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At least 19 recordsLinked to original sources
PubMed2002

Genotoxicological characterisation of complex mixtures. Genotoxic effects of a complex mixture of perhalogenated hydrocarbons.

Toxicological and genotoxicological investigation of complex mixtures is one of the main focus of the recent research in toxicology. Testing complex mixtures present a formidable scientific problem since most recently available toxicological data has been obtained from single substance studies and is not simply transferable to mixtures of chemicals. Although there are no special strategies and standard protocols available for determining toxic and genotoxic effects of complex mixtures, the fundamental concepts of evaluation are the same as those for single substances. The focus of interest of the submitted paper is the genotoxicological characterisation of a complex mixture of mostly perhalogenated hydrocarbons which is generated as a waste product from the plasma etching process in the semiconductor industry. By use of several in vitro test systems (comet assay and micronucleus test), the clastogenic potency of the mixture was tested in various human cell types (lymphocytes and normal bronchial epithelial cells) and in rat hepatocytes. Results demonstrated that the complex perhalogenated hydrocarbons mixture causes DNA single-strand breaks and micronuclei formation, and direct concentration-to-effect correlations were proved in all experiments. The presence of an external metabolising system (S9 mix from rat hepatocytes) in human cell culture systems did not cause any change of the observed effects when compared to experiments performed in the absence of the S9 mix. Therefore, we conclude that the mixture acts as direct genotoxicant and that there is no detoxification by the external enzyme system.Further, convincing and reproducible results of the in vitro comet assay and the micronucleus assay in primary human cell cultures indicated these tests may be utilized for the genotoxicological analyses of complex mixtures with concern to human health hazard.

Animals↗
PubMed1995

Evaluation of the nephrotoxicity of complex mixtures containing organics and metals: advantages and disadvantages of the use of real-world complex mixtures.

As part of a multidisciplinary health effects study, the nephrotoxicity of complex industrial waste mixtures was assessed. Adult, male Fischer 344 rats were gavaged with samples of complex industrial waste and nephrotoxicity evaluated 24 hr later. Of the 10 tested samples, 4 produced increased absolute or relative kidney weight, or both, coupled with a statistically significant alteration in at least one of the measured serum parameters (urea nitrogen (BUN), creatinine (CREAT), and BUN/CREAT ratio). Although the waste samples had been analyzed for a number of organic chemicals and 7 of the 10 samples were analyzed also for 12 elemental metals and metalloids, their nephrotoxicity was not readily predicted from the partial chemical characterization data. Because the chemical form or speciation of the metals was unknown, it was not possible to estimate their contribution to the observed biological response. Various experimental approaches, including use of real-world complex mixtures, chemically defined synthetic mixtures, and simple mixtures, will be necessary to adequately determine the potential human health risk from exposure to complex chemical mixtures.

Animals↗
PubMed2002

Application of biologically based computer modeling to simple or complex mixtures.

The complexity and the astronomic number of possible chemical mixtures preclude any systematic experimental assessment of toxicology of all potentially troublesome chemical mixtures. Thus, the use of computer modeling and mechanistic toxicology for the development of a predictive tool is a promising approach to deal with chemical mixtures. In the past 15 years or so, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been applied to the toxicologic interactions of chemical mixtures. This approach is promising for relatively simple chemical mixtures; the most complicated chemical mixtures studied so far using this approach contained five or fewer component chemicals. In this presentation we provide some examples of the utility of PBPK/PD modeling for toxicologic interactions in chemical mixtures. The probability of developing predictive tools for simple mixtures using PBPK/PD modeling is high. Unfortunately, relatively few attempts have been made to develop paradigms to consider the risks posed by very complex chemical mixtures such as gasoline, diesel, tobacco smoke, etc. However, recent collaboration between scientists at Colorado State University and engineers at Rutgers University attempting to use reaction network modeling has created hope for the possible development of a modeling approach with the potential of predicting the outcome of toxicology of complex chemical mixtures. We discuss the applications of reaction network modeling in the context of petroleum refining and its potential for elucidating toxic interactions with mixtures.

Computer Simulation↗
PubMed2002

The genotoxicity of priority polycyclic aromatic hydrocarbons in complex mixtures.

Risk assessment of complex environmental samples suffers from difficulty in identifying toxic components, inadequacy of available toxicity data, and a paucity of knowledge about the behavior of geno(toxic) substances in complex mixtures. Lack of information about the behavior of toxic substances in complex mixtures is often avoided by assuming that the toxicity of a mixture is simply the sum of the expected effects from each mixture component, i.e. no synergistic or antagonistic interactions. Although this assumption is supported by research investigating non-genotoxic end-points, the literature describing the behavior of genotoxic substances in complex mixtures is sparse and, occasionally, contradictory. In this study, the results of polycyclic aromatic hydrocarbon (PAH) analyses on freshwater bivalves were used to prepare realistic mixtures containing up to 16 PAHs. The SOS genotoxicity of the mixtures and each component were then assessed in an effort to evaluate the additivity of PAH genotoxicity. At nominal PAH concentrations above 1 microg/ml, observed genotoxic responses were far lower than those predicted under the assumption of additivity. At nominal concentrations below 0.75 microg/ml, differences are smaller and occasionally negligible, indicating that the genotoxicity of unsubstituted homocyclic PAHs is additive or slightly less than additive. Other researchers who have investigated the mutagenicity, carcinogenicity, and DNA binding activity of mixtures containing unsubstituted homocyclic PAHs have also reported additive effects. Therefore, the mutagenic risk posed by simple, well-characterized mixtures of priority PAHs can reasonably be estimated as the sum of the risks posed by the mixture components. Current data indicate that less-than-additive effects likely result from saturation of metabolic pathways needed to activate mutagenic PAHs.

Animals↗
PubMed1998

Mutation spectra of complex mixtures.

Mutation spectra of complex mixtures or simple binary mixtures have been determined thus far only in Salmonella. This review summarizes these studies, which have involved a variety of complex mixtures, chemical fractions of the mixtures, and single compounds that are representative of the primary chemical classes within the mixtures. For the particulate organics from urban air and municipal waste incinerator emissions, cigarette smoke condensate, and organic extracts of chlorinated drinking water, the mutation spectrum of the mixture reflected the dominance of one or a few chemical classes within the mixture. The mutation spectra of sunlight and cigarette smoke in Salmonella were similar to those found in the p53 gene of skin or lung tumors in people associated with exposure to these two mutagens. These data provide possible mechanistic links between the types of mutations induced by complex environmental mutagens in an experimental organism (Salmonella) and the types of mutations found in humans exposed to the same environmental mutagens. The primary class of mutation produced by many mutagens within a chemical class (and even among different classes) is frequently the same. These studies indicate that, to some extent, complex mixture-induced mutation spectra can be modeled by the predominant mutagenic chemical class in that mixture and even by a single model compound in that chemical class. Such information should be useful in the interpretation of mutation spectra in molecular epidemiological studies where the exposure is primarily to a complex mixture.

Air Pollutants↗
PubMed2002

Application of stored waveform ion modulation 2D-FTICR MS/MS to the analysis of complex mixtures.

Component identification of complex mixtures, whether they are from polymeric formulations or combinatorial synthesis, by conventional MS/MS techniques generally requires component separation by chromatography or mass spectrometry. An automated means of acquiring simultaneous MS/MS data from a complex mixture without prior separation is obtained from stored waveform ion modulation (SWIM) two-dimensional FTICR MS/MS. The technique applies a series of SWIFT excitation waveforms whose frequency domain magnitude spectrum is a sinusoid increasing in frequency from one waveform to the next. The controlled dissociation of the precursor ions produces an associated modulation of the product ion abundances. Fourier transformation of these abundances reveals the encoded modulation frequency from which connectivities of precursor and product ions are observed. The final result is total assignment of product ions for each precursor ion in a mixture from one automated experiment. We demonstrated the applicability of SWIM 2D-FTICR MS/MS to two diverse samples of industrial importance. We characterized structured polyester oligomers and products derived from combinatorial synthesis. Fragmentation pathways identified in standard serial ion isolation MS/MS experiments were observed for trimethylolpropane/methyl hexahydrophthalic anhydride. A 20-component sample derived from combinatorial synthesis was fragmented, and the template ion along with another key fragment ion was identified for each of the 20 components.

Journal Article↗
PubMedDate not supplied

Salmonella mutagenicity of three complex mixtures assayed with the microsuspension technique. A WHO/IPCS/CSCM study.

In a collaborative study on complex mixtures, three complex mixtures and two pure compounds were assayed with the Salmonella microsuspension technique. The two pure compounds were benzo[a]pyrene (BaP) and 1-nitropyrene (1-NP). The three complex mixtures were standard reference materials (SRMs) from the U.S. National Institute of Standards and Technology, SRM 1649, SRM 1650 and SRM 1597. The two samples SRM 1649, an urban dust particulate matter, and SRM 1650, a diesel particulate matter, were sonicated with dichloromethane. Sample SRM 1597 was an extract of a coal tar sample with a complex mixture of polycyclic aromatic hydrocarbons. The microsuspension assay was performed with Salmonella strains TA98 and TA100 according to Kado et al. (1983) with minor modifications (Löfroth et al., 1988). The results showed that the microsuspension technique is a more sensitive assay than the plate incorporation method. Depending on sample, strain and metabolic condition the mutagenic responses were 3-37 times higher in the microsuspension assay than in the conventional plate incorporation assay. The microsuspension method is thus useful for environmental samples which are often available in only small amounts.

Air Pollutants↗
PubMed1993

Complex mixtures of air pollutants: characterizing the cancer risk of polycyclic organic matter.

Complex mixtures of polycyclic organic matter (POM) are used to illustrate the scientific problems and issues associated with characterizing the comparative risk of related complex mixtures. The complexity of mixtures in which the active components are not well characterized present special challenges, which include identifying the critical components of mixtures, their sources, and the appropriate biomarker(s) of exposure and dose; developing the appropriate experimental models for dose-response assessment; species extrapolation; and developing a scientific basis for predicting from one mixture to another. Strategies for addressing these issues include bioassay-directed chemical characterization of bioactive components of complex mixtures, apportionment methods to determine the source of biological activity and risk, DNA adduct methods to determine tissue exposure and target dose of mixtures, and comparative approaches to determining the relative similarity, potency, and risk of complex mixtures. Epidemiological data are available for humans exposed to POM from coke ovens, coal roofing tar, coal smoke, aluminum smelters, and cigarette smoke. These emissions are characterized and compared to POM from automotive emissions (diesel and gasoline), woodstove emissions, residential oil furnace emissions, and ambient air particles. The tumor potency and estimated cancer risks for these POM mixtures ranges over nearly three orders of magnitude.

Air Pollutants↗
PubMedDate not supplied

Complex mixtures: hazard identification and risk assessment.

Regarding risk evaluation of complex mixtures, the Working Group discussed the following topics: evaluation of the mixture as a whole, fractionation of the mixture, identification of the 'top ten' chemicals, and composite standards. It was concluded that no standard methodology for hazard identification and risk assessment of complex mixtures yet exists, but assessment of complex mixtures must proceed, using all available information, methods, technology, expertise and experience. The development of a decision tree for tackling complex mixtures was recommended, and the need to move forward with instituting standards for mixtures, especially in job-oriented situations, was emphasized.

Chemical Fractionation↗
PubMed1989

Emerging methodologies for assessment of complex mixtures: application of bioassays in the Integrated Air Cancer Project.

The assessment of complex mixtures of environmental pollutants requires new interdisciplinary strategies. Integration of bioassay methodologies into these strategies is an important tool that provides direct evidence of the toxicity of a mixture. Short-term genetic bioassays are now widely used in the cancer assessment of complex mixtures. New and emerging interdisciplinary methodologies for assessing complex mixtures using bioassays are illustrated by the U.S. EPA's Integrated Air Cancer Project (IACP). The goals of this project are to identify the major airborne carcinogens and their emission sources and to improve the methodology and data available for human exposure and risk assessment from airborne carcinogens. The research effort is focused primarily on characterizing the impact of complex mixtures of products of incomplete combustion, including gaseous, semi-volatile, and particle-bound organic species. Short-term genetic bioassays have been integrated into several analysis strategies, including environmental biomonitoring; bioassay-directed fractionation/characterization; transformation studies; source apportionment; and exposure, dosimetry, and risk assessment.

Air Pollutants↗
PubMedDate not supplied

Design and synthesis of visible isotope-coded affinity tags for the absolute quantification of specific proteins in complex mixtures.

Identification of proteins in complex mixtures by mass spectrometry is most useful when quantitative data is also obtained. We recently introduced isotope-coded affinity tags (ICAT reagents) for the relative quantification of proteins present in two or more biological samples. In this report, we describe a new generation of ICAT reagents that contain the following additional features: (1) a visible tag that allows the electrophoretic position of tagged peptides during separation to be easily monitored; (2) a photocleavable linker that allows most of the tag to be removed prior to mass spectrometric analysis; (3) an isotope tag that contains carbon-13 and nitrogen-15 atoms instead of deuterium to ensure precise comigration of light and heavy tagged peptides by reverse-phase HPLC. These reagents contain an iodoacetyl group that selectively reacts with peptide cysteine residues. Peptide modification chemistry is also reported that allows tagging of peptides that are devoid of cysteine. The synthesis of these visible isotope-coded affinity tags (VICAT reagents), and their reaction with peptides are described in this report. VICAT reagents containing a carbon-14 visible probe or an NBD fluorophore are described. These reagents are most useful for the determination of the absolute quantity of specific target proteins in complex protein mixtures such as serum or cell lysates.

Amino Acid Sequence↗
PubMed2007

Competitive inhibition of carcinogen-activating CYP1A1 and CYP1B1 enzymes by a standardized complex mixture of PAH extracted from coal tar.

A complex mixture of polycyclic aromatic hydrocarbons (PAH) extracted from coal tar, the Standard Reference Material (SRM) 1597, was recently shown to decrease the levels of DNA binding of the 2 strong carcinogens benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) in the human mammary carcinoma-derived cell line MCF-7 (Mahadevan et al., Chem Res Toxicol 2005;18:224-231). The present study was designed to further elucidate the biochemical mechanisms involved in this inhibition process. We examined the effects of SRM 1597 on the metabolic activation of BP and DBP toward DNA-binding derivatives in Chinese hamster cells expressing either human cytochrome P450 (CYP) 1A1 or CYP1B1. SRM 1597 inhibited BP-DNA adduct formation through the entire exposure time in cells expressing human CYP1A1, while it significantly inhibited adduct formation only up to 48 hr when co-treated with DBP. Conversely, human CYP1B1-expressing cells were unable to catalyze PAH-DNA adduct formation on treatment with SRM 1597 alone, and on co-treatment with BP or DBP. The data obtained from biochemical experiments revealed that SRM 1597 competitively inhibited the activity of both human enzymes as analyzed by 7-ethoxyresorufin O-deethylation assays. While the Michaelis-Menten constant (K(M)) was <0.4 microM in the absence of SRM 1597, this value increased up to 1.12 (CYP1A1) or 4.45 microM (CYP1B1) in the presence of 0.1 microg/ml SRM 1597. Hence the inhibitory effects of the complex mixture on human CYP1B1 were much stronger when compared to human CYP1A1. Taken together, the decreases in PAH-DNA adduct formation on co-treatment with SRM 1597 revealed inhibitory effects on the CYP enzymes that convert carcinogenic PAH into DNA-binding metabolites. The implications for the tumorigenicity of complex environmental PAH mixtures are discussed.

Aryl Hydrocarbon Hydroxylases↗
PubMed1982

Comparative tumor-initiating activity of complex mixtures from environmental particulate emissions on SENCAR mouse skin.

The value of the SENCAR mouse for testing tumorigenic properties of complex mixtures on mouse skin was studied. Seven complex mixtures were obtained as dichloromethane extracts of collected particulate emissions from three diesel-fueled automobiles, a heavy-duty diesel engine, a nonleaded gasoline-fueled automobile, a coke oven battery, and a roofing tar pot. These emissions were applied topically at multiple doses to both male and female SENCAR mice that were subsequently promoted with 12-O-tetradecanoylphorbol 13-acetate. Two statistical analyses were applied to the data to rank the samples and to provide 95% confidence intervals. One analysis used tumor multiplicity data, applied them to a nonlinear Poisson model, and the second analysis used tumor incidence data and applied them to a log-probit model. Both analyses ranked the complex mixtures in similar order. Benzo[a]pyrene content alone could not account for all the tumorigenic activity in each complex mixture, indicating that other components also contribute to the overall tumorigenic activity.

Administration, Topical↗
PubMed1990

Dose-related differences in DNA adduct levels in rodent tissues following skin application of complex mixtures from air pollution sources.

Dose-related differences in the binding of DNA reactive intermediates for three environmentally important complex mixture particulate extracts and a well-studied carcinogen, benzo[a]pyrene (BaP), were examined in female C-57 mice following multiple topical treatments ranging from 1 to 120 mg/mouse. Particulate extracts from coke oven, coal soot and diesel exhaust were selected as model complex mixtures based on short-term mutagenicity assays, animal bioassays for carcinogenicity or epidemiological studies, where increased incidences of lung cancer in exposed populations were detected. Positive and negative control animals were treated with 1.2 mg BaP or acetone respectively. DNA was isolated from skin, lung and liver 24 h following the last application and analyzed for DNA adducts using the nuclease P1 version of the 32P-postlabeling assay. Each of the particulate extracts produced distinct patterns of DNA adducts. A diagonal zone of radioactivity, presumably representing multiple putative DNA adducts, was observed for coke-oven, coal-soot- and diesel-modified DNA samples. One adduct, common to all three complex-mixture-modified DNA samples, co-migrated with the major BaP adduct observed following treatment with BaP alone. Based on the BaP concentration for each of the extracts it seems unlikely that this adduct is derived from BaP alone. It is possible that an adduct is formed with chromatographic properties similar to the major BaP-derived adduct detected in mice treated with BaP alone. This adduct was detected in all tissues examined and represented approximately 12-34% of the total number of adducts detected within the diagonal radioactive zone for all coke-oven- and coal-soot-exposed tissues (skin, lung and liver). In contrast, this adduct represented 49-67% of the total radioactivity recovered from the diagonal zone of DNA isolated from lungs of animals exposed to diesel extract. The highest total number of adducts resulted from the metabolism of coke oven extract followed by coal soot and diesel treatments respectively. A dose-dependent increase in adduct formation was observed for all tissues in the diesel- and coal-soot-treatment mice. Liver and lung, but not skin, DNA adduct levels increased in a dose-dependent manner in the coke-oven-treated mice. The percentage of dose administered, detected as DNA adducts increased in all tissues as the dose decreased for all three complex mixtures. These data have important implications for risk assessment of these complex mixtures.

Adenosine Triphosphate↗
PubMed1994

Induction of mutation spectra by complex mixtures: approaches, problems, and possibilities.

More complex environmental mixtures have been evaluated for mutagenic activity at the hisD3052 allele of Salmonella, primarily in strain TA98, than in any other target or mutation assay. Using colony probe hybridization to detect a common hot spot deletion, followed by polymerase chain reaction and DNA sequencing, we have generated 10 mutation spectra from three classes of mixtures (i.e., urban air, cigarette smoke condensate, and municipal waste incinerator emissions). The mutation spectra are distinctly different among the three classes of mixtures; however, the spectra for samples within the same class of mixture are similar. In addition to the hot spot mutation, the mixtures induce complex mutations, which consist of a small deletion and a base substitution. These mutations suggest a mechanism involving misinsertion of a base opposite a DNA adduct followed by a slippage and mismatch. A role for DNA secondary structure also may be the basis for the mutational site specificity exhibited by the various mixtures. The results suggest that unique mutation spectra can be generated by different classes of complex mixtures and that such spectra are a consequence of the dominance of a particular chemical class or classes within the mixture. The problems associated with this type of research are discussed along with the potential value of mutation spectra as a tool for exposure and risk assessment.

Environmental Pollutants↗
PubMed2006

Multisubstrate biodegradation kinetics for binary and complex mixtures of polycyclic aromatic hydrocarbons.

Biodegradation kinetics were studied for binary and complex mixtures of nine polycyclic aromatic hydrocarbons (PAHs): Naphthalene, 1-methylnaphthalene, 2-methylnaphthalene, 2-ethylnaphthalene, phenanthrene, anthracene, pyrene, fluorene, and fluoranthene. Discrepancies between the observed biodegradation rates and those predicted by a sole-substrate model indicate that significant substrate interactions occurred in both the binary and complex-mixture experiments. For all compounds except naphthalene, biodegradation was enhanced. The observations were compared to predictions from two multisubstrate biodegradation kinetic models: One that accounts for competitive inhibition, and one that does not. Both models are fully predictive in that parameters had been determined from an independent set of sole-substrate experiments. In the binary experiments, the major multisubstrate effect was biomass enhancement as a result of growth on naphthalene. Substrate interactions were orders of magnitude larger for most compounds in the complex mixtures, but significant competitive inhibition effects counteracted some of the biomass enhancement effect. The present study has demonstrated that the sole-substrate model is inadequate to describe multisubstrate biodegradation kinetics for a broad range of PAH mixtures. Whereas the multisubstrate model without inhibition did an adequate job of predicting the observed effects in some cases, we advocate the use of the multisubstrate model with inhibition for similar modeling efforts in light of the evidence that the model was correct more often than not. Theory supports its use because of the common enzyme pathways for biodegradation of PAHs.

Biomass↗
PubMed1990

Statistical aspects of experimental studies with complex mixtures.

Some formal concepts are introduced relating to the statistical design and analysis of experiments with complex mixtures. Aspects relating to the chemical analysis of complex mixtures, identification of their major components, continuous monitoring of samples or related issues are not addressed. As a surrogate for experimental studies in general, the discussion is oriented towards the situation of long-term animal experiments. When complex mixtures of unknown components are to be tested, samples collected under a standardized protocol must be applied to the different exposure groups in such a way that the experimental groups differ only in the dose of the exposure they receive. If the composition of a mixture is known, selected components may be combined in experimental testing in order to study the nature of their joint effect. Careful consideration guided by a priori knowledge about the individual compounds' dose-response relationships is required to design and analyse such experiments. There is an apparent need to avoid confusion by unifying the terminology in this field.

Animals↗