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Background: All forms of asbestos are now banned in 52 countries. Safer products have replaced many materials that once were made with it. Nonetheless, many countries still use, import, and export asbestos and asbestos-containing products, and in those that have banned other forms of asbestos, the so-called "controlled use" of chrysotile asbestos is often exempted from the ban. In fact, chrysotile has accounted for > 95% of all the asbestos used globally., Objective: We examined and evaluated the literature used to support the exemption of chrysotile asbestos from the ban and how its exemption reflects the political and economic influence of the asbestos mining and manufacturing industry., Discussion: All forms of asbestos, including chrysotile, are proven human carcinogens. All forms cause malignant mesothelioma and lung and laryngeal cancers, and may cause ovarian, gastrointestinal, and other cancers. No exposure to asbestos is without risk. Illnesses and deaths from asbestos exposure are entirely preventable., Conclusions: All countries of the world have an obligation to their citizens to join in the international endeavor to ban the mining, manufacture, and use of all forms of asbestos. An international ban is urgently needed. There is no medical or scientific basis to exempt chrysotile from the worldwide ban of asbestos.

Background: Previous studies of DDT and breast cancer assessed exposure later in life when the breast may not have been vulnerable, after most DDT had been eliminated, and after DDT had been banned., Objectives: We investigated whether DDT exposure in young women during the period of peak DDT use predicts breast cancer., Methods: We conducted a prospective, nested case-control study with a median time to diagnosis of 17 years using blood samples obtained from young women during 1959-1967. Subjects were members of the Child Health and Development Studies, Oakland, California, who provided blood samples 1-3 days after giving birth (mean age, 26 years). Cases (n = 129) developed breast cancer before the age of 50 years. Controls (n = 129) were matched to cases on birth year. Serum was assayed for p,p'-DDT, the active ingredient of DDT; o,p'-DDT, a low concentration contaminant; and p,p'-DDE, the most abundant p,p'-DDT metabolite., Results: High levels of serum p,p'-DDT predicted a statistically significant 5-fold increased risk of breast cancer among women who were born after 1931. These women were under 14 years of age in 1945, when DDT came into widespread use, and mostly under 20 years as DDT use peaked. Women who were not exposed to p,p'-DDT before 14 years of age showed no association between p,p'-DDT and breast cancer (p = 0.02 for difference by age)., Conclusions: Exposure to p,p'-DDT early in life may increase breast cancer risk. Many U.S. women heavily exposed to DDT in childhood have not yet reached 50 years of age. The public health significance of DDT exposure in early life may be large.

The hexavalent oxidation state of chromium [Cr(VI)] is a well-established human carcinogen, although the mechanism of cancer induction is currently unknown. Intracellular reduction of Cr(VI) forms Cr(V), which is thought to play a fundamental role in the mechanism of DNA damage by this carcinogen. Two separate pathways of DNA damage, an oxidative pathway and a metal-binding pathway, have been proposed to account for the lesions observed in cell systems. We have used a model Cr(V) complex, N,N-ethylenebis(salicylidene-animato)oxochromium(V) [Cr(V)-Salen], to investigate the oxidative pathway of DNA damage and to elucidate the lesions generated from this oxidation process. Reaction of Cr(V)-Salen with synthetic oligonucleotides produced guanine-specific lesions that were not 8-oxo-2'-deoxyguanosine, based on the inability of iridium(IV) to further oxidize these sites. Oxidation products were identified using a 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-G) containing oligonucleotide to increase the yields of product for identification by electrospray ionization mass spectrometry. The guanine-based lesions observed by mass spectrometry corresponded to the lesions guanidinohydantoin and spiroiminodihydantoin. The effects of these Cr(V)-Salen-induced lesions on DNA replication fidelity was assayed using a polymerase-based misincorporation assay. These lesions produced G --> T transversion mutations and polymerase stops at levels greater than those observed for 8-oxo-G. These data suggest a model by which chromate can cause DNA damage leading to mutations and cancer.

The products of hexavalent chromium [Cr(VI)] reduction by glutathione (GSH) alone or in the presence of equimolar quantities of aspartate (Asp) and/or glutamate (Glu) and a chromium-containing material extracted from bovine liver were studied by ultraviolet-visible spectrum (UV-vis) studies, electrospray mass spectrometry (ES-MS), electron paramagnetic resonance (EPR), and nuclear magnetic resonance (NMR). Reduction of chromate by GSH was followed by UV-vis and NMR, revealing the formation of a paramagnetic complex in which GSH acts as a ligand. ES-MS and EPR measurements provided unequivocal evidence of a dimeric Cr(V)(2)GSH(2) species in which the two metal ions are bridged by the Gamma-Glu carboxylate. The analysis of the (1)H and (13)C shifts experienced by GSH protons and the values of paramagnetic contributions to proton spin-lattice relaxation rates provided a set of constraints for structural determination. The same experiments were repeated in the presence of an equimolar concentration of Asp, revealing the formation of a dimeric Cr(V) paramagnetic complex in which the two metals are now bridged by Asp. Nuclear magnetic resonance dispersion profiles show that water is not displaced by Asp and that the correlation time of this complex is slowed by the increased complexity. When Glu is also included in the solution in equimolar concentration to GSH and Asp, data are consistent with the formation of many mono- and dinuclear species, with the three ligands competing with each other. Finally, the spectroscopic investigation of the chromium-containing material extracted from bovine liver revealed the presence of a complicate mixture of Cr(IV) or Cr(V) complexes, among which some Cr(V)-GSH species are present alone or with other ligands in the metal coordination sphere.

Induction of DNA damage by carcinogenic hexavalent chromium compounds [Cr(VI)] results from its reduction to lower oxidation states. Reductive metabolism of Cr(VI) generates intermediate Cr(V/IV)species, organic radicals, and finally Cr(III), which forms stable complexes with many biological ligands, including DNA. To determine the biological significance of different reaction products, we examined genotoxic responses and the formation of DNA damage during reduction of Cr(VI) by its biological reducer, cysteine. We have found that cysteine-dependent activation of Cr(VI) led to the formation of Cr-DNA and cysteine-Cr-DNA adducts as well as interstrand DNA cross-links. The yield of binary and ternary DNA adducts was relatively constant at different concentrations of Cr(VI) and averaged approximately 54 and 45%, respectively. Interstrand DNA cross-links accounted on average for 1% of adducts, and their yield was even less significant at low Cr(VI) concentrations. Reduction of Cr(VI) in several commonly used buffers did not induce detectable damage to the sugar-phosphate backbone of DNA. Replication of Cr(VI)-modified plasmids in intact human fibroblasts has shown that cysteine-dependent metabolism of Cr(VI) resulted in the formation of mutagenic and replication-blocking DNA lesions. Selective elimination of Cr-DNA adducts from Cr(VI)-treated plasmids abolished all genotoxic responses, indicating that nonoxidative, Cr(III)-dependent reactions were responsible for the induction of both mutagenicity and replication blockage by Cr(VI). The demonstration of the mutagenic potential of Cr-DNA adducts suggests that these lesions can be explored in the development of specific and mechanistically important biomarkers of exposure to toxic forms of Cr.

Mycotoxins that commonly contaminate staple food grains pose a health hazard to animals and humans. Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia and porcine pulmonary edema and has been implicated in the etiology of esophageal cancer (EC) in the Transkei, South Africa. Various studies have indicated that nitrosamines induce EC, and F. verticillioides enhancement of nitrosamine-induced EC in rats has been reported. Dietary catechol (CAT), a constituent of cigarette smoke, was previously found to be a cocarcinogen with methyl-N-nitrosamine for inducing esophageal tumors in rats. In the present study we therefore investigated the cytotoxic effects of FB1, diethylnitrosamine (DEN), and CAT on a human esophageal epithelial cell line (SNO) using the methylthiazol tetrazolium assay. For each treatment, toxin concentrations ranged from 2.165 to 34.64 micro M. The results showed that the cytotoxic response of SNO cells was highest in cells treated with 34.64 micro M FB1. SNO cells treated with DEN + FB1 showed greater cytotoxicity than did cells treated with FB1 alone, whereas FB1 appeared to inhibit the cytotoxic effect exerted by CAT alone. The results of this study provide further evidence for the involvement of FB1 in the etiology of esophageal carcinoma.

We used cytogenetic analysis to carry out a cohort study in which the major objective was to test the association between frequency of chromosomal aberrations and subsequent risk of cancer. In spite of the extensive use of the cytogenetic analysis of human peripheral blood lymphocytes in biomonitoring of exposure to various mutagens and carcinogens on an ecologic level, the long-term effects of an increased frequency of chromosomal aberrations in individuals are still uncertain. Few epidemiologic studies have addressed this issue, and a moderate risk of cancer in individuals with an elevated frequency of chromosomal aberrations has been observed. In the present study, we analyzed data on 8,962 cytogenetic tests and 3,973 subjects. We found a significant and strong association between the frequency of chromosomal aberrations and cancer incidence in a group of miners exposed to radon, where a 1% increase in frequency of chromosomal aberrations was followed by a 64% increase in risk of cancer (p < 0.000). In contrast, the collected data are inadequate for a critical evaluation of the association with exposure to other chemicals.

Malignant mesothelioma is a highly aggressive tumor of the serous membranes, which in humans results from exposure to asbestos and asbestiform fibers. Although occupational malignant mesothelioma is still the most common form of this lesion, naturally contaminated soil can play an important role in the development of environmental malignant mesothelioma in some parts of the world. Fifty cases of malignant mesothelioma (MM) from southern Turkey with no occupational history of asbestos exposure were reviewed regarding pathologic and clinical features. A case of hyaline fibrous plaque of the pleura was also included in this series. Histologically the cases were classified as epithelial (36 cases); sarcomatous (7 cases); and biphasic (7 cases). One of the sarcomatous cases was desmoplastic. Ultrastructural examination of the tumor tissue in three cases revealed long-surface microvilli in epithelial cells. Interstitial cells of the lung in one case showed electron-dense asbestos fibers in the cytoplasm. Mineralogical analyses of the lung tissue in three cases of MM and the case of pleural plaque showed high amounts of asbestos fibers most consistent with tremolite and actinolite. The clinical and pathologic features of our cases support that the environmental inhalation of asbestos is still a major health problem in some parts of Turkey.

Chromium has been used commercially in the United States for more than 100 years in metal alloys and other compounds, as a pigment, and in the tanning and metal plating industries, and many studies have looked at its effects in terms of occupational health. But, although scientists know that Cr(VI) is a human carcinogen and that it can cause other deleterious health effects including kidney and liver damage, certain questions remain about the metal's effects, such as which routes of exposures are dangerous for humans.

In the 1950s evidence of an ongoing epidemic of lung cancer in the United States and Western Europe led researchers to examine the role of outdoor air pollution, which was considered by some to be a likely cause. Although epidemiologic research quickly identified the central role of cigarette smoking in this epidemic, and despite progress in reducing outdoor air pollution in Western industrialized countries, concerns that ambient air pollution is causing lung cancer have persisted to the present day. This concern is based on the fact that known carcinogens continue to be released into outdoor air from industrial sources, power plants, and motor vehicles, and on a body of epidemiologic research that provides some evidence for an association between outdoor air pollution and lung cancer. This article reviews the epidemiologic evidence for this association and discusses the limitations of current studies for estimating the lung cancer risk in the general population. It also identifies research needs and suggests possible approaches to addressing outstanding questions.

Exposures to asbestos and synthetic fibers remain areas of great concern in the field of occupational lung disease. Despite extensive study, the health effects associated with fibers remains an area of substantial controversy. In particular, effects of fibers at relatively low doses, particularly for mesothelioma, remain a matter of evolving opinion, especially when integrated with the divergence of opinion on relative pathogenicity of different fiber types. Mechanistic studies continue to provide a window into pathogenesis and some hope for understanding dose-response relationships at the lower levels seen in contemporary Western workplaces and the general environment. Changes in clinical assessment based on use of new chest imaging techniques beyond the traditional plain film are also an area of evolution and begin to challenge B-reading as the definitive tool for noninvasive assessment of disease. Public health concerns have to a great extent been transported to the developing world where there is a strong trend toward increased use of asbestos, although it has been virtually eliminated from commerce in most developed countries. For nonasbestos fibers, the major unsettled issues are their relative potencies as carcinogens for the human lung and mesothelium and the need to sort out the relation between physical and chemical properties of these fibers and their pathogenicity. The recent discovery of "flock worker's lung" due to synthetic fibers once again alerts us to emerging diseases associated with new technologies.

Radon is a well-established human carcinogen for which extensive data are available, extending into the range of exposures experienced by the general population. Mounting epidemiologic evidence on radon and lung cancer risk, now available from more than 20 different studies of underground miners and complementary laboratory findings, indicates that risks are linear in exposure without threshold. Radon is also a ubiquitous indoor air pollutant in homes, and risk projections imply that radon is the second leading cause of lung cancer after smoking. Recommended control strategies in the United States and other countries, which include testing of most homes and mitigation of those exceeding guideline levels, have been controversial. Further research is needed, drawing on molecular and cellular approaches and continuing the follow-up of the underground miner cohorts, and scientists should work toward constructing mechanistically based models that combine epidemiologic and experimental data to yield risk estimates with enhanced certainty.

Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute--chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concentrations of TCA in blood required to induce liver cancer approach the mM range. Concentrations of DCA in blood associated with carcinogenesis are in the sub-microM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPAR-alpha that are observed in rodents. This may be attributed to lower levels of expressed PPAR-alpha in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis.

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.

The existing extensive laboratory data on trichloroethylene (TCE) and its two metabolites, dichloroacetic (DCA) and trichloroacetic (TCA), are used to explore the relationship among these three compounds. Under the hypothesis that these compounds induce liver tumors in mice through promotion of preexisting initiated cells, it is demonstrated that DCA alone could be responsible for all the response of carcinomas in liver of B6CF(1) mice. The focus of this paper is on how a plausible biological assumption could impact on low-dose risk estimates, rather than on the risk estimate per se. The findings suggest that low-dose risk estimates to humans would be overestimated unless the different background rates between mice and humans are properly accounted for.

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.

Trichloroethylene is an organic chemical that has been used in dry cleaning, for metal degreasing, and as a solvent for oils and resins. It has been shown to cause liver and kidney cancer in experimental animals. This article reviews over 80 published papers and letters on the cancer epidemiology of people exposed to trichloroethylene. Evidence of excess cancer incidence among occupational cohorts with the most rigorous exposure assessment is found for kidney cancer (relative risk [RR] = 1.7, 95% confidence interval [CI] 1.1-2.7), liver cancer (RR = 1.9, 95% CI(1.0-3.4), and non-Hodgkin's lymphoma (RR = 1.5, 95% CI 0.9-2.3) as well as for cervical cancer, Hodgkin's disease, and multiple myeloma. However, since few studies isolate trichloroethylene exposure, results are likely confounded by exposure to other solvents and other risk factors. Although we believe that solvent exposure causes cancer in humans and that trichloroethylene likely is one of the active agents, we recommend further study to better specify the specific agents that confer this risk and to estimate the magnitude of that risk.

Chemicals that were bioassayed by the National Toxicology Program (NTP) and that also produce allergic dermatitis (ACD) in humans were evaluated for their tumorigenic characteristics. The impetus for the study was that most contact sensitizers, i.e., those that produce ACD, and genotoxic carcinogens are chemically similar in that they are electrophilic, thereby producing adducts on macromolecules including protein and DNA. This similarity in chemical behavior suggests that many contact sensitizers might be environmental carcinogens. All of the published NTP bioassays by early 1996 that had both genotoxicity and carcinogenicity studies were included in this analysis. The NTP chemicals had been chosen for bioassay without regard to their ability to produce ACD. Of the 209 chemicals that were bioassayed, there were 36 (17%) that were known to be human contact sensitizers; about half of these were positive on tumor bioassays. The contact sensitizers differed from the NTP sample as a whole by having a proportionately larger number of nongenotoxic chemicals by the Ames Salmonella assay, presumably because more of them were selected on the basis of widespread usage rather than structural resemblance to known carcinogens. Compared to the nongenotoxic chemicals, the genotoxics were stronger carcinogens in that they had a higher incidence of positive tumor bioassays, with twice the number of organs in which tumors were induced. The nongenotoxic chemicals had a preference for tumor induction in parenchymal tissues in contrast to epithelial tissues. The contact sensitizers showed essentially the same characteristics as the whole NTP sample when stratified according to genotoxicity. Judging by the chemicals that were chosen primarily for their widespread use rather than for their structural resemblance to carcinogens, the addition of a test for contact sensitization to the Ames test as a screening tool would increase the tumorigenic detection efficiency by about 40% because of the nongenotoxic tumorigens. A ballpark estimate suggests that there could be several thousand contact sensitizers for humans in commercial use that are rodent tumorigens.

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.

Assessment of human health risks of environmental agents has often been limited to consideration of the potential for the agent to cause cancer or general systemic toxicity after long-term exposure. The U.S. Environmental Protection Agency (U.S. EPA) is increasingly moving toward the development of integrated assessments, which consider all potential health end points including developmental toxicity, neurotoxicity, immunotoxicity, reproductive effects, and germ cell mutagenicity. The U.S. EPA has a responsibility to assess risks to nonhuman species or ecosystems when appropriate data are available. An example of a recent integrated human health and ecological risk assessment can be found in the U.S. EPA Mercury Study Report to Congress. This report covers the following topics in separate volumes: an inventory of anthropogenic mercury emissions in the United States; an exposure assessment using measured and predicted values and including indirect dietary exposure; an evaluation of human health risks; an assessment of ecologic risk wherein water criteria are presented for several wildlife species; an overall integrated characterization of human and nonhuman risk; and a discussion of risk management considerations. In the evaluation of human health risk, genetic toxicology data were considered for three forms of mercury: elemental, inorganic (divalent), and methylmercury. These data were used in judgments of two types of potential health effects (carcinogenicity and germ cell mutagenicity). In assessment of potential carcinogenicity of inorganic and methylmercury, genetic toxicity data were key. Data for clastogenicity in the absence of mutagenicity supported the characterization of inorganic and methylmercury as materials that produce carcinogenic effects only at high, toxic doses. The evidence for clastogenicity, coupled with information on metabolism and distribution, resulted in a judgment of a moderate degree of concern (or weight of evidence) that inorganic mercury can act as a human germ cell mutagen. For methylmercury, the degree of concern for germ cell mutagenicity is high.

Susceptibility to environmental carcinogenesis is the consequence of a complex interplay between intrinsic hereditary factors and actual exposures to potential carcinogenic agents. We must learn the nature of these interactions as well as the genetic defects that confer enhanced risk. In some genetic diseases an increased cancer risk correlates with a defect in the repair or replications of damaged DNA. Examples include xeroderma pigmentosum (XP), ataxia telangiectasia, Fanconi's anemia, and Bloom's syndrome. In Cockayne's syndrome the Specific defect in transcription-coupled repair (TCR) does not predispose the patients to the sunlight-induced skin cancer characteristic of XP. The demonstration of TCR in the XP129 partial revertant of XP-A cells indicates that ultraviolet (UV) resistance correlates with repair of cyclobutane pyrimidine dimers in active genes. Repair measured as an average over the genome can be misleading, and it is necessary to consider genomic locations of DNA damage and repair for a meaningful assessment of the biological importance of particular DNA lesions. Mutations in the p53 tumor suppressor gene are found in many human tumors. TCR accounts for the resulting mutational spectra in the p53 gene in certain tumors. Li-Fraumeni syndrome fibroblasts expressing only mutant p53 are more UV-resistant and exhibit less UV-induced apoptosis than normal human cells or heterozygotes for mutations in only one allele of p53. The p53-defective cells are deficient in global excision repair capacity but have retained TCR. The loss of p53 function may lead to greater genomic instability by reducing the efficiency of global DNA repair while cellular resistance may be assured through the operation of TCR and the elimination of apoptosis.

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.

Cancer cells are produced by the accumulation of genetic alterations in somatic cells. Those genetic alterations are produced by xenobiotics, which enter the human body from the environment, and by autobiotics, which are produced in the human body. Food contains many different types of xenobiotic mutagens/carcinogens and tumor promoters. Food can influence the formation of autobiotic mutagens/carcinogens and give rise to tumor-promoting conditions. In spite of this, it can also contain many antimutagenic, anticarcinogenic, and antitumor-promoting substances. Carcinogenic risk and anticarcinogenic efficacy are hard to express quantitatively; however, holistic approaches that are designed to improve lifestyle are realistic for cancer prevention.

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.

Molecular epidemiology has significant potential in preventing cancer and other diseases caused by environmental exposures (related to lifestyle, occupation, or ambient pollution). This approach attempts to prevent cancer by incorporating laboratory methods to document the molecular dose and preclinical effects of carcinogens, as well as factors that increases individual susceptibility to carcinogens. Recently we have carried out validation studies of biologic markers such as carcinogen--DNA and carcinogen--protein adducts, gene and chromosomal mutations, alterations in target oncogenes or tumor suppressor genes, polymorphisms in putative susceptibility genes (individual P450s, glutathione transferase M1), and serum levels of micronutrients. This research involves adults, infants, and children exposed to varying levels of carcinogens, as well as cancer cases and controls. On a group level, dose-response relationships have frequently been seen between various biomarkers and environmental exposures such as polycyclic aromatic hydrocarbons, cigarette smoke (active and passive), and ambient indoor and workplace air pollution. However, there is significant interindividual variation in biomarkers that appears to reflect a modulating effect on biomarkers (hence potential risk) by genetic and acquired susceptibility factors. Ongoing retrospective and nested case-control studies of lung and breast cancer are examining the association between biomarkers and cancer risk. Results of these studies are encouraging; they suggest that biomarkers, once validated, can be useful in identifying populations and individuals at risk in time to intervene effectively.

Nongenotoxic carcinogens are chemicals that induce neoplasia without it or its metabolites reacting directly with DNA. Chemicals classified as nongenotoxic carcinogens have been assumed to act as tumor promoters and exhibit threshold tumor dose-responses. This is in contrast to genotoxic carcinogens that are DNA reactive, act as tumor initiators, and are assumed to exhibit proportional responses at low doses. In this perspective, we examine the basic tenets and utility of this classification for evaluating human cancer risk. Two classes of so-called nongenotoxic chemical carcinogens selected for review include cytotoxic agents that induce regenerative hyperplasia (trihalomethanes and inducers of alpha 2-microglobulin nephropathy) and agents that act via receptor-mediated mechanisms (peroxisome proliferators and dioxin). Major conclusions of this review include: a) many chemicals considered to be nongenotoxic carcinogens actually possess certain genotoxic activities, and limiting evaluations of carcinogenicity to their nongenotoxic effects can be misleading; b) some nongenotoxic activities may cause oxidative DNA damage and thereby initiate carcinogenesis; c) although cell replication is involved in tumor development, cytotoxicity and mitogenesis do not reliably predict carcinogenesis; d) a threshold tumor response is not an inevitable result of a receptor-mediated mechanism. There are insufficient data on the chemicals reviewed here to justify treating their carcinogenic effects in animals as irrelevant for evaluating human risk. Research findings that characterize the multiple mechanisms of chemical carcinogenesis should be used quantitatively to clarify human dose-response relationships, leading to improved scientifically based public health decisions. Excessive reliance on oversimplified classification schemes that do not consider all potential contributing effects of a toxicant can obscure the actual causal relationships between exposure and cancer outcome.

Preventable environmental causes of cancer, including tobacco smoke and other carcinogens in the diet, workplace, and ambient environment are responsible for the vast majority of human cancers. This paper reviews recent molecular epidemiologic studies that have focused on environmental carcinogenesis and environment-host interactions. Biomarkers such as carcinogen-DNA and carcinogen-protein adducts, mutations in reporter or target genes (e.g., HPRT, GPA, ras, p53), or genetic or acquired susceptibility factors (e.g., polymorphisms in the P450 or glutathione-S-transferase genes and serum levels of antioxidants) have shown significant potential in prevention. They should be useful in early identification of at risk individuals and in designing and monitoring interventions (smoking cessation, exposure reduction, and chemoprevention).

Strategies for cancer prevention generally come from observational epidemiology and must include monitoring for the effects of the actions. The measurement-iterative loop allows us to refine our approach to cancer prevention. When available, clinical trials can also provide strategies for control. Exposure-specific strategies are described; these are such things as health promotion and behavior modification, legislative approaches, treatment for addiction, changes in the food supply, chemoprevention, occupational and environmental regulation, immunization, identification of persons with enhanced genetic susceptibility, and improved surveillance systems. For some exposures such as tobacco, zero exposure is the goal. For others, prudent avoidance or exposures as low as reasonably achievable are appropriate approaches. Research on how to impact deeply ingrained lifestyle and cultural factors has high priority.

We present a model to plan a rational strategy for cancer prevention that has two main functions--assessment and intervention. The assessment function includes three main components: to identify populations at high cancer risk, which may be due to their ethnic group, occupational and environmental exposures, family history, cigarette smoking, or other risk factors; to assess exposure to known carcinogens through the general and occupational environments, lifestyle factors, and the home as well as to document known carcinogens using human tissue banks and develop and validate questionnaires to target known risk factors for each of the most common cancers; and to conduct research studies of high-risk populations, including studies on mechanism and genetic testing. The intervention function includes three components: development of population-based intervention programs using the results from the research studies; evaluation of intervention programs; and modification of existing intervention programs and implementation of new ones. The above-proposed prevention strategy depends to a great extent on population-based cancer registries. Existing cancer registries around the United States should be strengthened and other dimensions should be added to their charge to augment their function in prevention research. To convert existing population-based cancer registries, particularly those that serve multiethnic and multicultural populations, into Cancer Prevention Research Registries (CPRRs), three types of data in addition to their existing required data complement should be incorporated. These are exposure information including occupational history, host factors information, and information about family history of cancer and associated conditions. The primary goal of the CPRRs should be to support cancer prevention research in its widest sense. Future research needs must be designed to investigate each of the components of the prevention strategy as well as its integrated performance. Regardless of what we do in the future, we must now promote healthier lifestyles, prevent exposure to known carcinogens, and improve early detection procedures.

Evidence that much cancer is preventable derives from observations of time trends and geographic patterns of cancer, birth cohort changes, high risks in groups with well-defined exposures, and experimental studies. In an effort to identify additional opportunities for reducing the impact of cancer on society, this conference assessed avoidable causes of cancer. The magnitude and extent of preventable causes of cancer are subjects of intense debate, with discrepancies often related to the use of different time frames and different weights for epidemiologic and toxicologic evidence. There is much agreement, however, about the exposures that increase risk, notably tobacco, alcohol, diet, radiation, medications, occupational exposures, general environmental exposures, and infectious agents. Interactions between carcinogenic exposures and genetic susceptibility are also important. Concerted efforts are needed to identify avoidable causes of cancer and to apply knowledge already obtained to reduce the cancer burden.

The sum of the evidence supports the necessity to continue to investigate the developmental effects of estrogenic and antiestrogenic compounds when exposure occurs early in life. Additional studies will answer questions relevant to the molecular definition of the developmental or carcinogenic effects of estrogens such as hormone-induced gene alterations. These studies also support the need to use the neonatal mouse model to demonstrate the consequences of reproductive and nonreproductive stem-cell exposure to estrogenic compounds.

The International Agency for Research on Cancer has given the designations of "sufficient evidence" of carcinogenicity of 1,3-butadiene in experimental animals and "limited evidence" of carcinogenicity in humans. To investigate the carcinogenic effect in humans, we conducted a cohort mortality study among 364 men who were assigned to any of three 1,3-butadiene production units located within several chemical plants in the Kanawha Valley of West Virginia, including 277 men employed in a U.S. Rubber Reserve Plant which operated during World War II. The butadiene production units included in this study were selected from an index developed by the Union Carbide Corporation, which listed for each chemical production unit within their South Charleston, West Virginia and Institute, West Virginia, plants all products, by-products, and reactants. Departments included in the study were those where butadiene was a primary product and neither benzene nor ethylene oxide was present. A total of 185 deaths were observed; the standardized mortality ratio (SMR) for all causes of death was 91, reflecting lower mortality among the study population than the U.S. population. The study found a significantly elevated standardized mortality ratio (SMR) for lymphosarcoma and reticulosarcoma based on four observed cases (SMR = 577; 95% CI = 157-1480), which persisted in an analysis using county referent rates. An excess of lymphosarcoma and reticulosarcoma among all workers and among workers with routine exposure to 1,3-butadiene was also observed in the only other cohort of 1,3-butadiene production workers previously studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Critics of comparative risk assessment (CRA), the increasingly common practice of juxtaposing disparate risks for the purpose of declaring which one is the "larger" or the "more important," have long focused their concern on the difficulties in accommodating the qualitative differences among risks. To be sure, people may disagree vehemently about whether "larger" necessarily implies "more serious," but the attention to this aspect of CRA presupposes that science can in fact discern which of two risks has the larger statistical magnitude. This assumption, encouraged by the indiscriminate calculation of risk ratios using arbitrary point estimates, is often incorrect: the fact that environmental and health risks differ in unknown quantitative respects is at least as important a caution to CRA as the fact that risks differ in known qualitative ways. To show how misleading CRA can be when uncertainty is ignored, this article revisits the claim that aflatoxin contamination of peanut butter was "18 times worse" than Alar contamination of apple juice. Using Monte Carlo simulation, the number 18 is shown to lie within a distribution of plausible risk ratios that ranges from nearly 400:1 in favor of aflatoxin to nearly 40:1 in the opposite direction. The analysis also shows that the "best estimates" of the relative risk of aflatoxin to Alar are much closer to 1:1 than to 18:1. The implications of these findings for risk communication and individual and societal decision-making are discussed, with an eye toward improving the general practice of CRA while acknowledging that its outputs are uncertain, rather than abandoning it for the wrong reasons.

It has been hypothesized that organochlorine pesticides and other environmental and dietary estrogens may be associated with the increased incidence of breast cancer in women and decreased sperm concentrations and reproductive problems in men. However, elevation of organochlorine compounds such as dichlorodipehenyldichloroethylene (DDE) and polychlorinated biphenyls (PCBs) in breast cancer patients is not consistently observed. Reanalysis of the data showing that male sperm counts decreased by over 40% during 1940 to 1990 indicated that inadequate statistical methods were used and that the data did not support a significant decline in sperm count. Humans are exposed to both natural and industrial chemicals which exhibit estrogenic and antiestrogenic activities. For example, bioflavonoids, which are widely distributed in foods, and several industrial compounds, including organochlorine pesticides and various phenolic chemicals, exhibit estrogenic activity. Humans are also exposed to chemicals which inhibit estrogen-induced responses such as the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chlorinated aromatics, polynuclear aromatic hydrocarbon combustion products, and indole-3-carbinol, which is found in cruciferous vegetables. Many of the weak estrogenic compounds, including bioflavonoids, are also antiestrogenic at some concentrations. A mass balance of dietary levels of industrial and natural estrogens, coupled with their estimated estrogenic potencies, indicates that the dietary contribution of estrogenic industrial compounds is 0.0000025% of the daily intake of estrogenic flavonoids in the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Several metal or metalloid ions exist in multiple oxidation states and can undergo electron transfer reactions that are important in biological and environmental systems. There are endogenous metal ions such as iron, copper, and cobalt that participate in oxidation-reduction reactions with species of oxygen like molecular dioxygen, superoxide, and hydrogen peroxide. These reactions may be modulated by endogenous reducing agents such as glutathione, ascorbate, and tocopherol. The reactions can be described in terms of thermodynamics through the use of standard electrode potentials. A favorable reaction will depend on the concentrations of the reactants and may depend on the pH and/or on the presence of organic ligands that form complexes with the metal or metalloid. Arsenate (As(V)) can react with glutathione in buffered aqueous solutions to produce arsenite (As(III)) and oxidized glutathione. This reaction may be important in the methylation reactions of arsenic. Arsenic species can decrease the red blood cell levels of reduced glutathione, but the products of oxidation and the mechanism of oxidation are more complex than those found in water alone. Chromium (VI) is thought to interact with DNA after first reacting with a reducing agent such as glutathione to form lower oxidation states of chromium. These examples illustrate the importance of oxidation-reduction reactions for toxic metals and metalloids.

The genetic effects of environmental pollutants include mutations in somatic cells or germinal cells that are the direct result of exposure to toxicants. Biomarkers that detect such mutagenic effects have been developed and tested in field studies on wildlife populations. However, another class of genetic effects resulting from pollution exposure exists. Specifically, changes in allele frequencies of populations will occur as a result of population bottlenecks, inbreeding, or selection at loci critical for survival in polluted environments. We describe how such genetic alterations can be studied at the population level using the techniques of molecular genetics, and we predict the development of a new field, evolutionary toxicology, that will address such issues.

The recent development of techniques to measure levels of carcinogens covalently bound to DNA provides the opportunity to use DNA adducts as molecular dosimeters of exposure to environmental carcinogens and mutagens. This is especially important because epizootiologic studies have shown a positive association between environmental carcinogens, such as polycyclic aromatic hydrocarbons, and increased prevalence of neoplasms and related lesions, primarily in liver, of benthic fish species from a wide range of urban and industrialized areas. In studies with wild fish and mammalian species the 32P-postlabeling assay, as developed for aromatic compounds, has been used most extensively because of its high sensitivity and ability to detect structurally uncharacterized adducts. The results to date of field and laboratory studies show that hepatic DNA adducts detected in fish are associated with increased exposure to environmental polycyclic aromatic compounds in the preponderance of species examined, whereas in the limited studies with wild mammals, such a relationship is equivocal at present. The findings with fish suggest that DNA adducts, as measured by 32P-postlabeling, have the potential to be effective molecular dosimeters of exposure to environmental carcinogenic aromatic compounds and thereby may lead to an improved understanding of the etiology of neoplasia in wild teleosts.

The study of human cancers has provided evidence that malignant progression is associated with genetic change. It has been suggested that some genetic alterations in tumors may be the result of direct or indirect processes related to environmental chemical exposure. This hypothesis has been supported by genetic evidence in liver tumors which has associated aflatoxin B1 exposure with the detection of inactivating DNA mutations within the human p53 tumor suppressor gene. The detection of activating ras oncogene mutations at high frequency in liver tumors of feral fish suggest that the survey of mutations in genes, such as p53 or other genes, might provide a genetic signature for specific chemical exposure in tissues of aquatic animals derived from environmentally damaged sites.

Fiber length and persistence are thought to be determinants for the development of toxic, fibrogenic, and carcinogenic effects of fibrous dusts. When the solubilities of chrysotile asbestos (CA) and basalt fibers (BF) were compared by measuring the loss of silica and magnesium in Leineweber's solution, CA was shown to be the more soluble. In a 6-month inhalation experiment, chrysotile at a mean concentration of 25 mg/m3 had a higher clearance rate than other comparable dusts. In acute toxicity studies, chrysotile and basalt fibers were administered intraperitoneally. At a dose of 1.7 g/kg body weight of CA, one third of the animals died. A dose of 2.7 g/kg body weight killed all the animals. With BF, even at a dose of 10 g/kg body weight all the animals survived. When the two fibers were administered over a 6-month period, either intratracheally or by inhalation, fibrotic lesions were more common in the group that received CA. Intraperitoneal administration of CA led to three times as many deaths from peritoneal mesothelioma as administration of BF. It appears, therefore, that in spite of its higher solubility and lower persistence, CA was the more toxic, fibrogenic and carcinogenic fiber, which gives rise to the hypothesis that the surface chemistry of the fibers is the determinant for biological activity.

Occupational exposure to arylamines such as benzidine, 2-naphthylamine, and 4-aminobiphenyl is associated with exceptionally elevated risks of bladder cancer (up to 100-fold or more). In one plant, all 15 workers involved in distilling naphthylamine developed bladder cancer, suggesting that for high levels of exposure to potent carcinogens individual susceptibility is irrelevant. More recently, exposure to other arylamines also has been suggested to increase the risk of bladder cancer in humans. In addition, cohort and case-control studies suggest that several job titles or exposures may involve elevated risks of bladder cancer. Some of these jobs or exposures (such as in the aluminum industry) are associated with exposure to arylamines. Arylamines are found also in tobacco smoke, and different sources of evidence suggest that they can explain the risk of bladder cancer, which has been shown clearly in smokers. Epidemiologic analyses of timing of exposure in workers occupationally exposed to arylamines or in air-cured tobacco smokers suggest that arylamines exert both an early- and a late-stage activity, compatible with a two-mutation theory of bladder carcinogenesis.