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We reported the evaluations of the carcinogenicity of fluoro-edinite, silicon carbide, and carbon nanotubes performed by IARC working group in October 2014. For carbon nanotubes (CNTs), multi-walled carbon nanotube (MWCNT)-7 was classified as Group 2B, and MWCNTs without MWCNT-7 and single-walled carbon nanotubes (SWCNTs) were classified as not classifiable in terms of their carcinogenicity to humans. There is sufficient evidence of carcinogenicity for MWCNT-7 in experimental animals, limited evidence for other MWCNTs, and inadequate evidence for SWCNTs. The mechanic evidence for CNTs was not strong. Fluoro-edinite was classified as carcinogenic to humans (Group 1) on the basis of sufficient evidence of carcinogenicity to humans and experimental animals. Silicon carbide was classified into silicon carbide fibers and whiskers. Silicon carbide fibers were evaluated as possibly carcinogenic to humans (Group 2B) on the basis of limited evidence of carcinogenicity to humans. Silicon carbide whiskers were evaluated as probably carcinogenic to humans (Group 2A) on the basis of sufficient evidence of carcinogenicity to experimental animals and the similarity of their physicochemical properties to those of asbestos in terms of the mechanism of carcinogenicity. We report the process of progression in meeting and discuss how to determine the evidence and the evaluation of the carcinogenicity of the three materials.

Identification of specific molecular changes (fingerprints) is important to identify cancer etiology. Exploitable biomarkers are related to DNA, epigenetics, and proteins. DNA adducts are the turning point between environmental exposures and biological damage. DNA mutational fingerprints are induced by carcinogens in tumor suppressor and oncogenes. In an epigenetic domain, methylation changes occurs in specific genes for arsenic, benzene, chromium, and cigarette smoke. Alteration of specific microRNA has been reported for environmental carcinogens. Benzo(a)pyrene, cadmium, coal, and wood dust hits specific heat-shock proteins and metalloproteases. The multiple analysis of these biomarkers provides information on the carcinogenic mechanisms activated by exposure to environmental carcinogens.

An increasing number of genetic polymorphisms in drug-metabolizing enzymes (DME) were identified among different ethnic groups. Some of these polymorphisms are associated with an increased cancer risk, while others remain equivocal. However, there is sufficient evidence that these associations become significant in populations overexposed to environmental carcinogens. Hence, genetic differences in expression activity of both Phase I and Phase II enzymes may affect cancer risk in exposed populations. In Lebanon, there has been a marked rise in reported cancer incidence since the 1990s. There are also indicators of exposure to unusually high levels of environmental pollutants and carcinogens in the country. This review considers this high cancer incidence by exploring a potential gene-environment model based on available DME polymorphism prevalence, and their impact on bladder, colorectal, prostate, breast, and lung cancer in the Lebanese population. The examined DME include glutathione S-transferases (GST), N-acetyltransferases (NAT), and cytochromes P-450 (CYP). Data suggest that these DME influence bladder cancer risk in the Lebanese population. Evidence indicates that identification of a gene-environment interaction model may help in defining future research priorities and preventive cancer control strategies in this country, particularly for breast and lung cancer.

Human biomarker measurements in tissues including blood, breath, and urine can serve as efficient surrogates for environmental monitoring because a single biological sample integrates personal exposure across all environmental media and uptake pathways. However, biomarkers represent a "snapshot" in time, and risk assessment is generally based on long-term averages. In this study, a statistical approach is proposed for estimating long-term average exposures from distributions of spot biomarker measurements using intraclass correlations based upon measurement variance components from the literature. This methodology was developed and demonstrated using a log-normally distributed data set of urinary OH-pyrene taken from our own studies. The calculations are generalized for any biomarker data set of spot measures such as those from the National Health and Nutrition Evaluation Studies (NHANES) requiring only spreadsheet calculations. A three-tiered approach depending on the availability of metadata was developed for converting any collection of spot biomarkers into an estimated distribution of individual means that can then be compared to a biologically relevant risk level. Examples from a Microsoft Excel-based spreadsheet for calculating estimates of the proportion of the population exceeding a given biomonitoring equivalent level are provided as an appendix.

The common genetic polymorphism for SULT1A1 is Arg213His polymorphism, which may affect the sulfation process of various environmental carcinogens and thus is suggested to be related to susceptibility of several cancers. However, studies on the association between SULT1A1 Arg213His polymorphism and cancer susceptibility are inconsistent. To assess the relationship between Arg213His polymorphism and environmental-related cancers systematically, we performed a meta analysis from 20 case-control studies including 5,915 cases and 7,900 controls. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of risk, we found a significant association between SULT1A1 Arg213His polymorphism and environment-related cancers (for dominant model: OR 1.22, 95% CI 1.07-1.39, P = 0.003). When stratified by ethnicity, a significant risk was observed in Asian cases, compared with controls (for dominant model: OR 1.69, 95% CI 1.17-2.43, P = 0.005). When we chose only smokers in our analysis, we also found a significantly increased risk between Arg213His polymorphism and susceptibility of environment-related cancers for participants exposed to a smoking environment. In conclusion, SULT1A1 Arg213His polymorphism, ethnicity, smoking may modulate environment-related cancer risk. Studies on gene-gene interactions in the sequential or concurrent metabolic pathway and gene-environment interactions need to be further conducted to explore the susceptibility of cancer occurrence.

Environmental electrophilic chemical carcinogens are detoxified via mercapturic acid pathway to be excreted as mercapturic acid derivatives. Mercapturic acid pathway is also involved in the metabolism of pro-apoptotic and toxic endogenous electrophiles such as 4-hydroxynonenal (HNE). HNE is a common denominator in stress induced signaling and is a pro-apoptotic second messenger that affects cell cycle signaling in a concentration dependent manner. It can regulate signaling for apoptosis, differentiation, and gene expression by interacting with the transcriptional factors, transcriptional repressors, membrane receptors and other proteins. First two rate limiting enzymes of the mercapturic acid pathway, GSTs that conjugate HNE to glutathione (GSH), and RLIP76 that excludes GHS-HNE conjugate from cells, regulate the intracellular concentration of HNE. Thus GSTs and RLIP76 can have a profound effect on cell cycle signaling. Our studies have established that increased HNE levels in cells promote apoptotic signaling while at decreased levels below its basal constituted levels HNE promote proliferation. A major outcome of these findings is that by blocking the mercapturic acid pathway mediated detoxification of HNE through the inhibition of RLIP76 catalyzed transport of GS-HNE, a complete remission of many human cancer xenografts in mice can be achieved.

Over the last few years there has been an increasing effort in identifying environmental and occupational carcinogenic agents and linking them to the incidence of a variety of human cancers. The carcinogenic process itself is multistage and rather complex involving several different mechanisms by which various carcinogenic agents exert their effect. Amongst them are epigenetic mechanisms often involving silencing of tumor suppressor genes and/or activation of proto-oncogenes, respectively. These alterations in gene expression are considered critical during carcinogenesis and have been observed in many environmental- and occupational-induced human cancers. Some of the underlying mechanisms proposed to account for such differential gene expression include alterations in DNA methylation and/or histone modifications. Throughout this article, we aim to provide a current account of our understanding on how the epigenetic pathway is involved in contributing to an altered gene expression profile during human carcinogenesis that ultimately will allow us for better cancer diagnostics and therapeutic strategies., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Although we have greatly benefited from the use of traditional epidemiological approaches in linking environmental exposure to human disease, we are still lacking knowledge in to how such exposure participates in disease development. However, molecular epidemiological studies have provided us with evidence linking oxidative stress with the pathogenesis of human disease and in particular carcinogenesis. To this end, oxidative stress-based biomarkers have proved to be essential in revealing how oxidative stress may be mediating toxicity induced by many known carcinogenic environmental agents. Therefore, throughout this review article, we aim to address the current state of oxidative stress-based biomarker development with major emphasis pertaining to biomarkers of DNA, lipid and protein oxidation., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

A variety of biomarkers have been used to monitor exposed populations to determine potential health hazards from their exposure to environmental toxic agents. However, the majority of these biomarkers have been focused onto the identification of biological damage from the exposure. Therefore, there is a need to develop functional biomarkers that can identify exposure-induced functional deficiencies. More importantly, these deficiencies should be positioned along pathways that are responsible for the development of specific diseases. One of such pathways belongs to the extensive and complex DNA-repair machinery. The machinery thus becomes a large target for damage from environmental toxic agents. The hypothesis is that damage to any component of a repair pathway will interfere with the pathway-specific repair activities. Therefore, when cells from exposed populations are challenged with a DNA-damaging agent in vitro, the in vivo exposure-induced repair deficiency will be dramatically amplified and the deficiency will be detectable in a challenge assay as increased chromosome aberrations, micronuclei or un-repaired DNA strand breaks. The challenge assay has been used in different laboratories to show that a variety of exposed populations (with exposure to air pollutants, arsenic, benzene, butadiene, cigarette smoke, incense smoke, lead, mercury, pesticides, uranium or xylene but not to low concentrations of air pollutants or butadiene) expressed abnormal challenge response. The predicted health consequences of some of these studies have also been validated. Therefore, the challenge assay is a useful functional biomarker for population studies. Details of the challenge assay and its application will be presented in this review., (Copyright 2009 Elsevier GmbH. All rights reserved.)

Overt neoplasia is often the result of a chronic disease process encompassing an extended segment of the lifespan of any species. A common pathway in the natural history of the disease is the appearance of focal proliferative lesions that are known to act as precursors for cancer development. It is becoming increasingly apparent that the emergence of such lesions is not a cell-autonomous phenomenon, but is heavily dependent on microenvironmental cues derived from the surrounding tissue. Specific alterations in the tissue microenvironment that can foster the selective growth of focal lesions are discussed herein. Furthermore, we argue that a fundamental property of focal lesions as it relates to their precancerous nature lies in their altered growth pattern as compared to the tissue where they reside. The resulting altered tissue architecture translates into the emergence of a unique tumor microenvironment inside these lesions, associated with altered blood vessels and/or blood supply which in turn can trigger biochemical and metabolic changes fueling tumor progression. A deeper understanding of the role(s) of tissue and tumor microenvironments in the pathogenesis of cancer is essential to design more effective strategies for the management of this disease.

This report provides a summary of deliberations conducted under the charge for members of Module D participating in the Naphthalene State-of-the-Science Symposium (NS(3)), Monterey, CA, October 9-12, 2006. The charge directed the panel to ascertain to the best of its ability a consensus judgment of the state-of-the-science concerning the potential for a genotoxic mode of action for naphthalene and its metabolites, with implications for low-dose extrapolations of cancer risk estimates for exposed populations. Where scientific uncertainties remained, the panel was asked to identify which scientific uncertainties (if any) could be resolved through targeted, timely, cost-effective research. The report provides a brief summary of naphthalene genotoxicity; identifies those areas where there is a general scientific consensus regarding the effects of naphthalene; identifies areas of uncertainty regarding the effects of naphthalene; and key questions that currently limit our ability to assess the genotoxic risks of naphthalene. The report also outlines a set of six studies that could resolve some of these key uncertainties.

The recent article by Costa and Klein (2006) contains several inaccuracies about the federal drinking water standard for chromium. The federal drinking water standard for chromium is 100 ppb, not 50 ppb as stated by Costa and Klein, and it is based on non-carcinogenic effects, not a one in one million cancer risk level. The question of whether or not hexavalent chromium is carcinogenic via the oral route is the focus of much current interest and has major implications for regulation of chromium in drinking water and soil. The chronic drinking water study of hexavalent chromium currently being conducted by the National Toxicology Program will provide further information that will be useful in addressing this question.

Cancer in children is a major concern in many countries. An important question is whether these childhood cancers are caused by something, or are just tragic random events. Causation of at least some children's cancers is suggested by direct and indirect evidence, including epidemiological data, and animal studies that predict early life sensitivity of humans to carcinogenic effects. Candidate risk factors include genotoxic agents (chemicals and radiation), but also diet/nutrition, and infectious agents/immune responses. With regard to likelihood of risks posed by genotoxicants, there are pros and cons. The biological properties of fetuses and infants are consistent with sensitivity to preneoplastic genotoxic damage. Recent studies of genetic polymorphisms in carcinogen-metabolizing enzymes confirm a role for chemicals. On the other hand, in numerous epidemiological studies, associations between childhood cancers and exposure to genotoxicants, including tobacco smoke, have been weak and hard to reproduce. Possibly, sensitive genetic or ontogenetic subpopulations, and/or co-exposure situations need to be discovered to allow identification of susceptible individuals and their risk factors. Among the critical knowledge gaps needing to be bridged to aid in this effort include detailed tissue and cellular ontogeny of carcinogen metabolism and DNA repair enzymes, and associations of polymorphisms in DNA repair enzymes with childhood cancers. Perinatal bioassays in animals of specific environmental candidates, for example, benzene, could help guide epidemiology. Genetically engineered animal models could be useful for identification of chemical effects on specific genes. Investigations of interactions between factors may be key to understanding risk. Finally, fathers and newborn infants should receive more attention as especially sensitive targets.

Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Although lung cancer has been established as a consequence of hexavalent chromium exposure in smokers and nonsmokers, some cancers of other tissues of the gastrointestinal and central nervous systems have also been noted. Except for a few reports from China, little is known about the health risks of environmental exposures to chromium. Likewise, there has been a lack of epidemiological studies of human exposure to hexavalent Cr by drinking water or ingestion, and it has been suggested that humans can perhaps tolerate hexavalent Cr at higher levels than the current drinking water standard of 50 ppb. This review highlights the most recent data on the induction of skin tumors in mice by chronic drinking-water exposure to hexavalent chromium in combination with solar ultraviolet light. This experimental system represents an important new animal model for chromate-induced cancers by ingestion of drinking water, and it suggests by extrapolation that chromate can likely be considered a human carcinogen by ingestion as well. The potential use of this animal model for future risk assessment is discussed.

Genetic and environmental interactions determine cancer risks but some cancer incidence is primarily a result of inherited genetic deficits alone. Most cancers have an occupational, viral, nutritional, behavioral or iatrogenic etiology. Cancer can sometimes be controlled through broad public health interventions including industrial hygiene and engineering controls. Chromium and nickel are two human carcinogens associated with industrial exposures where public health measures apparently work. Carcinogenic mechanisms of these metals are examined by electron-spin-resonance-spectroscopy and somatic-mutation-and-recombination in Drosophila melanogaster in this report. Both metals primarily affect initiation processes in cancer development suggesting important theoretical approaches to prevention and followup.

Exposure biomarkers for carcinogens in humans include the measurement of the genotoxin or its active metabolite in blood, urine or other tissues, and the determination of the interaction products (adducts) of the carcinogen with protein or DNA. The latter approach may indicate the amount of genotoxically active material that has reached the tissue under study and provides invaluable information for molecular epidemiological studies. Protein adducts are not repaired and are considered primarily as exposure monitors, but DNA adducts may give further information about the mutagenic significance of the exposure. The techniques available for measurement of protein and DNA adducts include mass spectrometry, immunoassay, high performance liquid chromatography with UV, fluorescence or electrochemical detection, 32P-postlabelling (for DNA only) and accelerator mass spectrometry. The lowest limits of sensitivity of the protein adduct measurements is less than 1 pmol adduct/g protein, and the procedures for DNA adduct determination have sensitivities ranging from of 1 adduct in 10(8) to 1 in 10(11) nucleotides. All these techniques are capable of measuring environmental, occupational and dietary exposures to a variety of genotoxic compounds, as exemplified in this review.

At least six types of gene-environment interactions (GEI) have been proposed (Kouhry and Wagener, 1993). In the first type, neither the environmental exposure (EE) nor the genetic risk factor (GRF) have any effect by themselves, but interaction between them causes disease. This is the case of phenylalanine exposure and the phenylketonuria genotype. Type 2 is a situation in which the GRF has no effect on disease in the absence of exposure, but exacerbates the effects of the latter. This is the most important type of GEI in relation to metabolic susceptibility genes and human carcinogenesis. The third type is the converse of the second (EE is ineffective per se, but enhances the effect of GRF). Type 4 occurs when both FE and GRF increase the risk for disease, but the combination is interactive or synergistic: an example is the interaction between Xeroderma Pigmentosum and LWV radiation. Types 5 and 6, according to the classification proposed by Kouhry, refer to cases in which the GRF is protective. The model of GEI that is emerging as the most important in chemical carcinogenesis refers to metabolic susceptibility genes. The general population can be divided into subgroups depending on their susceptibility to the action of carcinogens, based on their ability to metabolize such compounds to electrophilic, reactive metabolites (which form adducts with DNA), or, respectively, electrophobic metabolites that are excreted. The present contribution is a short review of the relevant literature, with particular emphasis on some polymorphisms involved in dietary exposures. In addition, the practical implications of genetic testing in this field are discussed.

The variable interindividual ability to metabolize environmental toxicants, also known as metabolic polymorphism, may be of substantial importance in the modulation of cancer risk. The ethnic distribution of these polymorphisms could be interesting in order to establish an association with cancer risk or even to establish selective advantage of some genotypes. Cytochrome P450 2E1 (CYP2E1) is a secondary enzyme that can metabolize ethanol, and glutathione S-transferase (GSTM1) is thought to be involved in the detoxification of epoxides and polycyclic aromatic hydrocarbons. Mutation in these genes was investigated in a random sample of healthy subjects from São Paulo, Brazil, which included 206 Caucasians and 86 mulattoes. Pst I restriction fragment length polymorphism (RFLP) in the 5'-flanking region of the CYP2E1 gene has been identified in 10.2% of Caucasian individuals and in 11.6% of mulattoes. For GSTM1 the frequency of the null genotype was significantly higher in Caucasian individuals (60.2%) than in mulattoes (41.9%). Allele frequencies were (1) CYP2E1 locus: P = 0.949, q = 0.051, se(p) = se(q) = 0.011 among Caucasians; and p = 0.942; q = 0.058; se(P) = se'(q) = 0.018 among mulattoes; and (2) GSTM1 locus: p = 0.224, q = 0.776, se(p) = se(q) = 0.022 among Caucasians; and p = 0.353; q = 0.647; se(p) = se(q) = 0.041 among mulattoes.

This article addresses the evidence that trichloroethylene (TCE) or its metabolites might mediate tumor formation via a mutagenic mode of action. We review and draw conclusions from the published mutagenicity and genotoxicity information for TCE and its metabolites, chloral hydrate (CH), dichloroacetic acid (DCA), trichloroacetic acid (TCA), trichloroethanol, S-(1, 2-dichlorovinyl)-l-cysteine (DCVC), and S-(1, 2-dichlorovinyl) glutathione (DCVG). The new U.S. Environmental Protection Agency proposed Cancer Risk Assessment Guidelines provide for an assessment of the key events involved in the development of specific tumors. Consistent with this thinking, we provide a new and general strategy for interpreting genotoxicity data that goes beyond a simple determination that the chemical is or is not genotoxic. For TCE, we conclude that the weight of the evidence argues that chemically induced mutation is unlikely to be a key event in the induction of human tumors that might be caused by TCE itself (as the parent compound) and its metabolites, CH, DCA, and TCA. This conclusion derives primarily from the fact that these chemicals require very high doses to be genotoxic. There is not enough information to draw any conclusions for trichloroethanol and the two trichloroethylene conjugates, DCVC and DCVG. There is some evidence that DCVC is a more potent mutagen than CH, DCA, or TCA. Unfortunately, definitive conclusions as to whether TCE will induce tumors in humans via a mutagenic mode of action cannot be drawn from the available information. More research, including the development and use of new techniques, is required before it is possible to make a definitive assessment as to whether chemically induced mutation is a key event in any human tumors resulting from exposure to TCE.

Individual susceptibility to cancer may result from host factors including differences n metabolism, DNA repair, altered expression of protooncogenes and tumor suppressor genes, and nutritional status. Since most carcinogens require metabolic activation before binding to DNA, variations in an individual's metabolic phenotype that have detected in enzymes involved in activation and detoxification should play an essential role in the development of environmental cancer. This phenotypic metabolic variation has now been related to genetic polymorphisms, and many genes encoding carcinogen-metabolizing enzymes have been identified and cloned. Consequently, allelic variants or genetic defects that give rise to the observed variation and new polymorphisms have been recognized. Development of simple polymerase chain reaction (PCR)-based assays has enabled identification of an individual's genotype for a variety of metabolic polymorphisms. Thus, recent knowledge of the genetic basis for individual metabolic variation has opened new possibilities of studies focusing on increased individual susceptibility to environmentally induced cancer, which are reviewed with special reference to smoking-induced lung cancer. Cancer susceptibility due to chemical exposure is likely to be determined by an individual's phenotype for a number of enzymes (both activating and detoxifying) relevant to that of a single carcinogen or mixtures of carcinogens. Given the number and variability in expression of carcinogen-metabolizing enzymes and the complexity of chemical exposures, assessment of a single polymorphic enzyme (genotype) may not be sufficient. Mutations in the p53 gene are among the most common genetic changes in human cancer. The frequency and type p53 mutations can act as a fingerprint of carcinogen exposure and may therefore provide information about external etiological agents, intensity of exposure, and host factors affecting the tumorigenesis process. In human lung cancer, p53 mutations (both the mutation pattern and frequency) have been linked with tobacco smoking; the type of mutation most frequently observed is G:C to T:A transversion, a mutation preferentially induced by benzo[a]pyrene diol epoxide. An association between the presence of this transversion and the genotype deficient in glutathione S-transferase M1-mediated detoxification has been observed in lung cancer. Taken together, these findings suggest that determination of metabolic at risk genotypes in combination with levels of DNA adducts in target (surrogate) tissues and the p53 mutation pattern should allow the identification of susceptible individuals and subgroups in carcinogen-exposed populations.

The induction of a mutator phenotype has been hypothesized to cause the accumulation of multiple mutations in the development of cancer. Recent evidence suggests that the mutator phenotype is associated with DNA repair deficiencies. We have been using a challenge assay to study exposed populations to test our hypothesis that exposure to environmental toxicants induce DNA repair deficiency in somatic cells. In this assay, lymphocytes were irradiated in vitro to challenge cells to repair the radiation-induction DNA strand breaks. An increase of chromosome aberrations in the challenged cells from toxicant-exposed populations compared to nonexposed populations is used to indicate abnormal DNA repair response. From studies of cigarette smokers, butadiene-exposed workers, and uranium-exposed residents, the assay showed that these exposed populations had mutagen-induced abnormal DNA repair response. The phenomenon was also demonstrated using experimental animals. Mice were exposed in vivo to two different doses of N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) and their lymphocytes were challenged with one dose of a radiomimetic chemical, bleomycin, in vitro. These challenged lymphocytes showed an MNNG dose-dependent increase of abnormal DNA repair response. In a population that was potentially exposed to teratogens--mothers having children with neural tube defects--lymphocytes from these mothers did not have the abnormal response in our assay. In studies with patients, we reported that lymphocytes from Down's syndrome patients have the abnormal DNA repair response. Lymphocytes from skin cancer-prone patients (epidermodysplasia verruciformis) have normal response to gamma-ray challenge but abnormal response to UV-light challenge. These patient studies also indicate that the challenge assay is useful in documenting the radiosensitivity of Down's syndrome and the UV sensitivity in EV patients. In most cases, the challenge assay is more sensitive in detecting biological effects than the standard chromosome aberration assay. Our series of studies indicates that the challenge assay can be used to document biological effects from exposure to mutagens and that the effect is an abnormal DNA repair response. This abnormality can increase the risk for development of cancer. The repair deficiency is currently being validated using a plasmid transfection (host-reactivation) assay. The need to integrate chromosome aberration and the challenge assays with other relevant assays for better documentation of biological effects and for more precise prediction of health risk will be presented. Our experience in using genetic polymorphism and host-reactivation assays will be discussed.

Environmental, occupational, and recreational exposures to carcinogens contribute to cancer risk in humans. Cancer formation is a multistage process involving tumor initiation, promotion, conversion, and progression. Carcinogens can affect any of these stages through genetic and epigenetic mechanisms. The association of a suspected carcinogenic exposure and cancer risk can be studied in populations with classic epidemiologic techniques. However, these techniques are not applicable to the assessment of risk in individuals. Molecular epidemiology, in contrast, is a field that integrates molecular biology, in vitro and in vivo laboratory models, biochemistry, and epidemiology to infer individual cancer risk. Carcinogen-macromolecular adduct levels, and somatic cell mutations can be measured to determine the biologically effective dose of a carcinogen. Molecular epidemiology also explores host cancer susceptibilities, such as carcinogen metabolic activation, DNA repair, endogenous mutation rates, and inheritance of mutated tumor suppressor genes. Substantial interindividual variation for each of these biologic end points has been shown and, therefore, highlights the need for assessing cancer risk on an individual basis. Given the pace of the last decade, it is feasible that the next 10 years will allow molecular epidemiologists to develop a cancer-risk profile for an individual that includes assessment of a number of factors. This will help focus preventive strategies and strengthen quantitative risk assessments.

A definition of ecological oncology is given and its subject is discussed. Primary attention is paid to insufficiently studied aspects of this novel scientific discipline: the influence of carcinogens on the natural biocenoses and their role in the evolutional processes, the transformation of carcinogens by living organisms, and the ecological monitoring of environmental carcinogenic substances.

Specific and sensitive methods are now available to detect DNA and protein adducts induced by a variety of carcinogens. These measurements of individual exposures are now starting to be used in cancer epidemiological studies. In this paper the requirements and the problems in implementation of the studies are discussed, as well as aspects of interpretation of the results in relation to assessments of past exposure and biological relevance to the disease process.

The induction of cancer by chemicals as presently understood involves a series of steps, some of which require the passage of time. Many substances that are potent carcinogens in experimental animals are known to exist in nature and occur as part of the human diet. In addition, many of the substances that are known to inhibit experimental carcinogenesis also exist in the human diet. Thus, in addition to industrially produced carcinogens, humans can be presumed to have evolved in an environment that contains both carcinogens and anti-carcinogens. There is also a great deal of experimental and human epidemiologic data on the influence of lipids, proteins and carbohydrates on cancer incidence rates; however, much of those data are confusing and conflicting.

A brief review is presented of some types of chemical carcinogens and their metabolic activation to DNA-binding intermediates, and of the influence of modifiers of carcinogenesis on the probability of tumor development. The relationship between human exposure to one group of carcinogens--the tobacco specific nitrosamines--and the development of tobacco-related cancers is discussed.

No population in the world is known to be resistant to cancer development, but there seems to be differences between individuals in susceptibility to cancer development following exposure to environmental carcinogenic risk factors. The age dependency of cancer may be interpreted both with regard to carcinogenic exposure and resistance to tumour development. Studies of migrant populations have pointed both to the fact that apparent resistance to cancer in certain populations is spurious, and to characteristic susceptibility to certain tumour types as for instance nasalpharangyal cancer and skin cancer. "Host factors"--either genetically in origin or environmentally induced--may be responsible for differences in susceptibility. It is concluded that there is abundant epidemiological evidence of the role of environmental factors in cancer causation, and that possible interactions between tumour-producing and risk modifying factors should be further exploited.

In principle, it is possible to identify and eliminate chemicals in our environment that cause cancer, but practical considerations make it very difficult to achieve this goal. Since we will be exposed to carcinogens for some time to come, we must try to understand how known carcinogens work at the molecular level if we are to develop more rational approaches for preventing their action. This knowledge is also important if we are to proceed logically in developing better procedures for early diagnosis and treatment. Since somatic cell mutations produced by exposure to chemical carcinogens represent key events in the initiation of tumors, we must try to understand which genes are involved, what kind of mutations trigger transformation and how carcinogens produce these alterations of DNA. In this paper I discuss metabolic activation of chemicals to produce carcinogens that react with DNA, consider repair of the covalent adducts that are produced when carcinogens react with DNA, and point out some key questions that must be answered before we can understand how carcinogens work. Then I outline some recent progress in the molecular biology of human oncogenes and indicate how we are using site-specific mutagenesis in preselected codons of the c-Ha ras protooncogene in an attempt to define which carcinogen-induced DNA adducts transform normal protooncogenes into active oncogenes.

The recent data on metabolic activation of carcinogens are presented. Molecular mechanisms of activation, induction methods for systems providing biotransformation of xenobiotics as well as the comparative analysis of these systems (host, cell and cell free) are characterized from the standpoint of their use in short-term tests. The prospects of application of various metabolic activation systems are shown.

This brief overview pointed out the feasibility of applying the recently developed short-term bioassays for carcinogens/mutagens to the field of epidemiology. The simplicity and economy of these test systems permitted their adaptation for large-scale screening for intrinsic and extrinsic carcinogens with an eye to detecting subpopulations with elevated sensitivity to particular carcinogens.

Although rates of occupational cancer can be excessive in certain industries, less than 5% of all cancers seem attributable to exposure to carcinogens in the workplace. For example, workers in hard-rock mining and the woodworking industries are at increased risk; cigarette smoking has a synergistic effect. There is conclusive evidence of carcinogenicity for fewer than 20 substances, including asbestos, arsenic, chromium, nickel, cadmium, radon, several aromatic hydrocarbons and certain herbicides. Most of the hundreds of organic compounds known to be mutagenic in in-vitro tests have not been shown to be carcinogenic in epidemiologic studies. Both laboratory and epidemiologic approaches, however, can identify probable causes of cancer and permit the application of effective preventive measures. In addition, it is still possible for the alert individual clinician to make the initial discovery of an occupational hazard.

The field of chemical carcinogenesis is reviewed, with emphasis on three aspects: 1) environmental chemicals are a major cause of human cancer; 2) most chemical carcinogens require metabolic activation by mixed-function oxidases to electrophilic metabolites that form strong covalent chemical bonds with cellular macromolecules and thereby initiate the carcinogenic process; and 3) several systems are available in which normal cells can be transformed by chemical carcinogens into malignant cancer cells. Much has been learned about the cellular mechanisms of chemical carcinogenesis using these systems. They also have considerable potential to be used as prescreens for environmental carcinogens.

The early work in the field of chemical carcinogenesis accomplished by Dr. Boyland has provided us with key concepts that can be applied today in the prevention of many kinds of human cancer. Broad understanding of the complex processes of cancer causation was achieved in the last 50 years. Thus, research on the action of chemical carcinogens through their reactive metabolites, the detection of such agents through rapid in vitro bioassays by the product of their interaction with DNA, and the consequences related thereto, has been applied to the qualitative and quantitative implications of such an interaction in relation to the etiology of human cancers. Beginning knowledge of the mechanisms of tumor promotion provides further means of controlling neoplastic processes because of the distinct qualitative and quantitative properties of promoters. The promotion phenomenon contributes extensively to the development of human cancer of the lung and nutritionally-linked cancers such as those in the colon, breast, or prostate. Their quantitative effects may be easier to limit than those due to genotoxic carcinogens, which would help substantially to lower the incidence of these important cancers.