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1.
Skin Pharmacol Physiol ; 21(3): 136-49, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18523411

RESUMO

Cosmetic formulations may contain nano-emulsions and microscopic vesicles consisting of traditional cosmetic materials, although it is uncertain whether they should be qualified as actual nanomaterials. Vesicle materials do not penetrate into living human skin. Vesicle formulations may enhance or reduce skin absorption of ingredients, albeit at a limited scale. Sunscreens contain TiO2 or ZnO nanoparticles (NP), which are efficient UV filters. A number of studies suggest that insoluble NP do not penetrate into or through human skin. The results of in vivo toxicity tests showed that TiO2 and ZnO NP are non-toxic. In vitro and in vivo cytotoxicity, genotoxicity, photogenotoxicity, acute toxicity, sensitisation and ecotoxicology studies on TiO2 NP found no difference in the safety profile of micro- or nano-sized materials, all of which were non-toxic. Although some in vitro investigations on TiO2 particles reported cell uptake, oxidative cell damage or genotoxicity, these results may be secondary to phagocytosis of cells exposed to excessive particle concentrations. Studies on wear debris nano- and microparticles support the traditional view that toxicity of small particles is related to their chemistry, rather than their particle size. There is little evidence supporting a general rule that adverse effects of particles on the skin or other tissues increase with smaller particle size, or produce novel toxicities relative to those of larger particles. Overall, the current evidence suggests that nano-sized cosmetic or sunscreen ingredients pose no potential risk to human health, whereas their use in sunscreens has large benefits, such as the protection of human skin against skin cancer.


Assuntos
Cosméticos/toxicidade , Fármacos Dermatológicos/toxicidade , Pele/efeitos dos fármacos , Protetores Solares/toxicidade , Cosméticos/química , Fármacos Dermatológicos/química , Humanos , Nanopartículas , Tamanho da Partícula , Protetores Solares/química
2.
Food Chem Toxicol ; 46(6): 2214-23, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18417263

RESUMO

Although in vitro skin absorption studies often detect small residues of applied test material in the epidermis/dermis, it is uncertain whether the residue is within the living skin. We studied the dermal absorption of a hair dye hydroxyanthraquinone-aminopropyl methyl morpholinium methosulphate (HAM) in human skin in vivo and in vitro. In vivo, skin (back and scalp) received 0.5% HAM in a commercial formulation at 20microg/cm2 After 0.5 or 48h, skin was tape stripped, followed by cyanoacrylate biopsies (CAB). Sebum from scalp sites was collected for 48h. In vitro, skin was treated with 20mg/cm2 dye for 0.5h, penetration determined after 24h. In vivo, at 0.5h, total recovery (back) was 0.67microg/cm2 (tape strips+CAB). Fluorescence microscopy showed HAM in the hair follicle openings (HFO). At 0.5h, scalp tape strips contained 1.80microg/cm2, HFO 0.82microg/cm2. At 48h, HFO contained 0.21microg/cm2, sebum 0.80microg/cm2. In vivo, skin residues were in the non-living skin and eliminated via desquamation and sebum secretion. In vitro, the SC contained 1.50microg/cm2, epidermis/dermis 0.86microg/cm2, receptor fluid<0.04microg/cm2, a total of 0.90microg/cm2 was considered to be bioavailable. In vitro epidermis/dermis residues were nearly identical to those located in non-living skin in vivo. In conclusion, in vitro percutaneous penetration studies may produce seemingly bioavailable material , which raises the need for a Threshold of Skin Absorption (TSA) addressing a negligible dermal absorption in order to avoid unnecessary in vivo toxicity studies on substances that produce no significant human systemic exposure.


Assuntos
Antraquinonas/farmacocinética , Antraquinonas/toxicidade , Tinturas para Cabelo/farmacocinética , Tinturas para Cabelo/toxicidade , Morfolinas/farmacocinética , Morfolinas/toxicidade , Absorção Cutânea/fisiologia , Alternativas aos Testes com Animais , Animais , Antraquinonas/química , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Tinturas para Cabelo/química , Folículo Piloso/metabolismo , Humanos , Técnicas In Vitro , Microscopia de Fluorescência , Morfolinas/química , Sebo/metabolismo , Espectrofotometria Ultravioleta
3.
Toxicol Lett ; 163(1): 65-76, 2006 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-16243460

RESUMO

BACKGROUND: Vitamin A is widely used in cosmetic preparations. Given that oral Vitamin A and its metabolites present a potential reproductive risk, the present study investigated the effect of topical Vitamin A on human endogenous plasma levels of Vitamin A and its metabolites. METHODS: Two groups of 14 female volunteers of child-bearing age were kept on a Vitamin A-poor diet and treated topically for 21 days with creams containing 0.30% retinol or 0.55% retinyl palmitate on approximately 3000 cm2 of their body surface area, amounting to a total of approximately 30,000 IU Vitamin A/subject/day. After a 12-day wash-out period, the study groups received single oral doses of 10,000 IU or 30,000 IU retinyl palmitate (RP), corresponding to the maximal EU allowance during pregnancy or three-times higher, respectively. Blood samples were collected over 24h on study days -3 (pre-study), 1, 21 (first and last days of topical treatment) and 34 (oral administration) at 0, 1, 2, 4, 6, 8, 12, 14-16 h and 24 h after treatment for determination of plasma concentrations of retinol (REL), retinyl palmitate (RP), oleate (RO) and stearate (RS), 9-cis-, 13-cis-, all-trans- (AT), 13-cis-4-oxo- or AT-4-oxo-retinoic acids (RAs). RESULTS: With the exception of transient mild (RP-group) to moderate (REL-group) local irritation on the treatment sites, no adverse local or systemic effects were noted. On days 1 or 21 of topical treatment, no changes were measured in individual or group mean plasma Cmax, AUC0-24 h or other pharmacokinetic parameters of REL, retinyl esters or RAs relative to pre-study data. In contrast, single oral doses of RP at 10,000 IU or 30,000 IU produced dose-related and sustained increases in Cmax and AUC0-24 h values of plasma RP, RO, RS, 13-cis- and 13-cis-4-oxo-RAs, as well as a transient increase in AT-RA. In conclusion, our results provide evidence that human topical exposure to retinol- or retinyl ester-containing cosmetic creams at 30,000 IU/day and maximal use concentrations do not affect plasma levels of retinol, retinyl esters or RAs, whereas single oral doses at 10,000 IU or 30,000 IU produce significant increases in plasma retinyl esters and RAs.


Assuntos
Vitamina A/análogos & derivados , Vitamina A/administração & dosagem , Vitamina A/farmacocinética , Administração Oral , Administração Tópica , Adulto , Cosméticos , Diterpenos , Feminino , Humanos , Ésteres de Retinil , Medição de Risco , Vitamina A/sangue
4.
Regul Toxicol Pharmacol ; 33(3): 285-99, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11407932

RESUMO

Modern sunscreen products provide broad-spectrum UV protection and may contain one or several UV filters. A modern UV filter should be heat and photostable, water resistant, nontoxic, and easy to formulate. Identification of a substance that meets these criteria is as difficult as discovering a new drug; hundreds of new molecules are synthesized and screened before a lead candidate is identified. The most important aspect in the development of a new UV filter is its safety. In our laboratories, the safety of new ultraviolet filters is assessed by an initial in vitro screen including photostability, cytotoxicity, photocytotoxicity, genotoxicity, and photogenotoxicity tests. These tests are performed in mammalian, yeast, and bacterial cell systems. Skin penetration potential is measured in vitro using human skin or, when required by regulations, in vivo. Because modern sunscreens are selected on the basis of their retention on and in the stratum corneum and are formulated as poorly penetrating emulsions, they generally have very low to negligible penetration rates. The safety and efficacy of UV filters are regulated and approved by national and international health authorities. Safety standards in the European Union, United States, or Japan stipulate that new filters pass a stringent toxicological safety evaluation prior to approval. The safety dossier of a new UV filter resembles that of a new drug and includes acute toxicity, irritation, sensitization, phototoxicity, photosensitization, subchronic and chronic toxicity, reproductive toxicity, genotoxicity, photogenotoxicity, carcinogenicity, and, in the United States, photocarcinogenicity testing. The margin of safety of new UV filters for application to humans is estimated by comparing the potential human systemic exposure with the no-effect level from in vivo toxicity studies. Only substances with a safe toxicological profile and a margin of safety of at least 100-fold are approved for human use. Finally, prior to marketing, new UV filters undergo stringent human testing to confirm their efficacy as well as the absence of irritation, sensitization, photoirritation, and photosensitization potential in man. UV filters not only protect against acute skin injury, such as sunburn, but also against long-term and chronic skin damage, including cellular DNA damage, photoinduced immune suppression, and, by extension, skin cancer. The protection provided by modern sunscreens against UV-induced skin cancer was shown in animal photocarcinogenicity studies and confirmed by numerous in vitro, animal, and human investigations: UV filters protect the p53 tumor suppressor gene from damage and prevent UV-induced immune suppression. Recent studies suggest that sunscreens protect against precursor lesions of skin cancer, such as actinic keratoses. Additional benefits of ultraviolet filters include prevention of photodermatoses, such as polymorphic light eruption, and, possibly, photoaging. Modern sunscreens are safe for children and adults. Percutaneous penetration and irritation rates of topically applied substances in children and adults are similar. The principal protective measure is to keep children out of the sun and/or to cover them with protective clothes; however, sunscreens are a safe and effective and often the only feasible defense of children against UV radiation. In conclusion, sunscreens are safe protective devices that undergo stringent safety and efficacy evaluation.


Assuntos
Neoplasias Cutâneas/prevenção & controle , Queimadura Solar/prevenção & controle , Protetores Solares/farmacologia , Adulto , Animais , Criança , Pré-Escolar , Dano ao DNA , Avaliação Pré-Clínica de Medicamentos , Humanos , Lactente , Recém-Nascido , Compostos Orgânicos/efeitos adversos , Compostos Orgânicos/farmacocinética , Compostos Orgânicos/farmacologia , Saúde Pública , Medição de Risco , Segurança , Protetores Solares/efeitos adversos , Protetores Solares/farmacocinética , Testes de Toxicidade , Raios Ultravioleta/efeitos adversos
5.
Cancer Chemother Pharmacol ; 39(3): 259-66, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-8996530

RESUMO

Recent studies in human bone-marrow culture and healthy human volunteers suggest that lenograstim [glycosylated, recombinant human granulocyte colony-stimulating factor (rHuG-CSF) produced in Chinese hamster ovary (CHO) cells] has greater in vivo potency than filgrastim [nonglycosylated, methionine-extended recombinant human granulocyte colony-stimulating factor (rmetHuG-CSF) produced in Escherichia coli]. To confirm and extend these results we investigated the in vivo potency of both products in normal rats and neutropenic CD rats as an animal model of chemotherapy-induced neutropenia. In normal rats, groups of eight normal male CD rats received four subcutaneous doses of 10, 30, or 100 micrograms/kg filgrastim or lenograstim on days 1-4 of the study, whereas a control group received the vehicle. Blood samples were collected from each animal before treatment (day -5) and on days 2, 3, 5, 8, and 12 of the study for determination of red blood cell (RBC), platelet, white blood cell (WBC), and differential counts. rHuG-CSF and r-metHuG-CSF produced increased WBC counts, principally due to elevated absolute neutrophil counts (ANCs); on days 2, 3, and 5, all groups receiving rG-CSF had ANCs that increased in a progressive and dose-related manner. With the exception of a single value, mean ANCs obtained on days 2, 3, and 5 in lenograstim-treated groups were higher (statistically significant on day 3 at 30 and 100 micrograms/kg and on day 5 at 10, 30, and 100 micrograms/kg) than the respective values obtained in filgrastim-treated groups. No compound-related effect was noted in RBC or platelet parameters. Neutropenia was induced in male CD rats (12 animals/group) with a single intraperitoneal dose of 50 mg/kg cyclophosphamide (CPA) on day 0. On days 1-4, CPA-treated groups were treated with the vehicle (control) or with filgrastim or lenograstim at 30 or 100 micrograms/kg per day. An additional group was not treated with CPA and served as the absolute control group. Blood was collected from alternating subgroups on study day -5 (pretest) and on days 2, 3, 4, 5, 6, 8, 9, and 12 for determination of RBC, platelet, WBC, and differential counts. No major adverse in-life effect was noted in neutropenic rats. Maximal depression of WBCs and ANCs occurred on day 5, followed by recovery to normal values by days 9 (ANC) and 12 (WBC). On day 3 and days 5-9, rHuG-CSF- and metHuG-CSF-treated groups had marked and dose-related increases in WBCs as compared with CPA-treated controls, principally due to elevated ANCs. With the exception of a few values, mean ANC values obtained in lenograstim-treated groups were consistently higher than the respective values obtained in filgrastim-treated groups; the difference was statistically significant on day 3 (30-microgram/kg groups) and on days 6 and 8 (100-microgram/kg groups). In conclusion, treatment of normal and neutropenic CD rats with lenograstim resulted in a dose-related elevation of ANCs that was consistently and significantly higher than the response to identical doses of filgrastim. These results suggest that lenograstim, the glycosylated form of rG-CSF, has superior in vivo potency in normal and neutropenic animals as compared with filgrastim, the nonglycosylated form of rG-CSF.


Assuntos
Adjuvantes Imunológicos/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Neutropenia/sangue , Neutrófilos/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Contagem de Eritrócitos/efeitos dos fármacos , Filgrastim , Lenograstim , Contagem de Leucócitos/efeitos dos fármacos , Masculino , Neutropenia/tratamento farmacológico , Contagem de Plaquetas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia
6.
Lab Anim ; 29(3): 335-8, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7564220

RESUMO

This study was performed to investigate the potential effects of nocturnal, low-intensity light upon ovarian morphology of female Sprague-Dawley rats and to investigate the cause for ovarian changes which had been observed in an earlier study following transient exposure of control female Sprague-Dawley rats to indirect light of minimal intensity during the nocturnal 12-h dark cycle. Twenty female Sprague-Dawley CD rats (initial age: 5 weeks) were kept for 8 weeks under our standard laboratory conditions including a daily 12-h light cycle (light intensity: approximately 200 lux) followed by a 12-h dark cycle with exposure to an indirect light source of low intensity (approximately 30 lux). Ten female control rats of comparable age from a concurrent toxicology study housed in an adjacent animal room under our standard 12 h light/dark cycle served as controls. At the end of the study the rats were sacrificed, necropsied and the ovaries were evaluated histopathologically. In 5 of the 20 animals we found ovarian atrophy consisting of decreased number and size of corpora lutea and increased number of tertiary follicles and/or follicular cysts. Most corpora lutea present in these ovaries were old, indicating the absence of recent ovulations. In contrast, the incidence of ovarian changes in the control group was 0/10. In conclusion, nocturnal exposure of female Sprague-Dawley rats to light of minimal intensity produced a substantial incidence of ovarian changes and suggests that the incidence of ovarian atrophy observed in a previous study may have been due to transient exposure to indirect nocturnal light of minimal intensity.


Assuntos
Luz/efeitos adversos , Ovário/patologia , Ratos Sprague-Dawley/anatomia & histologia , Criação de Animais Domésticos , Animais , Atrofia , Corpo Lúteo/patologia , Escuridão , Feminino , Ratos
7.
Hum Exp Toxicol ; 12(2): 87-98, 1993 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8096721

RESUMO

Trends in survival and body weight were evaluated in 2140 control Sprague-Dawley-derived [Crl: COBS-CD(SD)BR and Crl: COBS-VAF CD(SD)BR] rats used for 24-month rat carcinogenicity studies between 1979 and 1991. Body weight and survival were remarkably stable in the CD-COBS rats used during 1979-1987: at 24 months, the mean survival in males was 68 +/- 5%, and 60 +/- 5% in females. With the CD-COBS-VAF rat, a variant of the CD-COBS strain used between 1988 and 1991, the survival at 24 months dropped to 41 +/- 3% in males, and 44 +/- 7% in females compared to the CD-COBS. The CD-COBS-VAF rat had a significantly reduced life span (P < 0.001 at 24 months), a significant increase in mean body weight (males at 6 months: 672 +/- 24 g vs. 536 +/- 6 g; females: 359 +/- 7 g vs 308 +/- 3 g; P < 0.001) and food consumption (males at 6 months: 31.3 +/- 3.3 vs. 25.4 +/- 2.1 g d-1; females: 22.0 +/- 2.7 g v. 20.3 +/- 2.0 g d-1; P < 0.001). CD-COBS-VAF rats which failed to survive up to study termination had individual body weights at 3, 6 and 12 months which were significantly higher (P < 0.001) than those which survived until 24 months. Our historical data base of control rats (CD-COBS and CD-COBS-VAF) in carcinogenicity studies revealed a significant (males: P < 0.001); females: P < 0.01) and inverse linear relation between mean 3-month body weight and 24-month survival. When compared to CD-COBS animals, CD-COBS-VAF rats showed an increase in the incidence of pituitary tumours in males, mammary fibroadenomas in females, an increase in the incidence of severity of glomerulonephrosis, and a greater incidence of animals which died without any obvious pathology. It is concluded that, in our Sprague-Dawley substrains, both the individual and the group mean body weights in early adult life appear predictive for the individual and group life expectancy. The decrease in longevity in the CD-COBS-VAF rat is principally due to disease and degeneration processes associated with fast growth and high body weight.


Assuntos
Peso Corporal/fisiologia , Longevidade/fisiologia , Ratos Sprague-Dawley/fisiologia , Envelhecimento/fisiologia , Animais , Testes de Carcinogenicidade , Dieta , Ingestão de Alimentos , Meio Ambiente , Feminino , Longevidade/genética , Masculino , Neoplasias/epidemiologia , Neoplasias/veterinária , Tamanho do Órgão/fisiologia , Ratos , Ratos Sprague-Dawley/genética , Caracteres Sexuais
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