Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies.
Assessment of percutaneous absorption in vitro provides key information when predicting dermal absorption in vivo. Confirmation of skin membrane integrity is an essential component of the in vitro method, as described in test guideline OECD 428. Historically, assessment of the membrane's permeability to tritiated water (T2O) and the generation of a permeability coefficient (Kp) were used to confirm that the skin membrane was intact prior to application of the test penetrant. Measuring electrical resistance (ER) across the membrane is a simpler, quicker, safer and more cost effective method. To investigate the robustness of the ER integrity measure, the Kp values for T2O for a range of human and animal skin membranes were compared with corresponding ER data. Overall, for human, rat, pig, mouse, rabbit and guinea pig skin, the ER data gave a good inverse association with the corresponding Kp values; the higher the Kp the lower the ER values. In addition, the distribution across a large dataset for individual skin samples was similar for Kp and ER, allowing a cut-off value for ER to be established for each skin type. Based on CTL's (Syngenta Central Toxicology Laboratory) standard static diffusion cells and databridge, we propose that intact skin should have an ER equal to or above (in kOmega): human (10), mouse (5) guinea pig (5), pig (4) rat (3), and rabbit (0.8). We conclude that measurement of ER across in vitro skin membranes provides a robust measurement of skin barrier integrity and is an appropriate alternative to Kp for T2O in order to identify intact membranes that have acceptable permeability characteristics for in vitro percutaneous absorption studies.
Davies
D J
DJ
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK. diane.davies@syngenta.com
Ward
R J
RJ
Heylings
J R
JR
D000287:Administration, Topical; D000818:Animals; D017097:Electric Impedance; D004817:Epidermis / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010539:Permeability; D017410:Practice Guidelines as Topic; D011817:Rabbits; D051381:Rats; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D013552:Swine; D014316:Tritium / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000592:standards; D014867:Water / Q000008:administration & dosage / Q000592:standards
D014867:Water; D014316:Tritium; C033961:tritium oxide