Coffee drinking: the rationale for treating it as a potential effect modifier of carcinogenic exposures

Clinical and epidemiological studies on cancer etiology seldom treat coffee drinking as a potential effect modifier. Yet caffeine exerts significant effects upon a large variety of physiologic, cellular and molecular systems. Caffeine, the world's most popular drug, is also a fundamental research tool, widely used in clinical studies on drug metabolism, and in experimental studies on cell cycle checkpoints, DNA repair, and apoptosis, among many other. Caffeine can profoundly alter cell cycle checkpoint function and several mechanisms of DNA repair, as well as carcinogen metabolism. The impact of caffeine on cell cycle checkpoint function occurs in spite of it being nonmutagenic in traditional mutagenesis assays. A complex body of biologic evidence suggests that caffeine-containing beverages can both enhance and antagonise potentially carcinogenic exposures. However, most pathways leading to the ultimate effects in human beings remain unknown. It is unclear whether any of the hundreds of compounds contained in coffee and tea exert a direct and significant carcinogenic effect per se in any human tissue at usual conditions of use. Reasons exist to consider that coffee may sometimes be an indirect, positive confounder. The study of interactions between caffeine-containing beverages and environmental agents in well defined groups of healthy and diseased people could yield new insights into checkpoint signal transduction and other mechanisms of carcinogenesis. Information on the use of caffeine-containing beverages should more often be integrated in studies on the role of gene–environment interactions in the pathogenesis of cancer.     

Occupational cancer in developed countries

Studies of occupational exposures have made major contributions to our understanding of human carcinogenesis. About one third of the factors identified as definite or probable human carcinogens were first investigated in the workplace and these exposures exact a considerable toll on working populations. There are many additional workplace exposures that are suspect carcinogens that require further evaluation to ensure a safe work environment. Information from occupational investigations is also relevant to the general population because many occupational exposures can be found outside the workplace. Much of our understanding about occupational cancer has been obtained from studies largely composed of white men in developed countries. The movement of industry from developed to developing countries underscores the need for future investigations to include more diverse populations.     

Mechanisms of nickel carcinogenesis

Recent investigations on possible mechanisms of nickel carcinogenesis are reviewed, emphasizing cellular uptake and intracellular translocation of nickel, morphological transformation of cells by nickel compounds, chromosomal damage, DNA strandbreaks and DNA-protein complexes produced by nickel compounds, mutagenic effects of nickel, influence of nickel on the helical transition of B-DNA to Z-DNA, nickel-induced infidelity of DNA synthesis, free radicals and lipid peroxidation induced by nickel exposures, nickel inhibition of DNA repair, nickel as a tumor promotor, nickel inhibition of natural-killer (NK) cell activity, manganese and magnesium antagonism of nickel carcinogenesis, and speculation that Ni2+ might replace Zn2+ in finger-loop domains of transforming proteins. The weight of evidence supports the following tentative conclusions: differences in the carcinogenic activities of nickel compounds may reflect variations in their capacities to provide nickel ions (eg, Ni2+) at critical sites within target cells; Ni2+ can initiate carcinogenesis, possibly by mutagenesis, chromosome damage, formation of Z-DNA, inhibition of DNA excision-repair or epigenetic mechanisms; Ni2+ can function as a tumor promoter; Ni2+ can enhance tumor progression by inhibiting NK cell activity; and nickel carcinogenesis can be suppressed or modified by certain other metals (eg, manganese and magnesium).     

Environmental exposures and gene regulation in disease etiology

Health or disease is shaped for all individuals by interactions between their genes and environment. Exactly how the environment changes gene expression and how this can lead to disease are being explored in a fruitful new approach to environmental health research, representative studies of which are reviewed here. We searched Web of Science and references of relevant publications to understand the diversity of gene regulatory mechanisms affected by environmental exposures with disease implications. Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Furthermore, chemically induced changes in gene regulation are associated with serious and complex human diseases, including cancer, diabetes and obesity, infertility, respiratory diseases, allergies, and neurodegenerative disorders such as Parkinson and Alzheimer diseases. The reviewed studies indicate that genetic predisposition for disease is best predicted in the context of environmental exposures. And the genetic mechanisms investigated in these studies offer new avenues for risk assessment research. Finally, we are likely to witness dramatic improvements in human health, and reductions in medical costs, if environmental pollution is decreased.     

Food mutagens

Several lines of evidence indicate that diet and dietary behaviors can contribute to human cancer risk. One way that this occurs is through the ingestion of food mutagens. Sporadic cancers result from a gene-environment interactions where the environment includes endogenous and exogenous exposures. In this article, we define environment as dietary exposures in the context of gene-environment interactions. Food mutagens cause different types of DNA damage: nucleotide alterations and gross chromosomal aberrations. Most mutagens begin their action at the DNA level by forming carcinogen-DNA adducts, which result from the covalent binding of a carcinogen or part of a carcinogen to a nucleotide. However the effect of food mutagens in carcinogenesis can be modified by heritable traits, namely, low-penetrant genes that affect mutagen exposure of DNA through metabolic activation and detoxification or cellular responses to DNA damage through DNA repair mechanisms or cell death. There are some clearly identified (e.g., aflatoxin) and suspected (e.g., N-nitrosamines, polycyclic aromatic hydrocarbons or heterocyclic amines) food mutagens. The target organs for these agents are numerous, but there is target-organ specificity for each. Mutagenesis however is not the only pathway that links dietary exposures and cancers. There is growing evidence that epigenetic factors, including changes in the DNA methylation pattern, are causing cancer and can be modified by dietary components. Also DNA damage may be indirect by triggering oxidative DNA damage. When considering the human diet, it should be recognized that foods contain both mutagens and components that decrease cancer risk such as antioxidants. Thus nutritionally related cancers ultimately develop from an imbalance of carcinogenesis and anticarcinogenesis. The best way to assess nutritional risks is through biomarkers, but there is no single biomarker that has been sufficiently validated. Although panels of biomarkers would be the most appropriate, their use as a reflection of target-organ risk remains to be determined. Also even when new biomarkers are developed, their application in target organs is problematic because tissues are not readily available. For now most biomarkers are used in surrogate tissues (e.g., blood, urine, oral cavity cells) that presumably reflect biological effects in target organs. This article reviews the role of food mutagens in mutagenesis and carcinogenesis and how their effects are modified by heritable traits and discusses how to identify and evaluate the effects of food mutagens.     

Assessing the cancer risk from foods

Assessing the carcinogenicity of a compound and then determining what dosage is appropriate for human beings is a complex process. Carcinogens act either by altering deoxyribonucleic acid (DNA) or by promoting the growth of already altered cells. Carcinogenicity is evaluated with the use of structural analysis, in vitro mutagenesis assays, epidemiological findings, and dose-response studies in laboratory animals. In the animal studies, high doses are administered. Once a compound is found to be carcinogenic, the dose that will pose an acceptable cancer risk to human beings--one in a million--must be extrapolated from the high-dose data. This virtually safe dose (VSD) will be the allowable dosage for human contact. The extrapolation from high-dose animal studies to a VSD for human beings is based on the models for carcinogenic mechanisms. Debate exists as to how many interactions with DNA the carcinogen must have to initiate neoplastic growth and whether there exists a threshold for carcinogenic action below which there is no risk of cancer. The extrapolation model that is chosen greatly affects the VSD. Knowing how this extrapolation to a VSD is done will help dietitians better understand how allowable levels for carcinogens in foods are determined.     

Occupational cancer epidemiology in the coming decades

Occupational studies have identified many of the established chemical carcinogens. Studies in the next millennium will be needed to identify the hazardous agents in occupations known to have high cancer rates, to assess human risks from animal carcinogens that have not been well evaluated epidemiologically, to provide information on women and minorities, to evaluate interactions with genetic factors and other risk factors, to contribute to our understanding of risks from the spread of chemicals from the workplace to the general environment, and to identify mechanisms of cancer. The traditional retrospective cohort design will be insufficient to meet these needs. Population-based case-control, nested case-control, prospective cohorts, and cross-sectional designs will assume more important roles because of the need to collect information on nonoccupational risk factors and biological tissues. Improvement in the assessment of quantitative exposures is needed for the efficient evaluation of interactions between occupational exposures, genetic factors, and nonoccupational exposures.     

Interclonal variation of heavy metal interactions in Salix viminalis

In the complex chemistry of soil, interactions between metals can be expected and these affect the uptake of the metals by the plants. The role of the metal-metal interaction may vary between different plants. This study was performed to investigate if variations exist in the interactions between Cd, Cu, and Zn on toxicity and accumulation of these metals in different clones of Salix viminalis. Two studies were performed. First, to study interaction at uptake, 10 clones with high or low accumulation capacity of Cd, Cu, and Zn, respectively, were treated with 0.3 microM Cd, 0.1 microM Cu, and 3 microM Zn (all three metals at the same time or separately). Second, to study the effect of one of the metals on the sensitivity of the plant to the other metals, three clones with high or low sensitivity to each of the three metals were used in a modified Weibull analysis. Examination of the results shows that interclonal variation exists in effects of metal interaction on metal accumulation and sensitivity exists. The uptake experiment showed that accumulation of Cu was decreased by the other metals, but only in clones with high Cu-accumulating properties because of decreased net uptake of Cu. The accumulation of Zn in roots was increased two- to threefold in all clones in the presence of the other metals because of a decreased translocation of Zn to the shoot. The accumulation of Cd was not changed by the presence of the other metals in any of the clones. The second experiment showed that the effect of interactions between the different metals on metal toxicity was present in all clones but appeared most frequently in the clone with high Zn resistance. Synergistic effects between Cu and Zn in the Zn-resistant clone suggested that this clone had evolved an additional site of toxic action that was absent in the other clones.     

Oncogene proteins as biomarkers in the molecular epidemiology of occupational carcinogenesis

Summary The use of oncogene proteins as biomarkers offers a new approach to the molecular epidemiologic evaluation of occupational carcinogenesis. The ras oncogene-encoded p21 protein represents a prototype for this type of study, since it is known to be activated by common occupational carcinogens, is frequently found in human tumors of occupational concern, and, at least in certain instances, appears to be expressed relatively early in the disease process, allowing the possibility of early detection and intervention. Herein, we review our experience with the use of immunologic detection of p21 in cohorts with cancer or at risk for the development of cancer due to their occupational exposures. The results suggest that p21 (particularly when used with other oncoproteins and biomarkers such as PAH-DNA adducts) will indeed be a useful addition to the growing armamentarium of molecular epidemiologic biomarkers in the study of occupational carcinogenic mechanisms and in the detection and prevention of occupational cancers.This paper was delivered at the presentation of the Robert R. J. Hilker Award in Occupational Medicine, Chicago, Illinois, March 30, 1990     

Application of Text Mining in Risk Assessment of Chemical Mixtures: A Case Study of Polycyclic Aromatic Hydrocarbons (PAHs)

Background: Cancer risk assessment of complex exposures, such as exposure to mixtures of polycyclic aromatic hydrocarbons (PAHs), is challenging due to the diverse biological activities of these compounds. With the help of text mining (TM), we have developed TM tools—the latest iteration of the Cancer Risk Assessment using Biomedical literature tool (CRAB3) and a Cancer Hallmarks Analytics Tool (CHAT)—that could be useful for automatic literature analyses in cancer risk assessment and research. Although CRAB3 analyses are based on carcinogenic modes of action (MOAs) and cover almost all the key characteristics of carcinogens, CHAT evaluates literature according to the hallmarks of cancer referring to the alterations in cellular behavior that characterize the cancer cell.Objectives: The objective was to evaluate the usefulness of these tools to support cancer risk assessment by performing a case study of 22 European Union and U.S. Environmental Protection Agency priority PAHs and diesel exhaust and a case study of PAH interactions with silica.Methods: We analyzed PubMed literature, comprising 57,498 references concerning priority PAHs and complex PAH mixtures, using CRAB3 and CHAT.Results: CRAB3 analyses correctly identified similarities and differences in genotoxic and nongenotoxic MOAs of the 22 priority PAHs and grouped them according to their known carcinogenic potential. CHAT had the same capacity and complemented the CRAB output when comparing, for example, benzo[a]pyrene and dibenzo[a,l]pyrene. Both CRAB3 and CHAT analyses highlighted potentially interacting mechanisms within and across complex PAH mixtures and mechanisms of possible importance for interactions with silica.Conclusion: These data suggest that our TM approach can be useful in the hazard identification of PAHs and mixtures including PAHs. The tools can assist in grouping chemicals and identifying similarities and differences in carcinogenic MOAs and their interactions. https://doi.org/10.1289/EHP6702     

Public health risk assessment associated with heavy metal and arsenic exposure near an abandoned mine (Kirki,Greece)

The ‘Agios Philippos’ lead–zinc mine in the Kirki region (NE Greece) is now closed, but its legacy of heavy metal contamination remains at the site. At present, management of the contaminated land is of major concern. The area is in a reclamation process and requires immediate remediation action, whereas human risks need to be carefully evaluated. In order to assess these risks, samples from around the mine were collected and analyzed and a scenario involving the oral, dermal, and inhaled doses of arsenic and heavy metals was formulated. A Monte Carlo approach was undertaken, in order to model the average daily dose and quantify the corresponding hazard index and cancer risk. A toxicological risk was associated with samples collected in the vicinity of the mine (floatation, mine tailings) and a pronounced carcinogenic risk for arsenic was evident at the broader occupational/environmental setting. These findings urge for immediate rehabilitation actions that will mitigate population exposures and promote long-term environmental safety in the area.     

Response predictions for organisms water-exposed to metal mixtures: a meta-analysis

To develop a multimetal toxicity model requires insight into the relationships between the composition of metal mixtures and their toxicological effects on organisms. As a first step in developing such a model, quantitative data from binary and higher mixture studies of Cu, Cd, and Zn were compiled and used to assess trends in toxicological effects on various organisms. The findings of this meta-analysis show relatively little occurrence of additive effects compared with antagonistic and synergistic effects. This observation held true irrespective of test species, environmental compartment, or metal concentrations in the mixture. However, the type of effect was significantly correlated with the metal combination tested and the selected toxicological endpoint. It was also found that different methods were used for assessing deviation from additivity in the various individual studies. For robust comparison, standardization on this point is required. Toxicological responses of organisms to metal mixtures were shown to be hard to predict and were often slightly less than or slightly more than additive. The interactions observed could not be explained by metal-metal interactions alone. We therefore conclude that with current scientific knowledge it is not yet possible to predict responses to metal mixtures in individual cases; at best this is possible only in terms of general patterns. Nevertheless, in the context of environmental risk policy, the assumption of additivity produces a conservative prediction of toxicity, because toxicity of a metal mixture will be either predicted correctly or overpredicted by default in approximately 75% of all cases. The use of models based on noninteraction is satisfactory from this regulatory perspective.     

Hard metal exposures. Part 2: Prospective exposure assessment

Hard metal exposures may precipitate lung disease in exposed workers. This article reports on a project investigating the relationship between local exhaust hood air flow levels and workplace hard metal exposures. Airborne cobalt, chromium, and cadmium exposure concentrations, and ventilation system function were monitored for three consecutive days prior to installation of three new ventilation systems, and then were followed monthly for one year. Work activities included wet and dry grinding of saw blades, brazing, welding, and setup. Work task exposures were highly variable over the period of the study. Ventilation air flows failed to meet design goals due to low total air volume and poor distribution; however, worker exposures to metals were controlled in most cases. Hood design, worker acceptance, and use of the hoods were as important in controlling exposures as were exhaust hood air flow levels.     

职业人群的金属生物监测进展

人类接触金属的机会很多,一些金属的有害作用颇受关注。开展生物监测是评价人体接触金属和受金属影响的重要途径。本文从生物监测技术的发展、指标的应用和影响因素诸方面综述金属生物监测的最新进展。     

Genetic trace metal disturbances

Genetic trace metal disturbances can be at three levels. Trace metals play an important role in the metabolism of genetic macromolecules and the information transfer system. Deficiency or excess of trace metals caused either by dietary or genetic factors will affect the normal functioning of the whole organism. The roles of trace metals in carcinogenesis/mutagenesis and ageing are typical of this category. The second level of genetic trace metal disturbances affect the metabolic pathway of the trace metal itself. Biochemical derangement resulting from genetic defects cause aberrant metabolism of the element and thus disease symptoms. Diseases caused by abnormal metabolism of copper, zinc, iron, and molybdenum are discussed. Trace metal disturbances can also be the result of other genetic diseases. This aspect of genetic trace metal disturbances is least investigated. However, information should be important for improving the existing treatment protocol for the more common inborn errors of metabolism, such as phenylketonuria.     

An application of the biotic ligand model to predict the toxic effects of metal mixtures

The rapidly developing biotic ligand model (BLM) allows us to predict the toxicity of heavy metals in water of various chemistries; however, the current BLM predicts the toxicity of a single metal and not the toxic effects of metal mixtures. The toxic mechanisms of heavy metals are not yet completely understood, but hypocalcemia is suggested to be the most likely toxic mechanism for some metals. The BLM, which predicts the toxicity of metals by the amount of metals binding to ligand, is modified to predict the toxicity by the proportion of nonmetal binding ligand that is available for calcium uptake under the assumption that the organisms die because of hypocalcemia when so few ligands are available for calcium uptake. Because the proportion can be computed when multiple metals are present, the toxic effects of metal mixtures can be predicted. Zinc, copper, and cadmium toxicity to rainbow trout (Oncorhynchus mykiss) are considered. All data are collected from the literature, and a meta-analysis using the modified version of the BLM is conducted. The present study found that the proportion of nonmetal binding ligand is a constant value for any test condition. The proportion is not influenced by water chemistry or by metal species. Using the nature of constant proportion, toxicities of metals are well estimated. In addition, the toxic effects of metal mixtures are the simple sum of the toxicities of each metal (additive effect) corresponding to the bioavailable form of the metals. In terms of total concentration of metals in water, however, nonadditive effects, such as antagonism and synergism, are possible.     

Charting the map of life

Scientists expect that mapping the human genome will lead to a host of innovations in biology and research. For example, it may become possible to use DNA microarrays to accurately diagnose cancer and infectious disease subtypes and to predict clinical outcomes. Scientists might also use the genome to look at the interactions of the environment, genetic makeup, and toxic exposures, including the ability of certain beneficial genes to detoxify the body and resist disease. But despite the great potential of the field of genomics, scientists caution that public expectations need to be tempered by reality. People are as much a product of their environment as they are of their genes, say experts, and to suggest that genetics is the sole determinant that defines humans as individuals stretches the science beyond the current data.