Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles.

Titanium dioxide (TiO(2)) is included in some sunscreen formulations to physically block ultraviolet radiation. A dermal penetration study was conducted in minipigs with three TiO(2) particles (uncoated submicron sized, uncoated nano-sized, and dimethicone/methicone copolymer-coated nanosized) applied 5% by weight in a sunscreen. These and control formulations were topically applied to minipigs at 2 mg cream/cm(2) skin (4 applications/day, 5 days/week, 4 weeks). Skin (multiple sites), lymph nodes, liver, spleen, and kidneys were removed, and the TiO(2) content was determined (as titanium) using inductively coupled plasma mass spectroscopy. Titanium levels in lymph nodes and liver from treated animals were not increased over the values in control animals. The epidermis from minipigs treated with sunscreens containing TiO(2) showed elevated titanium. Increased titanium was detected in abdominal and neck dermis of minipigs treated with uncoated and coated nanoscale TiO(2). Using electron microscopy-energy dispersive x-ray analysis, all three types of TiO(2) particles were found in the stratum corneum and upper follicular lumens in all treated skin samples (more particles visible with coated nanoscale TiO(2)). Isolated titanium particles were also present at various locations in the dermis of animals treated with all three types of TiO(2)-containing sunscreens; however, there was no pattern of distribution or pathology suggesting the particles could be the result of contamination. At most, the few isolated particles represent a tiny fraction of the total amount of applied TiO(2). These findings indicate that there is no significant penetration of TiO(2) nanoparticles through the intact normal epidermis.

Quantitative determination of skin penetration of PEG-coated CdSe quantum dots in dermabraded but not intact SKH-1 hairless mouse skin.

Many cosmetics, sunscreens, and other consumer products are reported to contain nanoscale materials. The possible transdermal absorption of nanoscale materials and the long-term consequences of the absorption have not been determined. We used polyethylene glycol coated cadmium selenide (CdSe) core quantum dots (QD; 37 nm diameter) to evaluate the penetration of nanoscale material into intact, tape stripped, acetone treated, or dermabraded mouse skin. QD were suspended in an oil-in-water emulsion (approximately 9 microM) and the emulsion was applied at 2 mg/cm(2) to mouse dorsal skin pretreated as follows: intact; tape stripped to remove the stratum corneum; acetone pretreated; dermabraded to remove stratum corneum and epidermis. QD penetration into the skin was monitored in sentinel organs (liver and regional draining lymph nodes) using inductively coupled plasma mass spectrometry analysis of cadmium (from the CdSe QD). No consistent cadmium elevation was detected in the sentinel organs of mice with intact, acetone pretreated, or tape-stripped skin at 24- and 48-h post-QD application; however, in dermabraded mice, cadmium elevations were detected in the lymph nodes and liver. QD accumulation (as cadmium) in the liver was approximately 2.0% of the applied dose. The passing of QD through the dermabraded skin was confirmed using confocal fluorescence microscopy. These results suggest that transdermal absorption of nanoscale materials depends on skin barrier quality, and that the lack of an epidermis provided access to QD penetration. Future dermal risk assessments of nanoscale materials should consider key barrier aspects of skin and its overall physiologic integrity.

Determination of caffeine and sympathomimetic alkaloids in weight loss supplements by high-performance liquid chromatography.

Reversed-phase high-performance liquid chromatography utilizing photodiode array detection is used for the simultaneous determination of caffeine and nine alkaloids from Citrus aurantium (CA) and ephedra (EA) contained in dietary weight loss products. Since the Food and Drug Administration (FDA) ban of EA, manufacturers have substituted CA in their weight loss formulations, usually combined with high levels of caffeine. The alkaloids contained in CA have some physiological effects similar to those of the EA alkaloids and are, therefore, cause for concern. Caffeine has been shown to potentiate the toxicity of the EA alkaloids. Recently, a federal judge overturned the absolute ban and allowed marketing of low levels (<10 mg/day) of total EA alkaloids. To support an absolute ban, the FDA is now compelled to perform dose-dependent toxicology studies to determine the toxic dose(s) of EA. The toxicity of the CA compounds is largely unknown, especially in combination with caffeine. The described method enables quantitation over a wide range of product formulations. Recoveries range from 91% to 100% from a variety of fortified plant matrices.

Migration of intradermally injected quantum dots to sentinel organs in mice.

Topical exposure to nanoscale materials is likely from a variety of sources including sunscreens and cosmetics. Because the in vivo disposition of nanoscale materials is not well understood, we have evaluated the distribution of quantum dots (QDs) following intradermal injection into female SKH-1 hairless mice as a model system for determining tissue localization following intradermal infiltration. The QD (CdSe core, CdS capped, poly[ethylene glycol] coated, 37 nm diameter, 621 nm fluorescence emission) were injected intradermally (ID) on the right dorsal flank. Within minutes following intradermal injection, the highly UV fluorescent QD could be observed moving from the injection sites apparently through the lymphatic duct system to regional lymph nodes. Residual fluorescent QD remained at the site of injection until necropsy at 24 h. Quantification of cadmium and selenium levels after 0, 4, 8, 12, or 24 h in multiple tissues, using inductively coupled plasma mass spectrometry (ICP-MS), showed a time-dependent loss of cadmium from the injection site, and accumulation in the liver, regional draining lymph nodes, kidney, spleen, and hepatic lymph node. Fluorescence microscopy corroborated the ICP-MS results regarding the tissue distribution of QD. The results indicated that (1) ID injected nanoscale QD remained as a deposit in skin and penetrated the surrounding viable subcutis, (2) QD were distributed to draining lymph nodes through the sc lymphatics and to the liver and other organs, and (3) sentinel organs are effective locations for monitoring transdermal penetration of nanoscale materials into animals.

Multiresidue determination of sulfonamides in edible catfish, shrimp and salmon tissues by high-performance liquid chromatography with postcolumn derivatization and fluorescence detection.

A liquid chromatographic (LC) method for determining 14 sulfonamide (SA) (sulfanilamide, sulfadiazine (SDZ), sulfathiazole, sulfapyridine, sulfamerazine (SMR), sulfamethazine (SMZ), sulfamethizole, sulfamethoxypyridazine, sulfachloropyridazine (SCP), sulfamonomethoxine, sulfadoxine, sulfamethoxazole, sulfadimethoxine (SDM), and sulfaquinoxaline (SQX)) residues in edible catfish, shrimp and salmon tissues was developed and validated at 5, 10 or 20 ng g(-1). The method was then used to determine residues in tissues of catfish, shrimp and salmon dosed with six selected sulfonamides (sulfadiazine, sulfamerazine, sulfamethazine, sulfachloropyridazine, sulfadimethoxine and sulfaquinoxaline). All assays were within U.S. Food and Drug Administration guidelines for recovery and intra-assay variability. The method was developed to determine possible sulfonamide residues in aquacultured catfish, shrimp and salmon produced for food.

Steady state pharmacokinetics of oral treatment with 13-cis-retinoic acid or all-trans-retinoic acid in male and female adult rats.

Male and female Sprague-Dawley rats were orally gavaged with 13-cis-retinoic acid (7.5 or 15 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg) for 7 consecutive days. Blood was collected out to 8 hr after the last gavage on day 7. HPLC serum concentrations of 13-cis-retinoic acid, all-trans-retinoic acid, and 13-cis-4-oxo-retinoic acid were subjected to model independent pharmacokinetic analyses. Peak serum levels of 563 to 1640 ng/ml were observed for rats treated with 13-cis-retinoic acid at 1.5-2 hr after gavage. Peak serum levels of 183 to 267 ng/ml at 1.5 hr after gavage were observed for all-trans-retinoic acids. The elimination half-life of 13-cis-retinoic acid was about 1.5 hr while the elimination half-life of all-trans-retinoic acid was slightly longer. There were no sex differences for any parameter. Serum levels resulting from the 7.5 mg/kg 13-cis-retinoic acid were similar to those of human Accutane users.

Trace analysis of ethinyl estradiol in casein diet using gas chromatography with electron capture detection.

Ethinyl estradiol (EE2) is an extremely potent synthetic estrogen and a common component in oral contraceptives. The drug has a well-characterized pharmacological profile and is used as a positive control in toxicological investigations of compounds having estrogenic activity. An analytical method developed for the determination of low microg/kg levels of EE2 in a casein-based rodent diet is presented. A methanol extract of casein diet is purified for instrumental analysis by a 3-fold solid-phase extraction process. The sample extract is derivatized with pentafluoropropionic anhydride to the pentafluoropropionyl product and analyzed by capillary gas chromatography with electron-capture detection. Recoveries of EE2 from casein diet fortified at 5, 10, and 50 microg/kg average 88.8% and have a relative standard deviation (%) of 7.2. The method limit of detection in a casein-based diet is 1 microg/kg.

Liquid chromatography analysis of erythromycin A in salmon tissue by electrochemical detection with confirmation by electrospray ionization mass spectrometry.

A rapid and sensitive method is described for the quantitation of erythromycin A (EA) in edible salmon tissue by liquid chromatography (LC) analysis using either electrochemical detection (ED) or electrospray ionization mass spectrometric (ESI/MS) detection. The salmon tissue is extracted with 10 mM ammonium formate. The extract is then purified by solid phase extraction using a hydrophilic-lipophilic balanced (HLB) polymeric-based C18 packing, followed by partitioning of EA into methylene chloride at alkaline pH, evaporation, and final dilution. The mean recoveries of EA at 50, 100, 200, and 400 ppb levels in fortified salmon tissue were 63.8 +/- 6.0 and 75.5 +/- 5.4% by LC-ED and LC-ESI/MS, respectively. There was no evidence of formation of the anhydro-EA (m/z 716) decomposition product of EA (m/z 734) that was reported to occur by other published methods.