Abstract  The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

Abstract  Cytochrome P4501A1 is a substrate-inducible microsomal enzyme that oxygenates polycyclic aromatic hydrocarbons, such as the carcinogen benzo(a)pyrene, as the initial step in their metabolic processing to water-soluble derivatives. Enzyme induction reflects increased transcription of the cognate CYP1A1 gene. The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin is the most potent known cytochrome P4501A1 inducer. Two regulatory proteins, the aromatic (aryl) hydrocarbon receptor (AhR) and the AhR nuclear translocator (Arnt), mediate induction. AhR and Arnt are prototypical members of the basic helix-loop-helix/Per-Arnt-Sim class of transcription factors. Mechanistic analyses of cytochrome P4501A1 induction provide insights into ligand-dependent mammalian gene expression, basic helix-loop-helix/Per-Arnt-Sim protein function, and dioxin action; such studies also impact public health issues concerned with molecular epidemiology, carcinogenesis, and risk assessment.

Abstract  The syntheses of diol epoxides 4a,b and 5a,b of the mutagenic hydrocarbon fluoranthene (1) are described. Standard methodology is applied to the synthesis of targets 4a,b but fails for the synthesis of 5a,b. The latter two diol epoxides can be assembled by a route utilizing stereoselective, directed epoxidations. Simple molecular orbital calculations have been used to predict the reactivity of the diol epoxides in their opening to triol carbocations. Diol epoxides 4a,b are predicted to be substantially more reactive than isomers 5a,b. The more reactive pair, 4a,b, may yield carbocations capable of alkylating cellular genetic material. This prediction is borne out in terms of the relative mutagenicity of the diol epoxides in a bacterial screen.

Abstract  MultiCASE has the ability to automatically determine the structural features responsible for the biological activity of chemicals. In the present study, 93 chemicals tested for their ability to induce chromosomal ‘malsegregation' in the yeast Saccharomyces cerevisiae were analyzed. This ‘malsegregation' mimics molecular events that occur during human development and carcinogenesis resulting in an effective loss of one chromosome of an autosomal pair and duplication of the homologue. Structural features associated with the ability to induce such chromosome loss and duplication were identified and compared with those obtained from examination of other toxicological data bases. The most significant structural similarities were identified between the induction of chromosomal malsegregation and several toxicological phenomena such as cellular toxicity, induction of sister chromatid exchanges in vitro and rodent developmental toxicity. Very significant structural similarities were also found with systemic toxicity, induction of micronuclei in vivo and human developmental toxicity. Less significant structural overlaps were found between yeast malsegregation and rodent carcinogenicity, DNA reactivity and mutagenicity, and the induction of chromosome aberrations in vitro and sister chromatid exchanges in vivo. These overlaps may indicate mechanistic similarities between the induction of chromosomal malsegregation and other toxicological phenomena. The predictivity of the SAR model derived from the present data base is relatively low, however. This may be merely a reflection of the small size and composition of the data base, however, further analyses suggest that it reflects primarily the multiple mechanisms responsible for the induction of chromosomal malsegregation in yeast and the complexity of the phenomenon.

Abstract  The assessment of human cancer risk from chemical exposure requires the integration of diverse types of data. Such data involve effects at the cell and tissue levels. This report focuses on the specific utility of one type of data, namely DNA adducts. Emphasis is placed on the appreciation that such DNA adduct data cannot be used in isolation in the risk assessment process but must be used in an integrated fashion with other information. As emerging technologies provide even more sensitive quantitative measurements of DNA adducts, integration that establishes links between DNA adducts and accepted outcome measures becomes critical for risk assessment. The present report proposes an organizational approach for the assessment of DNA adduct data (e.g., type of adduct, frequency, persistence, type of repair process) in concert with other relevant data, such as dosimetry, toxicity, mutagenicity, genotoxicity, and tumor incidence, to inform characterization of the mode of action. DNA adducts are considered biomarkers of exposure, whereas gene mutations and chromosomal alterations are often biomarkers of early biological effects and also can be bioindicators of the carcinogenic process.

Abstract  Epstein-Barr virus-transformed human lymphoblastoid cell lines are suitable for detection of sister chromatid exchange (SCE) induced by mutagens-carcinogens because they have shown a stable chromosome number and stable frequency of spontaneous SCE for more than two years in culture. Their spontaneous and induced SCE frequencies were practically the same as those of phytohemagglutinin-stimulated lymphocytes from the same blood donors. The SCE responses of one established cell line, NL3, to 13 typical mutagens and five nonmutagens were examined. This cell line responded to all the mutagens tested but not to the nonmutagens. The SCE-inducing activities of these chemicals were well correlated with their mutagenic activities assayed with the Salmonella system by Ames' and Sugimura's groups, although there were a few but significant deviations.

Abstract  Extracts of soots obtained from various sources were applied to the skin of mice in an effort to identify carcinogens in these mixtures and to link these materials to the etiology of human cancer. Samples of coal chimney soot, coke oven materials, industrial carbon black, oil shale soot, and gasoline vehicle exhaust materials have been examined by this method. The studies reported here have been constructed to compare the carcinogenic and tumorigenic potency of extracts from various particulate emissions: coke ovens, diesel and gasoline vehicles and a roofing tar pot. Automobile emission samples were obtained by collecting the diluted and cooled exhaust on Teflon-coated glass fiber filters. Coke oven and roofing tar samples were particulate emission samples collected by impaction and filtration. The organic components associated with each of the particles were extracted with dichloromethane and dermally applied to SENCAR mice. All agents were applied as tumor initiators by using a five-dose protocol. Selected extracts were also applied as complete carcinogens and as tumor promotors. Statistical analyses of the resulting tumor data were performed by using nonlinear Poisson and probit models. The results from these experiments provide a suitable data base for comparative potency estimation of complex mixtures.

Abstract  BACKGROUND/METHODS: The treatment of psoriasis with high-dose exposure to oral psoralen and ultraviolet-A light (i.e., PUVA) substantially increases the risk of cutaneous squamous cell cancer, but not of basal cell cancer, within a decade of beginning treatment. To assess the persistence of cancer risk among individuals treated with PUVA, including those who discontinued therapy long ago and those without substantial exposure to other carcinogens, we prospectively studied a cohort of 1380 patients with psoriasis who were first treated during the period from January 1, 1975, through October 1, 1976, and evaluated risk factors associated with the development of cutaneous squamous cell cancers and basal cell cancers after 1985. RESULTS: From 1975 through 1996, 237 patients developed 1422 cutaneous squamous cell cancers. From 1986 through 1996, 135 (12.5%) of 1081 patients without a prior squamous cell cancer developed 593 such tumors. From 1975 through 1997, 247 patients developed 1042 basal cell cancers; these patients included 151 individuals with a first basal cell cancer after 1985. Among those without a squamous cell or a basal cell cancer in the first decade of the prospective study, a strong dose-related increase in the risk of squamous cell cancer was observed in the subsequent decade (adjusted relative risk [> or =337 treatments versus <100 treatments] = 8.6; 95% confidence interval = 4.9-15.2). Risk of basal cell cancer was substantially increased only in those patients exposed to very high levels of PUVA (> or =337 treatments). CONCLUSIONS: High-dose exposure to PUVA is associated with a persistent, dose-related increase in the risk of squamous cell cancer, even among patients lacking substantial exposure to other carcinogens and among patients without substantial recent exposure to PUVA. Exposure to PUVA has far less effect on the risk of basal cell cancer. The use of PUVA for psoriasis should be weighed against the increased cancer risk.

Abstract  INTRODUCTION An increased risk of lung cancer among asphalt workers has been suggested in epidemiological studies largely based on routine statistics and record linkages [Partanen and Boffetta, 1994]. Given the importance of bitumen and its fume as occupational and environmental exposures, it is important to clarify whether (i) asphalt workers are at increased risk of cancer of the lung, and possibly other organs, and (ii) whether any excess risk can be attributed to exposure to bitumen fume or other agents, such as coal tar. The International Agency for Research on Cancer (IARC) and its collaborators assembled a retrospective cohort of asphalt workers from the asphalt industry (road paving, asphalt mixing, and roofing) in seven European countries (Denmark, Finland, France, Germany, the Netherlands, Norway, and Sweden) and Israel. The primary goal of the study was to assess whether an increased risk of lung cancer is associated with bitumen fume exposure. Details on the study design and the detailed results of the mortality analysis have been reported [Boffetta et al., 2001]. In a companion paper, we report the results of the analysis of mortality based on employment in specific job groups [Boffetta et al., 2003]. In this article, we report results based on assessment of exposure to bitumen and other agents.

Abstract  In Xuan Wei County, Yunnan Province, lung cancer mortality rates are among China's highest in males and females. Previous studies have shown a strong association of lung cancer mortality with air pollution from "smoky" coal combustion. In the present quantitative risk assessment of indoor air pollution study, the result strongly shows an obvious on-site exposure-response relationship between benzo[a]pyrene concentration in indoor air and lung cancer mortality and strongly supports the hypothesis that indoor air pollution is the main risk factor in inducing lung cancer in Xuan Wei County. In the present case-control study, the result shows that in females, the presence of lung cancer is statistically significantly associated with chronic bronchitis and family history of lung cancer. The results also suggest an association of lung cancer with duration of cooking food, but not with passive smoking. In males, the presence of lung cancer is associated with smoking, bronchitis, family history of lung cancer, and personal history of cooking food.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. Principal component analysis (PCA) was used to study polynuclear aromatic hydrocarbon (PAH) profiles in indoor air. Fifteen PAHs were measured in ten different homes in Columbus (Ohio, USA) which had different indoor emission characteristics such as gas utilities, wood-burning fireplaces, and cigarette smokers. Different PAH concentration patterns emerged depending upon the emission sources present in the different homes. Of these, cigarette smoking appeared to have the greatest impact on the indoor PAH concentrations. The PCA allowed convenient displays of the multidimensional data set from which the PAH concentration characteristics could be elucidated. The interrelationship between PAHs was also studied by correlation analysis.

Abstract  Workers in the coking, foundry, and aluminum industry can be exposed to high concentrations of polycyclic aromatic hydrocarbons (PAHs) and are at increased risk for lung cancer, as are cigarette smokers. In recent years several studies on workers in the foundry and coking industries have been reported. In these studies, white blood cell(WBC) DNA was used for analysis of PAH-DNA adducts. Theoretically, DNA adduct formation is a more relevant biological parameter for assessing exposure risk than PAH in the work atmosphere, or the amount of a metabolite in the urine, because adduct levels reflect that part of the dose that escapes detoxification and binds to DNA. We analyzed WBC DNA from coke-oven workers and from workers in an aluminum production plant and demonstrated the presence of PAH-DNA adducts. Forty-seven percent of the coke-oven workers had detectable levels of PAH-DNA adducts in their WBC compared with 27% of the controls (p < 0.05), measured with ELISA. In both groups, smokers had significantly higher levels of PAH-DNA adducts than did nonsmokers. In the aluminum workers, no PAH-DNA adducts were detected by ELISA, although the benzo[a]pyrene concentrations in the work atmosphere were comparable to those of the coke-oven workers. The more sensitive 32P-postlabeling assay showed the presence of PAH-DNA adducts in 91% of the aluminum workers. There was no correlation of WBC adduct levels with the concentration of PAH in the work atmosphere. Recently we showed that total PAH-DNA adduct levels in WBC from lung cancer patients were much higher than those generally found in healthy smokers.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract  HEEP COPYRIGHT: BIOL ABS. 7 12 DI METHYL BENZ A ANTHRACENE BENZ A PYRENE 3 METHYL CHOLANTHRENE CARCINOGENS

Abstract  HEEP COPYRIGHT: BIOL ABS. Disulfiram, dimethyldithiocarbamate and benzyl thiocyanate, when added to the diet, inhibited 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor formation and adrenal necrosis in female Spraque-Dawley rats. A single oral administration of disulfiram given 24 hr before the carcinogen similarly inhibited DMBA-induced mammary tumor formation. In the mouse, disulfiram prevented the occurrence of tumors of the forestomach that resulted from benzo(a)pyrene in the diet but did not affect pulmonary adenoma formation in mice given this carcinogen by oral intubation.

Abstract  The fate of intratracheally installed 3H-benzo(a)pyrene in the isolated perfused rat lung of both control and 20-methylcholanthrene pretreated rats and in perfusion fluid was studied. The covalent binding of benzo(a)pyrene metabolites in the lung tissue itself was greatly enhanced by 20-methylcholanthrene pretreatment of rats. Similarly, the appearance of unchanged 3H-benzo(a)pyrene in the perfusion fluid of 20-methylcholanthrene-lung was decreased as compared to control lung perfusion. This was accompanied with the increase of water-soluble metabolites of benzo(a)-pyrene in the perfusion fluid of 20-methylcholanthrene-lung. When analyzing the metabolite profile of benzo(a)-pyrene in the lungs, especially the phenols (7-fold) and 9,10-diols (5-fold) were found to be increased.

Abstract  #While papillomatous tumors developed in the forestomach of female Ha/ICR mice after a 12-week chronic feeding period of benzo(a)pyrene (BP), no tumors developed in the glandular portion of stomach or in the lung or liver. Among all tissues examined, the forestomach showed the greatest increase of aryl hydrocarbon hydroxylase (AHH) activity following acute or chronic administration of BP. Single acute doses of BP induced AHH activity in forestomach, glandular stomach, lung, and small intestine, but not in the kidney and liver of these animals. Similarly, after chronic administration of BP, AHH activity was inducible in the forestomach, glandular stomach, and lung, but again not in the liver. Although the formation of tumors is associated with greater inducibility of AHH activity in the forestomach after BP administration, the relationship between tissue inducibility of AHH activity and susceptibility to BP carcinogenesis is still not clear. Further studies regarding the formation of specific carcinogenic epoxides of BP in tissues both susceptible (e.g., forestomach) and resistant to BP carcinogenesis would more clearly define the relationship between AHH inducibility and BP carcinogenesis.

Abstract  HEEP COPYRIGHT: BIOL ABS. The metabolism of the carcinogen (3H)benzo(a)pyrene by cultured human bronchial epithelium and cultured pulmonary alveolar macrophages from the same donor was studied. Explants of bronchus were prepared from surgical and autopsy specimens, and human pulmonary alveolar macrophages were isolated from peripheral lung by trypsinization and differential adhesion to plastic tissue culture dishes. After 7 days in culture the bronchus explant and pulmonary alveolar macrophages were exposed to (3H)benzo(a)pyrene, and binding to cellular macromolecules was studied. Aryl hydrocarbon hydroxylase activity was determined by the release of 3H water into the culture medium from metabolized (3H)benzo(a)pyrene. Variation in the binding level of benzo(a)pyrene to DNA and protein in pulmonary alveolar macrophages from different individuals showed 9- and 33-fold interindividual variation, respectively. The metabolism of benzo(a)pyrene was further investigated in macrophages. Binding of benzo(a)pyrene to macromolecules and aryl hydrocarbon hydroxylase activity were dependent on the length of time the explant was in culture and length of exposure to benzo(a)pyrene. Pretreatment of macrophages with benz(a)anthracene increased the binding level of benzo(a)pyrene and aryl hydrocarbon hydroxylase activity. When coincubated with benzo(a)pyrene, cycloheximide, 7,8-benzoflavone or actinomycin D reduced both the level of binding and activity of aryl hydrocarbon hydroxylase. When macrophage cultures were maintained at pO2 greater than atmospheric air, an increase in binding level and enzyme activity was found. The major metabolites of benzo(a)pyrene formed by macrophages were 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, (5-25% of total metabolites) 9,10-dihydroxy-9,10-dihydrobenzo(a)pyrene (16-39%) and 2 distinct peaks containing unidentified polar metabolites. A negative correction (r = -0.58; P 0.05) between binding of benzo(a)pyrene to protein and aryl hydrocarbon hydroxylase exists in pulmonary macrophages, but no correlation between data from bronchus and macrophages was found.

Abstract  Statistical tests of carcinogenicity are shown to have varying degrees of robustness to the effects of mortality. Mortality induced by two different mechanisms is studied - mortality due to the tumor of interest, and mortality due to treatment independent of the tumor. The two most commonly used tests, the life-table test and the Cochran-Armitage linear trend test, are seen to be highly sensitive to increases in treatment lethality using small-sample simulations. Increases in tumor lethality are seen to affect the performance of commonly used prevalence tests such as logistic regression. A simple survival-adjusted quantal response test appears to be the most robust of all the procedures considered.

Abstract  N/A.

Abstract  PAHs are mainly produced by combustion processes and consist of a number of toxic compounds. While the concentrations of individual PAHs in soil produced by natural processes (e.g., vegetation fires, volcanic exhalations) are estimated to be around 1—10 μg kg−1, recently measured lowest concentrations are frequently 10 times higher. Organic horizons of forest soils and urban soils may even reach individual PAH concentrations of several 100 μg kg−1. The PAH mixture in temperate soils is often dominated by benzofluoranthenes, chrysene, and fluoranthene. The few existing studies on tropical soils indicate that the PAH concentrations are relatively lower than in temperate soils for most compounds except for naphthalene, phenanthrene, and perylene suggesting the presence of unidentified PAH sources. PAHs accumulate in C-rich topsoils, in the stemfoot area, at aggregate surfaces, and in the fine-textured particle fractions, particularly the silt fraction. PAHs are mainly associated with soil organic matter (SOM) and soot-like C. Although the water-solubility of PAHs is low, they are encountered in the subsoil suggesting that they are transported in association with dissolved organic matter (DOM). The uptake of PAHs by plants is small. Most PAHs detected in plant tissue are from atmospheric deposition. However, earthworms bioaccumulate considerable amounts of PAHs in short periods. The reviewed work illustrates that there is a paucity of data on the global distribution of PAHs, particularly with respect to tropical and southern hemispheric regions. Reliable methods to characterize bioavailable PAH pools in soil still need to be developed.

Abstract  The nervous system has, since the earliest recorded history of workplace hazards, been a sensitive target organ for chemical exposures.w1 Technological advances as well as disasters such as the mercury exposures during the 1950s in Minimataw2 and the 1970s in Iraqw3 led to reduced workplace exposures during the mid 1900s and a consequent shift from the detection of obvious debility (for example, tremors, paralysis) detectable with even gross clinical methods,w4, w5 to the detection of subtle subclinical effects. Hänninen and colleagues1 were the first to tackle this issue by studying carbon disulfide exposures in the viscose rayon industry. Hänninen, a clinical psychologist at Finland’s Institute of Occupational Health, employed the tools of her discipline, and experimental psychologists brought in the tools employed in the laboratory. A new field, human behavioural neurotoxicology,w6 began to emerge.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. The level of expression of cytochromes P450 shows a wide interindividual variability, depending on the age and tissue investigated. Several lines of evidence indicate that the human foetal liver is an active site for the biotransformation of drugs, chemicals and hydrophobic endogenous molecules. Besides this high degree of maturity, many studies have shown a discrepancy in the onset of activities and suggested that cytochrome P450 isoforms developed independently. Thus, many cytochromes P450 are absent or barely detectable in the foetal liver and develop postnatally. The postnatal evolution of P450 was explored in a liver bank constituted with samples collected from neonates aged less than 24 h to 10 years. Three major groups of cytochrome P450 could be described: a first group of cytochromes P450 expressed in the foetal liver includes the CYP3A7 and 4A1, mostly active on endogenous substrates; a second group (termed early neonatal P450) includes CYP2D6 and 2E1. They su MH - BIOCHEMISTRY

Abstract  Developmental anomalies resulting from prenatal toxicity can be manifested in terms of both malformations among surviving offspring and prenatal death. Although these two endpoints have traditionally been analyzed separately in the assessment of risk, multivariate methods of risk characterization have recently been proposed. We examined this and other issues in developmental toxicity risk assessment by evaluating the accuracy and precision of estimates of the effective dose (ED05) and the benchmark dose (BMD05) using computer simulation. Our results indicated that different variance structures (Dirichlet-trinomial and generalized linear model) used to characterize overdispersion yielded comparable results when fitting joint dose response models based on generalized estimating equations. (The choice of variance structure in separate modeling was also not critical.) However, using the Rao-Scott transformation to eliminate overdispersion tended to produce estimates of the ED05 with reduced bias and mean squared error. Because joint modeling ensures that the ED05 for overall toxicity (based on both malformations and prenatal death) is always less than the ED05 for either malformations or prenatal death, joint modeling is preferred to separate modeling for risk assessment purposes.

Abstract  The assessment of health risks due to low levels of exposure to potential environmental hazards based on the results of toxicological experiments necessarily involves extrapolation of results obtained at relatively high doses to the low dose region of interest. In this paper, different statistical extrapolation procedures which take into account both time-to-response and the presence of competing risks are compared using a large simulated data base. The study was designed to cover a range of plausible dose response models as well as to assess the effects of competing risks, background response, latency and experimental design on the performance of the different extrapolation procedures. It was found that point estimates of risk in the low dose region may differ from the actual risk by a factor of 1000 or more in certain situations, even when precise information on the time of occurrence of the particular lesion of interest is available. Although linearized upper confidence limits on risk can be highly conservative when the underlying dose response curve is sublinear in the low dose region, they were found not to exceed the actual risk in the low dose region by more than a factor of 10 in those cases where the underlying dose response curve was linear at low doses.