In vitro evaluation of the permeation of cytotoxic drugs through reconstructed human epidermis and oral epithelium.

BACKGROUNDS: Occupational exposure to antineoplastic agents may represent a risk to health care workers, although the relevance of different exposure routes is not fully understood. The objectives of this study were to determine in vitro permeation of four widely used cytotoxic drugs (cisplatin, cyclophosphamide, doxorubicin, and fluorouracil) through two reconstituted tissue models representing human skin epidermis and oral mucosa. MATERIALS AND METHODS: Experiments were conducted with reconstructed models of human epidermis and oral epithelium, cultured in a chemically-defined medium under conditions simulating possible exposure scenarios (6 h duration, three concentrations corresponding to commonly used application doses). The amounts of drugs permeated through the tissues into the receptor media were determined using ultra performance liquid chromatography with photospectrometric detection. RESULTS: The highest epidermis permeations (P = 0.2 x 10(-3) - 1.5 x 10(-3) cm x h(-1)) were observed with three polar drugs (cisplatin, cyclophosphamide and fluorouracil), while permeation by more hydrophobic doxorubicin was minor (P(max) = 0.03 x 10(-3) cm x h(-1)). As expected, more pronounced tissue permeation was observed with the reconstructed oral epithelium having the maximum permeability coefficient (P = 180 x 10(-3) cm x h(-1)) for cisplatin and fluorouracil. Histological evaluation of the exposed tissues revealed cytotoxic effects at higher doses, especially for oral epithelium. CONCLUSION: Although the skin epidermis with keratinised stratum corneum provided relatively good protection, uptake (of at least some investigated drugs) via both types of tissue should not be underestimated. Our results provide basic experimental data on the skin and oral epithelia permeation for further modelling of exposure and health risk assessment.

[Evaporation of selected cytotoxic drugs and permeation of protective gloves--research into the occupational risks of health care personnel handling hazardous cytotoxic drugs (CYTO project)]. / Studie evaporace vybraných cytostatik a propustnosti ochranných rukavic v rámci výzkumu profesní záteze zdravotnických pracovníku exponovaných cytotoxickým protinádorovým lécivum (projekt CYTO).

BACKGROUNDS: The CYTO project studies an important aspect of healthcare provision -long-term occupational exposure, both threshold and below-threshold, to chemical agents with carcinogenic and mutagenic properties, with the major focus on antineoplastic drugs.This contribution presents experimental results from the first stages of the project's experimental work, i.e. an evaluation of the physico-chemical characteristics of cytostatic agents (evaporation) and an investigation into protective glove permeation. MATERIALS AND METHODS: In co-operation with IUTA (Institut für Energie- und Umwelttechnik e.V., Duisburg, Germany), the vapour pressure of paclitaxel, doxorubicin and dacarbazine was measured following OECD guideline No. 104: Vapour pressure curve--vapour pressure balance. Furthermore, the evaporation of cytostatic drugs was examined in actual laboratory conditions by monitoring the airborne concentration using the passive sampling technique. Besides the evaporation of selected drugs, the permeation of cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil and paclitaxel through different types of gloves (vinyl, latex, nitrile) was assessed. RESULTS: Although our experiments showed relatively slow evaporation of the evaluated cytostatic drugs (the highest pressure in paclitaxel was 0.024 Pa), equilibrium concentrations may go up to milligrams per cubic metre. Nevertheless, analytical measurements of airborne contamination did not confirm these concentration levels. The glove permeation experiments with cytostatics showed good resistance of nitrile gloves (which were impermeable to all five drugs). Other materials should be avoided while handling cytostatic agents (e.g. maximum permeation of cyclophosphamide through latex was 19 microg/sq cm/hr). CONCLUSION: Although the volatility of cytostatic agents is low, it cannot be neglected considering the chronic character of exposure. However, in order to estimate actual occupational exposure, future research should focus on the development of sensitive analytical methods. Nevertheless, dermal uptake is supposed to be the major route of exposure and use of protective gloves is necessary to minimize potential risks. Our simulated time-dependent permeation experiments with cytostatic agents and different glove materials showed that good protection is provided only by nitrile gloves. The results obtained in this study will be used for the modelling of exposure doses and health risk assessment in the subsequent stages of the CYTO research project.