Publications (10)9.08 Total impact
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Article: A Comparative Potency Method for Cancer Risk Assessment: Clarification of the Rationale, Theoretical Basis, and Application to Diesel Particulate Emissions*
Risk Analysis 05/2006; 3(2):133 - 137. · 2.37 Impact Factor -
Article: Comparative Potency Method for Cancer Risk Assessment: Application to Diesel Particulate Emissions1
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ABSTRACT: An estimation of the human lung cancer “unit risk” from diesel engine particulate emissions has been made using a comparative potency approach. This approach involves evaluating the tumorigenic and mutagenic potencies of the particulates from four diesel and one gasoline engine in relation to other combustion and pyrolysis products (coke oven, roofing tar, and cigarette smoke) that cause lung cancer in humans. The unit cancer risk is predicated on the linear nonthreshold extrapolation model and is the individual lifetime excess lung cancer risk from continuous exposure to 1 μg carcinogen per m3 inhaled air. The human lung cancer unit risks obtained from the epidemiologic data for coke oven workers, roofing tar applicators, and cigarette smokers were, respectively, 9.3 × 10−4, 3.6 × 10−4, and 2.2 × 10−6 per μg particulate organics per m3 air. The comparative potencies of these three materials and the diesel and gasoline engine exhaust particulates (as organic extracts) were evaluated by in vivo tumorigenicity bioassays involving skin initiation and skin carcinogenicity in SENCAR mice and by the in vitro bioassays that proved suitable for this analysis: Ames Salmonella microsome bioassay, L5178Y mouse lymphoma cell mutagenesis bioassay, and sister chromatid exchange bioassay in Chinese hamster ovary cells. The relative potencies of the coke oven, roofing tar, and cigarette smoke emissions, as determined by the mouse skin initiation assay, were within a factor of 2 of those determined using the epidemiologic data. The relative potencies, from the in vitro bioassays as compared to the human data, were similar for coke oven and roofing tar, but for the cigarette smoke condensate the in vitro tests predicted a higher relative potency. The mouse skin initiation bioassay was used to determine the unit lung cancer risk for the most potent of the diesel emissions. Based on comparisons with coke oven, roofing tar, and cigarette smoke, the unit cancer risk averaged 4.4 × 10−4. The unit lung cancer risks for the other, less potent motor-vehicle emissions were determined from their comparative potencies relative to the most potent diesel using three in vitro bioassays. There was a high correlation between the in vitro and in vivo bioassays in their responses to the engine exhaust particulate extracts. The unit lung cancer risk per μg particulates per m3 for the automotive diesel and gasoline exhaust particulates ranged from 0.20 × 10−4 to 0.60 × 10−4; that for the heavy-duty diesel engine was 0.02 × 10−4. These unit risks provide the basis for a future assessment of human lung cancer risks when combined with human population exposure to automotive emissions.Risk Analysis 05/2006; 3(2):101 - 117. · 2.37 Impact Factor -
Article: DNA adducts and chronic degenerative diseases. Pathogenetic relevance and implications in preventive medicine
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ABSTRACT: Chronic degenerative diseases are the leading causes of death in developed countries. Their control is exceedingly difficult due to their multiplicity and diversity, the interconnection with a network of multiple risk factors and protective factors, the long latency and multistep pathogenesis, and the multifocal localization. Adducts to nuclear DNA are biomarkers evaluating the biologically effective dose, reflecting an enhanced risk of developing a mutation-related disease more realistically than the external exposure dose. The localization and accumulation of these promutagenic lesions in different organs are the composite result of several factors, including (a) toxicokinetics (first-pass effect); (b) local and distant metabolism; (c) efficiency and fidelity of DNA repair; and (d) cell proliferation rate. The last factor will affect not only the dilution of DNA adducts but also the possible evolution towards either destructive processes, such as emphysema or cardiomyopathies, or proliferative processes, such as benign or malignant tumors at various sites. They also include heart tumors affecting fetal myocytes after transplacental exposure to DNA-binding agents, blood vessel tumors, and atherosclerotic plaques. In this article, particular emphasis is given to molecular alterations in the heart, which is the preferential target for the formation of DNA adducts in smokers, and in human aorta, where an extensive molecular epidemiology project is documenting the systematic presence of adducts to the nuclear DNA of smooth muscle cells from atherosclerotic lesions, and their significant correlation with known atherogenic risk factors. Exocyclic DNA adducts resulting from lipid peroxidation, and age-related indigenous adducts (I-compounds) may also originate from endogenous sources, chronic infections and infestations, and inflammatory processes. Type II I-compounds are bulky DNA lesions resulting from oxidative stress, whereas type I I-compounds are presumably normal DNA modifications, which display positive correlations with median life span and are decreased in cancer and other pathological conditions. Profiles of type I I-compounds strongly depend on diet and are related to the antidegenerative effects of caloric/dietary restriction. Even broader is the possible meaning of adducts to mitochondrial DNA, which have been detected in rodents exposed to genotoxic agents and complex mixtures, as well as in untreated rodents, in larger amounts when compared to the nuclear DNA of the same cells. Mutations in mitochondrial DNA increase the number of oxidative phosphorylation-defective cells, especially in energy-requiring postmitotic tissues such as brain, heart and skeletal muscle, thereby playing an important role in aging and a variety of chronic degenerative diseases. A decreased formation of DNA adducts is an indicator of reduced risk of developing the associated disease. Therefore, these molecular dosimeters can be used as biomarkers in the prevention of chronic degenerative diseases, pursued either by avoiding exposure to adduct-forming agents or by using chemopreventive agents. Interventions addressed to the human organism by means of dietary measures or pharmacological agents have encountered a broad consensus in the area of cardiovascular diseases, and are deserving a growing interest also in cancer prevention. The efficacy of chemopreventive agents can be assessed by evaluating inhibition of nuclear DNA or mitochondrial DNA adduct formation in vitro, in animal models, and in phase II clinical trials in high-risk individuals.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 01/1997; · 2.85 Impact Factor -
Article: Mutagenicity and carcinogenicity of complex combustion emissions: Emerging molecular data to improve risk assessment
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ABSTRACT: The dichloromethane‐extractable particulate organics of various combustion emissions, as well as urban air, have been evaluated for their ability to induce mutations in Salmonella bacteria and skin tumors and DNA adducts in Sencar mice. The relative ranking of the organic extracts is similar for all three endpoints. Using these data with the comparative potency method of cancer risk assessment, human lung cancer unit risk estimates were calculated, and the extracts rank as follows: coke oven emissions > aluminum smelter emissions > urban air > diesel exhaust > tobacco smoke. These data emphasize the importance of exposure, because minimal exposure to a potent carcinogen, such as coke oven emissions, may pose similar or less risk than high exposure to a relatively weaker carcinogen, such as tobacco smoke. DNA sequence analysis of the mutations induced by organic extracts of combustion emissions and urban air in Salmonella bacteria suggest that each class of complex mixture induces a unique pattern of mutations and that each pattern is a consequence of the dominance of a particular chemical class or classes within the extract. The challenge for the future is to integrate these DNA sequence data and other molecular data into a comprehensive evaluation of complex combustion emissions to improve current risk assessment procedures.Toxicological and Environmental Chemistry 07/1995; 49(3):157-166. -
Article: Development of a toxicity test system using primary rat liver cells
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ABSTRACT: A model in vitro rat liver parenchymal cellular toxicity system employing cells obtained by the in situ collagenase perfusion technique has been developed to detect potential liver toxicants. The initial evaluation of this test system was accomplished using cadmium chloride, chromium chloride, cobalt chloride, mercuric chloride, nickelous chloride, sodium arsenite, sodium selenite, and ammonium vanadate. Linear regression analysis of the dose response curves was used to determine the effective concentration at which the viability was reduced to 50% (EC50). The relative toxicity of the compounds was as follows: Cd>V=As>Se>Hg>Cr=Co>Ni. Since several of the compounds with very similar EC50S had significantly different dose response slopes, an additional parameter, lowest effective concentration tested (LECT) was employed to assess the relative toxicity. The LECT was determined using the Williams test and the relative toxicity of the compounds was found to be Cd=Se>V>As=Hg>Co>Cr=Ni. The primary objective in developing this rat liver cellular toxicity test system was to employ an in vitro test system utilizing metabolically active primary cells from a potential target organ. This study demonstrates the utility of this test system in determining the relative liver cell toxicity of a series of inorganic agents of differing toxicity.In Vitro Cellular & Developmental Biology - Plant 04/1981; 17(11):1004-1010. · 1.50 Impact Factor -
Article: The utilization of the rabbit alveolar macrophage and Chinese hamster ovary cell for evaluation of the toxicity of particulate materials: II. Particles from coal-related processes
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ABSTRACT: Rabbit alveolar macrophage (RAM) and Chinese hamster ovary (CHO) cells were used in in vitro tests to evaluate the toxicity of particulate effluents from coal gasification, fluidized-bed combustion, and conventional coal combustion. Evaluation of the cytotoxicity of nine samples from coal energy-related processes showed that the sensitivity of the RAM assay was improved substantially when the test was conducted in serum-free media. A linear relationship was observed between percentage cell viability and ATP level in the particletreated cultures. In the RAM assay without serum the slope of the line was 1.0, which provided strong evidence that the mechanism of toxicity was similar in reducing cell viability and ATP. The cytotoxicity of the coal-related particles in the CHO clonal assay showed that the system was approximately equivalent to the RAM assay without serum. Conventional coal combustion fly ash (<3 μm) was the most toxic of the coal-related particles in the RAM and CHO system. Fluidized-bed combustion fly ash from a cyclone catch and fine (<3 μm) particles from the flue gas were also toxic in both cellular assays. Particles from the coal gasification process were the least cytotoxic in these studies.Environmental Research. -
Article: Mutagenic and carcinogenic potency of extracts of diesel and related environmental emissions: Summary and discussion of the results
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ABSTRACT: The proposed conversion from gasoline powered automobiles to diesel powered vehicels has prompted the Environmental Protection Agency to evaluate the potential health effects associated with exposure to diesel emissions. At present, there is no direct epidemiological link between this exposure and human health. Therefore, a research program was constructed to compare the health effects associated with diesel emissions with those from other emission sources for which epidemiological information was available. The emission sources chosen were cigarette smoke, roofing tar, and coke oven. An additional comparative emission source which was a gasoline catalyst engine. Respirable particles from a variety of combustion sources have the potential of being carcinogenic and mutagenic. The objective of these studies was to determine the relative biological activity of the organic material adsorbed on these particles in both in vitro mutagenesis and in vitro and in vivo bioassays. The organic extracts from the following series of emission sources were quantitatively bioassayed in a matrix of tests for their carcinogenic and mutagenic activity: (1) a light-duty Oldsmobile diesel 350 engine; (2) a heavy-duty Caterpillar diesel engine; (3) a light-duty Nissan engine; (4) a Volkswagen Rabbit diesel engine; (5) cigarette smoke; (6) roofing tar; (7) coke oven; and (8) a gasoline catalyst Mustang. The test matrix consisted of the following bioassay: reverse mutation in Salmonella typhimurium; mitotic recombination in Saccharomyces cerevisiae; DNA damage in Syrian hamster embryo cells (SHE); sister chromatid exchange in CHO cells; gene mutation in L5178Y mouse lymphoma cells, Balb/c 3T3 mouse embryo fibroblasts and CHO cells; viral enhancement of SHE cells; oncogenic transformation in Balb/c 3T3 cells; and skin tumor initiation in SENCAR and C57 black mice. The results of this test matrix are discussed.Environment International. -
Article: Mutagenic and carcinogenic potency of extracts of diesel and related environmental emissions: In vitro mutagenesis and oncogenic transformation
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ABSTRACT: Extracts from emissions of four diesel engines, a gasoline engine and three related environmental samples were tested in four in vitro assay systems designed to detect carcinogenic or mutagenic activity of chemicals. Samples from three of four diesel extracts, the gasoline engine, and all three related samples were positive in an enhancement of viral transformation assay. Two diesel samples, the gasoline engine extract and extract from coke oven emissions were positive for mutation induction in Chinese hamster ovary cells. Only the gasoline engine extract and the coke oven sample were positive in a DNA fragmentation assay using alkaline sucrose gradients. Experiments using chemical transformation of Syrian hamster embryo cells as an assay method have not been completed.Environment International. -
Article: The utilization of the rabbit alveolar macrophage and Chinese hamster ovary cell for evaluation of the toxicity of particulate materials: I. Model compounds and metal-coated fly ash
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ABSTRACT: Data are presented which detail the effects of model particulate compounds and fly ash particles on rabbit alveolar macrophage (RAM) and Chinese hamster ovary (CHO) cells. Silica, silicic acid, titanium dioxide, and size-fractionated (0–2, 2–5, and 5–8 μm) fly ash particles with and without coatings of nickel, lead, or cadmium oxides were the experimental particles. Silica was the most toxic particle studied. Cell viability and ATP in the RAM assay and colony survival in the CHO assay showed an almost identical response to silica and silicic acid. Titanium dioxide particles were relatively inert in the RAM and CHO systems, although a pronounced loss of ATP was observed in cells exposed in serum-free medium. Uncoated fly ash was relatively nontoxic in the RAM system when assayed by measurement of cell number and viability, ATP, and total protein. However, toxicity of the uncoated particles was demonstrated in the CHO clonal assay. The number of colonies formed at 1000 μg/ml particulate was reduced to 10.6, 28.5, and 82.2% of the control for the 0 to 2, 2 to 5-, and 5 to 8-μm size ranges. Nickel oxide-coated fly ash was more cytotoxic than the uncoated particles in both the RAM and CHO cell systems. Toxicity of NiO was similar to that obtained for the NiO-coated fly ash although the weight percentage of NiO in the ash was only 3%, suggesting that the particles enhanced toxicity. The lead oxide-coated fly ash was even more toxic than the nickel-coated particles; these particles were used to explore the effect of serum concentration on toxic responses. Cellular ATP was strongly affected in macrophages exposed in serum-free media and treated with PbO-coated fly ash; ATP ranged from 20 to 200 times less than that for the corresponding uncoated fly ash or untreated control. Nickel and lead did not dissociate from the fly ashes into the biological media. However, cadmium was rapidly released from the cadmium oxide-coated fly ash and provided an excellent model for study of the dissociation of toxic compounds from particle surfaces. The rate of dissociation of the metal was correlated with loss of ATP in RAM cultures. Cell numbers were unaltered after treatment with the CdO-coated fly ash as reported previously for soluble cadmium. The CdO-coated fly ash was considerably more toxic than would have been predicted on the basis of the amount of soluble cadmium released into the medium, also indicating that the association of the metal oxide with the fly ash enhanced toxicity.Environmental Research. -
Article: Mutagenicity of nitrodibenzopyranones in the Salmonella plate-incorporation and microsuspension assays
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ABSTRACT: The mutagenicity of three isomers of nitro-6H-dibenzo[b,d]pyran-6-one (NDBP), 2-NDBP, 3-NDBP and 4-NDBP, was characterized in the plate-incorporation (PI) and microsuspension (MS) assay using Salmonella typhimurium tester strains in the presence or absence of S9 mix. In both assays, all of the NDBPs showed mutagenicity in every strain. In the absence of S9 mix, TA98 was the strain most sensitive to the mutagenicity of NDBPs. The activity of NDBPs was reduced in TA98NR and TA98/1,8-DNP6 strains relative to TA98, suggesting that NDBPs cause frameshift mutation and that nitroreduction by ‘classical’ nitroreductase and acetylation are significant steps for their metabolic activation. Mutagenic potency of NDBPs in TA98 without S9 mix in the MS assay (2-NDBP 104 300 rev./μg, 3-NDBP 23 500 rev./μg, and 4-NDBP 15 300 rev./μg) was much higher than that in the PI assay (2-NDBP 38 rev./μg, 3-NDBP 162 rev./μg, and 4-NDBP 7 rev./μg). Although additional S9 mix increased the mutagenicity of NDBPs in the PI assay, the mutagenic potency of NDBPs in the MS assay using strains TA98 and TA100 was decreased by the addition of S9 mix. In the PI assay, frameshift and base-substitution activities of both isomers were enhanced by the addition of the pKM101 plasmid, suggesting the induction by these isomers of complex frameshifts (frameshifts with associated base substitutions) in strain TA98. In the PI assay, 2-NDBP generally exhibited more base-substitution than frameshift activity; however, the reverse was true for 3-NDBP. In the MS assay, both isomers exhibited more frameshift than base-substitution activity.Mutation Research/Genetic Toxicology.
