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PubMed1981

Spectrophotometric determination of chloramphenicol and its esters in complex drug mixtures.

When aromatic nitro compounds are reduced with zinc and calcium chloride and reacted with trisodium pentacyanoaminoferrate they give a purple product having an absorbance maximum between 480 and 540 nm. Applying this reaction, a quantitative method has been developed for the determination of chloramphenicol and its esters. Various reaction conditions have been standardized. Beer's law is obeyed in the concentration range of 4 to 32 micrograms/mL reaction mixture. Average recoveries and standard deviations were 99.78 +/- 0.627 and 99.90 +/- 0.660; 101.06 +/- 0.702; and 99.90 +/- 0.880% for chloramphenicol, chloramphenicol sodium succinate, and chloramphenicol palmitate, respectively. The method has also been applied to determine chloramphenicol and its esters as well as chloramphenical in the presence of combination drugs in dosage forms. The presence of benzocaine, lignocaine, sulfadiazine, nitrofurantoin, ascorbic acid, hydrocortisone, prednisolone, streptomycin, and tetracycline does not interfere with the proposed spectrophotometric procedure. The method does not require prior separation of chloramphenicol from combination drugs.

Capsules↗
PubMed1991

Assessment of biological activities of mixtures of polychlorinated dibenzo-p-dioxins: comparison between defined mixtures and their constituents.

As a first step to assess biological activities of complex mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), induction of 7-ethoxyresorufin O-deethylase (EROD) by defined mixtures and their constituents has been analysed in vitro. Two cell systems have been compared: primary hepatocyte cultures and hepatoma H4IIE cells. EC50 values of PCDDs were compared with that of the most potent compound, 2,3,7,8-Cl4DD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and expressed as 2,3,7,8-Cl4DD equivalents (TEs). TEs for three defined mixtures containing up to 49 PCDDs could be predicted from the sum of TEs for the 2,3,7,8-substituted congeners. Efficacies (maximal enzyme induction) of less potent PCDDs (1,2,3,4-Cl4DD, Cl8DD and of a mixture containing 86% Cl8DD and of benz(a)anthracene were lower in hepatocytes (by 33%) and in H4IIE cells (by 50%). The results suggest that biological activities of complex PCDD mixtures are largely due to additive effects of their 2,3,7,8-substituted constituents.

Animals↗
PubMedDate not supplied

A feasibility study of cumulative risk assessment methods for drinking water disinfection by-product mixtures.

Humans are exposed daily to complex mixtures of chemicals, including drinking water disinfection by-products (DBPs) via oral, dermal, and inhalation routes. Some positive epidemiological and toxicological studies suggest reproductive and developmental effects and cancer are associated with consumption of chlorinated drinking water. Thus, the U.S. Environmental Protection Agency (EPA) conducted research to examine the feasibility of evaluating simultaneous exposures to multiple DBPs via all three exposure routes. A cumulative risk assessment approach was developed for DBP mixtures by combining exposure modeling and physiologically based pharmacokinetic modeling results with a new mixtures risk assessment method, the cumulative relative potency factors (CRPF) approach. Internal doses were estimated for an adult female and an adult male, each of reproductive age, and for a child (age 6 yr) inclusive of oral, dermal, and inhalation exposures. Estimates of the daily internal doses were made for 13 major DBPs, accounting for activity patterns that affect the amount of human contact time with drinking water (e.g., tap water consumed, time spent showering), building characteristics (e.g., household air volumes), and physicochemical properties of the DBPs (e.g., inhalation rates, skin permeability rates, blood: air partition coefficients). A novel cumulative risk assessment method, the CRPF approach, is advanced that integrates the principles of dose addition and response addition to produce multiple-route, chemical mixture risk estimates using total absorbed doses. Research needs to improve this approach are presented.

Chlorine Compounds↗
PubMed1976

Analysis of alkaloid mixtures by charge-transfer complexation.

Binary mixtures of weak and strong UV-absorbing alkaloids were analyzed by a charge-transfer spectrophotometric method, utilizing iodine in ethylene dichloride as the acceptor. In the uncomplexed form, the strong absorbing alkaloid (papaverine, quinine, ergotamine, or reserpine) was measured at a wavelength where there was no interference from weak absorbers (at 335, 332, 315, or 300 nm, respectively). The weak absorbing alkaloid (ephedrine, codeine, atropine, or homatropine methylbromide) was determined by computing its contribution to the total charge-transfer band at 295 nm where absorbance was linearly additive for mixtures. The greater increase in the original epsilon-values of the weak absorbers upon complexation with iodine relative to the corresponding increase in the epsilon-values of the strong absorbers led to good recoveries even at the low dose ratios of the weakly absorbing, and often more potent, alkaloids.

Alkaloids↗
PubMed1986

Calculation of 2,3,7,8-TCDD equivalent concentrations of complex environmental contaminant mixtures.

Sufficient toxicological data are now available to permit use of conventional risk assessment techniques to estimate the hazards associated with human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). However, many real-world exposures involve complex mixtures of dibenzodioxins, dibenzofurans, and related compounds. Historical approaches to risk assessment on such mixtures have ranged from ignoring all compounds except 2,3,7,8-TCDD itself to assuming that all compounds have potencies equal to 2,3,7,8-TCDD. An alternative approach which uses existing literature data and analytical results to calculate the "2,3,7,8-TCDD equivalent" concentration of a mixture in order to "predict" its biological potency relative to 2,3,7,8-TCDD itself is advanced here. Previously reported in vivo acute and subchronic studies and some recently obtained analytical chemistry data are integrated here to clarify the utility of this important approach and to assess the uncertainties associated with its use. This predictive approach, and various conceptually similar ones, have now found wide applicability to the risk assessment process associated with exposure to complex mixtures of dioxins, dibenzofurans, and related compounds.

Alanine Transaminase↗
PubMed2002

International issues on human health effects of exposure to chemical mixtures.

In this article, we highlight new developments and recent studies concerning adverse human health effects related to chemical mixtures. One group of activities comprises the development of a new computer program for analyzing mixture studies and a mathematical model as a basis for combination rules that predict the toxicity of mixtures. Other new activities in the area of experimental studies are the application of gene expression technologies in mixture research, and pattern recognition as a tool in safety evaluation of complex mixtures. A "bottom-up" approach for chemosensory detection of mixtures has recently been presented. Other topics include a method for the safety evaluation of natural flavoring complexes, and an evaluation of the possible health effects of the simultaneous intake of food additives. Examples of issues related to mixtures of airborne chemicals are potential interaction of fine particles and gaseous pollutants in ambient air, nasal cancer associated with inhaled chemical mixtures, and the recommendation of a limit value for volatile organic compounds. Topics of a more strategic nature include studies concerning the public health effects of large airports, and the development of criteria for a harmonized classification of chemical mixtures. This overview illustrates that strategies to tackle the safety evaluation of combined exposures and complex mixtures as well as models facilitating the interpretation of findings in the context of risk assessment of mixtures have become increasingly important. It is true that exposure of humans to chemical mixtures is the rule rather than the exception, and therefore health risk assessments should focus on mixtures and not on single chemicals. It is also true, however, that humans have learned to cope with exposure to huge numbers of chemicals simultaneously (food, water, air, soil, and consumer products). Therefore, in view of limited resources for toxicological research, the focus in toxicology should be on priority mixtures--priority being determined by (estimated) health risk (= toxicity and exposure).

Air Pollutants↗
PubMedDate not supplied

The role of combined metal interactions in metal carcinogenesis: a review.

Exposures to complex mixtures of metals in the workplace or environment are more likely to occur than exposures to a single metal alone. The evidence shows that exposures to complex metal mixtures can enhance the risk of cancer in certain human populations. The findings of several studies have suggested, however, that certain metal-metal interactions can inhibit carcinogenic activity. The mechanisms of metal-metal interactions in human carcinogenesis are relatively unknown. Metals represent a highly diverse group of agents: each metal can act through different mechanisms and in one or more steps of the carcinogenic process. Some potential mechanisms may involve direct reactions of the metal with DNA or indirect mechanisms that include modification of DNA repair, DNA methylation status, and metabolic processes involved in DNA replication and expression. Lipid peroxidation and the generation of free radicals induced by certain metals can affect DNA integrity. This review will address the role of metals in carcinogenesis and how concomitant exposure to metal mixtures can influence cancer induction. The most current mechanistic data regarding metal interactions and its implications in human carcinogenesis will be discussed. Furthermore, research gaps will be identified to provide data that will improve risk assessments for complex metal mixtures encountered in the workplace and environment.

Cell Transformation, Neoplastic↗
PubMed2005

Parallel capillary electrophoresis for the quantitative screening of fermentation broths containing natural products.

Directed molecular evolution is a recursive process of controlled genetic diversification and functional screening. The success of this approach is dependent on both the quality of the genetic diversity and the ability to accurately screen a large population of individual genetic variants for those having improved function. In this paper, the application of parallel capillary electrophoresis to rapidly quantitate lovastatin production levels by Aspergillus terreus mutants is described. A parallel 96 capillary instrument analyzed 900 samples in 8 h. with a 100 mM MES at pH 5.2 running buffer. In this manner, the fermentation broths of thousands of mutated strains were efficiently and inexpensively screened for increased lovastatin production. The ability to develop high-throughput methods to both separate and quantitate the components of complex mixtures greatly facilitates the ability to apply evolutionary engineering methods to complex biological systems.

Aspergillus↗
PubMed1981

Use of nitrous acid-dependent decrease in mutagenicity as an indication of the presence of mutagenic primary aromatic amines. Non-specific reactions with phenols and benzo[alpha]pyrene.

Treatment of mutagenic primary aromatic amines with nitrous acid is known to decrease their mutagenicity. We examined some factors concerning the validity of using decreases in mutagenicity due to nitrous acid treatment as an indication of the presence of mutagenic primary aromatic amines in complex mixtures. We found that treatment of benzo[alpha]pyrene with nitrous acid for the extended periods of time previously employed leads to formation of three nitrobenzo[alpha]pyrene isomers. Some of the isomers are direct-acting mutagens for S. typhimurium with considerably greater mutagenicity than benzo[alpha]pyrene isomers. In attempts to minimize reaction of chemicals other than aromatic amines, we found that only very brief reaction periods are required for complete reaction of nitrous acid with representative aromatic amines, essentially eliminating their mutagenicity. During such brief reaction periods modification of benzo[alpha]pyrene is negligible, but phenols react readily. Chromatographic analysis indicated that reaction of nitrous acid with aromatic amines leads to the formation of families of products, thereby increasing the complexity of the mixtures in which the amines may occur. Thus, experiments examining the effects of nitrous acid on the mutagenic activity of complex mixtures must be carefully designed, and the results must be interpreted cautiously.

Amines↗
PubMed2006

Toxicity of jet fuel aliphatic and aromatic hydrocarbon mixtures on human epidermal keratinocytes: evaluation based on in vitro cytotoxicity and interleukin-8 release.

Jet fuels are complex mixtures of aliphatic (ALI) and aromatic (ARO) hydrocarbons that vary significantly in individual cytotoxicity and proinflammatory activity in human epidermal keratinocytes (HEK). In order to delineate the toxicological interactions among individual hydrocarbons in a mixture and their contributions to cutaneous toxicity, nine ALI and five ARO hydrocarbons were each divided into five (high/medium/low cytotoxic and strong/weak IL-8 induction) groups and intra/inter-mixed to assess for their mixture effects on HEK mortality and IL-8 release. Addition of single hydrocarbon to JP-8 fuel was also evaluated for their changes in fuel dermatotoxicity. The results indicated that when hydrocarbons were mixed, HEK mortality and IL-8 release were not all predictable by their individual ability affecting these two parameters. The lowest HEK mortality (7%) and the highest IL-8 production were induced with mixtures including high cytotoxic and weak IL-8 inductive ARO hydrocarbons. Antagonistic reactions not consistently correlated with ALI carbon chain length and ARO structure were evident and carried different weight in the overall mixture toxicities. Single addition of benzene, toluene, xylene or ethylbenzene for up to tenfold in JP-8 did not increase HEK mortality while single addition of ALI hydrocarbons exhibited dose-related differential response in IL-8. In an all ALI environment, no single hydrocarbon is the dominating factor in the determination of HEK cytotoxicity while deletion of hexadecane resulted in a 2.5-fold increase in IL-8 production. Overall, decane, undecane and dodecane were the major hydrocarbons associated with high cytotoxicity while tetradecane, pentadecane and hexadecane were those which had the greatest buffering effect attenuating dermatotoxicity. The mixture effects must be considered when evaluating jet fuel toxicity to HEK.

Aviation↗
PubMed2006

Optimization of homonuclear 2D NMR for fast quantitative analysis: application to tropine-nortropine mixtures.

Quantitative analysis by (1)H NMR is often hampered by heavily overlapping signals that may occur for complex mixtures, especially those containing similar compounds. Bidimensional homonuclear NMR spectroscopy can overcome this difficulty. A thorough review of acquisition and post-processing parameters was carried out to obtain accurate and precise, quantitative 2D J-resolved and DQF-COSY spectra in a much reduced time, thus limiting the spectrometer instabilities in the course of time. The number of t(1) increments was reduced as much as possible, and standard deviation was improved by optimization of spectral width, number of transients, phase cycling and apodization function. Localized polynomial baseline corrections were applied to the relevant chemical shift areas. Our method was applied to tropine-nortropine mixtures. Quantitative J-resolved spectra were obtained in less than 3 min and quantitative DQF-COSY spectra in 12 min, with an accuracy of 3% for J-spectroscopy and 2% for DQF-COSY, and a standard deviation smaller than 1%.

Complex Mixtures↗
PubMed2000

Exploring the glycan repertoire of genetically modified mice by isolation and profiling of the major glycan classes and nano-NMR analysis of glycan mixtures.

The production of mice with genetic alterations in glycosyltransferases has highlighted the need to isolate and study complex mixtures of the major classes of oligosaccharides (glycans) from intact tissues. We have found that nano-NMR spectroscopy of whole mixtures of N- and O-glycans can complement HPLC profiling methods for elucidating structural details. Working toward obtaining such glycan mixtures from mouse tissues, we decided to develop an approach to isolate not only N- and O-glycans, but also to separate out glycosphingolipids, glycosaminoglycans and glycosylphosphatidylinositol anchors. We describe here a comprehensive Glycan Isolation Protocol that is based primarily upon the physicochemical characteristics of the molecules, and requires only commonly available reagents and equipment. Using radiolabeled internal tracers, we show that recovery of each major class of glycans is as good or better than with conventional approaches for isolating individual classes, and that cross-contamination is minimal. The recovered glycans are of sufficient purity to provide a "glycoprofile" of a cell type or tissue. We applied this approach to compare the N- and O-glycans from wild type mouse tissues with those from mice genetically deficient in glycosyltransferases. N- and O-glycan mixtures from organs of mice deficient in ST6Gal-I (CMP-Sia:Galbeta1-4GlcNAc alpha2-6 sialyltransferase) were studied by the nano-NMR spectroscopy approach, showing no detectable alpha2-6-linked sialic acids. Thus, ST6Gal-I is likely responsible for generating most or all of these residues in normal mice. Similar studies indicate that this linkage is very rare in ganglioside glycans, even in wild-type tissues. In mice deficient in GalNAcT-8 (UDP-GalNAc:polypeptide O-Ser/Thr GalNAc transferase 8), HPLC profiling indicates that O-glycans persist in the thymus in large amounts, without a major change in overall profile, suggesting that other enzymes can synthesize the GalNAc-O-Ser/Thr linkage in this tissue. These results demonstrate the applicability of nano-NMR spectroscopy to complex glycan mixtures, as well as the versatility of the Glycan Isolation Protocol, which makes possible the concurrent examination of multiple glycan classes from intact vertebrate tissues.

Animals↗