Abstract for Plenary Talk 5.1

 

 

Beyond Skin Notation – Modeling Percutaneous Absorption

G. Johanson, Karolinska Institutet, Stockholm, Sweden

Background

This presentation is based on the notions that the risk of developing, or the magnitude of, systemic toxicity relates to the absorbed dose or dose rate rather than the external exposure and that the total absorbed dose is the sum of all exposure routes, including respiratory and dermal uptake. The dermal contribution may vary from a negligible fraction to a dominating part of the absorbed dose, depending on the characteristics of the exposure and the properties of the chemical.

The presentation discusses warning systems (skin notations and dermal uptake indices) for chemicals with high potential for systemic toxicity via skin, and then describes some examples of combined experimental and toxicokinetic models to assess dermal absorption and its contribution to total dose.

Skin notations

Most institutions that establish Occupational Exposure Limits (OELs), such as the Threshold Limit Value Chemical Substances (TLV-CS) committee of the American Conference of Governmental Industrial Hygienists (ACGIH) or the Maximum Allowable Concentration (MAK) committee in Germany use skin notations to warn for chemicals that may cause or aggravate systemic toxicity as a result of dermal exposure. The criteria used to assign such skin notations vary considerably between countries and institutions and are generally qualitative rather than quantitative in nature. For example, the criterion used in Sweden according the Swedish ordinance on OELs is: “Substances which can easily be absorbed percutaneously are marked…” (SWEA 2000). An additional problematic aspect, mostly not dealt with in the criteria for skin notation, is that of evaporation of volatile chemicals from the skin. Obviously, evaporation reduces the amount available for absorption, therefore the absorbed dose of a highly volatile substance is likely to be much smaller than that of a less volatile substance, all other factors being equal.

Data on dermal uptake rates of industrial chemicals are limited. Moreover, when several reports on uptake rates exist on the same chemical, it is not uncommon that these vary by 10 to 100-fold suggesting a large degree of variability and/or uncertainty in the measurements.

In view of all these problems, disagreements in skin notation between OEL lists are of no surprise. The assignments of skin notations would benefit from:

use of standardized methods to assess dermal absorption rates,

measurements of dermal absorption rates of more chemicals,

a unified and more rigorous approach to address the contribution of dermal absorption to systemic dose, and

an approach to address and include evaporation of chemical from skin.

Quantitative dermal uptake indices

A comparison between OEL listed chemicals with skin notation shows that their dermal absorption rates may vary by several orders of magnitude. This suggests that the contribution of dermal absorption may vary from a negligible to a significant or major fraction of the absorbed dose. The qualitative (yes/no) nature of the skin notations tends to neglect this potentially huge variability in dermal absorption. As an alternative or complement, we therefore propose a dermal uptake index (D in eq. 1, pD in eq. 2) that relates the contribution of dermal absorption rate (Pskin) to the respiratory uptake rate via inhalation at OEL (Presp). Similar approaches have implicitly or explicitly been used by many investigators as a basis for assigning skin notations. Both rates are calculated at steady-state and with fixed conditions (reflected by k) with respect to exposed skin area, pulmonary ventilation and relative respiratory uptake.

 

	(eq. 1)
pD = log10D + 8	(eq. 2)

Logarithmic transformation (eq. 2) and rounding off to the nearest integer is performed to facilitate the interpretation and to account for the wide range in D values. The correction factor 8 is chosen to obtain a positive range of integer values for pD. It includes the constant k in eq. 1.

When chemicals on various OEL lists are arranged according to their pD values, it becomes clear that the existing skin notations are not only inconsistent between institutions; they are also frequently inconsistent with the potential importance of dermal uptake.

Modeling dermal absorption

Dermal absorption and its contribution to systemic dose and toxicity may be assessed by a variety of models, including experimental, qualitative structure analysis relationship (QSAR, covered by several presentations at this conference) and toxicokinetic models, and combinations thereof. The four examples given below illustrate different combined uses of experimental and kinetic models.

Kezic and colleagues (2001) studied dermal absorption of liquid 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene, toluene, and m-xylene in volunteers. The solvents were applied for 3 min on the forearm. Skin permeation rates were back-calculated from exhaled air concentration time courses measured after both inhalation and dermal exposure. According to the authors, all solvents showed substantial skin absorption; although at present only toluene has a skin notation in the ACGIH TLV list.

The second example is that of Johanson and Boman (1991), who compared respiratory and dermal uptake to 2-butoxyethanol vapor in controlled human exposures. The volunteers were first exposed to the glycol ether vapor for 2 h via the mouth only and then to the same concentration for 2 h via skin only. By using a simple toxicokinetic model, i.e. assuming that the uptake is proportional to the area under the concentration-time curve (AUC) of the chemical in blood, and by comparing the mouth-only and the skin-only AUCs it was shown that, upon whole-body exposure, the dermal uptake rate exceeded the respiratory uptake rate of 2-butoxyethanol vapor. Other investigators have later obtained similar results for 2-butoxyethanol as well as for other glycol ether vapors. The use of respiratory protective equipment may give a false sense of protection for such substances.

Dermal absorption of o-xylene was assessed in human volunteers using a combination of real-time exhaled breath analysis and PBTK modeling (Thrall and Woodstock 2003). The subjects placed both legs in a tub containing the solvent in water. Exhaled breath was monitored before, during, and after exposure to track absorption and subsequent elimination of the compound in real time. The PBTK model was used to estimate the dermal permeability coefficient by fitting to the exhaled breath data.

The fourth example represents a new technique to assess dermal absorption of chemical vapor by thermal gravimetric analysis (TGA). It is presented in more detail separately at this conference (Rauma et al 2005, Rauma and Johanson 2005). In this in vitro model, skin weight changes of porcine skin are recorded during addition and removal of chemical vapors using a highly sensitive TGA balance and carefully controlled conditions. The time course of the weight changes reflects skin absorption and evaporation processes, while the weight increase at steady-state is defined by the skin:air partition coefficient of the chemical. The approach is an attempt to find a convenient alternative to the diffusion cells to determine transdermal fluxes and permeability coefficients.

References

Johanson G, Boman A (1991). Percutaneous absorption of 2-butoxyethanol vapour in man. Br J Ind Med 48:788-792.

Kezic S, Monster AC, van de Gevel IA, Kruse J, Opdam JJ, Verberk MM (2001) Dermal absorption of neat liquid solvents on brief exposures in volunteers. AIHAJ 62:12-18.

Rauma M, Isaksson T, Johanson G (2005) A new technique to assess dermal absorption of chemical vapor in vitro by thermal gravimetric analysis. OEESC, Stockholm.

Rauma M, Johanson G (2005) A computer-controlled system for generation of chemical vapors in in vitro dermal uptake studies. OEESC, Stockholm.

SWEA (2000) Occupational exposure limit values and measures against air contaminants. Swedish Work Environment Authority, AFS 2000:3.

Thrall K, Woodstock A (2003) Evaluation of the dermal bioavailability of aqueous xylene in F344 rats and human volunteers. J Toxicol Environ Health A 66:1267-1281.

Content last modified: 10 April 2005

 

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