Mass balance studies, dermal

Both of these approaches allow for assessment of systemic absorption by not conducting complete mass balance studies (e.g., expired air to catch absorbed compound metabolized to COj or HjO expired end products). In vivo dermal absorption studies not taking into account other routes of excretion must be interpreted with caution. One extension of this mass balance excretory analysis is to assess dermal absorption by only monitoring the primary excretory route for the compound studied. Dermal bioavailability has been assessed in exhaled breath using real-time ion trap mass spectrometry to track the uptake and ehmination of compounds (e.g., trichloroethylene) from dermal exposure in humans and rats (Poet et al., 2000). A physiologically based pharmacokinetic model can be used to estimate the total bioavailability of compoimds. The same approach was extended to determine the dermal uptake of volatile chemicals imder non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans (Thrall et al., 2000). 

The mass balance approach was used to develop an in vivo animal model for skin penetration of topically applied dmgs in hairless rats (Simonsen et al., 2002). Two dmgs, C-sahcylic acid and C-butyl salicylate were topically applied for the assessment of the model. Rapid and differentiated percutaneous absorption of both compounds was indicated by urinary excretion data. Total mass balance on the applied radioactivity was performed, and 90% recovery was achieved. Carver and Riviere (1989) conducted an extensive mass balance study with " C-labeled xeno-biotics after topical and intravenous administration to pigs. These authors reported that dermal absorption of C-benzoic acid, caffeine, malathion, parathion, progesterone, and testosterone was 25.7, 11.8, 5.2, 6.7, 16.2, and 8.8%, respectively, following topical administration to pigs. 

In this study, 4.4 mg of lead equivalent was applied to the skin under a covered wax/plastic patch on the forearms of human subjects of the applied dose, 1.3 mg of lead was not recovered from skin washings. The amount that actually remained in (or on) the skin and the mass balance of the fate of this lead was not determined it may have been absorbed or eliminated from the skin by exfoliation of epidermal cells. Thus, while this study provides evidence for dermal absorption of lead, it did not quantity the fraction of applied dose that was absorbed. The quantitative significance of the dermal absorption pathway as a contributor to lead body burden remains an uncertainty. The wax/plastic patch provided a means by which the lead compounds could permeate or adhere to the skin. The effect of concentration in aqueous solution may cause skin abrasion through enhanced acidity since the lead ion is acidic. Abraded skin is known to promote subsequent higher lead penetration. 

It is not uncommon for in vivo and in vitro dermal absorption studies to be compromised by lack of mass balance, e.g. recovery of <90% of the radiolabel. The OECD Test Guidelines specify that adequate recovery is a mean of 100 10 % of the radioactivity, and that recoveries outside this range must be justified (OECD, 2004a,b). The following three approaches exist for addressing incomplete recovery, but there is no harmonized approach ... 

Advances of in vivo methods for dermal absorption studies have shown promising results. Microdialysis has bear ranployed successfully for measuring dermal penetration of a wide variety of compounds. This technique has been used extensively in topieal bioavaUabUity and bioequivalenee studies. The noninvasive techniques for percutaneous absorption studies such as tape-stripping, ATR-FTIR, and skin surface biopsies arc also becoming popular because these can be used safely in humans. Regulatory bodies rely on mass balance approaches because all of the topically... 

Dermal microdialysis studies were reviewed separately from other studies because penetrant measurement in receiving chambers does not account for flux, nor does it justify metabolism. Moreover, dermal microdialysis may itself alter the barrier function of the skin, and there are unresolved issues relating to mass balance detection. 

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