correct inferences, using appropriate designs

Different disciplines approach cancer with different study designs, techniques and established bodies of knowledge. This article identifies some established epidemiological data and methods, which are useful for cross-disciplinary molecular and genetic studies of cancer but which are ignored by some researchers. First, the international variation in cancer risk is accounted for extensively by variation in environmental exposures; it is unlikely that even minute characterization of individual genomes will provide the best assessment of cancer risk in the absence of comparably detailed information on the environment. Second, epidemiological study-design methods are sometimes the most appropriate to answer molecular questions, particularly when using techniques such as expression microarrays or proteomics to establish differences among cancer subtypes or biomarkers in the setting of a non-experimental study. In such studies, it is essential to avoid bias, control confounding and undertake accurate replication. Established epidemiological data and methods will contribute to the best use of the new molecular technology.     

Vitamin D and prostate cancer

Vitamin D and its metabolites are best known for their actions in calcium and bone metabolism. However, epidemiological studies have suggested that an increased prostate cancer risk is associated with decreased production of vitamin D. In vitro and in vivo studies have shown that the biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25D), inhibits proliferation of cancer cells derived from multiple tissues, including the prostate. Although the mechanisms underlying the growth inhibitory effects of 1,25D have not been fully elucidated, in prostate cancer cells 1,25D reduces cell growth via a number of cellular pathways, including cell cycle arrest, induction of apoptosis, and altered activation of growth factor signaling. The hypercalcemia induced by 1,25D in vivo limits its use clinically as a therapeutic agent. However, several 1,25D analogs have been developed that reduce prostate tumor growth in rodent xenograft models without causing hypercalcemia. Additional studies are required in order to determine whether these 1,25D analogs will be useful therapeutic agents for the treatment of prostate cancer.     

Phytoestrogens and breast cancer

The role of phytoestrogens and consumption of phytoestrogen-rich foods such as soy containing isoflavones and whole grain products with lignans for the prevention of breast cancer is reviewed. It is concluded that soy-containing diet in adult women is not or only slightly protective with regard to breast cancer, but that it may be beneficial if consumed in early life before puberty or during adolescence supporting results of immigrant and epidemiological studies. No negative effects of soy on breast cancer have been observed. On the other hand, a diet low in lignans, resulting in a low plasma enterolactone concentration, increases risk both in a case-control and a prospective study, but some controversial results have also been obtained. Some of these results may be explained by the fact that the determinants of plasma or urinary enterolactone concentration are very different in different countries. In Scandinavia, the main determinants are whole grain cereal food, vegetables and berries. Whether the protective effect is caused by the phytoestrogens in the diet or whether they are only biomarkers of a healthy diet has not been established.     

Estrogen receptor beta in breast cancer—Diagnostic and therapeutic implications

More than 10 years have passed since the discovery of the second estrogen receptor, estrogen receptor β (ERβ). It is now evident that ERα is not the only ER in breast cancer cells; in fact, ERβ is expressed in the majority of breast cancers although at lower levels than in the normal breast. In addition, ERβ is expressed in breast cancer infiltrating lymphocytes, fibroblasts and endothelial cells, all known to influence tumor growth. By overexpressing or knocking-out ERβ in breast cancer cell lines, several researchers have investigated its function with respect to proliferation and tumor growth. It appears that ERβ is anti-proliferative, in many ways antagonising the function of ERα. Furthermore, phytoestrogens have a binding-preference for ERβ and several epidemiological studies indicate a breast cancer preventing effect of this class of compounds. Tamoxifen is one of the standard, adjuvant treatments for ERα positive breast cancer, classically thought to mediate its effect through ERα. However, in several recent studies, ERβ has been described as a potential marker for tamoxifen response. In summary, experimental, epidemiological as well as diagnostic studies point towards ERβ as an important factor in breast cancer, opening up the possibility for novel ERβ-selective therapies in the treatment of breast cancer.     

A Review of the Epidemiology of Trichloroethylene and Kidney Cancer

The occupational epidemiological studies of trichloroethylene (TCE) exposure and kidney cancer are reviewed. Seven occupational cohort studies, conducted in the U.S., Finland, and Sweden involving over 130,000 workers, do not report statistically increased risks of kidney cancer among TCE-exposed workers. These studies were based on well-defined cohorts and exposure assessments involving urine biomonitoring or some type of job exposure matrix. In contrast, two German studies reported eight- to eleven-fold increased risks for renal cancer among TCE-exposed workers. However, numerous methodological and analytical shortcomings severely limit any interpretation of the German studies. We conclude that the more reliable epidemiologic data do not support a causal relationship between kidney cancer and TCE exposure.     

Correlating observed odds ratios from lung cancer case-control studies to SNP functional scores predicted by bioinformatic tools

Bioinformatic tools are widely utilized to predict functional single nucleotide polymorphisms (SNPs) for genotyping in molecular epidemiological studies. However, the extent to which these approaches are mirrored by epidemiological findings has not been fully explored. In this study, we first surveyed SNPs examined in case-control studies of lung cancer, the most extensively studied cancer type. We then computed SNP functional scores using four popular bioinformatics tools: SIFT, PolyPhen, SNPs3D, and PMut, and determined their predictive potential using the odds ratios (ORs) reported. Spearman's correlation coefficient (r) for the association with SNP score from SIFT, PolyPhen, SNPs3D, and PMut, and the summary ORs were r=-0.36 (p=0.007), r=0.25 (p=0.068), r=-0.20 (p=0.205), and r=-0.12 (p=0.370), respectively. By creating a combined score using information from all four tools we were able to achieve a correlation coefficient of r=0.51 (p<0.001). These results indicate that scores of predicted functionality could explain a certain fraction of the lung cancer risk detected in genetic association studies and more accurate predictions may be obtained by combining information from a variety of tools. Our findings suggest that bioinformatic tools are useful in predicting SNP functionality and may facilitate future genetic epidemiological studies.     

Trichloroethylene and Human Cancer

Evidence to suggest that trichloroethylene may be a human carcinogen comes mainly from two small epidemiological studies with supporting evidence from human toxicity and genotoxicity studies and from rodent cancer bioassays. Careful analysis of these data reveal marked inconsistencies between the data, differences in the conclusions drawn by various authorities reviewing the same data and, for certain key human studies, a complete absence of exposure data. Much of the rodent cancer data may be dismissed as not indicative of a human hazard because the tumors result from either peroxisome proliferation, or as a consequence of exceptionally high metabolic rates that are found uniquely in mouse tissues, or because the tumors only occur in the presence of overt toxicity. A common mechanism invoked to account for the development of renal tumors in both rats and humans is unproven, there is contrary evidence to suggest that this mechanism does not result in renal cancer, and alternative mechanisms have been proposed. Overall, the uncertainty and lack of consistency throughout the trichloroethylene studies, whether they are in humans, in animals, or in tests in vitro, lead to the conclusion that it would be wholly inappropriate to classify trichloroethylene as a human carcinogen.     

Reanalysis of epidemiological evidence on lung cancer and passive smoking

ObjectiveTo assess the epidemiological evidence for an increase in the risk of lung cancer resulting from exposure to environmental tobacco smoke.DesignReanalysis of 37 published epidemiological studies previously included in a meta-analysis allowing for the possibility of publication bias.ResultsIf it is assumed that all studies that have ever been carried out are included, or that those selected for review are truly representative of all such studies, then the estimated excess risk of lung cancer is 24%, as previously reported (95% confidence interval 13% to 36%, P<0.001). However, a significant correlation between study outcome and study size suggests the presence of publication bias. Adjustment for such bias implies that the risk has been overestimated. For example, if only 60% of studies have been included, the estimate of excess risk falls from 24% to 15%.ConclusionA modest degree of publication bias leads to a substantial reduction in the relative risk and to a weaker level of significance, suggesting that the published estimate of the increased risk of lung cancer associated with environmental tobacco smoke needs to be interpreted with caution.

Key messages

• A systematic review of epidemiological studies on passive smoking estimated the increased risk of lung cancer as 24%
• There is clear evidence of publication bias in these studies
• Reanalysis of the data allowing for the possibility of publication bias substantially lowers the estimate of relative risk