Abstract  The aim of this work was to investigate the effect of enhancers and organic amines on the in-vitro percutaneous absorption of the major pharmacologically active compound, scutellarin, obtained from breviscapine extract. The donor vehicle consisted of isopropyl myristate-ethanol in a ratio of 4:1. Percutaneous absorption across full thickness rat skin was investigated in-vitro using 2-chamber diffusion cells, with reverse-phase HPLC for quantification of the permeating scutellarin. Organic amines increased scutellarin permeation by ion-pair formation. We also found that the cumulative amount of scutellarin over a period of 12 h of scutellarin was inversely related to the molecular weight of organic amines (r = 0.9134), as well as the logarithm of scutellarin permeability coefficient inversely related to the partition coefficient of organic amines (r = 0.8929). All the permeation enhancers tested increased the cumulative amount of scutellarin over a period of 12 h, and the order of this increase was n-methyl-2-pyrrolidone, oleic acid, menthol or Azone. Drug solubility in donor phase was markedly increased by Azone and n-methyl-2-pyrrolidone, and reduced by menthol and oleic acid. The combined effects of ethanolamine plus Azone, ethanolamine plus menthol, and Azone plus menthol were also investigated. Azone plus menthol had a synergistic effect on the cumulative amount of scutellarin over a period of 12 h.

Abstract  Ion chromatography along with matrix elimination was used to reliably determine trace levels of anionic contaminants in organic solvents. A 5-ml sample volume was injected directly into the instrument without any sample pretreatment. High-purity deionized water was used to deliver the sample to a preconcentration column, where the anions of interest were retained while the organic matrix was rinsed to waste. A sodium carbonate eluent eluted concentrated anions from the preconcentration column and separated them on a 2-mm pellicular anion-exchange column. The separated anions were detected by suppressed conductivity. This method was used to determine the anionic contaminants of isopropanol, acetone and N-methylpyrrolidone. Method detection limits for chloride, nitrate, sulfate and phosphate were all lower than 1 microg/l.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. RRM POLLUTION CONTROL DEODORIZING AGENT WOOD CARBONIZATION PRODUCT

Abstract  The objective of this study was to predict the inhalation toxicokinetics of chemicals in mixtures using an integrated QSAR-PBPK modelling approach. The approach involved: (1) the determination of partition coefficients as well as V(max) and K(m) based solely on chemical structure for 53 volatile organic compounds, according to the group contribution approach; and (2) using the QSAR-driven coefficients as input in interaction-based PBPK models in the rat to predict the pharmacokinetics of chemicals in mixtures of up to 10 components (benzene, toluene, m-xylene, o-xylene, p-xylene, ethylbenzene, dichloromethane, trichloroethylene, tetrachloroethylene, and styrene). QSAR-estimated values of V(max) varied compared with experimental results by a factor of three for 43 out of 53 studied volatile organic compounds (VOCs). K(m) values were within a factor of three compared with experimental values for 43 out of 53 VOCs. Cross-validation performed as a ratio of predicted residual sum of squares and sum of squares of the response value indicates a value of 0.108 for V(max) and 0.208 for K(m). The integration of QSARs for partition coefficients, V(max) and K(m), as well as setting the K(m) equal to K(i) (metabolic inhibition constant) within the mixture PBPK model allowed to generate simulations of the inhalation pharmacokinetics of benzene, toluene, m-xylene, o-xylene, p-xylene, ethylbenzene, dichloromethane, trichloroethylene, tetrachloroethylene and styrene in various mixtures. Overall, the present study indicates the potential usefulness of the QSAR-PBPK modelling approach to provide first-cut evaluations of the kinetics of chemicals in mixtures of increasing complexity, on the basis of chemical structure.

Abstract  Toxicity and exposure evaluations remain the two of the key components of human health assessment. While improvement in exposure assessment relies on a better understanding of human behavior patterns, toxicity assessment still relies to a great extent on animal toxicity testing and human epidemiological studies. Recent advances in computer modeling of the dose-response relationship and distribution of xenobiotics in humans to important target tissues have advanced our abilities to assess toxicity. In particular, physiologically based pharmacokinetic (PBPK) models are among the tools than can enhance toxicity assessment accuracy. Many PBPK models are available to the health assessor, but most are so difficult to use that health assessors rarely use them. To encourage their use these models need to have transparent and user-friendly formats. To this end the Agency for Toxic Substances and Disease Registry (ATSDR) is using translational research to increase PBPK model accessibility, understandability, and use in the site-specific health assessment arena. The agency has initiated development of a human PBPK tool-kit for certain high priority pollutants. The tool kit comprises a series of suitable models. The models are recoded in a single computer simulation language and evaluated for use by health assessors. While not necessarily being state-of-the-art code for each chemical, the models will be sufficiently accurate to use for screening purposes. This article presents a generic, seven-compartment PBPK model for six priority volatile organic compounds (VOCs): benzene (BEN), carbon tetrachloride (CCl(4)), dichloromethane (DCM), perchloroethylene (PCE), trichloroethylene (TCE), and vinyl chloride (VC). Limited comparisons of the generic and original model predictions to published kinetic data were conducted. A goodness of fit was determined by calculating the means of the sum of the squared differences (MSSDs) for simulation vs. experimental kinetic data using the generic and original models. Using simplified solvent exposure assumptions for oral ingestion and inhalation, steady-state blood concentrations of each solvent were simulated for exposures equivalent to the ATSDR Minimal Risk Levels (MRLs). The predicted blood levels were then compared to those reported in the National Health and Nutrition Examination Survey (NHANES). With the notable exception of BEN, simulations of combined oral and inhalation MRLs using our generic VOC model yielded blood concentrations well above those reported for the 95th percentile blood concentrations for the U.S. populations, suggesting no health concerns. When the PBPK tool kit is fully developed, risk assessors will have a readily accessible tool for evaluating human exposure to a variety of environmental pollutants.

Abstract  The purpose of this study was to investigate the effects of vehicles, enhancers, and polymer membranes on 3'-azido-3'-deoxythymidine (AZT) permeation across cadaver pig skin. Four binary vehicles (ethanol/water, isopropyl alcohol/water, polyethylene glycol 400/water, and ethanol/isopropyl myristate [IPM]) were tested for AZT solubility and permeability across pig skin; ethanol/IPM (50/50, vol/vol) demonstrated the highest AZT flux (185.23 microg/cm2/h). Next, the addition of various concentrations of different enhancers (N-methyl-2-pyrrolidone [NMP], oleic acid, and lauric acid) to different volume ratios of ethanol/IPM was investigated for their effect on AZT solubility and permeability across pig skin. The use of 2 combinations (ethanol/IPM [20/80] plus 10% NMP and ethanol/IPM [30/70] plus 10% NMP) resulted in increased AZT solubility (42.6 and 56.27 mg/mL, respectively) and also high AZT flux values (284.92 and 460.34 microg/cm2/h, respectively) without appreciable changes in lag times (6.25 and 7.49 hours, respectively) when compared with formulations using only ethanol/IPM at 20/80 and 30/70 volume ratios without addition of the enhancer NMP. Finally, AZT permeation across pig skin covered with a microporous polyethylene (PE) membrane was investigated. The addition of the PE membrane to the pig skin reduced AZT flux values to 50% of that seen with pig skin alone. However, the AZT flux value attained with ethanol/IPM (30/70) plus 10% NMP was 215.31 microg/cm2/h, which was greater than the target flux (208 mug/cm2/h) needed to maintain the steady-state plasma concentration in humans. The results obtained from this study will be helpful in the development of an AZT transdermal drug delivery system.

Abstract  IPA COPYRIGHT: ASHP The enhancing effects of 3 pyrrolidones on the transdermal penetration of fluorouracil (5-fluorouracil), triamcinolone acetonide, indomethacin and flurbiprofen were studied in vitro using full-thickness rat skin. The pyrrolidones enhanced the penetration of the penetrants, especially the lipophilic derivatives, which showed great enhancing effects on the penetration of fluorouracil and indomethacin. The more lipophilic pyrrolidones showed greater enhancing effects on the solubility and penetration of hydrophilic penetrants than those of lipophilic penetrants. The pyrrolidones also enhanced the solubility of the penetrants in isopropyl myristate. All enhancers accumulated to a great extent in the skin and enhanced the skin retention of the drugs. It was concluded that the pyrrolidone derivatives enhance the flux of penetrants in the skin by increasing their solubility.

Abstract  IPA COPYRIGHT: ASHP To investigate the effects of various penetration enhancers on indomethacin (IND) and urea permeation, in vitro permeation experiments with hairless rat skin were conducted. Laurocapram, isopropyl myristate (IPM), sodium oleate, and eucalyptol (cineol) increased fluxes of both agents to a great extent. Many enhancers increased lipid fluidity, skin partitioning of IND, extraction of ceramides from cornified cells, and thermodynamic activity of IND to varying extents. A good correlation was observed between increase in stratum corneum lipid fluidity and partitioning of IND into skin, between increase in fluidity and flux or decrease in lag time for IND, between removal of ceramides and skin partitioning of IND, and between removal of ceramides and flux of urea. The order of enhancement potency tested with IND was laurocapram>oleic acid>glyceryl monooleate (monoolein)>sodium oleate>eucalyptol and IPM, and the order with urea was octyl alcohol (n-octanol)>eucalyptol>laurocapram=glyceryl monooleate=oleic acid>sodium oleate>(+)-limonene (d-limonen)>IPM.

Abstract  The influence of the solvent used for spin-coating on the homogeneity of poly(N-vinylcarbazole) (PVK) films is investigated. Homogenous films are obtained only by the use of toluene, solution in tetrahydrofuran (THF) and chloroform results in radially oriented inhomogeneities and films prepared by use of N-methylpyrrolidone and dimethylacetamide show particle formation during spin-coating. Layered nano-composite thin films are prepared by spin-coating a PVK film on top of a nano-structured titanium dioxide ( TiO2) layer. The TiO2 thin films are prepared by a sol-gel process using an amphiphilic copolymer as structure-directing agent. Structural characterisation of the TiO2 :PVK nano-composite films is done by field emission scanning electron microscopy (FESEM) and grazing-incidence small-angle scattering (GISAXS). Bare TiO2 films are probed for comparison. Light is basically only absorbed in the ultraviolet regime and absorption slightly increases upon addition of PVK, which makes the layered TiO2 :PVK nano-composite thin films good candidates for UV photovoltaic devices. Furthermore, absorption remains stable over a period of several days.

Abstract  IPA COPYRIGHT: ASHP The effects of N-methylpyrrolidone (N-methyl-2-pyrrolidone; MP) on the permeation of zidovudine (azidothymidine; AZT) in isopropyl myristate through rat skin were studied in vitro. AZT permeation was significantly enhanced by MP. When 50 mul of solution containing 12 mg/ml zidovudine and 20% MP was applied, the plasma level of AZT was about one muM one-2 h after application, although the concentration decreased rapidly and was undetectable at 6 h. Although 34% of the applied dose remained in solution on rat skin at 10 h, MP was not detected. When ethylene-vinyl acetate copolymer (EVA) membrane was used for the controlled release of MP, a considerable plasma AZT level was maintained for 10 h. It was concluded that MP significantly enhances the permeation of AZT through rat skin, with sustained plasma levels achieved with the addition of EVA membrane.

Abstract  N-alkyl-2-pyrrolidones are a class of materials that are increasingly used in food, drug, cosmetic and industrial applications; however, toxicological data is only available for a few members of the class. The acute oral toxicity, primary dermal irritation and primary ocular irritation of N-methyl-, N-ethyl-, N-hydroxyethyl-, N-isopropyl-, N-cyclohexyl-, N-octyl-, N-dodecyl-, N-coco- and N-tallow-2-pyrrolidone are reported. Additionally, N-octyl-, N-decyl-, N-dodecyl-, N-tetradecyl-, N-hexadecyl- and N-octadecyl-2-pyrrolidone had the primary ocular and dermal irritation indices measured as a 2% aqueous suspension. These data show a wide range of toxicities dependent upon the alkyl substituent.

Abstract  BACKGROUND: There is evidence that exposure to chlorinated solvents may be associated with childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET) risk. Animal models suggest genes related to detoxification and DNA repair are important in the carcinogenicity of these pollutants; however, there have been no human studies assessing the modifying effects of these genotypes on the association between chlorinated solvents and childhood M/PNET risk.

PROCEDURE: We conducted a case-only study to evaluate census tract-level exposure to chlorinated solvents and the risk of childhood M/PNET in the context of detoxification and DNA repair genotypes. Cases (n = 98) were obtained from Texas Children's Hospital and MD Anderson Cancer Center. Key genotypes (n = 22) were selected from the Illumina Human 1M Quad SNP Chip. Exposure to chlorinated solvents (methylene chloride, perchloroethylene, trichloroethylene, and vinyl chloride) was estimated from the US EPA's 1999 Assessment System for Population Exposure Nationwide (ASPEN). Logistic regression was used to estimate the case-only odds ratios and 95% confidence intervals (CIs).

RESULTS: There were 11 significant gene-environment interactions associated with childhood M/PNET risk. However, after correcting for multiple comparisons, only the interaction between high trichloroethylene levels and OGG1 rs293795 significantly increased the risk of childhood M/PNET risk (OR = 9.24, 95% CI: 2.24, 38.24, Q = 0.04).

CONCLUSIONS: This study provides an initial assessment of the interaction between ambient levels of chlorinated solvents and potentially relevant genotypes on childhood M/PNET risk. Our results are exploratory and must be validated in animal models, as well as additional human studies.

Abstract  An aromatic chiral diacid monomer, 5-[4-(2-phthalimidiylpropanoylamino)-benzoylamino]isophthalic acid was synthesized in five steps under conventional heating in high yield and purity. A series of soluble, thermally stable and optically active polyamides (PA)s containing pendent groups made of phthalimide, flexible L: -alanine and benzamide sequence have been successfully synthesized under microwave irradiation. Excellent yields and very short reaction time were the main characteristics of this method. The same polymerization reactions were also carried out by conventional thermal heating and the results are compared. The resulting PAs had inherent viscosity in the range of 0.50-0.79 dL g(-1). All of the these polymers are readily dissolved in various solvents such as N-methyl-2-pyrrolidinone, N,N-dimethylacetamide and N,N-dimethylformamide and showed glass-transition temperature above 200 degrees C. Thermogravimetric analysis demonstrated that the 10% weight-loss temperatures in nitrogen were 372 and 422 degrees C for selected two PAs. All of these polymers showed optical rotation which is due to successful insertion of L: -alanine in the structure of chiral diacid monomer.

Abstract  Potential risk factors in renal cell carcinoma (RCC) were studied in a case-control study of 315 RCC cases and 313 hospital and 336 population controls. Risk factors included medical history, radiation exposure, predominant lifetime occupation, exposure to high-risk industries, and summary of important risk factors by a linear logistic regression model based on the comparison of RCC cases and controls selected from hospitals and the general population for 33 variables. A significant increase in urologic, cardiovascular, malignant, digestive, and metabolic disease was observed among cases over population controls. Exposure to radiation increased the risk, especially in females. A predominant lifetime occupation as a professional decreased the risk, whereas work as an operative increased the risk significantly. Work in petroleum-related and dry-cleaning industries were associated with elevated risk. Multivariate analysis comparing cases with each of the control groups for males and females identified obesity as the most important risk factor in RCC. Weight control at an early age might help to prevent the occurrence of a significant proportion of this rare but increasing malignant disease.

Abstract  A number of short-term methods have been developed in recent years to test chemical compounds and other agents for metagenic activity. These tests involve a number of species, both mammalian and nonmammalian, and are conducted both in vivo and in vitro. A correlation has been shown between the mutagenicity and the carcinogenicity of a compund. It has been estimated that approximately 80% (B.N. Ames, pers. comm.; M.S. Legator, pers. comm.) of all mutagenic compounds are also carcinogenic, although not all carcinogens are mutagens. Therefore, the value of tests to determine the mutagenicity of a compound is important in that these tests may, at least in some cases, give some indication of the carcinogenicity of that chemical as well. The mutagenicity tests alone, however, cannot difinitively identify a carcinogen. However, some of these test can be used for monitoring at-risk population groups and to aid in the evaluation of acceptable exposure standards. Mutational events may occur either at the gene level, where they result in mutant alleles, or at the chromosome level, where they cause chromosomal aberrations (usually the deletions or addition of some part of the chromosome arm). These may occur either during meiosis (in germ cells resulting in possible genetic transmission of that mutation) or during mitosis (occurring in somatic cells and not hereditary). Chromosomal aberrations may be either numerical or structural. Numerical abberations affect the whole chromosome set by the addition or deletion of one or more chromosomes from the cell. Structural anomalies, however, are generally deletions, breaks, gaps, or translocations in choromosomes and do not affect the chromosome number. Although many of these mutational events may result in cellular death, many may be repaired. In addition to the genetic end points of gene mutation or chromosomal aberration primary DNA damage may result from chemical mutagenesis. There are a number of tests that evaluate damage-induced genetic recombination. These include mitotic crossing over, gene coversion, sister chromatid exchange, and unscheduled DNA synthesis, as well as others.

Abstract  In recent years physiologically based pharmacokinetic models have come to play an increasingly important role in risk assessment for carcinogens. The hope is that they can help open the black box between external exposure and carcinogenic effects to experimental observations, and improve both high-dose to low-dose and interspecies projections of risk. However, to date, there have been only relatively preliminary efforts to assess the uncertainties in current modeling results. In this paper we compare the physiologically based pharmacokinetic models (and model predictions of risk-related overall metabolism) that have been produced by seven different sets of authors for perchloroethylene (tetrachloroethylene). The most striking conclusion from the data is that most of the differences in risk-related model predictions are attributable to the choice of the data sets used for calibrating the metabolic parameters. Second, it is clear that the bottom-line differences among the model predictions are appreciable. Overall, the ratios of low-dose human to bioassay rodent metabolism spanned a 30-fold range for the six available human/rat comparisons, and the seven predicted ratios of low-dose human to bioassay mouse metabolism spanned a 13-fold range. (The greater range for the rat/human comparison is attributable to a structural assumption by one author group of competing linear and saturable pathways, and their conclusion that the dangerous saturable pathway constitutes a minor fraction of metabolism in rats.) It is clear that there are a number of opportunities for modelers to make different choices of model structure, interpretive assumptions, and calibrating data in the process of constructing pharmacokinetic models for use in estimating “delivered” or “biologically effective” dose for carcinogenesis risk assessments. We believe that in presenting the results of such modeling studies, it is important for researchers to explore the results of alternative, reasonably likely approaches for interpreting the available data—and either show that any conclusions they make are relatively insensitive to particular interpretive choices, or to acknowledge the differences in conclusions that would result from plausible alternative views of the world.

Abstract  The acute toxicity (96-hr median lethal concentrations (LC50s) of ten chlorinated isomers of benzene, phenol, ethane, and ethylene to the American flagfish (Jordanella floridae) were determined in both static and flow-through systems. Chronic toxicity to embryo-larval fish was also estimated from hatching success and post-hatch survival as well as fry growth rates and survival. Maximum acceptable toxicant concentrations (MATC) were estimated where possible. In general, for both acute and chronic toxicity tests, the order of increasing relative toxicity based on the water-borne exposure concentrations was: chloroethanes, chloroethylenes, chlorobenzenes, and chlorophenols. Within groups, more highly chlorinated isomers were usually more toxic. The presence of suspended or colloidal 1,2,4,5-tetrachlorobenzene was observed in acute toxicity testing and affected toxicity estimates.

Abstract  N-Methyl-2-pyrrolidone (NMP) increased the skin permeation of estradiol (E2) in Yucatan micropig epidermis using a modified Franz-type diffusion cell. The addition of NMP significantly increased the fluxes of E2 from water and soybean oil. The flux and skin concentration of E2 were higher from soybean oil than from water and increased with increasing NMP concentrations in soybean oil. Correlation was observed with E2 flux and skin concentration (R(2) = 0.804) NMP enhanced E2 skin permeation because NMP made E2 skin concentration higher. Thus, NMP (10%) was added to the oily gel made by isocetyl isostearate and hydrogenated phospholipid. E2 permeation from the gel without NMP was the same as that from soybean oil suspension. The flux of E2 from the gel with NMP was 0.6 microg/h per cm(2) and might be sufficient for estrogen replacement therapy.

Abstract  A method for simultaneous determination of 5-hydroxy-N-methylpyrrolidone and 2-hydroxy-N-methylsuccinimide in urine is described. These compounds are metabolites of N-methyl-2-pyrrolidone, a powerful and widely used organic solvent. 5-Hydroxy-N-methylpyrrolidone and 2-hydroxy-N-methylsuccinimide were purified from urine by adsorption to a C8 solid-phase extraction column and then elution by ethyl acetate-methanol (80:20). After evaporation, the samples were derivatised at 100 degrees C for 1 h by bis(trimethylsilyl)trifluoroacetamide. Ethyl acetate was then added and the samples were analysed by gas chromatography-mass spectrometry in the electron impact mode. The extraction recovery for 5-hydroxy-N-methylpyrrolidone was about 80% while that for 2-hydroxy-N-methylsuccinimide was about 30%. The intra-day precision for 5-hydroxy-N-methylpyrrolidone was 2-4% and the between-day precision 4-21% (4 and 60 microg/ml). The intra-day precision for 2-hydroxy-N-methylsuccinimide was 4-8% and the between-day precision 6-7% (2 and 20 microg/ml). The detection limit was 0.2 microg/ml urine for both compounds. The method is applicable for analysis of urine samples from workers exposed to N-methyl-2-pyrrolidone.

Abstract  Contact angle relaxation studies were performed on a base hydrolyzed PMDA-ODA polyimide surface using methanol, pyridine and 1-methyl-2-pyrrolidinone (NMP) as probe liquids. The results were fitted parametrically to the molecular-kinetic theory to obtain the relevant molecular parameters that govern wetting rates. The probe liquid NMP appeared to have the greatest interaction of the three solvents studied with the modified polyimide surface. The differences in wetting rates are explained to result from the hydrogen bonding capability of the probe liquids with the modified polyimide surface and due to the difference between bulk and surface pKa of the modified polyimide.

Abstract  Mortality studies have indicated that workers in agriculture and forestry may be at increased risk of developing malignant lymphoma and multiple myeloma. The authors report the findings from a case-control study of 734 male malignant lymphoma and multiple myeloma patients (International Classification of Diseases (ICD) 200-203) registered with the New Zealand Cancer Registry in the period 1977-1981 and aged 20 years or more at time of registration. Controls also were males chosen from the cancer registry with four controls per case, matched on age and year of registration. The case group contained a significant excess of the occupational category involving agriculture and forestry (odds ratio = 1.25, 95% confidence limits = 1.00, 1.56). This excess was almost entirely among those aged less than 65 years at time of registration (odds ratio = 1.45, 95% confidence limits = 1.08, 1.95), particularly among patients with multiple myeloma (ICD 203) (odds ratio = 2.22, 95% confidence limits = 1.31, 3.75) and the category including nodular lymphoma, mycosis fungoides, and unspecified non-Hodgkin's lymphoma (ICD 202) (odds ratio = 1.76, 95% confidence limits = 1.03, 3.02). Mortality from malignant lymphoma and multiple myeloma increased significantly during the period 1955-1979.

Abstract  Developments in toxicology and environmental science e field[29]: Perchloroethylene