Generation of 400 µW at 17.5 µm using a two-color Yb fiber chirped pulse amplifier.

We have demonstrated the generation of 400 µW of power at ~18 µm by difference-frequency mixing the 1038 and 1105 nm from a two-color, chirped pulse amplification Yb fiber system. A two-color seed is selected from a continuum source and amplified to 300 mW of total power in a two-stage Yb fiber amplifier.

Pharmacokinetics of acrylamide after oral administration in male rats.

Acrylamide (AMD) is a commonly used industrial chemical. However, it produces a dying back type of peripheral neuropathy in animals and man. This study was performed to investigate the pharmacokinetics of AMD after oral administration at 50 mg/g ([1-(14)C]AMD) in male Sprague-Dawley rats. Absorption from the gastrointestinal tract was rapid and radioactivity was detected in blood 5 min post-administration. The peak plasma concentration occurred 38 min after administration and was equivalent to 47 µg/ml. The elimination pattern for plasma was fitted to a one-compartment model with 6 h half-life. However, in the blood the elimination pattern was fitted to a two-compartment model with 7.93 and 374 h for distribution and elimination phases, respectively. Tissue concentrations of radioactivity determined at 28 and 144 h post-administration differed substantially. After 28 h the highest activity was in the gastric content, followed by stomach, lung, bone marrow and skin, while after 144 h the order of total radioactivity was lung>bone marrow>esophagus. The activities in the rest of the organs in both experiments were very low. The excretion study revealed that the kidney is the major route of elimination and the majority of radioactivity in urine was excreted during the first 12 h. The feces contained approximately 10% of the administered dose after 144 h. This study indicated that AMD is rapidly absorbed from the rat's gastrointestinal tract, distributed and eliminated from the body. AMD bound but did not accumulate in the erythrocytes or the neural tissues.

Comparison between oral and dermal bioavailability of soil-adsorbed phenanthrene in female rats.

Phenathrene is a major coal tar component found in hazardous waste disposal sites. The purpose of this study was to evaluate the extent to which phenanthrene adsorption to either of 2 different soils affects the manner in which phenanthrene is subsequently handled in orally and dermally exposed adult female rats. Absorption from the gastrointestinal tract was relatively rapid for all treatments with maximum plasma concentration of radioactivity occurring within 1 h following oral administration. After dermal application, the time to reach maximum plasma concentration (12 h) was the same in all 3 phenanthrene treatment groups although sandy soil lowered the area under the plasma concentration time curve (AUC) compared to the pure and clay soil groups. Dermal exposure increased absorption half-lives 8-fold compared to oral exposure in the pure group and 15-fold in each of the soil groups. After oral or dermal treatment with phenanthrene alone or adsorbed to soil, the urine represented the primary excretion route of 14C activity. Ileum contained the highest tissue concentration of radioactivity in all oral treatment groups. However, the skin application site contained the highest concentration of radioactivity followed by ileum after dermal exposure. Phenanthrenequinone and 9,10-phenanthrene dihydrodiol were the major urinary metabolites detected in the 0-12-h urine of all treatment groups in both routes of administration. The data suggest that the oral exposure route for phenanthrene is a greater health risk than the dermal route. However, the presence of sandy or clay soil tends to delay the elimination of phenanthrene from the plasma.

Evaluation of the use of uncertainty factors in deriving RfDs for some chlorinated compounds.

Risk assessment of exposure to chemicals having a toxic endpoint routinely uses the reference dose (RfD) approach based on uncertainty factors of 10. The purpose of this investigation was to evaluate whether the magnitude of the U.S. Environmental Protection Agency (EPA) 10x uncertainty factors has scientific merit when compared with data from recent human and animal experimental studies. A compilation and comparison of ratios between LOAEL/NOAEL (lowest observed adverse effect level/no observed adverse effect level) and subchronic/chronic values was made for six chlorinated compounds, namely, carbon tetrachloride, methylene chloride, pentachlorophenol, monochlorobenzene, chlorpyrifos, and 1,1-dichloroethane. Data sets demonstrated that 91.3% of the LOAEL/NOAEL ratios were < or = 6 while 87% of the ratios for the same parameter were < or = 5. Furthermore, subchronic/chronic ratios were < or = 3.5. From our investigation we concluded that automatic safety factors of 10x are not scientifically supportable and are overly conservative for the chlorinated compounds studied here.

Pharmacokinetics of benzophenone-3 after oral exposure in male rats.

Benzophenone-3 (BZ-3) is one of the UV-absorbing agents that has been used in industry and medicine for more than 30 years. Millions of consumers are exposed to benzophenones on a daily basis owing to the widespread use of these compounds in many of the products on the market, such as lipsticks, hair sprays, hair dyes, shampoo and detergent bars and sunscreen lotions. This study was performed to investigate the pharmacokinetics of BZ-3 after oral administration at 100 mg kg-1 body weight in male Sprague-Dawley rats. Absorption from the gastrointestinal tract was rapid because BZ-3 was detected in blood 5 min after administration. The peak plasma concentration (Cmax) was 25.6 +/- 4.6 micrograms ml-1 and the time of occurrence (tmax) was 3.0 +/- 0.4 h. The half-life of absorption of BZ-3 was 0.71 h. The elimination pattern was biphasic with alpha and beta half-lives of elimination of 0.88 and 15.90 h, respectively. The results of this study indicate the presence of strong binding between the plasma protein and BZ-3. Tissue distribution studies at 6 h indicate that the liver contained the highest concentration of free (58.9 +/- 23.8 micrograms) and total (free+bound or conjugated) BZ-3 (2087 +/- 60.1 micrograms), followed by kidney and testes, respectively. Urine and feces analysis indicate that urine was the major route of excretion, followed by feces. Further analysis of urine samples also indicates that conjugation of BZ-3 with glucuronic acid was the major systemic elimination route for the compound.

A comparative study of the kinetics and bioavailability of pure and soil-adsorbed naphthalene in dermally exposed male rats.

The aim of this study was to utilize pharmacokinetic techniques to assess the bioavailability of sandy or clay soil-adsorbed naphthalene vs chemical alone following dermal treatment of male rats. Animals were exposed to 43 micrograms total of 14C-naphthalene (pure or adsorbed to one of two soils) introduced into a shallow glass cap covering a 13-cm2 area on the skin of each rat. While both soils delayed the time to reach maximum plasma concentration of radioactivity and significantly increased the half-life of plasma absorption, only sandy soil significantly decreased the peak plasma concentration of radioactivity versus the pure compound. Within 12 h after dermal application, approximately 50% of the naphthalene dose was excreted in the urine of the pure and clay soil-adsorbed groups. However, when naphthalene was adsorbed to sandy soil, the percentages of the initial dose excreted in the urine collected between 0-12 h and 12-24 h were nearly equal (33-39%). Furthermore, sandy soil adsorption shifted the secondary excretion route from expired air to feces and significantly lowered the amount of radioactivity in expired air relative to naphthalene alone. In the presence of sandy soil, a significantly larger amount of radioactivity washed off of the skin application sites. In all groups the predominant urinary metabolites determined by high performance liquid chromatography were 2,7- and 1,2-dihydroxynaphthalenes.

Soil decreases the dermal penetration of phenol in male pig in vitro.

Skin is a primary route of exposure to phenol, a major chemical found in hazardous waste sites. The effect of soil adsorption on the dermal bioavailability of phenol was assessed by applying [14C]phenol alone (P) or with sandy (P-S) or clay (P-C) soil to dermatomed male pig skin samples in flow-through diffusion cells. Maximum penetration of P-S and P-C was significantly decreased by one-half and by two-thirds, respectively, compared to P. Furthermore, the penetration of phenol into receptor fluid and the amount bound to skin were significantly lower when phenol was adsorbed to either soil versus P. While less radioactivity penetrated skin with soil-adsorbed phenol treatment than P, significantly more radioactivity was loosely adsorbed to skin and could be easily washed off of the skin surface by soap and water. Only a small fraction (< 5%) of the chemical was metabolized by skin to hydroquinone and catechol in all treatment groups. The results of this study indicate that the bioavailability and thus the potential health risk from dermal exposure to phenol is reduced if the chemical is adsorbed to soil.

Metabolism of benzophenone-3 in rats.

Benzophenone-3 [2-hydroxy-4-methoxybenzophenone (HMB), oxybenzone, Spectra-Sorb UV-9 light absorber] is used in many cosmetics and sunscreens as a UV absorber. This study was conducted to investigate the metabolism of HMB (100 mg/kg body weight administered orally). 2,4-Dihydroxybenzophenone (DHB), 2,2'-dihydroxy-4-methoxybenzophenone (DHMB), and 2,3,4-trihydroxy-benzophenone (THB) metabolites were identified as free and conjugated forms by HPLC analysis. HMB was rapidly absorbed, metabolized, and detected in plasma (as free and protein bound) at 5 min postadministration. The parent compound and metabolites (free and conjugated) were detected at 6 hr in most tissues. DHB was present in most tissues with the highest concentration in the liver. DHMB was only detected as the conjugated form in liver, spleen, and heart. Trace amounts of THB were also detected in biological samples. Urine was the primary route, whereas feces was the secondary route of elimination of HMB and its metabolites. This study revealed O-dealkylation as the major pathway of HMB metabolism.

Development and validation of a high-performance liquid chromatographic method for the determination of benzophenone-3 in rats.

A precise, accurate, selective and sensitive liquid chromatographic method for the determination of benzophenone-3 in rat biological fluids and different tissues has been developed. The minimum detection limit for benzophenone-3 was 2.0 ng ml-1 and the retention time was 6.01 min. Standard curves for benzophenone-3 were linear in a wide range of concentrations in methanol and different body fluids, ranging from 6.25 ng ml-1 to 100 micrograms ml-1. To detect benzophenone-3 in rat whole blood after oral administration, HCl hydrolysis was required. Benzophenone-3 was found to produce a peak blood concentration 1 h after administration. Free benzophenone-3 in urine represented a very small percentage during the first 12 h after administration, while a higher concentration of the glucuronide conjugate was detected in the same time period.

Soil adsorption alters kinetics and bioavailability of trichloroethylene in orally exposed female rats.

Soil contamination with dangerous toxic chemicals remains one of the most difficult problems in this era. Bioavailability of a chemical absorbed through gastrointestinal tract exposure from contaminated soil may differ from that seen following exposure to the pure chemical. In this study 4.6 microCi of 14C-TCE (trichloroethylene) alone, or adsorbed to clay or sandy soil, was administered to female Sprague-Dawley rats. Maximum plasma levels of radioactivity were highest in the presence of clay soil. However, they were similar for TCE alone and sandy-soil-adsorbed chemical. The half-life (t1/2) of absorption was statistically longer and the half-life of elimination was statistically shorter in the presence of sandy soil compared with TCE alone. There were no differences in the area under the plasma concentration-time curves between groups. Liver and kidney exhibited the highest tissue concentrations of radioactivity in all groups. Urine was the primary route of excretion followed by expired air in the pure- and clay-soil-adsorbed groups. However, equal amounts of the dose were excreted in both urine and expired air of the sandy-soil-adsorbed group with a significant increase of radioactivity in expired air throughout the 72-h study period. Trichloroethanol was the major urinary metabolite of TCE.

Bioavailability of aspirin and salicylamide following oral co-administration in human volunteers.

BC powder (I) is a commercially available analgesic containing the active ingredients aspirin and salicylamide. The kinetics of I, BC powder minus aspirin (II), and BC powder minus salicylamide (III) were evaluated in 13 volunteers. Ten minutes after administration of I, aspirin reached a maximum concentration of 12.9 micrograms/mL, while salicylamide concentration reached a peak value of 3.4 micrograms/mL. However, when III was administered, aspirin was not detected at 10 min and only reached a concentration of 0.4 microgram/mL at 2 and 6 h. Furthermore, the area under the plasma concentration versus time curve for aspirin when III was administered was sixfold less compared with treatment with I. The area under the curve for aspirin metabolites was significantly different in I versus III. After treatment with II, a delay in salicylamide peak concentration was observed. Gentisamide was not detected throughout the study. This study demonstrates that salicylamide significantly enhances plasma levels of aspirin with potential therapeutic implications.

Toxicity and metabolism of trichloroethylene in rat hepatocytes.

Trichloroethylene (TCE) hepatotoxicity is controversial. The present study was designed to investigate the mechanism of TCE hepatotoxicity. The toxicity of equimolar concentrations (5.7 mM) of TCE and its two major metabolites, trichloroacetic acid (TCA) and trichloroethanol (TCL), was determined. TCE cell viability was dose- and time-dependent. Enzyme leakage correlated with decrease in cell viability; significantly increased leakage started at 1.9 mM treatment. 5.7 mM TCA or TCL was not toxic compared with the same dose of TCE. Hepatocytes isolated from phenobarbital pretreated rats exhibited no significant alteration in toxicity parameters when exposed to 1.9 and 5.7 mM concentrations of TCE. While the phenobarbital pretreatment increased the rate of metabolism of TCE. The present study suggests that TCE toxicity occurs before the formation of TCA and TCL.

Synthesis and biological activity of some new pyrimidine and thienopyrimidine derivatives.

The readily available 4-mercapto-6-methyl-2-phenyl-5-acetylpyrimidine (1) was alkylated with a variety of activated halomethylene compounds to give the corresponding thieno [2,3-d] pyrimidine derivatives 3a-h via the intermediate alkylmercaptopyrimidine derivatives 2b-h. The biological activity of the new compounds was screened against several strains of bacteria.

Synthesis of some 1,2,4-triazine derivatives with potential biological activity.

6-Substituted benzyl-3-thioxo-1,2,4-triazin-5-ones 5a-e and the 4-amino derivatives 12c, e were prepared and converted into their corresponding 3-methylthio derivatives 6a-e and 13c, e, respectively of compounds 6a-e with primary and secondary amines gave the corresponding 3-amino-1,2,4-triazin-5-ones 7a-i and 8a, b. Cyclocondensation of compounds 6a-e and 13c, e with anthranilic acid was proved to give the corresponding triazino [3,2-b] quinazolindiones 9a-e and the 1-amino derivatives 11a, b.

Subchronic vaginal toxicity studies of Alcide Allay gel and liquid in guinea pigs.

Alcide Allay, an antimicrobial preparation produced in gel and liquid forms, was evaluated for vaginal toxicity in guinea pigs. 1.0 g/kg Allay gel or placebo was administered intravaginally once per day over a 30 day period while 2.5 g/kg Allay liquid (containing either of two concentrations of sodium chlorite and lactic acid as active ingredients) or placebo was applied vaginally three times per day for 10 days. At the conclusion of the studies, hematology, blood and urine clinical chemistry tests and necropsies were performed. RBC, HGB, HCT, MCHC and direct bilirubin increased while CO2, SGPT and CPK decreased in blood after Allay liquid treatment. Creatinine, urea nitrogen and uric acid in urine were statistically reduced in the liquid groups. Hematology and clinical chemistry parameters were within the normal range of values reported in the literature for guinea pigs, indicating no clinical significance due to drug treatment. Significant differences in organ body/weight ratios were observed between controls and Allay gel and liquid groups. However, only the livers in the gel study and the vaginas in both studies were changed histologically.

Synthesis of some indole derivatives with potential antiinflammatory activity.

2-Methylindole-3-acethydrazide (1) was reacted with arylisothiocyanate to give the corresponding 4-arylthiosemicarbazides 2a-d. Cyclization of the latter gave the corresponding 3-mercapto-5-[3-(2-methylindolyl)methyl]-1,2,4-triazoles 3a-d. Compounds 3a-c reacted with chloroacetic acid to give the corresponding indolyl-1,2,4-triazolythioglycolic acids 4a-c. The methylmercapto derivative 5 was also obtained from 3a and methyliodide. The hydrazide 1 was also reacted with carbon disulfide to give the corresponding indolymethyl-1,3,4-oxadiazole-2-thione (6) which was condensed with piperidine and formaldehyde to give the corresponding Mannich base 7. Condensation of 1 with aromatic aldehydes gave the corresponding hydrazones 8a-c which were converted into the corresponding oxadiazolines 9a-c.

Comparative disposition and elimination of chlordane in rats and mice.

The absorption, distribution and elimination of orally administered cis-[14C]chlordane (1.0 mg/kg) was determined in male Sprague-Dawley rats and C57BL/6JX mice. Absorption appeared somewhat slower in mice, but total [14C]chlordane equivalents at peak blood concentration (113 ng/ml at 8 h) exceeded the maximum which occurred in rats (81 ng/ml at 2 h). Peak tissue residues in both species were observed within 4 h, suggesting that the radiocarbon responsible for the latent peak blood levels in mice was eliminated rather than sequestered by the tissues. This was supported by the findings that peak tissue residue levels were lower in mice, and that the initial fecal elimination rate was higher than in rats. At 12 h, 34% and 7% of the doses were excreted in mouse and rat feces, respectively; by 3 days, both species had voided 83% of the dose in the feces. Clearance rates of tissue residues were markedly faster in the rat, and consequently, the total body burden resulting from chronic exposure to chlordane will be far greater in mice than in rats.