Abstract  The effect of solvents of varying polarity on the absorption and fluorescence emission of the Schiff base, 2-{[3-(1H-benzimidazole-2-yl) phenyl]carbonoimidoyl}phenol, was studied using Lippert-Mataga bulk polarity function, Reichardt's microscopic solvent polarity parameter and Kamlet's multiple linear regression approach. The spectral properties follow Reichardt's microscopic solvent polarity parameter better than Lippert-Mataga bulk polarity parameter, indicating the presence of both general solute-solvent interactions and specific interactions. Catalan's multiple linear regression approach indicates the major role of solvent polarizability/dipolarity influence compared with solvent acidity or basicity. The solvatochromic effect was utilized to calculate the dipole moments of ground and excited states of the Schiff base using different methods. Bathochromic shift in the emission spectrum and the increase in dipole moment in the excited state signifies the intramolecular charge transfer character in the emitting singlet state. Fluorescence quenching by aniline was also studied in 1,4-dioxane and n-butanol, and the results were analyzed using sphere of action static quenching and finite sink approximation models.

Abstract  There is a great deal of interest in formulating oxygenated diesel fuels that produce low particulate emissions. The most common oxygenating additives for diesel fuels include the glycol ethers, glycol esters, alcohols, ethers, and ketones. It is important to characterize the mixture properties of diesel fuel with oxygenate additives, to assess the degree of departure of the oxygenated fuels from the base fuel. In part 1 of this series (10.1021/ef2003415), we explored a series of linear oxygenating fluids with the advanced distillation curve method to assess the mixture volatility. Here, we apply that technique to a series of cyclic molecules: 2-methyl-1,3-dioxolane, 1,4-dioxane, 1,3-dioxane, cyclohexanone, and 2-cyclohexylethanol. We find that the more volatile additives cause significant early departures from the distillation curves of diesel fuel, while the less volatile additives act more to displace the entire curve. We also note that the additive affects the curve shape and temperature profile even after being totally depleted, an observation similar to that made in earlier studies of oxygenate additive mixtures.

Abstract  Lipase from Burkholderia cepacia (lipase BC) and lipase B from Candida antarctica (CALB) show an increase of the transesterification activity in toluene (up to 2.4- and 1.7-fold, respectively), when lyophilized with 18-crown-6. Nevertheless, the increase was observed only for low (less than 100) 18-crown-6/lipase molar ratio, while at higher ratios, the activity decreased for both enzymes to values lower than those obtained in the absence of the additive. In 1,4-dioxane, the activation is lower for lipase BC (1.7-fold) and for CALB (1.5-fold). Concerning enantioselectivity, tested in the kinetic resolution of 6-methyl-5-hepten-2-ol, only in the case of CALB, an effect of the additive (the E value varied from about 120 to 280) was observed. In water, 4% (w/w) of 18-crown-6 caused a loss of activity in the hydrolysis of p-nitrophenyl laurate of about 88 and 99.75%, compared to that observed in the absence of the crown ether for CALB and lipase BC, respectively. These data and the conformational analysis of both lipases, carried out by FT/IR spectroscopy indicate that the enzyme inactivation in water and in organic solvents at 18-crown-6/lipase molar ratios, higher than 100 might be due to conformational changes caused by the additive. Instead, at molar ratios lower than 100, 18-crown-6 might increase the activity - particularly, in toluene - thanks to the fact that in its presence, the enzyme has an hydrogen bonds pattern, more similar to that in water. This suggests that the additive would be able to provide the enzyme with more water.

Abstract  1,4-Dioxane is a probable human carcinogen, and an important emerging water contaminant. In this study, the biodegradation of dioxane by 20 bacterial isolates was evaluated, and 13 were found to be capable of transforming dioxane. Dioxane served as a growth substrate for Pseudonocardia dioxanivorans CB1190 and Pseudonocardia benzenivorans B5, with yields of 0.09 g protein g dioxane(-1) and 0.03 g protein g dioxane(-1), respectively. Cometabolic transformation of dioxane was observed for monooxygenase-expressing strains that were induced with methane, propane, tetrahydrofuran, or toluene including Methylosinus trichosporium OB3b, Mycobacterium vaccae JOB5, Pseudonocardia K1, Pseudomonas mendocina KR1, Ralstonia pickettii PKO1, Burkholderia cepacia G4, and Rhodococcus RR1. Product toxicity resulted in incomplete dioxane degradation for many of the cometabolic reactions. Brief exposure to acetylene, a known monooxygenase inhibitor, prevented oxidation of dioxane in all cases, supporting the hypothesis that monooxygenase enzymes participated in the transformation of dioxane by these strains. Further, Escherichia coli TG1/pBS(Kan) containing recombinant plasmids derived from the toluene-2- and toluene-4-monooxygenases of G4, KR1 and PKO1 were also capable of cometabolic dioxane transformation. Dioxane oxidation rates measured at 50 mg/L ranged from 0.01 to 0.19 mg hr(-1) mg protein(-1) for the metabolic processes, 0.1-0.38 mg hr(-1) mg protein(-1) for cometabolism by the monooxygenase-induced strains, and 0.17-0.60 mg hr(-1) mg protein(-1) for the recombinant strains. Dioxane was not degraded by M. trichosporium OB3b expressing particulate methane monooxygenase, Pseudomonas putida mt-2 expressing a toluene side-chain monooxygenase, and PseudomonasJS150 and Pseudomonas putida F1 expressing toluene-2,3-dioxygenases. This is the first study to definitively show the role of monooxygenases in dioxane degradation using several independent lines of evidence and to describe the kinetics of metabolic and cometabolic dioxane degradation.

Abstract  The goal of this study was to characterise the surface properties of completely degradable composite, polylactic acid and calcium phosphate glass, scaffolds. The composite scaffolds are made by solvent casting or phase-separation, using chloroform and dioxane as a solvent respectively. The surface properties were measured on composite films which were made using the same procedure as for the three-dimensional (3D) scaffolds without the pore-creating step. The surface morphology, roughness, wettability and protein adsorption capacity of the films was measured before and after sterilisation with ethylene oxide. The results reveal the influence of solvent type, glass weight content and sterilisation on the wettability, surface energy and protein adsorption capacity of the materials. The addition of glass particles increase the hydrophylicity, roughness and protein adsorption capacity of the surface. This effect, however, depends on the extent of the coating of the glass particles by the polymer film, which is much higher for dioxane films than for chloroform films. This information can be used to interpret and understand the biological behaviour of the 3D scaffolds made of this composite materials.

Abstract  The antiangiogenic effects of three novel anilinoquinazoline derivatives were studied with the aim to find new multi-kinase inhibitors as anticancer agents. The compounds are characterized by dioxolane, dioxane and dioxepine rings and bear the same aniline substituent in 4 position as vandetanib, known antiangiogenic agent. The in vitro assays were carried out on human umbilical vein endothelial cells (HUVECs), whereas in vivo angiogenesis was evaluated by means of Matrigel plug assay. The results showed that these compounds exert, even though to different extents, antiangiogenic activity affecting the various step of the process that leads to the formation of new blood vessels. At high concentrations they induced antiproliferative effects, whereas at non-cytotoxic concentrations they inhibited cell migration and the formation of tubular structures in Matrigel. In in vitro assays the dioxolane derivative 1 was more effective than vandetanib. Indeed, it inhibited the effects induced by exogenous VEGF and FGF-2 on both cell proliferation and morphogenesis, whereas vandetanib was completely ineffective. Moreover, all the compounds, as vandetanib, counteracted the FGF-2-induced increase in the hemoglobin content in the Matrigel plugs. Our results showed that all the three novel derivatives possess both in vitro and in vivo antiangiogenic activity, with compound 1 more effective than vandetanib to inhibit in vitro angiogenesis induced by exogenous cytokines.

Abstract  Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD(50) values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m(3) identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal toxicity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, or organ weight changes. A 6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day(-1)), Poloxamer 235 (tested up to 1.0 g/kg day(-1)), and Poloxamer 338 (at 0.2 or 1.0 g/kg day(-1)) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day(-1)) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day(-1) for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anticarcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multidrug-resistant cancer cells. In clinical testing, Poloxamer 188 increased the hydration of feces when used in combination with a bulk laxative treatment. Compared to controls, one study of angioplasty patients receiving Poloxamer 188 found a reduced myocardial infarct size and a reduced incidence of reinfarction, with no evidence of toxicity, but two other studies found no effect. Poloxamer 188 given to patients suffering from sickle cell disease had decreased pain and decreased hospitilization, compared to controls. Clinical tests of dermal irritation and sensitization were uniformly negative. The Cosmetic Ingredient Review (CIR) Expert Panel stressed that the cosmetic industry should continue to use the necessary purification procedures to keep the levels below established limits for ethylene oxide, propylene oxide, and 1,4-dioxane. The Panel did note the absence of reproductive and developmental toxicity data, but, based on molecular weight and solubility, there should be little skin penetration and any penetration of the skin should be slow. Also, the available data demonstrate that Poloxamers that are introduced into the body via routes other than dermal exposure have a rapid clearance from the body, suggesting that there would be no risk of reproductive and/or developmental toxicity. Overall, the available data do not suggest any concern about carcinogenesis. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used, and at what concentration, indicates a pattern of use. Based on these safety test data and the information that the manufacturing process can be controlled to limit unwanted impurities, the Panel concluded that these Poloxamers are safe as used.

Abstract  1,4-Dioxane biodegradation was investigated in microcosms prepared with groundwater and soil from an impacted site in Alaska. In addition to natural attenuation conditions (i.e., no amendments), the following treatments were tested: (a) biostimulation by addition of 1-butanol (a readily available auxiliary substrate) and inorganic nutrients; and (b) bioaugmentation with Pseudonocardia dioxanivorans CB1190, a well-characterized dioxane-degrading bacterium, or with Pseudonocardia antarctica DVS 5a1, a bacterium isolated from Antarctica. Biostimulation enhanced the degradation of 50 mg L(-1) dioxane by indigenous microorganisms (about 0.01 mg dioxane d(-1) mg protein(-1)) at both 4 and 14 degrees C, with a simultaneous increase in biomass. A more pronounced enhancement was observed through bioaugmentation. Microcosms with 50 mg L(-1) initial dioxane (representing source-zone contamination) and augmented with CB1190 degraded dioxane fastest (0.16 +/- 0.04 mg dioxane d(-1) mg protein(-1)) at 14 degrees C, and the degradation rate decreased dramatically at 4 degrees C (0.021 +/- 0.007 mg dioxane d(-1) mg protein(-1)). In contrast, microcosms with DVS 5a1 degraded dioxane at similar rates at 4 degrees C and 14 degrees C (0.018 +/- 0.004 and 0.015 +/- 0.006 mg dioxane d(-1) mg protein(-1), respectively). DVS 5a1 outperformed CB1190 when the initial dioxane concentration was low (500 microg L(-1), which is representative of the leading edge of plumes). This indicates differences in competitive advantages of these two strains. Natural attenuation microcosms also showed significant degradation over 6 months when the initial dioxane concentration was 500 microg L(-1). This is the first study to report the potential for dioxane bioremediation and natural attenuation of contaminated groundwater in sensitive cold-weather ecosystems such as the Arctic.

Abstract  The distribution of 1,4-dioxane in the waters from 27 sites in 12 rivers including the Shinano River, the longest river in Japan, was investigated in 2002. 1,4-Dioxane was detected in concentrations ranging from 0.02 to 0.49 microg/L. The monthly variations in the 1,4-dioxane concentrations at 6 sites along the Shinano River showed mutually different patterns, and the concentrations did not correlate with the concentrations of the biochemical oxygen demand and the suspended substances. The annual mean concentrations were from 0.02 microg/L at sites located in the middle reaches to 0.11 microg/L at the river mouth. The 1,4-dioxane concentration in the Shinano River has shown a downward trend from 1989 to 2003.

Abstract  Tizoxanide [2-(hydroxy)-N-(5-nitro-2-thiazolyl)benzamide, TIZ] is a new potent anti-infective agent which may enhance current therapies for leishmaniasis, Chagas disease and viral hepatitis. The aim of this study was to identify the conformational preferences that may be related to the biological activity of TIZ by resolving its crystal structure and characterizing various physicochemical properties, including its experimental vibrational and C-13 nuclear magnetic resonance properties, behavior on heating and solubility in several solvents at 25 degrees C. TIZ crystallizes from dimethylformamide as the carboxamide tautomer in the triclinic system, space group P(-1) (No. 2) with the following unit cell parameters at 173(2) K: a = 5.4110(3) angstrom, b = 7.3315(6) angstrom, c = 13.5293(9) angstrom, alpha = 97.528(3), beta = 95.390(4), gamma = 97.316(5), V= 524.41(6) angstrom(3), Z = 2, D-c = 1.680 g/cm(3), R-1 = 0.0482 and wR(2) = 0.0911 for 2374 reflections. This modification of TIZ has a 'graphitic' structure and is composed of tightly packed layers of extensively hydrogen-bonded molecules. The various spectroscopic data [Diffuse Fourier transform infrared (DRIFT) and FT-Raman, recorded in the range 3600-500 and 4000-200 cm(-1) respectively, and solid-state C-13 NMR] were consistent with the structure determined by X-ray crystallography. From DSC, TG and thermomicroscopy, it was concluded that TIZ is thermally stable as a solid and that melting is not an isolated event from the one-step thermal decomposition that it undergoes above 270 degrees C. This modification of TIZ is practically insoluble in water and slightly soluble in polar aprotic solvents such as dimethylsulfoxide, dimethylformamide and dioxane. (c) 2012 Elsevier B.V. All rights reserved.

Abstract  A number of equations have been proposed by workers in the field of liquid state and, upon exploration, these have been found to meet success of varying degrees. Khasare has proposed a new equation of state involving intermolecular potential with three-model parameters. This equation of state has been applied to the binary liquid mixture of benzene, tetrahydrofuran and carbon tetrachloride in 1-4 dioxane. It is observed that there is a close agreement with experimental values for ultrasonic wave velocity, molar volume and, to some degree, volume expansion coefficient. Model parameters are fairly constant over the liquid phase 10 K above m.p. and 10 K below b.p.

Abstract  Four three-dimensional (3D) Cd-based metal-organic frameworks (MOFs), [Cd(pyip)(dmf)] (1), [Cd(pyip)-(doa)] (2), [Cd(pyip)(pz)] (3) and [Cd(pyip)(bipy)(H2O)(0.5)] (4) (dmf = N,N'-dimethylformamide, doa = 1,4-dioxane, pz = pyrazine, bipy = 4,4'-bipyridine) have been rationally designed and systematically synthesized by using S-(pyridine-4-yl)isophthalic acid (H(2)pyip) and Cd(NO3)(2)center dot 4H(2)O under solvothermal conditions. Compound 1 possesses a mineral-like 3,6-connected rtl network, and compounds 2-4 exhibit a 3,5-connected interpenetrating hms network constructed with 2-fold layers and bridging coligands pillars (doa, pz, and bipy), respectively. In compounds 2-4, doa, pz, and bipy act as pillars to extend the distance between the two layers from 7.34 to 11.36 A, and the different conformations and lengths of the coligands have layers. Additionally, the four compounds exhibit strong luminescent latter three compounds exhibit robust architectures as evidenced by 2 influenced the angles between the bridging ligands and the emissions in the solid state at room temperature, and the their permanent porosity and high thermal stability.

Abstract  The kinetics of the acylation of alpha-chymotrypsin by a series of substituted phenyl p-nitrobenzoates have been studied by stopped flow and conventional spectrophotometry. Electron withdrawal in the leaving group accelerates the rate of acylation, and the p value obtained for eight esters is +1.96. The pH- and pD-independent acylation rate constants are, respectively, 1.40 X 10(4) M-1S-1 and 1.23 X 10(4) M-1S-1 for p-nitrophenyl p-nitrobenzoate, and, respectively, 2.19 X 10(3) M-1S-1 and 1968 X 10(3) M-1S-1 for p-nitrophenyl benzoate at 25 degrees. An analysis of structure-reactivity results and kinetic solvent isotope effects indicates a mechanism for acylation by phenylbenzoates in which initial reaction is a nucleophilic attack by an imidazole of the enzyme (His 57). Subsequently, there is rapid transfer of the acylating group to the serine 195 from the acylimidazole species. The kinetic solvent isotope effects for acylation by p-nitrophenyl phenyl acetate and p-nitrophenyl phenyl acetate and p-nitrophenyl hydrocinnamate, in 5%, v/v, acetonitrile, are 1.3 and 2.0, respectively. The latter ester is inhibited more than is p-nitrophenyl benzoate when 5%, v/v, dioxane is substituted for 5%, v/v, acetonitrile as co-solvent. In the presence of 5%, v/v, dioxane a change in the kinetic solvent isotope effect to 1.7 is found for p-nitrophenyl benzoate and p-nitrophenyl phenylacetate while that for the analogous hysdrocinnamate ester is unaffected. The results for the latter substrate are in accord with a general base-catalysed mechanism. Electron-withdrawal groups in the phenyl ring of phenyl acetates accelerate the enzyme acylation yielding a leaving group p of 2.05. The kinetic solvent isotope effects for acylation by p-nitrophenyl thiolacetate and by p-nitrophenyl acetate are close to 2.0. The mechanism of acylation of chymotrypsin by phenyl acetates is not unambiguously defined using these data.

Abstract  DGBE was evaluated in a forward gene mutation assay at the HGPRT locus of CHO cells in culture and in an in vivo mouse bone marrow micronucleus test for cytogenetic damage. DGBE did not elicit a positive response in the CHO/HGPRT assay when tested up to a maximum concentration of 5000 mu g/ml with and without and external metabolic activation system (S-9). In the micronucleus test employing three post-treatment bone marrow sampling times (24, 48 and 72 hr), DGBE was ineffective in increasing the incidence of micronucleated polychromatic erythrocytes (MN-PCE) when tested in both sexes up to a maximum tolerated dose of 3300 mg/kg body weight. Thus, these data and those of others indicate a general lack of genotoxic potential for DGBE in short-term tests.

Abstract  Rats treated dermally with diethylene glycol butyl ether for 13 weeks at the maximum attainable volume of 2 ml/kg were examined for evidence of subchronic neurotoxicity at 124 h after the initiation of first exposure and prior to treatment on days 7, 14, 35, 63, and 91. No mortality was recorded, and body weights and food consumption were unaffected. Functional observational battery and motor activity tests revealed no indications of a neurotoxic effect. No neurotoxicity or other systemic toxicity was observed at 2 g/kg/d, the highest dose tested.

Abstract  Defining the biophysics underlying the remarkable MRI phase contrast reported in high field MRI studies of human brain would lead to more quantitative image analysis and more informed pulse sequence development. Toward this end, the dependence of water 1H resonance frequency on protein concentration was investigated using bovine serum albumin (BSA) as a model system. Two distinct mechanisms were found to underlie a water 1H resonance frequency shift: (i) a protein-concentration-induced change in bulk magnetic susceptibility, causing a shift to lower frequency, and (ii) exchange of water between chemical-shift distinct environments, i.e., free (bulk water) and protein-associated ("bound") water, including freely exchangeable 1H sites on proteins, causing a shift to higher frequency. At 37 °C the amplitude of the exchange effect is roughly half that of the susceptibility effect.

Abstract  The UV-visible photolysis of ferrioxalate in the presence of hydrogen peroxide (the UV-vis/ferrioxalate/H2O2 process) is investigated for the treatment of contaminated groundwater and industrial wastewater. This process generates the hydroxyl radical, which is a strong oxidant and reacts rapidly with most organic compounds present in solution. Tap water spiked with various organic pollutants, a process water containing chlorobenzene, a tank-bottom water containing a mixture of benzene, toluene and xylenes (BTX), a wastewater containing 1,4-dioxane and another wastewater containing methanol, formaldehyde and formic acid were treated with the UV-vis/ferrioxalate/H2O2 process and the efficiency compared with alternative oxidation processes, including the UV/H2O2 and UV-vis/Fe(II)/H2O2 (UV-Fenton) processes. The destruction of specific compounds and group parameters, such as TOC and BOD, were used to examine the relative energy efficiencies of the alternative processes. The data indicate that in nearly all cases, the new UV-vis/ferrioxalate/H2O2 process has a much higher efficiency (by a factor of about 3 to 30) than does either the UV-vis/Fe(II)/H2O2 process or the UV/H2O2 process. It is concluded that this new process is very efficient and useful for the treatment of moderate to highly contaminated waters.

Abstract  Using death as an endpoint, it has been demonstrated that tetrachloroethylene (TCE) produces a greater-than-additive effect when given orally in combination with several other compounds. We have attempted to determine more sensitive indicators which would respond in a synergistic fashion when animals are exposed by inhalation to combinations of organic solvents. Male rats were exposed for 4 hr to various concentrations of TCE, dioxane, butyl ether (BE), acetonitrile (ACN), trichloropropane (TCP), and dichloropropane (DCP). The serum enzymes, glutamic oxalacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), glucose-6-phosphatase (G-6-Pase), and ornithine carbamyl transferase (OCT) were measured in rats prior to exposure, immediately after exposure, and at 24 and 48 hr after exposure. The enzymes, SGOT, SGPT and OCT, were markedly elevated as a result of exposure to the above compounds, whereas G-6-Pase was only occasionally altered. Neither TCE in combination with dioxane, BE, or ACN nor TCP with DCP resulted in a greater-than-additive effect. On the contrary, in many instances the effects were significantly less-than-additive when tested for interaction.

Abstract  A six compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the disposition of diethylene-1,4-dioxide (dioxane) and its principal metabolite beta-hydroxyethoxyacetic acid in rats, mice, and humans. The model was developed from experimentally measured partition coefficients (reported here for the first time) as well as pharmacokinetic data previously reported. The completed PB-PK model adequately described data from gavage and intravenous studies in rats, as well as inhalation studies in rats and humans. Substantial nonlinearities were observed in the kinetic behavior of dioxane under high exposure conditions (water concentrations greater than 0.1% dioxane and atmospheric concentrations greater than 300 ppm dioxane). The PB-PK model was subsequently used to prepare quantitative estimates of the "plausible upper bounds" on carcinogenic risk for human populations exposed to dioxane in air or water. Based on these quantitative estimates, it appears that human populations continuously exposed to 740-3700 ppb dioxane in air or 20,000-120,000 ppb dioxane in water would be unlikely to experience increased frequencies of tumors.

Abstract  Female Sprague-Dawley rats were given 0, 168, 840, 2550 or 4200 mg/kg of 1,4-dioxane 21 and 4 h before sacrifice. Hepatic DNA damage (by the alkaline elution technique), ornithine decarboxylase activity (ODC), reduced glutathione content, cytochrome P-450 content and serum alanine aminotransferase activity (ALT) were determined. Treatment with 1,4-dioxane increased hepatic DNA damage and cytochrome P-450 content at doses of 2550 and 4200 mg/kg. Large increases in the activity of hepatic ODC were observed at 840, 2550 and 4200 mg/kg of 1,4-dioxane. Thus the data suggest that 1,4-dioxane is a weak genotoxic carcinogen in addition to being a strong promoter of carcinogenesis (a non-genotoxic carcinogen).

Abstract  A cancer bioassay conducted in 1974 (Kociba et al.) indicated that rats given drinking water containing dioxane at a dose of 1184 mg.kg-1.d-1 produced an increased incidence of liver tumors. Applying the linearized multistage extrapolation model to these data, the administered dose estimated to present a human cancer risk of 1 in 100,000 (10(-5)) was 0.01 mg.kg-1.d-1. As in customary regulatory policy, this estimate assumed that humans were about 5.5 times more sensitive than rats on a mg/kg basis. However, this approach did not consider that the metabolism of dioxane is saturable at high doses. Based on experience with similar chemicals, it is known that the conventional risk extrapolation method may overestimate the most likely human cancer risk. In order to determine more accurately the likely human response following lifetime exposure to dioxane, a physiologically-based pharmacokinetic (PB-PK) model was developed. The objective of this study was to establish a quantitative relationship between the administered dose of dioxane and the internal dose delivered to the target organ. Using this PB-PK model, and assuming that the best dose surrogate for estimating the liver tumor response was the time-weighted average lifetime liver dioxane concentration, the cancer risk for humans exposed to low doses of dioxane was estimated. The dose surrogate in humans most likely to be associated with a tumorigenic response of 1 in 100,000 is 280 mumol/l, equivalent to an administered dose of about 59 mg.kg-1.d-1. The 95% lower confidence limit on the dose surrogate at the same response level is 1.28 mumol/l, equivalent to an administered dose of 0.8 mg.kg-1.d-1. This PB-PK analysis indicated that conventional approaches based on the administered doses in the rodent bioassay, if uncorrected for metabolic and physiological differences between rats and humans, will overestimate the human cancer risk of dioxane by as much as 80-fold.

Abstract  Using 3H-dioxane, the distribution of dioxane among a number of tissues and various subcellular fractions of rat liver was studied. At various times after i.p. injection, dioxane was found to distribute more or less uniformly among various tissues (liver, kidney, spleen, lung, colon and skeletal muscle), consistent with its polar/nonpolar nature. Studies of the nature of dioxane binding, however, revealed that the extent of “covalent” binding (as measured by incorporation into lipid-free, acid-insoluble tissue residues) was significantly higher in the liver (the main carcinogenesis target tissue), spleen and colon than that in other tissues. Investigations of the subcellular distribution in liver indicated that most of the radioactivity was in the cytosol, followed by the microsomal, mitochondrial and nuclear fractions. The binding of dioxane to the macromolecules in the cytosol was mainly noncovalent. The percent covalent binding was highest in the nuclear fraction, followed by mitochondrial and microsomal fractions and the whole homogenate. Pretreatment of rats with inducers of microsomal mixed-function oxidases had no significant effect on the covalent binding of dioxane to the various subcellular fractions of the liver. There was no microsome-catalyzed in vitro binding of 3H- or 14C-dioxane to DNA under conditions which brought about substantial binding of 3H-benzo[a]pyrene.

Abstract  In the preceding communication (I), we summarized our studies on the metabolism in vivo of dioxane which identified p-dioxane-2-one to be the major urinary metabolite. It is well documented that the activity of mixed-function oxidases (MFO) metabolizing foreign compounds can be modulated by various inducers, repressors and inhibitors (2-4). In order to investigate the involvement of MFO in the metabolism in vivo of dioxane, the effect of several such agents on the excretion of E-dioxane-2-one was studied. Male Sprague-Dawley rats (95-130 g) were used throughout. Three typical inducers of MFO were employed: phenobarbital (PB), the polychlorinated biphenyls, Aroclor 1254 (PCB) (Monsanto Chemical Co.), and 3-methylcholanthrene (MC). PB was dissolved in 0. 9% saline and administered i.p. at a dose of 80 mg/kg daily for 4 consecutive days prior to dioxane administration. PCB and MC were dissolved in corn oil; PCB was given at a single dose of 500 mg/kg 4 days prior to dioxane administration and MC at 40 mg/kg 24 hr prior to dioxane administration. Control rats received equivalent amounts of saline or corn oil. To repress the synthesis of cytochrome P-450 (5), cobaltous chloride (60 mg/kg) was injected s. c. 24 hr prior to dioxane administration. Dioxane (3 g/kg) was given i. p. and urine samples were collected at 8- or 12-hr intervals andtreated as previously (1). 2,4-Dichloro-6-phenylphenoxy ethylamine (DPEA), a potent, long-acting inhibitor of MFO (6, 7) (gift of Dr. R. E. McMahon. Eli Lilly Co. ), was dissolved in saline and given at the dose of 15. 9 mglkg 30 min prior to dioxane administration and 8, 16 and 24 hr thereafter. The amount of p-dioxane-2-one present in urine was determined by analytical gas chromatography using purified synthetic reference compound as standard.