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PubMed1989

Elevated blood pressure and heart rate in rats exposed to a coal-derived complex organic mixture.

The susceptibility of the cardiovascular system to exposure to a high-boiling coal liquid (heavy distillate, HD) was studied in the rat using an isoproterenol (ISO) myocardial infarction model. Male Fischer rats were exposed to HD by inhalation (0.7 mg/l), 6 h/day, 5 days/week, for 6 weeks. After a 10-day recovery period, sham-exposed and HD-exposed rats were injected subcutaneously with 0, 20, 40 or 60 mg ISO/kg body weight. Blood pressure, heart rate, electrocardiogram and 99mTc uptake by the heart were measured 1 day later. A dose-related increase was observed in the uptake of 99mTc by the hearts of both sham-exposed and HD-exposed animals after ISO injection; however, uptake by the sham-exposed group was significantly greater than that of exposed groups. The most striking observation was a 20% elevation in arterial blood pressure of HD-exposed rats over that of sham-exposed animals when no ISO was injected. These results suggest that the cardiovascular system could be detrimentally affected by exposure to coal-derived complex mixtures and, possibly, to other complex organic mixtures.

Administration, Inhalation↗
PubMed2006

Quantitative analysis of complex peptide mixtures using FTMS and differential mass spectrometry.

Label-free LC-MS profiling is a powerful quantitative proteomic method to study relative peptide abundances between two or more biological samples. Here we demonstrate the use of a previously described comparative LC-MS method, differential mass spectrometry (dMS), to analyze high-resolution Fourier transform mass spectrometry (FTMS) data for detection and quantification of known peptide differences between two sets of complex mixtures. Six standard peptides were spiked into a processed plasma background at fixed ratios from 1.25:1 to 4:1 to make two sets of samples. The resulting mixtures were analyzed by microcapillary LC-FTMS and dMS. dMS successfully identified five out of the six peptides as statistically significant differences (p <or= 0.005). In this experiment, the smallest fold change reliably detected by our method was 1.5:1, and the errors of estimated ratios of concentrations were less than 20% for peptides spiked at 1.5:1 to 4:1. We conclude that LC-FTMS coupled with dMS is a useful label-free quantitative MS method that can be used to detect subtle yet statistically significant peptide differences in complex protein mixtures, including plasma samples.

Amino Acid Sequence↗
PubMed1999

Subchronic inhalation studies of complex fragrance mixtures in rats and hamsters.

Users of consumer products are invariably and intentionally exposed to complex mixtures in such products. With finished fragrance products, these mixtures may represent 100 or more fragrance raw materials (FRMs). The objective of the described studies was to evaluate the safety of finished fragrance products via the inhalation route. In total, the finished products contained approximately 100 FRMs at concentrations of 1% or greater. Major FRMs evaluated included benzyl acetate, coumarin, hydroxycitronellal, musk ketone, 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta-gamma-2-be nzopyran (HHCB) and phenyl ethyl alcohol. Groups of rats or hamsters were exposed by inhalation (whole body) to the mixtures at 5, 9 or 50 mg/m3 for 4 h per day, 5 days per week for 6 or 13 weeks. For each of the fragrance products, the doses used generally represented a ten- to 100-fold exaggeration of levels expected to be achieved during typical use by consumers. With one exception, the fragrances were aerosolized prior to introduction into the inhalation chamber. The exception product was formulated with a propellant, packaged in a pressurized container and expelled with an automated actuator. In all studies, chamber concentrations of fragrance were monitored. Particle sizes ranged from 0.5 to 7.5 microm, depending on the study. Subchronic exposure to all fragrance mixtures resulted in no toxicologically significant effects on animal survival, behavior, body weights or weight gains, organ weights, or in hematology, clinical chemistry, or urinalysis parameters. No gross pathological or histopathological findings related to test material exposures were observed. These studies support the conclusions that the fragrance mixtures would not pose a hazard to product users based on repeated and exaggerated inhalation exposures of animals.

Administration, Inhalation↗
PubMed1984

The analysis of coupling networks in a complex oligosaccharide mixture derived from the Fc region of rabbit immunoglobulin G using 1H-1H correlated NMR spectroscopy combined with double quantum NMR spectroscopy.

In glycoproteins, even for those containing a single glycosylation site, diversity is manifest in the occurrence of a family of structurally-related yet distinct oligosaccharides. To date this 'microheterogeneity' is universal in mammalian glycoproteins. A method is described, using 1H-1H correlated and double quantum nuclear magnetic resonance NMR spectroscopy, for the assignment of proton resonances within a mixture of complex-type oligosaccharides derived from the Fc region of rabbit immunoglobulin G. The ability to assign resonances in heterogeneous populations will be of importance in the chemical shift analysis of the 1H-NMR spectra of glycopeptides since these cannot generally be separated on the basis of their carbohydrate sequence. The resulting assignments will be necessary before conformational studies on glycopeptides using nuclear Overhauser effects can be made.

Animals↗
PubMed1997

Detection of very complex taste mixtures: generous integration across constituent compounds.

Mixtures of compounds can often be tasted even when all of their components are too weak to be tasted separately. Such mixtures are said to be integrative. Integration was demonstrated by mixing compounds in concentrations proportional to their separate detection thresholds and then measuring the detection threshold of the mixture as a whole by forced choice with plain water. Mixtures of 3, 6, 12, and 24 compounds were thus evaluated. With earlier data on two-, three-, and four-component mixtures (Stevens, J. C. Detection of taste in mixture with other tastes: Issues of masking and aging. Chem. Senses 21:211-221; 1996.), the results show that the concentration of any constituent compound goes down in approximate proportion to the number of compounds with which it is in mixture. This nearly complete integration seems to describe mixtures of like-quality compounds, of unlike-quality compounds, and of both like- and unlike-quality compounds. Integrative mixtures of the sort studied here provide a model for the detection of the ultracomplex stimuli of everyday life, such as foods and drinking waters. Although the degree of integration may trail off slightly with mixtures of high complexity, the present result proffers no limit on the number of compounds that can be at least partially integrated. In principle, integration permits the detection of natural substances whose myriad components could all be far below threshold. The mechanism of taste integration is speculative, but the facts are congenial to the hypothesis of multiple parallel channels for the processing of intensity and quality.

Adolescent↗
PubMed1998

Detection of very complex taste mixtures.

Mixtures can often be tasted when all components are too weak to be tasted separately. Such mixtures are said to be integrative. Integration was demonstrated by mixing compounds in concentrations proportional to their separate detection thresholds and then measuring the detection threshold of the mixture as a whole by forced choice with plain water. Mixtures of 3, 6, 12 and 24 compounds were thus evaluated. With earlier data on 2-, 3- and 4-component mixtures, the results show that the concentration of any constituent compound goes down in approximate proportion to the number of compounds with which it is in mixture. This nearly complete integration describes mixtures of like-quality compounds, of unlike-quality compounds, and of both like- and unlike-quality compounds together. Integrative mixtures provide a model for the detection of the ultracomplex stimuli of everyday life, such as foods and drinking waters. Although the degree of integration may trail off slightly with mixtures of high complexity, the results proffer no limit on the number of compounds that can be at least partially integrated. In principle, integration permits detection of natural substances whose myriad components could all be far below threshold. The mechanism of taste integration is speculative, but the facts are congenial to the hypothesis of multiple parallel channels for the processing of intensity and quality.

Food↗
PubMed2006

Analysis of complex protein mixtures with improved sequence coverage using (CE-MS/MS)n.

Identification of proteins, in a complex protein mixture, using one-dimensional high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) analysis of its digest, usually suffers from low sequence coverage. There are several reasons for the low coverage including undersampling, wide concentration dynamic range of the proteins in a complex protein mixture, and wide range of electrospray ionization efficiency of peptides under each mobile-phase composition. To address this low sequence coverage, we introduce a novel technique, (CE-MS/MS)n, which utilizes the most significant advantages of CE-MS/MS, including economy of sample size, fast analysis time, and high separation efficiency, to increase the sequence coverage of a complex protein mixture. Based on these characteristics, (CE-MS/MS)n can be performed in which multiple CE-MS/MS subanalyses (injections followed by analyses) are analyzed and experimental variables are manipulated during each CE-MS/MS subanalysis in order to maximize sequence coverage. (CE-MS/MS)n is a practical technique since each CE-MS/MS subanalysis consumes <10 nL, and each CE-MS/MS subanalysis takes approximately 10 min; therefore, several subanalyses can be performed in approximately 1 h consuming only nanoliters of the sample. Two techniques have been introduced to address the undersampling: (1) (CE-MS/MS)n using dynamic exclusion. In this technique, several CE-MS/MS analyses (injection followed by separation) were performed in one run using the dynamic exclusion capability of the mass spectrometer until all peptide peaks were analyzed by MS/MS. (2) Gas-phase fractionation. In this technique, (CE-MS/MS)n is performed by scanning a narrow mass range (every approximately 100 m/z) during each CE-MS/MS subanalysis without using dynamic exclusion. Under this condition, in each subanalysis, the number of peptides available for MS/MS analysis is significantly reduced, and peptides with the same nominal masses are analyzed, thereby increasing sequence coverage. Additionally, to address the lack of detection of low-level peptides in a mixture containing a wide concentration dynamic range, the concentration of the sample was systematically increased in each subanalysis (while utilizing dynamic exclusion) so that low-intensity peptides would rise above the mass spectrometer threshold and, consequently, undergo MS/MS analysis. Moreover, to alter the ionization efficiency of peptides with low electrospray ionization efficiency, and to change the migration behavior of comigrating peptides under a specific liquid composition, the CE background electrolyte was modified in several subanalyses to further improve sequence coverage. The combination of the above-mentioned techniques was applied to the analysis of the tryptic digests of three well-characterized protein mixtures: a six-protein mixture with average MW of approximately 26,000 (standard I), a six-protein mixture with an average MW approximately 49,000 (standard II), and a more complex protein mixture containing 55 proteins (E. coli ribosomal proteins). In approximately 1 h, when the MS/MS of the peptides were manually checked, all peptides that produced peaks under electrospray ionization in the scanned range of the analysis (500-2000 m/z) and within the practical fragmentation capability of the MS (peptides with MW <3500) were identified for standard I by consuming only 200 fmol of each protein. When searched against a Swissprot database, the average sequence coverage for the standard I, II, and E. coli's ribosomal proteins were 57, 34, and 15%, respectively.

Amino Acid Sequence↗
PubMed2006

Developments in mass spectrometry for the analysis of complex protein mixtures.

State-of-the-art proteomics workflows involve multiple interdependent steps: sample preparation, protein-peptide separation, mass spectrometry and data analysis. While improvements in any of these steps can increase the depth and breadth of analysis, advances in mass spectrometry have catalysed many of the most important developments. We discuss common classes of mass analysers and how these analysers are put together to produce some of the most popular mass spectrometry platforms. The capabilities of these platforms determine how they can be used in a variety of common proteomic strategies and, in turn, what types of biological questions can be addressed. Moving forward, powerful new hybrid mass spectrometers and application of emerging types of tandem mass spectrometry promise that our ability to analyse complex mixtures of proteins will continue to advance.

Complex Mixtures↗
PubMed1990

Application of an alternative approach for using the SOS chromotest to screen complex indeterminate mixtures.

We report on the application of an alternative approach to screen two complex indeterminate mixtures for genotoxic activity with the SOS chromotest, a simple quantitative colorimetric short-term bacterial genotoxicity assay. Considering the mixtures as a complex matrix, we evaluated the shape of the dose response curve of the direct acting reference genotoxin 4-nitroquinoline-1-oxide (4-NQO) with and without the matrix and found for one mixture a previously unrecognized genotoxic potential.

Colorimetry↗
PubMed2001

Resolution of GC-MS data of complex PAC mixtures and regression modeling of mutagenicity by PLS.

The present work describes a strategy to predict the mutagenicity of very complex mixtures of polycyclic aromatic compounds (PAC) from gas chromatography-mass spectrometry (GC-MS) patterns of the mixtures, each containing 260 compounds on average. The mixtures, 13 organic extracts of exhaust particles, were characterized by full scan GC-MS. The data were resolved into peaks and spectra for individual compounds by an automated curve resolution procedure. Similarity between spectra was evaluated for peaks that appeared within a time interval of 4 min, using a similarity index of 0.8 to ascertain that the same compound was represented by the same variable name (retention time) in all samples. The resolved chromatograms were integrated, resulting in a predictor matrix of size 13 x 721, which was used as input to a multivariate regression model. Partial least-squares projections to latent structures (PLS) were used to correlate the GC-MS chromatograms to mutagenicity as measured in the Ames Salmonella assay. The best model (high r2 and Q2) was obtained with 52 variables. These variables covary with the observed mutagenicity, and may subsequently be identified chemically. Furthermore, the regression model can be used to predict mutagenicity from GC-MS chromatograms of other organic extracts.

Air Pollutants↗
PubMed2002

Multi-adsorbent preconcentration/focusing module for portable-GC/microsensor-array analysis of complex vapor mixtures.

A small multi-adsorbent preconcentration/focusing module for a portable GC with microsensor-array detector designed to determine complex mixtures of volatile and semi-volatile organic compounds encountered in indoor working environments is described. Candidate adsorbents were assessed on the basis of analyte thermal-desorption bandwidth and efficiency, chromatographic peak shape, and breakthrough volume against mixtures of organic compounds ranging over four orders of magnitude in vapor pressure. A capillary packed with just 12.3 mg of adsorbent material comprising Carbopack B (8 mg), Carbopack X (2.5 mg) and Carboxen 1000 (1.8 mg) provided the best tradeoff in operating variables, while maintaining sufficient capacity for a 1 L air sample containing a mixture of up to 43 compounds, each at 100 parts-per-billion, at an ambient relative humidity of up to 100%. On-column focusing and temperature programming were used to enhance chromatographic separations, and detection limits as low as 100 parts-per-trillion were achieved for a 1 L air sample using an integrated array of polymer-coated surface-acoustic-wave (SAW) sensors. Implications for field analysis of indoor air quality are emphasized.

Acoustics↗
PubMed2000

Assessing the aquatic toxicity of complex hydrocarbon mixtures using solid phase microextraction.

Assessing the ecotoxicity of hydrocarbon mixtures is complicated by the complex nature of these mixtures. Traditional analytical methods for characterizing hydrocarbon contamination are not good predictors of potential ecotoxicity because these methods fail to characterize the bioavailability of individual hydrocarbon components. Recent research indicates that hydrocarbons act by a common narcotic mode of action and that ecotoxicity occurs when the molar concentration in organism lipid exceeds a critical threshold. Since the ecotoxicity of narcotic mixtures appears to be additive, ecotoxicity thus depends upon the partitioning of individual hydrocarbons from the environment to lipids and the total molar sum of individual hydrocarbons in lipids. These insights have led previous investigators to advance the concept of 'biomimetic' extraction as a novel analytical tool for assessing narcosis-type or 'baseline'. Drawing from this earlier work, a simple method to quantify bioavailable petroleum hydrocarbons (BPHs) in hydrocarbon-contaminated aqueous and soil/sediment samples was developed. The proposed method combines the essential features of biomimetic extraction for simulating the bioconcentration process with the analytical advantages of solid phase microextraction (SPME). The procedure for determining BPH involves two steps. The sample is first equilibrated with a SPME fiber that serves as a surrogate for organism lipids. The total moles of hydrocarbons that partition to the SPME fiber is then quantified using GC/FID. The capability of this method to predict ecotoxicity was assessed by comparing BPH measurements for hydrocarbon contaminated aqueous samples to corresponding toxicity test results for rainbow trout. Results indicate that BPH analyses correlate to the observed acute toxicity. Consequently, BPH analyses offer a promising, cost-effective screening tool for predicting aquatic toxicity of complex hydrocarbon mixtures.

Animals↗
PubMed1991

Risk characterization framework for noncancer end points.

The nature of both indoor air exposures and noncancer end points present significant issues for risk characterization. Noncancer end points are multidimensional, affecting various organs, and are assumed to have thresholds. Symptoms also vary in severity within a population. In addition to the complexity of noncancer risk assessment, indoor air exposures are typified by the presence of complex mixtures, which further complicates the complex nature of noncancer risk characterization. Most noncancer risk assessment efforts have focused on defining acceptable daily intakes or reference doses (RfD) rather than estimating incidence and severity of the wide range of effects within an exposed population. The risk characterization framework has been developed to accommodate the RfD approach but, more importantly, to address the multidimensional nature of noncancer risk characterization. Newly emerging methods and standard EPA risk assessment guidelines for noncancer effects and complex mixtures were used as guides for developing the framework. Information and data needs have been identified from the framework. Peak, average, and cumulative doses from indoor air exposures are highly dependent on variable indoor air concentrations and affected by time-activity patterns. Susceptibility also plays a significant role in noncancer end points and, unlike susceptibility in cancer risk assessment, is quantifiable. This paper highlights the risk characterization framework for noncancer health risks that we developed in cooperation with the U.S. Environmental Protection Agency Environmental Criteria and Assessment Office. Additionally, a preliminary application of the framework to a complex mixture of volatile organic compounds from indoor sources is illustrated.

Air Pollution, Indoor↗
PubMed1999

Quantitative analysis of complex protein mixtures using isotope-coded affinity tags.

We describe an approach for the accurate quantification and concurrent sequence identification of the individual proteins within complex mixtures. The method is based on a class of new chemical reagents termed isotope-coded affinity tags (ICATs) and tandem mass spectrometry. Using this strategy, we compared protein expression in the yeast Saccharomyces cerevisiae, using either ethanol or galactose as a carbon source. The measured differences in protein expression correlated with known yeast metabolic function under glucose-repressed conditions. The method is redundant if multiple cysteinyl residues are present, and the relative quantification is highly accurate because it is based on stable isotope dilution techniques. The ICAT approach should provide a widely applicable means to compare quantitatively global protein expression in cells and tissues.

Affinity Labels↗
PubMedDate not supplied

Sources of variation in the mutagenic potency of complex chemical mixtures based on the Salmonella/microsome assay.

Twenty laboratories worldwide participated in a collaborative trial sponsored by the International Programme on Chemical Safety on the mutagenicity of complex mixtures as expressed in the Salmonella/microsome assay. The U.S. National Institute of Standards and Technology provided homogeneous reference samples of urban air and diesel particles and a coal tar solution to each participating laboratory, along with samples of benzo[a]pyrene and 1-nitropyrene which served as positive controls. Mutagenic potency was characterized by the slope of the initial linear component of the dose-response curve. Analysis of variance revealed significant interlaboratory variation in mutagenic potency, which accounted for 57-96% of the total variance on a logarithmic scale, depending on the sample, strain and activation conditions. Variation among replicate extractions of organic material (required for the air and diesel particles) and among replicate bioassays within the same laboratory was also appreciable. The average potencies for air and diesel particles in laboratories using Soxhlet extracts were not significantly different from those in laboratories using sonication, although there was larger interlaboratory variation for the Soxhlet method. Repeatability (which approximates the coefficient of variation within laboratories) ranged from 18 to 40% for air and diesel particles extracted using sonication, depending on the strain and activation conditions. Repeatability of Soxhlet-extracted air and diesel particles, however, ranged from about 37 to 89% including outliers and from about 11 to 31% excluding outliers. Repeatability of the coal tar sample and the 2 positive controls was in the range 18-34%. Reproducibility (which approximates the coefficient of variation between laboratories) was generally at least twice repeatability, and exceeded 100% for Soxhlet-extracted air and diesel particles, as well as 1-nitropyrene. Reanalysis of the data omitting observations of more than 1500 revertants/plate generally had little effect on these results. Elimination of outlying observations had limited impact, with the exception of Soxhlet-extracted air and diesel particles. In this case, reproducibility of bioassay results was notably improved, due largely to the omission of results for replicate extractions which varied more than 5-fold within one laboratory. Normalization of the log potency slopes for the mixtures by the corresponding slopes for benzo[a]pyrene tended to reduce this variation, although variation was increased after normalization by 1-nitropyrene. Adjustment for the percentage of organic matter extracted from the air and diesel particulate samples had little effect on variation for sonication-extracted particles, whereas variation was reduced for diesel particles and increased for air particles for Soxhlet.

Air Pollutants↗
PubMed2005

Curve-fitting method for direct quantitation of compounds in complex biological mixtures using 1H NMR: application in metabonomic toxicology studies.

A new software tool has been developed that provides automated measurement of signal intensities in NMR spectra of complex mixtures without using data reduction procedures. The algorithm finds best-fit transformations between signals in reference compound spectra and the corresponding signals in analyte spectra. Unlike other algorithms, it is insensitive to variation in chemical shift and can even be used for relative quantitation of compounds whose identities have not yet been established. Additionally, the parameters of the transformation provide information and error metrics that may assist in the streamlining of quality control. The approach presented is general in scope but has been tested by application to peak quantitation in NMR spectra of biofluids. Replicate NMR measurements of solutions of biologically important compounds at various concentrations were made. Further NMR data were collected on urine samples from human, rat, and mouse, which were "spiked" with reference compound solutions at known concentrations. Finally, existing data from an independent toxicology project involving several hundred samples were analyzed, and the consistency of the measurements for metabolites that give multiple NMR signals was assessed. The results of all these tests give confidence that the technique can be used in automated quantitation of compounds in large NMR data sets with minimal operator intervention.

Animals↗
PubMed2003

Single olfactory sensory neurons simultaneously integrate the components of an odour mixture.

Most odours are complex mixtures. However, the capacities of olfactory sensory neurons (OSNs) to process complex odour stimuli have never been explored in air-breathing vertebrates. To face this issue, the present study compares the electrical responses of single OSNs to two odour molecules, delivered singly and mixed together, in rats in vivo. This work is the first aimed at demonstrating that single OSNs simultaneously integrate several chemical signals and which, furthermore, attempts to describe such processes for the whole concentration range over which single OSNs can work. The results stress that complex interactions occur between components in odour mixtures and that OSN responses to such mixtures are not simply predictable from the responses to their components. Three types of interactions are described. They are termed suppression, hypoadditivity and synergy, in accord with psychophysical terminology. This allows us to draw links between peripheral odour reception and central odour coding. Indeed, events occurring in single OSNs may account for the dominating or even the masking effects of odour molecules in complex mixtures, i.e. for the prevailing action of a minor component in the final qualitative perception of a mixture. We conclude that our observations with binary mixtures anticipate the complexity of processes which may rise at the level of a single OSN in physiological conditions. Following this hypothesis, a natural odour would induce a multi-chemical integration at the level of single OSNs which may result in refining their individual odour-coding properties, leading them to play a crucial role in the final performance of the olfactory system.

Action Potentials↗
PubMed1996

Generalization among related complex odorant mixtures and their components: analysis of olfactory perception in the spiny lobster.

We investigated the processing of odorant mixtures containing two to seven components by the spiny lobster Panulirus argus. The chemicals tested were food-related compounds that are attractive to spiny lobsters, and include adenosine-5'-monophosphate, betaine, L-cysteine, L-glutamate, DL-succinate, taurine, and ammonium. Components were tested at concentrations that produced search behavioral responses of equal magnitude in unconditioned animals. Responses of unconditioned animals to mixtures and their components reveal hypoadditivity, in which the response to a mixture is less than the sum of the responses to that mixture's components. Aversive conditioning coupled with generalization testing was used to evaluate generalization and hence perceptual similarity between related mixtures. Animals were conditioned to either an individual odorant, a four-compound mixture, or a seven-compound mixture, followed by generalization testing with submixtures or larger mixtures containing the conditioned stimulus. Animals tended not to generalize, but significant generalization between a more simple conditioned stimulus and more complex mixtures containing that conditioned stimulus occurred in 2 of 11 cases, and significant generalization between a conditioned mixture and its submixtures was observed in 4 of 9 cases. Both the number and chemical identity of components of mixtures may contribute to the degree of generalization between mixtures. Overshadowing, in which the ability to learn about a chemical is affected by simultaneous presentation of other chemicals, occurred in two of three cases. We discuss implications of these findings with respect to elemental and configural processing of odorant mixtures in the spiny lobster, possible neural mechanisms responsible for these results, and the potential utility of generalization and overshadowing to the spiny lobster's natural behavior.

Animals↗