Human exposure to endocrine disrupters: carcinogenic risk assessment

Human exposure to endocrine disrupters (EDs) is widespread and is considered to pose a growing threat to human health. Recent advances in molecular and genetic research and better understanding of mechanisms of blastic cell transformation have led to efforts to improve cancer risk assessment for populations exposed to this family of xenobiotics. In risk assessment, low dose extrapolation of cancer incidence data from both experimental animals and epidemiology studies has been largely based on models assuming linear correlation at low doses, despite existence of evidence showing otherwise. Another weakness of ED risk assessment is poor exposure data in ecological studies. Those are frequently rough estimates derived from contaminated items of local food basket surveys. Polyhalogenated hydrocarbons are treated as examples. There is growing sense of urgency to develop a biologically based dose response model of cancer risk, integrating emerging data from molecular biology and epidemiology to provide more realistic data for risk assessors, public, public health managers and environmental issues administrators.     

Cancer molecular epidemiology: new horizons of prophylaxis

Perspectives of malignant neoplasm prophylaxis based on molecular biology achievements are discussed. Gene variants critical to development of hereditary cancer syndromes, genes modulating malignant neoplasm development risk without hereditary cancer syndrome development, and genes determining tendency of individuals for different malignant neoplasm progress risk increasing lifestyle factors are examined. Molecular epidemiology by using large scale population analysis of cancerogenesis linked genetic polymorphisms prevalence allows determination of risk groups at the most earlier stages of cell transformation or even before the onset of cell malignization and development of goal-based prophylaxis measures based on polymorphism and corresponding cancer type. Epidemiologic analysis of this type allows for earlier diagnostics in risk groups, therapy efficacy increase, disability decrease. Specific therapy on molecular level may be possible in the future.     

Epidemiology in protection and prevention against environmental mutagens/carcinogens Examples from occupational medicine

Subjects occupationally exposed to potential mutagens/carcinogens represent the most suitable groups for epidemiological studies aimed at assessing the risk for the individual or the offspring. Several cancer risks to humans have been detected by epidemiological studies performed in occupational settings. Cancer epidemiology studies have been able (a) to identify specific occupations or agents associated with the risk; (b) to verify the results of experimental studies; (c) to test the effectiveness of changes in production or preventive measures in decreasing risks. Reproductive epidemiology has suggested a risk of spontaneous abortions or of malformation in the offspring of workers exposed to some chemicals or occupations, but data are often conflicting due to methodological problems. With the aim of early assessment of risk in mind, the epidemiological use of indicators of exposure or of the early effect of exposure to genotoxic agents is increasingly applied to occupational groups. Cytological monitoring of subjects at risk of occupational cancer of lung or bladder is carried out mainly to diagnose precancerous lesions of target tissues. Cytogenetic methods (chromosome aberrations, SCE, micronuclei) in somatic cells provide a means for detecting early effects of occupational exposure to known or potential mutagens/carcinogens in selected groups of individuals, but their significance is widely debated. Monitoring of urinary mutagenicity, as applied in nurses handling cytostatic drugs, is an example of how an indicator of exposure to genotoxins can be used to evaluate the impact of preventive measures. Among the perspectives, biochemical epidemiology seems to be promising in detecting individuals genetically susceptible to cancer.     

Issues in Exposure and Dose Assessment for Epidemiology and Risk Assessment

Epidemiologic studies have been effective in identifying human environmental and occupational hazards. However, most epidemiologic data has been difficult to use in quantitative risk assessments because of the vague specification of exposure and dose. Toxicologic animal studies have used applied doses (quantities administered, or exposures with fixed duration) and well characterized end points to determine effects. However, direct use of animal data in human risk assessment has been limited by uncertainties in the extrapolation. The applied dose paradigm of toxicology is not suited for cross species extrapolation, nor for use in epidemiology as a dose metric because of the complexity of human exposures. Physiologically based pharmacokinetic (PBPK) modeling can estimate the time course of tissue concentrations in humans, given an exposure-time profile, and it has been used for extrapolating findings from animals to humans. It is proposed that human PBPK modeling can be used in appropriately designed epidemiologic studies to estimate tissue concentrations. Secondly, tissue time courses can be used to form dose metrics based on the type and time course of adverse effects. These dose metrics will strengthen the determination of epidemiologic dose-response relationships by reducing misclassification. Findings from this approach can be readily integrated into quantitative risk assessment.     

Molecular epidemiology of the late radiation effects

The scientific bases, problems, methods and prospects for the development of a new scientific direction "Molecular epidemiology of late consequences of ionizing radiation influence on the man" are reviewed. It is marked, that for two decades on the basis of achievements in the field of molecular biology, biochemistry, genetics and genomics it has arisen and is developing the important direction in infectious and non-infectious epidemiology--molecular epidemiology. Molecular epidemiology is a new section of epidemiology on border with molecular biology and genetics, integrating efforts of epidemiologists, molecular biologists, genetics and researchers from many other areas of knowledge in a direction of an estimation of individual risk of development of chronic diseases at practically healthy people, development of recommendations on their preventive maintenance in cohorts of risk and, hence, in all population by studying by molecular methods of an etiology of illnesses, mechanisms of a susceptibility to them, and also biological mechanisms and frequency of their development in human cohorts. Special development in molecular epidemiology was noticed for the methods named biomarkers, subdivided on 4 categories: 1) markers of an internal dose; 2) markers of an effective dose; 3) markers of preclinical biological effects; 4) markers of a susceptibility. Use of biomarkers in molecular-epidemiological researches appeared especially productive in oncology. As radiogenic cancers are the main remote consequence of exposure to ionizing radiations, approaches and achievements of molecular epidemiology of nonradiation cancers are perspective at becoming of molecular epidemiology of radiation effects, with an object to solve problems concerning mechanisms and features of radiation carcinogenesis, risk assessment, distribution and preventive maintenance of radiogenic cancers in cohorts of professionals of the various branches having contact to sources of ionizing radiation, and the population, exposed to radiation medically.     

Molecular epidemiology: new rules for new tools?

Molecular epidemiology combines biological markers and epidemiological observations in the study of the environmental and genetic determinants of cancer and other diseases. The potential advantages associated with biomarkers are manifold and include: (a) increased sensitivity and specificity to carcinogenic exposures; (b) more precise evaluation of the interplay between genetic and environmental determinants of cancer; (c) earlier detection of carcinogenic effects of exposure; (d) characterization of disease subtypes-etiologies patterns; (e) evaluation of primary prevention measures. These, in turn, may translate into better tools for etiologic research, individual risk assessment, and, ultimately, primary and secondary prevention. An area that has not received sufficient attention concerns the validation of these biomarkers as surrogate endpoints for cancer risk. Validation of a candidate biomarker's surrogacy is the demonstration that it possesses the properties required for its use as a substitute for a true endpoint. The principles underlying the validation process underwent remarkable developments and discussion in therapeutic research. However, the challenges posed by the application of these principles to epidemiological research, where the basic tool for this validation (i.e., the randomized study) is seldom possible, have not been thoroughly explored. The validation process of surrogacy must be applied rigorously to intermediate biomarkers of cancer risk before using them as risk predictors at the individual as well as at the population level.     

Updates to astronaut radiation limits: radiation risks for never-smokers

New epidemiology assessments of the life span study (LSS) of the atomic bomb survivors in Japan and of other exposed cohorts have been made by the U.S. National Academy of Sciences, the United Nations Committee on the Effects of Atomic Radiation, and the Radiation Research Effects Foundation in Japan. The National Aeronautics and Space Administration (NASA) uses a 3% risk of exposure-induced death (REID) as a basis for setting age- and gender-specific dose limits for astronauts. NASA's dose limits originate from the report of the National Council on Radiation Protection and Measurements (NCRP) in the year 2000 based on analysis of older epidemiology data. We compared the results of the recent analysis of the LSS to the earlier risk projections from the NCRP. Using tissue-specific, incidence-based risk transfer from the LSS data to a U.S. population to project REID values leads to higher risk and reduced dose limits for older astronauts (>40 years) compared to earlier models that were based on mortality risk transfer. Because astronauts and many other individuals should be considered as healthy workers, including never-smokers free of lifetime use of tobacco, we considered possible variations in risks and dose limits that would occur due to the reference population used for estimates. After adjusting cancer rates to remove smoking effects, radiation risks for lung and total cancer were estimated using a mixture model, with equal weights for additive and multiplicative transfer, to be 20% and 30% lower for males and females, respectively, for never-smokers compared to the average U.S. population. We recommend age- and gender-specific dose limits based on incidence-based risk transfer for never-smokers that could be used by NASA. Our analysis illustrates that gaining knowledge to improve transfer models, which entail knowledge of cancer initiation and promotion effects, could significantly reduce uncertainties in risk projections.     

Research on smoking and lung cancer: a landmark in the history of chronic disease epidemiology

This paper describes the history of the epidemiologic research on lung cancer prior to 1970 and its effect on chronic disease epidemiology. In the 1930s, epidemiology was largely concerned with acute infectious diseases. As the evidence grew that the incidence of lung cancer was increasing among men, however, epidemiologists undertook research into the etiology of the disease. In 1950, Doll and Hill, in England, and Wynder and Graham, in the United States, published substantial case-control studies that implicated the use of tobacco as a major risk factor for the disease. A controversy developed over the credibility of this finding and was increased in 1954 when a cohort study by Doll and Hill and another by Hammond and Horn each gave estimates that the risk of lung cancer was greatly increased among smokers relative to the risk among comparable non-smokers. An account is given of the disputes surrounding these and related studies. The controversy had a stimulating effect in fostering the developing discipline of chronic disease and epidemiology.     

A Probabilistic Human Health Risk Assessment for Environmental Exposure to Dibutylphthalate

In the European Union, Directive 92/32/EC and EC Council Regulation (EC) 793/93 require the risk assessment of industrial chemicals. In this framework, it is agreed to characterise the level of “risk” by means of the deterministic quotient of exposure and effects parameters. Decision makers require that the uncertainty in the risk assessment be accounted for as explicitly as possible. Therefore, this paper intends to show the advantages and possibilities of a probabilistic human health risk assessment of an industrial chemical, dibutylphthalate (DBP). The risk assessment is based on non-cancer endpoints assumed to have a threshold for toxicity. This example risk assessment shows that a probabilistic risk assessment in the EU framework covering both the exposure and the effects assessment is feasible with currently available techniques. It shows the possibility of comparing the various uncertainties involved in a typical risk assessment, including the uncertainty in the exposure estimate, the uncertainty in the effect parameter, and the uncertainty in assessment factors used in the extrapolation from experimental animals to sensitive human beings. The analysis done did not confirm the reasonable worst-case character of the deterministic EU-assessment of DBP. Sensitivity analysis revealed the extrapolation procedure in the human effects assessment to be the main source of uncertainty. Since the probabilistic approach allows determination of the range of possible outcomes and their likelihood, it better informs both risk assessors and risk managers.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC publication No. 13. The need for biological risk assessment in reaching decisions about carcinogens

The prudent assumption that carcinogen bioassays in rodents predict for human carcinogenicity is examined. It is suggested that in certain cases, as for example the induction of tumors against a high incidence in controls, or in situations in which high dose toxicity may be a critical factor in the induction of cancer, the probability that animal bioassays predict for humans may be low. The term 'biological risk assessment' is introduced to describe that part of risk assessment concerned with the relevance of specific animal results to the induction of human cancer. Biological risk assessment, which is almost entirely dependent on an understanding of carcinogenesis mechanisms, is an important addition to present mathematical modeling used to predict the effects of animal carcinogens that have been demonstrated after high dose exposure, to the effects of the much smaller doses to which humans are perceived to be exposed. Evidence for the conclusions reached by biological risk assessment may sometimes be supported by a careful review of human epidemiological data.     

Molecular epidemiological approaches to the study of the genotoxic effects of urban air pollution.

Direct epidemiological observations suggest that exposure to high levels of urban air pollution may result in increased risk of lung cancer, sufficient to account for a few (approximately 1-3) percent of total lung cancer incidence. Extrapolation from occupational exposure and risk data suggests that among potential carcinogens present in polluted urban air, polycyclic aromatic hydrocarbons (PAHs) may make a major contribution to air pollution-associated lung cancer risks. The use of biomarkers of genotoxocity in large-scale population studies may help to reduce the uncertainty involved in the assessment of such risks, especially those associated with relatively low pollution levels such as nowadays found in many Western cities. Increases in biomarkers of exposure to urban air PAHs as well as biomarkers of early effects have been detected in situations of relatively high levels of air pollution (e. g., ambient PAH concentrations of the order of a few tens of micrograms per cubic meter). Evidence has also been found about the modulation genetic damage accumulation in different individuals by polymorphisms in genes involved in the activation or detoxification of PAHs, especially of polymorphisms GSTM1 and CYP1A1 genes. However, the inconsistencies in the currently reported effects of genetic polymorphisms suggest that additional factors may also be important in the modulation of individual susceptibility to the accumulation of PAH-derived genetic damage. Biomarkers studies in populations exposed to relatively low ambient PAH concentrations (below 20 microg/m(3)) have not demonstrated clear dose-related effects (e.g., on DNA adduct levels), possibly because of the existence of multiple sources and routes of human exposure to PAHs in addition to inhalation of urban air (including, for example, home heating, environmental tobacco smoke and diet), and the consequent difficulty of adequately and specifically assessing atmospheric air-related exposure. This makes it imperative that molecular epidemiology studies be designed in such a way as to allow adequate assessment of exposure to urban air PAHs at the individual level and over short-, medium- and long-term time periods which correspond to the expression times of different biomarkers.     

Kaempferol enhances cisplatin's effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cMyc

Background  

Ovarian cancer is one of the most significant malignancies in the western world. Studies showed that Ovarian cancers tend to grow resistance to cisplatin treatment. Therefore, new approaches are needed in ovarian cancer treatment. Kaempferol is a dietary flavonoid that is widely distributed in fruits and vegetables, and epidemiology studies have revealed a protective effect of kaempferol against ovarian cancer risk. Our early studies also found that kaempferol is effective in reducing vascular endothelial growth factor (VEGF) expression in ovarian cancer cells. In this study, we investigated kaempferol's effects on sensitizing ovarian cancer cell growth in response to cisplatin treatment.     

The p53 tumour suppressor gene: a model for molecular epidemiology of human cancer

The gene encoding the tumour suppressor protein p53 is one of the most commonly mutated genes in human cancers. Analysis of the mutational events that target the p53 gene has revealed evidence for both exogenous and endogenous mutational mechanisms. For example, the p53 mutational spectrum reveals evidence for a direct causal effect of ultraviolet radiation in skin cancer, of aflatoxin B1 in liver cancer and of tobacco smoke in lung cancer. This novel field, molecular epidemiology of human cancer risk, has added a new dimension to classical associative epidemiology by providing a direct link between human cancer and carcinogen exposure.     

Liquid chromatographic-photodiode array mass spectrometric analysis of dietary phytoestrogens from human urine and blood

Dietary phytoestrogens have been implicated in the prevention of chronic diseases. However, it is uncertain whether the phytoestrogens or the foods associated with phytoestrogens account for the observed effects. We report here a new liquid chromatography photodiode array mass spectrometry (LC-PDA-MS) assay for the determination of nanomolar amounts of the most prominent dietary phytoestrogens (genistein, dihydrogenistein, daidzein, dihydrodaidzein, glycitein, O-desmethylangolensin, hesperetin, naringenin, quercetin, enterodiol, enterolactone) in human plasma or serum and urine. This assay was found to be suitable for the assessment of quercetin exposure in an onion intervention study by measuring urinary quercetin levels. Other successful applications of this assay in clinical and epidemiologic studies validated the developed method and confirmed previous results on the negative association between urinary isoflavone excretion and breast cancer risk.     

Determination and risk assessment of toxic metals in lipsticks from Europe and China

BackgroundThe presence of toxic toxic metals in lipstick can pose a health risk to many consumers of this type of cosmetics, especially for women. Thus, the aim of this study was to assess consequences attributed to dermal and oral exposure to toxic metals in lipsticks manufactured in China and Europe as determined by non-cancer and cancer risks assessment models from SCCS and USEPA, respectively.MethodThe treatment of the samples was carried out by calcination using muffle furnaces and the determination of Al, Cd and Pb were determined by inductively coupled plasma optical emission spectrometry (ICP-OES).ConcentrationsThe concentration of Cd and Pb in the study samples does not exceed the limits stablished for the FDA (00,228 mg kg⁻¹·day⁻¹ for Cd and 000,343 mg kg⁻¹·day⁻¹ for Pb, respectively) but they do not comply with the Regulation of the European Parliament, which prohibits the presence of these two metals in cosmetics. Neither European Union nor United States have established maximum levels for Al in cosmetics.ConclusionsThe cancer risk assessment of Cd and Pb metals resulted in a total cancer risk less than 1. The results of non-cancer oral risk assessment for Pb had a MoS result of 88 for China and 62 for Europe, suggesting that Pb poses a risk for the human health, especially in samples manufactured in Europe.     

矿区生态风险评价研究述评

作为世界上矿产资源最丰富的国家之一,我国的矿山开采活动在给经济发展注入强大拉动力的同时,也给矿区生态环境带来了巨大的生态风险。总结前人相关研究,在对比分析了矿区生态风险及其评价与区域生态风险评价异同的基础上,初步明晰矿区生态风险具有风险源的多样性、空间影响边界的模糊性、随空间距离的衰减性及时间累积的延续性等特性。目前矿区生态风险评价的矿区类型过多集中于金属矿区的重金属污染等单项风险,对综合生态风险评价的重视不充分,多基于景观格局、生态环境问题视角,结果多对斑块或生态系统风险评价进行拼接,欠缺基于空间异质性的整体综合;风险度量模型、指标体系法和空间分析法则是较为常用的矿区生态风险评价方法,但在模型模拟方面略显不足。基于现有研究进展,预期矿区独特性的体现、空间格局的关注、"3S"技术的综合应用、生态安全阈值的设定、不确定性表征、基于评价结果的风险规避等将有望成为未来研究的重点。     

Prospects for applying genotypic selection of somatic oncomutation to chemical risk assessment.

Genotypic selection methods detect rare sequence changes in populations of DNA molecules. These methods have been used to investigate the chemical induction of mutation and for the detection and diagnosis of cancer. The possible use of genotypic selection for improving current risk assessment practices is based on the premise that the frequency of somatic mutation is of critical importance in understanding and modeling carcinogenesis. If genotypic selection can measure the induction of specific mutations that disrupt normal cell/tissue homeostasis, then it could provide key mechanistic information for cancer risk assessment. For example, genotypic selection data might support a particular low-dose extrapolation method or characterize the relationship between rodent and human cancer risk. Strategies for evaluating the use of genotypic selection in cancer risk assessment include the concept of developing a battery of targets that detect a range of agent-specific effects. Ideal targets to examine by genotypic selection are the oncogene and tumor suppressor gene mutations frequently detected in human tumors because these are thought to represent tumor-initiating events. The most commonly occurring basepair (bp) substitutions within the ras and p53 genes are identified. Also, the battery of genotypic selection methods is defined in terms of the most important mutational specificities to include. In theory, the major basepair substitution mutations induced by 29 of 31 chemical carcinogens could be detected by analyzing three different mutations: G:C-->T:A, G:C-->A:T, and A:T-->T:A. Genotypic selection will have the greatest impact on risk assessment if measurement of spontaneous mutation is possible. Data from phenotypic selection assays suggest this corresponds to detection of mutant fractions of approximately 10(-7), and this would necessitate examining DNA samples containing >10(7) target molecules. Despite its apparent potential, considerable development and validation is needed before genotypic selection data can be applied to cancer risk assessment.     

Ecological Risk Assessment and Ecological Epidemiology for Contaminated Sites

After 20 years of development, ecological risk assessment is widely accepted. However, it is evolving in response to a variety of technical and societal pressures. First, pressure for greater simplicity and standardization arise from the expectation that risk assessments should require little time and resources but be defensible. Second, the advance of the environmental sciences and increasing awareness of the complexity of ecological responses generate pressure for greater realism. Third, the dominance of human health risk assessment generates a pressure to integrate ecological risk assessment with that dominant field. Fourth, the demand for cost-benefit analysis creates pressure for integration with environmental economics. Finally, the need to connect the practice of ecological epidemiology with risk-based decision-making creates a pressure of the formation of a single integrated ecological assessment practice.