Showing papers in "Critical Reviews in Toxicology in 1996"
TL;DR: The aquatic ecotoxicology of organotins is reviewed based on a multidisciplinary approach involving environmental chemical, toxicological, and ecological aspects, and the influence of speciation for bioavailability, basic modes of toxic action, and aquatic toxicity are discussed.
Abstract: Organotin compounds are ubiquitous contaminants in the environment. The high biological activity of some compounds toward aquatic organisms lead to deleterious impacts in aquatic ecosystems. Here, the aquatic ecotoxicology of organotins is reviewed based on a multidisciplinary approach involving environmental chemical, toxicological, and ecological aspects. Basic results were obtained both with field and laboratory studies, and some of the most important recent results and conclusions are critically reviewed. The contamination of and fate in aquatic systems is reported and linked with effects at different levels of biological organization. Major emphasis is placed on the development of a concept of ecotoxicology that encompasses not only effect assessment alone, but also integrates environmental chemistry with aquatic toxicology. Thereby, the influence of speciation for bioavailability, basic modes of toxic action, and aquatic toxicity are discussed. This case study on organotins allows to a certain extent generalizations to ecotoxicology in general.
955 citations
TL;DR: The potential for these compounds to produce estrogenic effects in the environment appears low and questions concerning the physiological effects of APEs and other environmental estrogens remain unanswered, there are indications that research is in progress that will lead to better understanding of the risks to humans and wildlife.
Abstract: Alkylphenol ethoxylates (APEs) and related compounds recently have been reported to be estrogenic because it has been demonstrated in laboratory studies that they mimic the effects of estradiol bothin vitro andin vivo. Chemicals referred to as “environmental estrogens” are suspected of causing health effects in both humans and wildlife through disruption of the endocrine system. In this review, the occurrence, environmental fate, and biological effects of APEs are presented. To provide understanding of the potential for endocrine disruption due to environmental estrogens, the physiology of estrogens in mammals and fish is also reviewed. The estrogenic potency of other environmental estrogens is compared to the potency of APE degradation products. The reproductive effects of estrogenic compounds are considered when evaluating the potential health effects of APEs. Given the reported environmental concentrations and bioconcentration factors of APE products, the potential for these compounds to produc...
503 citations
TL;DR: The plasticizer di(2-ethylhexyl) phthalate (DEHP), to which humans are extensively exposed, was found to be hepatocarcinogenic in rats and mice, and peroxisome proliferation as a whole phenomenon appears to be associated with the potential of tumor induction.
Abstract: The plasticizer di(2-ethylhexyl) phthalate (DEHP), to which humans are extensively exposed, was found to be hepatocarcinogenic in rats and mice. DEHP is potentially set free from objects made of synthetic materials (e.g., those used in medicine). Chronically, the greatest amounts are transferred to persons undergoing hemodialysis (up to 3.1 mg/kg b.w. per day) who would thus be considered the individuals most endangered by tumorigenesis. Although toxicokinetics seem to play a certain unclear role in the course of DEHP-related toxicity, toxicodynamic factors appear more decisive. DEHP is a representative of "peroxisome proliferators" (PP), a distinct group of substances that, in rodents, do not only induce peroxisomes but also specific enzymes in other organelles, organ growth, and DNA synthesis. The cluster of the characteristic effects of PP is generally, although perhaps not quite appropriately summarized as "peroxisome proliferation," and is strongest in the liver. The lowest observed effect level (LOEL) and the no observed effect level (NOEL) of peroxisome proliferation in the rat, as determined by the induction of specific enzymes (peroxisomal beta-oxidation, carnitine-acetyl-transferase, cytochrome P-452), DNA synthesis, and hepatomegaly, may be assumed as 50 and 25 mg/kg b.w. per day, respectively. DEHP and other carcinogenic PP are neither genotoxic nor tumor initiators, but they appear to be tumor promoters, also implicating a threshold level for the carcinogenic effect. Although a causal relationship between a particular effect of peroxisome proliferation and hepatocarcinogenesis is as yet unknown, peroxisome proliferation as a whole phenomenon appears to be associated with the potential of tumor induction, as shown by comparison of the relative strength of individual PP and by comparison of species and organ specificities. Likewise, LOEL and NOEL of rodent carcinogenesis, that is, 300 and 50 to 100 mg/kg b.w. per day, respectively, are above but not too far from the corresponding values for the investigated parameters of peroxisome proliferation. Thus, with respect to dose alone, worst-case exposure in hemodialysis patients is at least 16-fold below the LOEL of any characterized PP-specific effect of DEHP and approximately 100-fold below that of DEHP-related tumorigenesis. Also, primates are less responsive to PP than rats with respect to the investigated biochemical and morphological parameters. If this lower primate responsiveness is extrapolated to estimate carcinogenicity in humans, we might thus arrive at an even larger safety margin than when based on exposure alone. Doses of PP hypolipidemics that had clearly induced several indicators of peroxisome proliferation in rats did not cause any clear-cut enhancements in the peroxisomes of patients, even though most of these hypolipidemics were considerably stronger PP than DEHP. Thus, an actual threat to humans by DEHP seems rather unlikely. Accordingly, hepatocarcinogenesis was neither enhanced in workers exposed to DEHP nor in patients treated with hypolipidemics.
297 citations
TL;DR: Findings from both epidemiological and laboratory studies suggest that exposure to polychlorinated biphenyls and related halogenated aromatic hydrocarbons induces significant neurological and behavioral dysfunctions in humans and laboratory animals, particularly following exposure during gestation and lactation.
Abstract: The purpose of this review is to provide a selective, but critical, assessment of important findings derived from both epidemiological and laboratory studies suggesting that: (1) exposure to polychlorinated biphenyls (PCBs) and related halogenated aromatic hydrocarbons induces significant neurological and behavioral dysfunctions in humans and laboratory animals, particularly following exposure during gestation and lactation; (2) the neurochemical actions of PCBs depend on their structure and the developmental status of the animal at the time of exposure; and (3) the mechanisms responsible for these changes may involve alterations in basic cellular signaling processes and endocrine function that influence the synthesis and activity of important central nervous system neurotransmitters, the organization of the developing brain, and the behavioral responses to these environmental contaminants.
242 citations
TL;DR: The present review examines the scientific literature, primarily covering the past 10 years, dealing with reports describing various types of silver toxicity, with particular emphasis on the use of silver in topical antimicrobial preparations as toxicity relates to absorption through dermal wounds into the systemic circulation.
Abstract: Silver is generally considered to present a relatively low toxic threat to humans because unintentional exposure to large doses of the noble metal is quite rare. However, as the intentional utilization of silver in pharmaceutical preparations and devices increases, subtle toxic effects of silver may be predictable and expected. The present review examines the scientific literature, primarily covering the past 10 years, dealing with reports describing various types of silver toxicity. These reports consist of both in vitro and in vivo data dealing with immunological, mesenchymal, neural, and parenchymal cell types. Particular emphasis is given to (1) the use of silver in topical antimicrobial preparations as toxicity relates to absorption through dermal wounds into the systemic circulation and possible effects on delayed wound healing, (2) possible local silver toxicity via iontophoretic devices, (3) current theories relating to the toxicological mechanism of action of silver.
215 citations
TL;DR: The objective of this work is to summarize the main epidemiological and experimental findings pertaining to agents (physical and chemical) encountered in the occupational environment that might affect the male reproductive system and/or related pregnancy outcomes (spontaneous abortion, stillbirth, low birth weight, and birth defects and childhood malignancy in offspring).
Abstract: The etiology of male infertilities is largely undetermined, and our knowledge of exogenous factors affecting the male reproductive system is still limited. In particular, the role of specific environmental and occupational factors is incompletely elucidated. Various occupational (physical and chemical) agents have been shown to affect male reproductive functions in animals, but large differences in reproductive function and/or xenobiotic handling between species limit extrapolation to humans. When available, human data are often conflicting and, except in a few instances, usually refer to broad and heterogenous occupational categories or to groups of agents (e.g., solvents). It is often difficult to elucidate the role of a single agent because occupational exposure conditions are often complex and various confounding factors related to lifestyle (smoking, alcohol, and diet) or socioeconomic state may also affect sperm quality, fertility, or pregnancy outcomes. The objective of this work is to summarize the main epidemiological and, where relevant, experimental findings pertaining to agents (physical and chemical) encountered in the occupational environment that might affect the male reproductive system (sperm count, motility and morphology, libido, and fertility) and/or related pregnancy outcomes (spontaneous abortion, stillbirth, low birth weight, and birth defects and childhood malignancy in offspring). Some methodological issues related to research on the reproductive effects of toxicants are also discussed briefly.
165 citations
TL;DR: The etiological relationship between tobacco use and oral cancer has provided a comprehensive model for understanding carcinogenesis and fulfills the epidemiological criteria of causality: strength, consistency, temporality, and coherence.
Abstract: Globally, oral cancer is one of the ten common cancers. In some parts of the world, including the Indian subcontinent, oral cancer is a major cancer problem. Tobacco use is the most important risk factor for oral cancer. The most common form of tobacco use, cigarette smoking, demonstrates a very high relative risk--in a recent cohort study (CPS II), even higher than lung cancer. In areas where tobacco is used in a smokeless form, oral cancer incidence is generally high. In the West, especially in the U.S. and Scandinavia, smokeless tobacco use consists of oral use of snuff. In Central, South, and Southeast Asia smokeless tobacco use encompasses nass, naswar, khaini, mawa, mishri, gudakhu, and betel quid. In India tobacco is smoked in many ways; the most common is bidi, others being chutta, including reverse smoking, hooka, and clay pipe. A voluminous body of research data implicating most of these forms of tobacco use emanates from the Indian subcontinent. These studies encompass case and case-series reports, and case-control, cohort, and intervention studies. Collectively, the evidence fulfills the epidemiological criteria of causality: strength, consistency, temporality, and coherence. The biological plausibility is provided by the identification of several carcinogens in tobacco, the most abundant and strongest being tobacco-specific N-nitrosamines such as N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These are formed by N-nitrosation of nicotine, the major alkaloid responsible for addiction to tobacco. The etiological relationship between tobacco use and oral cancer has provided us with a comprehensive model for understanding carcinogenesis.
152 citations
TL;DR: Clinical and epidemiological data indicate that this manifestation is rarely, if ever, induced by pure cobalt metal dust alone, but requires the concomitant inhalation of other compounds such as tungsten carbide in the hard metal industry (hard metal disease).
Abstract: In the industry, the potential for exposure to cobalt metal dust is particularly important during the production of cobalt powder and the processing and use of hard metals and other cobalt-containing alloys. The different adverse health effects reported in these workers are reviewed. One of the main target organs is the respiratory tract, and this article concentrates on the lung parenchymal reactions induced by cobalt-containing dust. Clinical and epidemiological data indicate that this manifestation is rarely, if ever, induced by pure cobalt metal dust alone, but requires the concomitant inhalation of other compounds such as tungsten carbide in the hard metal industry (hard metal disease). Experimental studies demonstrate that cobalt metal and metallic carbides interact to produce an elective lung toxicity. Recent work on the mechanism of this interaction, which is based on the production of activated oxygen species, is reviewed. A practical implication in industrial hygiene should be that permissible exposure levels to Co dust might have to be different when exposure is to pure Co particles or an association with carbides.
134 citations
TL;DR: It is the working hypothesis that more intense smoking, deeper inhalation of the smoke, and higher smoke delivery of the organ-specific lung carcinogen NNK to the peripheral lung are major contributors to the increased risk of cigarette smokers for lung adenocarcinoma.
Abstract: In the U.S., there has been a steeper rise of the incidence of lung adenocarcinoma than of squamous cell carcinoma of the lung among cigarette smokers. Since 1950, the percentage of all cigarettes sold that had filter tips increased from 0.56 to 92% in 1980 and to 97% in 1990. The tobacco of the filter cigarettes is richer in nitrate than that of the nonfilter cigarettes manufactured in past decades. Because the smoker of cigarettes with lower nicotine yield tends to smoke more intensely and to inhale the smoke more deeply than the smoker of plain cigarettes, the peripheral lung is exposed to higher amounts of nitrogen oxides, nitrosated compounds, and lung-specific smoke carcinogens. It is our working hypothesis that more intense smoking, deeper inhalation of the smoke, and higher smoke delivery of the organ-specific lung carcinogen NNK to the peripheral lung are major contributors to the increased risk of cigarette smokers for lung adenocarcinoma. Bioassay data and biochemical studies in support of this concept are discussed.
113 citations
TL;DR: The studies in rodents and primates have facilitated development of methods to assess NNK bioactivation in humans, which will be applicable to studies of lung cancer susceptibility and prevention, and there are still important gaps in mechanistic understanding of NNK-induced tumorigenesis.
Abstract: This article reviews recent advances in the biochemistry and molecular biology of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific pulmonary carcinogen believed to be involved in the induction of lung cancer in smokers. Several aspects of NNK bioactivation are addressed, including identification of its metabolites in laboratory animals and humans, cytochrome P450 enzyme involvement in its metabolic activation, DNA and protein adduct formation, biological significance of the major DNA adducts formed, and mutations in oncogenes from tumors induced by NNK. Collectively, the presently available data provide a reasonably clear picture of NNK bioactivation in rodents, although there are still important gaps in our mechanistic understanding of NNK-induced tumorigenesis. The studies in rodents and primates have facilitated development of methods to assess NNK bioactivation in humans, which will be applicable to studies of lung cancer susceptibility and prevention.
113 citations
TL;DR: Bacterial systems have long been of use in toxicology, providing general models of enzymes and paradigms for biochemistry and molecular biology, and they have been adapted to practical genotoxicity assays.
Abstract: Bacterial systems have long been of use in toxicology. In addition to providing general models of enzymes and paradigms for biochemistry and molecular biology, they have been adapted to practical genotoxicity assays. More recently, bacteria also have been used in the production of mammalian enzymes of relevance to toxicology. Escherichia coli has been used to express cytochrome P450, NADPH-cytochrome P450 reductase, flavin-containing monooxygenase, glutathione S-transferase, quinone reductase, sulfotransferase, N-acetyltransferase, UDP-glucuronosyl transferase, and epoxide hydrolase enzymes from humans and experimental animals. The expressed enzymes have been utilized in a variety of settings, including coupling with bacterial genotoxicity assays. Another approach has involved expression of mammalian enzymes directly in bacteria for use in genotoxicity systems, particularly with Salmonella typhimurium. Applications include both the reversion mutagenesis assay and a system using a chimera with an SOS-response indicator and a reporter.
TL;DR: Using the N-nitrosoproline test, it has been shown that smoking contributes to endogenous nitrosation and likely increases NOC formation in vivo, thus adding to the burden of exposure by preformed carcinogenic NOC in tobacco products.
Abstract: One-third of all cancers worldwide can be attributed to various tobacco habits. Both in tobacco smoke and smokeless tobacco, carcinogenic N-nitroso compounds (NOC) are implicated as DNA-damaging agents in cancers of the aerodigestive tract and the pancreas. The exposure from nitrosamines in certain types of tobacco use such as "toombak" in Sudan could be as high as a few milligrams per day. Using the N-nitrosoproline test, it has been shown that smoking contributes to endogenous nitrosation and likely increases NOC formation in vivo. Smokeless tobacco, most widely used in the form of chewing of betel quid (BQ) with tobacco, was shown to particularly enhance endogenous nitrosation in the oral cavity, a site where chewing habits are causally associated with cancer. Poor oral hygiene was found to contribute to the formation of nitrosamines in the oral cavity. The evidence so far accumulated demonstrates that tobacco habits increase endogenous NOC formation, thus adding to the burden of exposure by preformed carcinogenic NOC in tobacco products. In snuff dippers, the unexpected higher level of HPB released from hemoglobin, an exposure marker for carcinogenic tobacco-specific nitrosamines, has been attributed to the endogenous formation of these carcinogens. Recent studies have demonstrated that besides carcinogenic tobacco-specific nitrosamines, reactive oxygen species derived from BQ ingredients could also play a role in the etiology of oral cancer in chewers. Although the use of chemopreventive agents may block nitrosation reactions in vivo in tobacco users, cessation of tobacco habits is the only safe way for an efficient reduction of cancer risk, in view of the high exposure to other (preformed) tobacco-related carcinogens.
TL;DR: In most samples from indoor air polluted with environmental tobacco smoke (ETS), the highest concentration of an individual TSNA is that of NNK, and the formation of the lung carcinogen NNK is favored during the smoldering of cigarettes, between puffs, when SS is generated.
Abstract: Chemical-analytical studies during the past 4 years led to several new observations on the formation of tobacco-specific N-nitrosamines (TSNA) and their occurrence in smokeless tobacco, mainstream smoke (MS), and sidestream smoke (SS) of American and foreign cigarettes. When snuff was extracted by means of supercritical fluid extraction with carbon dioxide containing 10% methanol, analysis of this material confirmed that the extraction with organic solvents had been partially incomplete. Epidemiological studies in the northern Sudan showed a high risk for oral cancer for users of toombak, a home-made oral snuff. Toombak contains 100-fold higher levels of TSNA than commercial snuff in the U.S. and Sweden. The TSNA content in the saliva of toombak dippers is at least ten times higher than that reported in the saliva of dippers of commercial snuff. Biomarker studies have shown corresponding high levels of hemoglobin adducts with metabolites of NNN and NNK as well as for urinary metabolites of NNK. These data supported the epidemiological findings. The analyses of MS of U.S. and foreign cigarettes smoked under FTC conditions revealed comparable data for the smoke of nonfilter cigarettes and filter cigarettes except in the case of low- and ultralow-yield cigarettes, which showed reduced TSNA yields. The MS of cigarettes made from Burley or dark tobacco is exceptionally high in TSNA, primarily because of the high nitrate content of those tobacco types. Taking puffs of larger volume and drawing puffs more frequently, practices observed among most smokers of cigarettes with low nicotine yield, results in high TSNA values in the MS. The formation of the lung carcinogen NNK is favored during the smoldering of cigarettes, between puffs, when SS is generated. Consequently, in most samples from indoor air polluted with environmental tobacco smoke (ETS), the highest concentration of an individual TSNA is that of NNK. When nonsmokers had remained for up to 2 h in a test laboratory with high ETS pollution, they excreted measurable amounts of NNK metabolites in the urine, indicative of the uptake of TSNA.
TL;DR: This review summarizes the present knowledge on the mechanistic basis of target organ selectivity of xenobiotics and investigates the role of accumulation by active transport of metabolites formed in other organs in the kidney-specific toxicity of certain polyhaloalkanes, polyhaliene, hydroquinones, and aminophenols.
Abstract: The kidney is a frequent target organ for toxic effects of xenobiotics. In recent years, the molecular mechanisms responsible for the selective renal toxicity of many nephrotoxic xenobiotics have been elucidated. Accumulation by renal transport mechanisms, and thus aspects of renal physiology, plays an important role in the renal toxicity of some antibiotics, metals, and agents binding to low molecular weight proteins such as α2u-globulin. The accumulation by active transport of metabolites formed in other organs is involved in the kidney-specific toxicity of certain polyhaloalkanes, polyhaloalkenes, hydroquinones, and aminophenols. Other xenobiotics are selectively metabolized to reactive electrophiles by enzymes expressed in the kidney. This review summarizes the present knowledge on the mechanistic basis of target organ selectivity of these compounds.
TL;DR: This review compares and contrast the metabolic activation and biological effects of two NHA, 7H-dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA), in order to better assess the contribution of NHA to the carcinogenic potency of complex mixtures and to develop biomarkers of the carcinogens process.
Abstract: Complex mixtures that are produced from the combustion of organic materials have been associated with increased cancer mortality. These mixtures contain homocyclic and heterocyclic polycyclic aromatic hydrocarbons (PAHs), many of which are known carcinogens. In particular, N-heterocyclic aromatic compounds (NHA) are present in these mixtures. Studies to determine the metabolic activation of these compounds have been undertaken. The purpose of this review is to compare and contrast the metabolic activation and biological effects of two NHA, 7H-dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA), in order to better assess the contribution of NHA to the carcinogenic potency of complex mixtures and to develop biomarkers of the carcinogenic process. DBC has both local and systemic effects in the mouse; it is a potent skin and liver carcinogen following topical application and a lung carcinogen following i.p. application. On the other hand, DBA is a moderate mouse skin carcinogen following topical application and a lung carcinogen following subcutaneous injection. The biological differences for DBC and DBA are reflected in target organ-specific proximate and mutagenic metabolites and DNA adduct patterns.
TL;DR: Comparative assays for lung tumorigenesis in female A/J mice were carried out for six of the TSNA and for two related compounds, N-nitrosodimethylamine (NDMA and N-Nitrosopyrrolidine (NPYR), which yielded the following ranking of potency: NDMA > NNK > NNAL > NPYR > NNN > NAB.
Abstract: Tobacco-specific N-nitrosamines (TSNA) are the most abundant, strong carcinogens in tobacco smoke. Seven TSNA have been identified in tobacco products: N'-nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB), N'-nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL), and 4-(methylnitrosamino)-4-3-pyridyl)butyric acid (iso-NNAC). The syntheses of these compounds are reviewed. The syntheses of 14C- and 3H-labeled NNK as well as metabolites of NNK and NNN are also discussed. Comparative assays for lung tumorigenesis in female A/J mice were carried out for six of the TSNA and for two related compounds, N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR). They yielded the following ranking of potency: NDMA > NNK > NNAL > NPYR > NNN > NAB. Iso-NNAL and iso-NNAC were inactive. These results are also compared with previous assays of TSNA carcinogenicity in rats and hamsters.
TL;DR: Based on the present information available, VOC emissions from new carpets are sufficiently low such that they should not adversely affect indoor air quality or pose significant health risk to people.
Abstract: This review article considers evidence regarding the toxicological impact of new carpet emissions on indoor air quality and human health. It compares emissions data from several studies and describes the dominant compounds found in those emissions. The toxicity of each these compounds is assessed for animal and human data, with a focus on inhalation exposure. Data for acute and chronic exposures are presented, and synergistic effects are considered. Differences and similarities between health responses caused by toxicity and/or by immunological reactions are discussed. Possible neurogenic pathways and associations between these and immune changes are considered as they might relate to inflammatory-based human reactions. Additionally, factors affecting human odor responses are described. The roles that a variety of psychological factors may also play in the etiology of potentially related phenomena, such as the sick building syndrome, pathogenic illness, and multiple chemical sensitivity, are considered. Gaps in the literature are identified within the article and suggestions for future research are offered. In particular, it is noted that few, if any, prior studies have evaluated both neurogenic and immune-mediated inflammation status within the same study. Based on the present information available, it is concluded that under normal environmental circumstances, VOC emissions from new carpets are sufficiently low such that they should not adversely affect indoor air quality or pose significant health risk to people.
TL;DR: In treating patients with MCS, the physician should first perform a complete history and physical examination, including a comprehensive evaluation of chemical exposure, and if the findings strongly suggest the presence of disease related to particular organ systems, further diagnostic evaluation should be undertaken.
Abstract: Patients are presenting in increasing numbers with multiorgan symptoms allegedly resulting from exposure to environmental chemicals. Among the symptoms expressed by patients with alleged multiple chemical sensitivities (MCS) are profound fatigue, mental confusion, myalgia, depression, anxiety, dizziness, headache, insomnia, loss of appetite, and numbness of the extremities, all in the absence of objective physical signs. Diagnostic criteria to assess the effects of environmental agents on organ systems are sorely needed because patients with MCS often have no tissue pathology or physiological abnormalities, but often do have diagnosable psychiatric illnesses. In treating patients with MCS, the physician should first perform a complete history and physical examination, including a comprehensive evaluation of chemical exposure. If the findings strongly suggest the presence of disease related to particular organ systems, further diagnostic evaluation should be undertaken. If abnormal findings are absent, psychiatric advice may be useful. The physician should keep an open mind about MCS but must also remember that a cause-effect relationship between exposure to multiple chemicals and symptoms has not been established.
TL;DR: It seems a reliable laboratory approach to identify both altered p53 and ras genes as biomarkers of human chronic or intermittent exposure to toxicants in a variety of occupational settings.
Abstract: Recent discoveries regarding the mechanistic role of oncogenes and tumor suppressor genes in cancer development have opened a new era of molecular diagnosis. It has been observed repeatedly that genetic lesions serve as tumor markers in a broad variety of human cancers. The ras gene family, consisting of three related genes, H-ras, K-ras, and N-ras, acquires transforming activity through amplification or mutation in many tissues. If not all, then most types of human malignancies have been found to contain an altered ras gene. Because the ras oncogenes actively participate in both early and intermediate stages of cancer, several highly specific and sensitive approaches have been introduced to detect these genetic alterations as biomarkers of exposure to carcinogens. There is also mounting evidence that implicate chemical-specific alterations of the p53 tumor suppressor gene detected in most human tumors. Therefore, it seems a reliable laboratory approach to identify both altered p53 and ras genes as biomarkers of human chronic or intermittent exposure to toxicants in a variety of occupational settings.