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Fumonisins (FB) are mycotoxins found in (italic)Fusarium verticillioides-infected maize grain worldwide. Attention has focused on FBs because of their widespread occurrence, acute toxicity to certain livestock, and their potential carcinogenicity. FBs are present at low levels in most field-grown maize but may spike to high levels depending on both the environment and genetics of the host plant. Among the strategies for reducing risk of FB contamination in maize supplied to the market, development and deployment of Fusarium ear mold-resistant maize germplasm is a high priority. Breeding for increased ear mold tolerance and reduced mycotoxin levels is being practiced today in both commercial and public programs, but the amount of resistance achievable may be limited due to complicated genetics and/or linkage to undesirable agronomic traits. Molecular markers can be employed to speed up the incorporation of chromosomal regions that have a quantitative effect on resistance (quantitative trait loci). Transgenic approaches to ear mold/mycotoxin resistance are now feasible as well. These potentially include genetically enhanced resistance to insect feeding, increased fungal resistance, and detoxification/prevention of mycotoxins in the grain. An example of the first of these approaches is already on the market, namely transgenic maize expressing Bacillus thuringiensis (Bt) toxin, targeted to the European corn borer. Some Bt maize hybrids have the potential to reduce FB levels in field-harvested grain, presumably through reduced feeding of Bt-susceptible insects in ear tissues. However, improved ear mold resistance per se is still an important goal, as the plant will still be vulnerable to noninsect routes of entry to (italic)Fusarium. A second approach, transgene-mediated control of the ability of Fusarium to infect and colonize the ear, could potentially be achieved through overexpression of specific antifungal proteins and metabolites, or enhancement of the plant's own defense systems in kernel tissues. This has not yet been accomplished in maize, although promising results have been obtained recently in other monocots versus other fungal and bacterial pathogens. Achieving reproducible and stable enhanced ear mold resistance under field conditions will be immensely challenging for biotechnologists. A third approach, transgene strategies aimed at preventing mycotoxin biosynthesis, or detoxifying mycotoxins in planta, could provide further protection for the grower in environments where FBs present a risk to the crop even when the maize is relatively resistant to Fusarium mold. In one example of such a strategy, enzymes that degrade FBs have been identified in a filamentous saprophytic fungus isolated from maize, and corresponding genes have been cloned and are currently being tested in transgenic maize.

The two important Fusarium ear rots of corn, Gibberella ear rot (Fusarium graminearum, formally F. moniliforme and allied species) and Fusarium ear rot (F. verticillioides and allied species) grow under different environmental conditions. F. graminearum grows well only between 26 and 28 degrees C and requires rain both at silking and during disease progression. F. verticillioides grows well at higher temperatures, and ear rot and fumonisin accumulation are associated with drought and insect stress and growing hybrids outside their areas of adaptation. In southern Transkei, where esophageal cancer has been associated with the consumption of F. verticillioides and fumonisin-contaminated corn, environmental conditions favor this fungus in most years. In the nearby areas where the soils, crops, food consumption, and populations are the same and where esophageal cancer is low, temperatures are cooler and F. graminearum is favored. Although F. verticillioides is associated with a disease of corn, it may be that this fungus is a mutualistic endophyte of the plant. Perhaps because of this, breeding for resistance to Fusarium ear rot has produced inconclusive results to date. The best available strategies for reducing the risk of fumonisin contents of maize are to ensure that hybrids are adapted to the environment and to limit drought stress and insect herbivory. It may also be necessary to make use of alternative strategies such as producing hybrids that contain enzymes to degrade fumonisin as it is produced.

Fusarium moniliforme Sheldon, a biological species of the mating populations within the (italic)Gibberella fujikuroi species complex, i.e., population A [= G. moniliformis (Sheld.) Wineland], is an example of a facultative fungal endophyte. During the biotrophic endophytic association with maize, as well as during saprophytic growth, F. moniliforme produces the fumonisins. The fungus is transmitted vertically and horizontally to the next generation of plants via clonal infection of seeds and plant debris. Horizontal infection is the manner by which this fungus is spread contagiously and through which infection occurs from the outside that can be reduced by application of certain fungicides. The endophytic phase is vertically transmitted. This type infection is important because it is not controlled by seed applications of fungicides, and it remains the reservoir from which infection and toxin biosynthesis takes place in each generation of plants. Thus, vertical transmission of this fungus is just as important as horizontal transmission. A biological control system using an endophytic bacterium, Bacillus subtilis, has been developed that shows great promise for reducing mycotoxin accumulation during the endophytic (vertical transmission) growth phase. Because this bacterium occupies the identical ecological niche within the plant, it is considered an ecological homologue to F. moniliforme, and the inhibitory mechanism, regardless of the mode of action, operates on the competitive exclusion principle. In addition to this bacterium, an isolate of a species of the fungus Trichoderma shows promise in the postharvest control of the growth and toxin accumulation from F. moniliforme on corn in storage.

Although humans vary in their response to chemicals, comprehensive measures of susceptibility have generally not been incorporated into human risk assessment. The U.S. EPA dose-response-based risk assessments for cancer and the RfD/RfC (reference dose-reference concentration) approach for noncancer risk assessments are assumed to protect vulnerable human subgroups. However, these approaches generally rely on default assumptions and do not consider the specific biological basis for potential susceptibility to a given toxicant. In an effort to focus more explicitly on this issue, this article addresses biological factors that may affect human variability and susceptibility to trichloroethylene (TCE), a widely used halogenated industrial solvent. In response to Executive Order 13045, which requires federal agencies to make protection of children a high priority in implementing their policies and to take special risks to children into account when developing standards, this article examines factors that may affect risk of exposure to TCE in children. The influence of genetics, sex, altered health state, coexposure to alcohol, and enzyme induction on TCE toxicity are also examined.

A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Additional dose metrics provided for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, and TCOH concentrations in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating cross-species differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution.

This article focuses on the various models for kidney toxicity due to trichloroethylene (TCE) and its glutathione-dependent metabolites, in particular S-(1,2-dichlorovinyl)-l-cysteine. Areas of controversy regarding the relative importance of metabolic pathways, species differences in toxic responses, rates of generation of reactive metabolites, and dose-dependent phenomena are highlighted. The first section briefly reviews information on the incidence and risk factors of kidney cancer in the general U.S. population. Epidemiological data on incidence of kidney cancer in male workers exposed occupationally to TCE are also summarized. This is contrasted with cancer bioassay data from laboratory animals, that highlights sex and species differences and, consequently, the difficulties in making risk assessments for humans based on animal data. The major section of the article considers proposed modes of action for TCE or its metabolites in kidney, including peroxisome proliferation, alpha(2u)-globulin nephropathy, genotoxicity, and acute and chronic toxicity mechanisms. The latter comprise oxidative stress, alterations in calcium ion homeostasis, mitochondrial dysfunction, protein alkylation, cellular repair processes, and alterations in gene expression and cell proliferation. Finally, the status of risk assessment for TCE based on the kidneys as a target organ and remaining questions and research needs are discussed.

Trichloroethylene (TCE) is both acutely toxic and carcinogenic to the mouse lung following exposure by inhalation. In contrast, it is not carcinogenic in the rat lung and is markedly less toxic following acute exposure. Toxicity to the mouse lung is confined almost exclusively to the nonciliated Clara cell and is characterized by vacuolation and increases in cell replication. Chloral, a metabolite of TCE that accumulates in Clara cells and has been shown to be the cause of the toxicity, also causes aneuploidy in some test systems. Cytotoxicity, increased cell division, and aneuploidy are known risk factors in the development of cancer and provide a plausible mode of action for TCE as a mouse lung carcinogen. All acute and chronic effects of TCE on the mouse lung are believed to be a direct consequence of high cytochrome P450 activity and impaired metabolism of chloral in Clara cells. Comparisons between species suggest that the ability of the human lung to metabolize TCE is approximately 600-fold less than that in the mouse. In addition, the human lung differs markedly from the mouse lung in the number and morphology of its Clara cells. Thus, the large quantitative differences between the metabolic capacity of the mouse lung and the human lung, together with the species differences in the number and morphology of lung Clara cells, suggest that the risks to humans are minimal and that other tumor sites should take precedent over the lung when assessing the potential risks to humans exposed to TCE.

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.

Studies were conducted in northern Bohemia to simultaneously evaluate personal exposures to air pollution in the form of respirable particles containing polycyclic aromatic hydrocarbons (PAHs) and biomarkers of exposure, biological effective dose, genetic effects, and metabolic susceptibility. The series of biomarkers included PAH metabolites in urine, urine mutagenicity, PAH-DNA adducts in white blood cells determined by 32P-postlabeling, PAH-albumin adducts determined by enzyme-linked immunosorbent assay (ELISA), DNA damage in lymphocytes detected by comet assay, chromosomal aberrations, sister chromatid exchanges, and glutathione S-transferase M1 (GSTM1) genotypes. For these studies, a group of women who work outdoors about 30% of their daily time was selected. In a pilot study, a group of women from a polluted area of the Teplice district (northern Bohemia) was compared with a group of women from a control district of southern Bohemia (Prachatice). In a follow-up repeated-measures study, a group of nonsmoking women from Teplice was sampled repeatedly during the winter season of 1993 to 1994. Personal exposure monitoring for respirable particles (< 2.5 microns) was conducted for the 24-hr period before collection of blood and urine. Particle extracts were analyzed for carcinogenic PAHs. In the pilot study and in the follow-up study, a highly significant correlation between individual personal exposures to PAHs and DNA adducts was found (r = 0.54, p = 0.016; r = 0.710, p < 0.001, respectively). The comet parameter (percentage DNA in tail; %T) correlated with exposures to respirable particles (r = 0.304, p = 0.015). The GSTM1 genotype had a significant effect on urinary PAH metabolites, urine mutagenicity, and comet parameters (% T and tail moment) when the GSTM1 genotype was considered as a single factor affecting these biomarkers. Multifactor analysis o variance considering exposure and adjusting the data for GSTM1, age, and diet showed that the effect of personal exposures to PAHs on the variability of biomarkers (DNA adducts, comet parameters, urine mutagenicity) might be higher than the effect of the GSTM1 genotype. These results show the importance of considering all potential factors that may affect the biomarkers being analyzed.

Progress over the past 30 years has revealed many strengths of the rainbow trout as an alternative model for environmental carcinogenesis research. These include low rearing costs, an early life-stage ultrasensitive bioassay, sensitivity to many classes of carcinogen, a well-described tumor pathology, responsiveness to tumor promoters and inhibitors, and a mechanistically informative nonmammalian comparative status. Low-cost husbandry, for example, has permitted statistically challenging tumor study designs with up to 10,000 trout to investigate the quantitative interrelationships among carcinogen dose, anticarcinogen dose, DNA adduct formation, and final tumor outcome. The basic elements of the trout carcinogen bioassay include multiple exposure routes, carcinogen response, husbandry requirements, and pathology. The principal known neoplasms occur in liver (mixed hepatocellular/cholangiocellular adenoma and carcinoma, hepatocellular carcinoma), kidney (nephroblastoma), swim bladder (adenopapilloma), and stomach (adenopapilloma). Trout possess a complex but incompletely characterized array of cytochromes P450, transferases, and other enzymic systems for phase I and phase II procarcinogen metabolism. In general, trout exhibit only limited capacity for DNA repair, especially for removal of bulky DNA adducts. This factor, together with a high capacity for P450 bioactivation and negligible glutathione transferase-mediated detoxication of the epoxide, accounts for the exceptional sensitivity of trout to aflatoxin B1 carcinogenesis. At the gene level, all trout tumors except nephroblastoma exhibit variable and often high incidences of oncogenic Ki-ras gene mutations. Mutations in the trout p53 tumor suppressor gene have yet to be described. There are many aspects of the trout model, especially the lack of complete organ homology, that limit its application as a surrogate for human cancer research. Within these limitations, however, it is apparent that trout and other fish models can serve as highly useful adjuncts to conventional rodent models in the study of environmental carcinogenesis and its modulation. For some problems, fish models can provide wholly unique approaches.

Heterocyclic aromatic amines (HAAs) are animal carcinogens and suspected human carcinogens which are formed in cooked foods at the low parts per billion level. HAAs in cooked meats were purified by either immunoaffinity chromatography or solid phase tandem extraction, which allowed for the simultaneous analysis of 11 HAAs by HPLC. The metabolism of two prominent HAAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), was investigated in animal models and in vitro with human tissues to develop strategies for human biomonitoring. MeIQx and IQ are rapidly absorbed from the gastrointestinal tract of rodents and transformed into several detoxification products which are excreted in urine and feces. Metabolites result from cytochrome P450-mediated ring oxidation at the C-5 position followed by conjugation to sulfate or beta-glucuronic acid. Other major metabolites include the phase II conjugates, N2-glucuronide and N2-sulfamate. A metastable N2-glucuronide conjugate of the genotoxic metabolite of N-hydroxy-MeIQx was also detected in urine and bile. The binding of both carcinogens to blood proteins was low and suggests that human biomonitoring through protein adducts may be difficult. These metabolic pathways exist in nonhuman primates and several of these pathways also occur in vitro with human liver. The urinary excretion of MeIQx in seven human subjects following consumption of cooked beef or fish ranged between 2 and 22 ng in 12 hr when determined by negative ion chemical ionization GC-MS. After acid hydrolysis of urine, the amount of MeIQx increased 4- to 10-fold in 6 of the 7 subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper describes a physiologically based toxicokinetic model for 1,3-butadiene uptake, distribution, and metabolic clearance in mice. Model parameters for metabolic activity were estimated from the correspondence between computer simulation studies and experimental results as published in the literature. The parameterized model was validated with independent literature data. With the resulting model, the relative importance of lung metabolism as compared to metabolism in the liver increased with decreasing ambient air concentrations. This was due to saturation of metabolism in the alveolar area of the lung, which occurred in the simulations at ambient air concentrations well below current threshold limit values. At higher air concentration, liver metabolism became relatively more important. The tendency toward increased importance of lung metabolism at low doses indicates the necessity of careful extrapolation of in vivo results to low doses. Moreover, this trend may also contribute to species difference in susceptibility to the carcinogenic activity of butadiene.

Detection of carcinogen-DNA adducts in DNA from exfoliated urothelial cells from animals and humans exposed to potential environmental carcinogens is described. In an animal model, 4-aminobiphenyl-DNA adducts were detected, and the shape of the dose-response curve was related to the levels of 4-aminobiphenyl-hemoglobin adducts. In a human study, five distinct adducts were two to nine times higher in smokers than in nonsmokers. The association of four adduct measures with smoking was corroborated by significant correlations with levels of 4-aminobiphenyl-hemoglobin adducts, type and number of cigarettes smoked, and/or urinary mutagenicity. One adduct seemed chromatographically similar to N-(deoxyguanosin-8-yl)-4-aminobiphenyl. This adduct showed the strongest correlation with 4-aminobiphenyl-hemoglobin adduct levels. These data suggest that noninvasive techniques can be applied to the study of carcinogen-DNA adducts in the target organ of humans at risk for urinary bladder cancer.

High levels of polynuclear aromatic hydrocarbon (PAH) carcinogens commonly occur in aquatic systems where neoplasms arise in fish and other animals. Enzymes that transform PAHs can act in initiating these diseases and can indicate the contamination of fish by carcinogens and other pollutants. Cytochrome P-450 has similar roles in activating PAH carcinogens in fish and mammalian species. PAHs and many chlorinated hydrocarbons, e.g., polychlorinated biphenyls (PCBs) induce a form of cytochrome P-450 in fish that is the primary catalyst of PAH metabolism. The induction of this P-450 in fish can accelerate the disposition of hydrocarbons, but can also enhance the formation of carcinogenic derivatives of PAHs. Invertebrates have lower rates of PAH metabolism than fish. These rates are not obviously inducible by exposure to PAHs or PCBs. The lower rates of foreign compound metabolism contribute to higher pollutant residue levels in bivalve mollusks (clams, mussels, etc.) than in fish and may limit the involvement of some procarcinogens (requiring activation) in disease processes in invertebrates. The induction of P-450 forms can indicate the exposure of fish to PAHs, PCBs, and other toxic compounds. This is not restricted to carcinogens. Environmental induction has been detected in fish from contaminated areas by use of catalytic assay, antibodies to fish P-450, and cDNA probes that hybridize with P-450 messenger RNA. Application of these methods can provide sensitive biological monitoring tools that can detect environmental contamination of fish by some carcinogens and tumor promoters.(ABSTRACT TRUNCATED AT 250 WORDS)

A large variety of environmental carcinogens are metabolically activated to electrophilic metabolites that can bind to nucleic acids and protein, forming covalent adducts. The formation of DNA-carcinogen adducts is thought to be a necessary step in the action of most carcinogens. Recently, a variety of new fluorescence, immunochemical, and radioactive-postlabeling procedures have been developed that allow the sensitive measurement of DNA-carcinogen adducts in organisms exposed to environmental carcinogens. In some cases, similar procedures have been developed for protein-carcinogen adducts. In an organism with active metabolic systems for a given carcinogen, adducts are generally much longer lived than the carcinogens that formed them. Thus, the detection of DNA- or protein-carcinogen adducts in aquatic foodstuffs can act as an indicator of prior carcinogen exposure. The presence of DNA adducts would, in addition, suggest a mutagenic/carcinogenic risk to the aquatic organism itself. Vertebrate fish are characterized by high levels of carcinogen metabolism, low body burdens of carcinogen, the formation of carcinogen-macromolecule adducts, and the occurrence of pollution-related tumors. Shellfish, on the other hand, have low levels of carcinogen metabolism, high body burdens of carcinogen, and have little or no evidence of carcinogen-macromolecule adducts or tumors. The consumption of carcinogen adducts in aquatic foodstuffs is unlikely to represent a human health hazard. There are no metabolic pathways by which protein-carcinogen or DNA-carcinogen adducts could reform carcinogens. Incorporation via salvage pathways of preformed nucleoside-carcinogen adducts from foodstuffs into newly synthesized human DNA is theoretically possible.(ABSTRACT TRUNCATED AT 250 WORDS)

The potential of biologic markers to provide more timely and precise risk assessments for environmental carcinogens is viewed against the current state-of-the-art in biological monitoring/molecular epidemiology. Biologic markers such as carcinogen-DNA adducts and oncogene activation are currently considered valid qualitative indicators of potential risk, but for most chemical exposures research is needed to establish their validity as quantitative predictors of cancer risk. Biologic markers have, however, already provided valuable insights into the magnitude of interindividual variation in response to carcinogenic exposures, with major implications for risk assessment.