The International Agency for Research on Cancer （IARC） evaluation of the carcinogenicity of outdoor air pollution： focus on China

The International Agency for Research on Cancer （IARC） has classified outdoor air pollution and the particulate matter （PM） in outdoor air pollution as carcinogenic to humans, as based on sufficient evidence of carcinogenicity in humans and experimental animals and strong support by mechanistic studies. The data with important contributions to the evaluation are reviewed, highlighting the data with particular relevance to China, and implications of the evaluation with respect to China are discussed. The air pollution levels in Chinese cities are among the highest observed in the world today and frequently exceed health based national and international guidelines. Data from high-quality epidemiologic studies in Asia, Europe, and North America consistently show positive associations between lung cancer and PM exposure and other indicators of air pollution, which persist after adjustment for important lung cancer risk factors, such as tobacco smoking. Epidemiologic data from China are limited but nevertheless indicate an increased risk of lung cancer associated with several air pollutants. Excess cancer risk is also observed in experimental animals exposed to polluted outdoor air or extracted PM. The exposure of several species to outdoor air pollution is associated with markers of genetic damage that have been linked to increased cancer risk in humans. Numerous studies from China, especially genetic biomarker studies in exposed populations, support that the polluted air in China is genotoxic and carcinogenic to humans. The evaluation by IARC indicates both the need for further research into the cancer risks associated with exposure to air pollution in China and the urgent need to act to reduce exposure to the population.     

Lack of effect of 94 GHz radio frequency radiation exposure in an animal model of skin carcinogenesis

Although there is no evidence that electromagnetic energy in the radio frequency radiation (RFR) band is mutagenic, there have been suggestions that RFR energy might serve as either a promoter or co-promoter in some animal models of carcinogenesis. Recent developments in electromagnetic technology have resulted in the manufacture of RFR sources capable of generating frequencies in the millimeter wavelength (MMW) range (30-300 GHz). Because absorption of MMW energy occurs in the skin, it is to be expected that long-term detrimental health effects, if any, would most likely be manifest in the skin. In this study we investigated whether a single (1.0 W/cm(2) for 10 s) or repeated (2 exposures/week for 12 weeks, 333 mW/cm(2) for 10 s) exposure to 94 GHz RFR serves as a promoter or co-promoter in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced SENCAR mouse model of skin carcinogenesis. Neither paradigm of MMW exposure significantly affected papilloma development, as evidenced by a lack of effect on tumor incidence and multiplicity. There was also no evidence that MMW exposure served as a co-promoter in DMBA-induced animals repeatedly treated with 12-O-tetradecanoylphorbol 13-acetate. Therefore, we conclude that exposure to 94 GHz RFR under these conditions does not promote or co-promote papilloma development in this animal model of skin carcinogenesis.     

分子流行病学的原理与应用及对人前列腺癌的研究

癌瘤形成是一个涉及瘤的起始、促进、转变、演进和建成的多阶段过程。与人癌危险（ｃａｎｃｅｒｒｉｓｋ）有关的致癌因子，有的已知，有的尚不清楚，包括遗传易感性，以及职业的、环境的、和生活方式等因子。可疑致癌因子与癌危险之间的联系通常是用经典流行病学方法来研究，就是将受到暴露的一组人群与年龄性别配对与未受到暴露的对照组比较。即使用此法证实有联系，但仍得不到其中的因果关系。况且，经典流行病学技术用以估计个体的癌危险，其应用性是有限的。分子流行病学是一新兴领域，着重于用分子遗传学和生化技术来评估个体的癌危险。它能在临床症状发生前，就能用生物学标志来鉴定癌危险，行施有效的干预。从体内外实验模型，综合基因结构、功能和异常的知识，并建立一系列与分子的和遗传的损伤，以及与瘤诊断和预后测定有关的生物学标志，分子流行病学潜在地帮助人们获知人类健康和疾病的更高认识，从而可更适当地推论到更大的人群中去。本文试图用概念图式介绍关键方法，来阐明这些原理，并提供如何用特定的研究技术来探讨前列腺细胞转化和癌变的问题。     

Molecular epidemiology in cancer research (review)

In recent years, a new tool known as 'molecular epidemiology' has been developed for cancer research. This approach evaluates molecular phenomena of the carcinogenesis process as related to exogenous and endogenous risk factors. Modern laboratory methodologies make available for similar studies many applicable endpoints. These techniques may be applied directly in tissues bearing risk for cancer development (target tissues) or in 'surrogate' tissues more easily recoverable but not prone to neoplastic transformation. Possible useful endpoints are related to metabolic cell activities, presence of toxic substances metabolites in various cell compartments, genotypic lesions or phenotypic alterations. The present article reports and briefly comments the main laboratory techniques used in molecular epidemiology studies, with particular reference to results obtained in humans undergoing environmental exposure to cancer risk factors. It is concluded that each single end point possesses specific attributes highlighting only. some aspects of the complex carcinogenesis process. Therefore, molecular epidemiology studies comparing multiple endpoints normally produce the most reliable and useful data, and should represent the gold standard in the field.     

Modern criteria to determine the etiology of human carcinogens

Rapid identification of human carcinogens before their dissemination into society, and exposure of worker and lay populations is an important goal of cancer research. Retroactively, verification of in-place human carcinogens is also required to target their removal, and other preventive and therapeutic strategies. The hierarchy of methods used historically for evaluation of carcinogenic potential is epidemiology > animal bioassays > mechanistic studies, and the focus has been on single agents that are genotoxic. However, mechanistic research has revealed several obligatory steps in carcinogenesis, tumor promotion, and progression that can now be used in screening studies with human cells in vitro and animal bioassays. These approaches should be combined with molecular epidemiology and molecular pathology to identify human carcinogens with more emphasis on evaluating combinations of suspect agents and mechanisms of action of epigenetic carcinogens.     

Toward precision medicine for preserving fertility in cancer patients: existing and emerging fertility preservation options for women

As the number of young cancer survivors increases, quality of life after cancer treatment is becoming an ever more important consideration. According to a report from the American Cancer Society, approximately 810,170 women were diagnosed with cancer in 2015 in the United States. Among female cancer survivors, 1 in 250 are of reproductive age. Anticancer therapies can result in infertility or sterility and can have long-term negative effects on bone health, cardiovascular health as a result of reproductive endocrine function. Fertility preservation has been identified by many young patients diagnosed with cancer as second only to survival in terms of importance. The development of fertility preservation technologies aims to help patients diagnosed with cancer to preserve or protect their fertility prior to exposure to chemo- or radiation therapy, thus improving their chances of having a family and enhancing their quality of life as a cancer survivor. Currently, sperm, egg, and embryo banking are standard of care for preserving fertility for reproductive-age cancer patients; ovarian tissue cryopreservation is still considered experimental. Adoption and surrogate may also need to be considered. All patients should receive information about the fertility risks associated with their cancer treatment and the fertility preservation options available in a timely manner, whether or not they decide to ultimately pursue fertility preservation. Because of the ever expanding number of options for treating cancer and preserving fertility, there is now an opportunity to take a precision medicine approach to informing patients about the fertility risks associated with their cancer treatment and the fertility preservation options that are available to them.     

Use of exposure information and animal cancer data in the prevention of environmental and occupational cancer

In order to prevent cancer, a hazard should optimally be identified before humans are exposed to it. Therefore, valid procedures should be available for predicting human risks on the basis of experimental results. The adequacy of experimental data for identifying potential human health risks have been the subject of scientific question and debate. Use of such results and of data on exposure in setting priorities for cancer prevention should, in principle, be feasible in view of the relatively good correlation between animal and human data. Studies have also revealed a reasonable quantitative relationship between carcinogenic potencies of several chemicals in laboratory rodents and humans. The ranking of cancer hazards on the basis of experimental data requires estimates of both the extent of human exposure and of the size of the exposed population. Occupational exposures can result in high individual exposures, whereas the general population is usually exposed to lower levels. Action for cancer prevention can be taken at both levels.     

Health effects of inhaled radon progeny∗

Abstract

To clarify etiology of lung cancer in nonsmoker females, various studies have been done. Particularly, host factors and environmental tobacco smoking (ETS) of females have been emphasized. However, traditional epidemiological data showed controversial results of sex or gender differences in lung cancer susceptibility and suggest presence of some confounders. One of them is that most of epidemiology studies are based on self-reports for ETS. To prevent misestimate effects of ETS via the self-report, exposure monitoring of ETS is required. On the other hand, focusing on genetic polymorphisms in metabolic enzymes and DNA repair, molecular epidemiological studies have been done in nonsmoker females. Therefore, this review considered: 1. gender differences in lung cancer; 2. effects of passive smoking on lung cancer; 3. exposure monitoring of ETS including genetic risks of lung cancer to clarify etiology of lung cancer in the nonsmoker females with molecular epidemiological discussion.     

Molecular epidemiology and biomarkers in etiologic cancer research: the new in light of the old.

The purpose of this review is to evaluate progress in molecular epidemiology over the past 24 years in cancer etiology and prevention to draw lessons for future research incorporating the new generation of biomarkers. Molecular epidemiology was introduced in the study of cancer in the early 1980s, with the expectation that it would help overcome some major limitations of epidemiology and facilitate cancer prevention. The expectation was that biomarkers would improve exposure assessment, document early changes preceding disease, and identify subgroups in the population with greater susceptibility to cancer, thereby increasing the ability of epidemiologic studies to identify causes and elucidate mechanisms in carcinogenesis. The first generation of biomarkers has indeed contributed to our understanding of risk and susceptibility related largely to genotoxic carcinogens. Consequently, interventions and policy changes have been mounted to reduce risk from several important environmental carcinogens. Several new and promising biomarkers are now becoming available for epidemiologic studies, thanks to the development of high-throughput technologies and theoretical advances in biology. These include toxicogenomics, alterations in gene methylation and gene expression, proteomics, and metabonomics, which allow large-scale studies, including discovery-oriented as well as hypothesis-testing investigations. However, most of these newer biomarkers have not been adequately validated, and their role in the causal paradigm is not clear. There is a need for their systematic validation using principles and criteria established over the past several decades in molecular cancer epidemiology.     

Electromagnetic Fields and Female Breast Cancer

The possibility that long term exposure to relatively weak power frequency electromagnetic fields (EMF) could increase the risk of breast cancer has been investigated during the past decade. The hypothesis is based on the assumption that magnetic field exposures suppress melatonin production and that melatonin is protective against breast cancer. Most epidemiological studies have indicated little or no overall effect of EMF exposure, but some early studies suggested effects among premenopausal women, particularly for estrogen receptor positive breast tumors. The early studies were often limited by small numbers, crude exposure information and lack of information on confounding factors. In more recent occupational studies, again no overall risk increases were reported, but some studies found increased risks in certain subgroups, although with no consistent pattern across studies. A recent very large occupational study with improved exposure assessment and enough statistical power also for subgroup analyses found no indications of increased risks in any subgroups. Most of the recent well-designed residential studies report no increased risks, and similar findings are reported in the majority of studies of bed heating devices. Overall, the weight of the evidence available today does not suggest an increased risk of breast cancer related to EMF exposure.     

The Chernobyl accident--an epidemiological perspective

Twenty-five years have passed since radioactive releases from the Chernobyl nuclear accident led to the exposure of millions of people in Europe. Studies of affected populations have provided important new data on the links between radiation and cancer—particularly the risk of thyroid tumours from exposure to iodine isotopes—that are important not only for a fuller scientific understanding of radiation effects, but also for radiation protection. It is now well documented that children and adolescents exposed to radioiodines from Chernobyl fallout have a sizeable dose-related increase in thyroid cancer, with the risk greatest in those youngest at exposure and with a suggestion that deficiency in stable iodine may increase the risk. Data on thyroid cancer risks to other age groups are somewhat less definitive. In addition, there have been reported increases in incidence and mortality from non-thyroid cancers and non-cancer end points. Although some studies are difficult to interpret because of methodological limitations, recent investigations of Chernobyl clean-up workers (‘liquidators’) have provided evidence of increased risks of leukaemia and other haematological malignancies and of cataracts, and suggestions of an increase in the risk of cardiovascular diseases, following low doses and low dose rates of radiation. Further careful follow-up of these populations, including the establishment and long-term support of life-span study cohorts, could provide additional important information for the quantification of radiation risks and the protection of persons exposed to low doses of radiation.     

Environmental and chemical carcinogenesis

People are continuously exposed exogenously to varying amounts of chemicals that have been shown to have carcinogenic or mutagenic properties in experimental systems. Exposure can occur exogenously when these agents are present in food, air or water, and also endogenously when they are products of metabolism or pathophysiologic states such as inflammation. It has been estimated that exposure to environmental chemical carcinogens may contribute significantly to the causation of a sizable fraction, perhaps a majority, of human cancers, when exposures are related to "life-style" factors such as diet, tobacco use, etc. This chapter summarizes several aspects of environmental chemical carcinogenesis that have been extensively studied and illustrates the power of mechanistic investigation combined with molecular epidemiologic approaches in establishing causative linkages between environmental exposures and increased cancer risks. A causative relationship between exposure to aflatoxin, a strongly carcinogenic mold-produced contaminant of dietary staples in Asia and Africa, and elevated risk for primary liver cancer has been demonstrated through the application of well-validated biomarkers in molecular epidemiology. These studies have also identified a striking synergistic interaction between aflatoxin and hepatitis B virus infection in elevating liver cancer risk. Use of tobacco products provides a clear example of cancer causation by a life-style factor involving carcinogen exposure. Tobacco carcinogens and their DNA adducts are central to cancer induction by tobacco products, and the contribution of specific tobacco carcinogens (e.g. PAH and NNK) to tobacco-induced lung cancer, can be evaluated by a weight of evidence approach. Factors considered include presence in tobacco products, carcinogenicity in laboratory animals, human uptake, metabolism and adduct formation, possible role in causing molecular changes in oncogenes or suppressor genes, and other relevant data. This approach can be applied to evaluation of other environmental carcinogens, and the evaluations would be markedly facilitated by prospective epidemiologic studies incorporating phenotypic carcinogen-specific biomarkers. Heterocyclic amines represent an important class of carcinogens in foods. They are mutagens and carcinogens at numerous organ sites in experimental animals, are produced when meats are heated above 180 degrees C for long periods. Four of these compounds can consistently be identified in well-done meat products from the North American diet, and although a causal linkage has not been established, a majority of epidemiology studies have linked consumption of well-done meat products to cancer of the colon, breast and stomach. Studies employing molecular biomarkers suggest that individuals may differ in their susceptibility to these carcinogens, and genetic polymorphisms may contribute to this variability. Heterocyclic amines, like most other chemical carcinogens, are not carcinogenic per se but must be metabolized by a family of cytochrome P450 enzymes to chemically reactive electrophiles prior to reacting with DNA to initiate a carcinogenic response. These same cytochrome P450 enzymes--as well as enzymes that act on the metabolic products of the cytochromes P450 (e.g. glucuronyl transferase, glutathione S-transferase and others)--also metabolize chemicals by inactivation pathways, and the relative amounts of activation and detoxification will determine whether a chemical is carcinogenic. Because both genetic and environmental factors influence the levels of enzymes that metabolically activate and detoxify chemicals, they can also influence carcinogenic risk. Many of the phenotypes of cancer cells can be the result of mutations, i.e., changes in the nucleotide sequence of DNA that accumulate as tumors progress. These can arise as a result of DNA damage or by the incorporation of non-complementary nucleotides during DNA synthetic processes. Based upon the disparity between the infrequency of spontaneous mutations and the large numbers of mutations reported in human tumors, it has been postulated that cancers must exhibit a mutator phenotype, which would represent an early event in cancer progression. A mutator phenotype could be generated by mutations in genes that normally function to guarantee genetic stability. These mutations presumably arise via DNA damage by environmental or endogenous agents, but it remains to be determined whether the acquisition of a mutator phenotype is a necessary event during tumor progression.     

Epidemiologische Studien zu Strahlenexposition und Gesundheit

Radiation epidemiology investigates the effects on human health of ionizing and non-ionizing radiation. Of particular interest is the carcinogenicity of radiation exposure. In Germany, numerous epidemiological studies on these topics have been conducted in the recent past, many of them in international collaboration. For example, studies assessing cancer risk in children living near nuclear installations, as well as a large case-control study on the risk of mobile telephone use and investigations on the UV radiation – skin cancer link have been performed. Medical practitioners are responsible for the practical implementation of radiation protection, especially in medical diagnostics and therapy. In addition, practitioners require knowledge of radiation health effects for consultation with their patients. This article provides an overview of the fundamentals of radiation epidemiology and of major radiation epidemiology studies in Germany.     

Can traditional epidemiology detect cancer risks caused by occupational exposure to pesticides?

In order to investigate the possible relationship between cancer and occupational exposure to pesticides, we reviewed the latest literature of the epidemiological studies in this area coming to the conclusion that, while several studies indicate a link between certain pesticides and certain tumors, this information is still insufficient, and further research on the health consequences of exposure to pesticides is needed. Moreover, provided there is a risk, it is often too limited to be detected by available epidemiological techniques. Therefore, in addition to the epidemiological studies, the development of new biology, gene technology and medical biotechnology methods may significantly enhance the specificity of the epidemiological studies. Thus, the fusion of molecular biology and epidemiology into molecular epidemiology may provide more specific methods for monitoring the occupational dependent carcinogenic risk of individuals and groups.     

The contribution of molecular epidemiology to the identification of human carcinogens: current status and future perspectives

BackgroundThe use of biological-based markers of exposure, intermediate effect, outcome, and susceptibility has become standard practice in cancer epidemiology, which has contributed to identification of several carcinogenic agents. Nevertheless, with the exception of biological agents, this contribution, in terms of providing sufficiently strong evidence as required by the International Agency for Research on Cancer (IARC) monographs, has been modest.Materials and methodsWe discuss the overall contribution of molecular epidemiology to identification of carcinogens, with focus on IARC monographs.ResultsFor many carcinogens, valid biological markers of exposure and mechanisms of actions are not available. Molecular markers are usually assessed in single biological samples, which may not represent the actual exposure or biological events related to carcinogens. The contribution of molecular epidemiology to identification of carcinogens has mainly been limited to the carcinogens acting through a genotoxic mechanism, i.e. when carcinogens induce DNA damage. A number of factors, including certain hormones and overweight/obesity, may show carcinogenic effects through nongenotoxic pathways, for which mechanisms of carcinogenicity are not well identified and their biomarkers are sparse.ConclusionLongitudinal assessment of biomarkers may provide more informative data in molecular epidemiology studies. For many carcinogens and mechanistic pathways, in particular nongenotoxic carcinogenicity, valid biological markers still need to be identified.     

Organochlorines and breast cancer risk

Organochlorines are a diverse group of synthetic chemicals that include polychlorinated biphenyls (PCBs), dioxins, and organochlorine pesticides such as dichlorodiphenyl-trichloroethane (DDT), lindane, and hexachlorobenzene. Although use of DDT and PCBs has been banned in the United States since the 1970s, some organochlorine compounds have accumulated and persisted within the environment. As a result, measurable amounts can still be found in human tissue. Because some organochlorine compounds act as estrogen agonists or antagonists within in vitro and experimental animal systems, a possible association of breast cancer risk with organochlorine exposure has been hypothesized and investigated. Although a few studies support this hypothesis, the vast majority of epidemiological studies do not. While some of these compounds may have other adverse environmental or health effects, organochlorine exposure is not believed to be causally related to breast cancer. Women concerned about possible organochlorine exposure can be reassured that available evidence does not suggest an association between these chemicals and breast cancer.     

Extremely low frequency electromagnetic fields (EMF) and brain cancer in adults and children: review and comment

Epidemiologic and experimental research on the potential carcinogenic effects of extremely low frequency electromagnetic fields (EMF) has now been conducted for over two decades. Cancer epidemiology studies in relation to EMF have focused primarily on brain cancer and leukemia, both from residential sources of exposure in children and adults and from occupational exposure in adult men. Because genotoxic effects of EMF have not been shown, most recent laboratory research has attempted to show biological effects that could be related to cancer promotion. In this report, we briefly review residential and occupational EMF studies on brain cancer. We also provide a general review of experimental studies as they relate both to the biological plausibility of an EMF-brain cancer relation and to the insufficiency of such research to help guide exposure assessment in epidemiologic studies. We conclude from our review that no recent research, either epidemiologic or experimental, has emerged to provide reasonable support for a causal role of EMF on brain cancer.     

Molecular epidemiology of physical activity and cancer.

As in other areas of epidemiology, researchers studying physical activity and cancer have begun to include laboratory analyses of biological specimens in their studies. The incorporation of these "biomarkers" into epidemiology has been termed molecular epidemiology and is an approach primarily developed to study chemical carcinogens. Thus far, there has been no discussion in the field on how the established molecular epidemiologic framework might be adapted for research into physical activity, what methodologic needs exist, what the goals of such an approach might be, and what limitations exist. This article relates the literature on molecular epidemiology to the needs of physical activity research and tries to set research priorities for the field as it moves in this new direction. Although this approach will be very useful for investigating the mechanisms through which physical activity exerts effects, there are several challenges for physical activity epidemiologists in adapting molecular epidemiologic approaches. Primarily, there are currently no available biomarkers that might be considered measures of exposure or biologically effective dose. In addition, most available biomarkers of intermediate effects have been tested in training studies at activity levels much higher than those seen in population-based epidemiologic studies. Thus, it is not clear whether these biomarkers are valid at lower activity levels. Furthermore, the nature of the relationship between activity and many available biomarkers depends very much on the context of the activity. Addressing these issues should be a priority if we are to develop a molecular epidemiologic paradigm for studying physical activity.     

Tobacco smoke carcinogens and lung cancer.

The complexity of tobacco smoke leads to some confusion about the mechanisms by which it causes lung cancer. Among the multiple components of tobacco smoke, 20 carcinogens convincingly cause lung tumors in laboratory animals or humans and are, therefore, likely to be involved in lung cancer induction. Of these, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles. This review focuses on carcinogens in tobacco smoke as a means of simplifying and clarifying the relevant information that provides a mechanistic framework linking nicotine addiction with lung cancer through exposure to such compounds. Included is a discussion of the mechanisms by which tobacco smoke carcinogens interact with DNA and cause genetic changes--mechanisms that are reasonably well understood--and the less well defined relationship between exposure to specific tobacco smoke carcinogens and mutations in oncogenes and tumor suppressor genes. Molecular epidemiologic studies of gene-carcinogen interactions and lung cancer--an approach that has not yet reached its full potential--are also discussed, as are inhalation studies of tobacco smoke in laboratory animals and the potential role of free radicals and oxidative damage in tobacco-associated carcinogenesis. By focusing in this review on several important carcinogens in tobacco smoke, the complexities in understanding tobacco-induced cancer can be reduced, and new approaches for lung cancer prevention can be envisioned.