Total dermal absorbed dose

Maximum value for total absorbed dose for each individual calculated by three methods based on the pharmacokinetic model for clearance after dermal exposure to 2,1+,5-T (l6). 

Of primary concern in exposure studies is the amount of compound actually entering the body via ingestion, inhalation, or dermal absorption. In order to evaluate the effectiveness of patches in predicting the absorbed dose, during two studies we attached patches to the clothing at strategic locations in addition to collecting total urine samples. As an example of the fluctuation in 2,4,5-T exposure from one patch to another, Table 1 provides information derived from individual patch analyses from four mist blower crewmembers. 

In vivo experiments on 4 human volunteers, to whom 0.0026 mg/cm2 of 14C-benzene was applied to forearm skin, indicated that approximately 0.05% of the applied dose was absorbed (Franz 1984). Absorption was rapid, with more than 80% of the total excretion of the absorbed dose occurring in the first 8 hours after application. Calculations were based on urinary excretion data and no correction was made for the amount of benzene that evaporated from the applied site before absorption occurred. In addition, the percentage of absorbed dose excreted in urine that was used in the calculation was based only on data from rhesus monkeys and may not be accurate for humans. In another study, 35-43 cm2 of the forearm was exposed to approximately 0.06 g/cm2 of liquid benzene for 1.25-2 hours (Hanke et al. 1961). The absorption was estimated from the amount of phenol eliminated in the urine. The absorption rate of liquid benzene by the skin (under the conditions of complete saturation) was calculated to be low, approximately 0.4 mg/cm2/hour. The absorption due to vapors in the same experiment was negligible. The results indicate that dermal absorption of liquid benzene is of concern, while dermal absorption from vapor exposure may not be of concern because of the low concentration of benzene in vapor form at the point of contact with the skin. No signs of acute intoxication due to liquid benzene dermally absorbed were noted. These results confirm that benzene can be absorbed through skin. However, non-benzene-derived phenol in the urine was not accounted for. 

In vitro experiments using human skin support the fact that benzene can be absorbed dermally. An experiment on the permeability of excised human skin with regard to benzene (specific activity 99.8 mCi/mmol total volume of applied benzene not reported) resulted in the absorption of 0.17 mg/cm2 after 0.5 hours and 1.92 mg/cm2 after 13.5 hours (Loden 1986). Following application of 5, 120,270, and 520 pL/cm2 of benzene to human skin, total absorption was found to be 0.01, 0.24, 0.56, and 0.9 pL/cm2, respectively. Thus, the total amount absorbed appears to increase linearly with dose. When exposure time (i.e., the time to complete evaporation) at each dose was measured and plotted as the ordinate of absorption, total absorption was found to increase linearly with exposure time. The percentage of the applied dose absorbed at each concentration was constant at about 0.2% (Franz 1984). 

This chapter provides an overview of factors affecting dermal absorption. Factors influencing absorption are among others related to the skin (e.g. anatomical site, difference between species, metabolism, etc.) and the exposure conditions (e.g. area dose, vehicle, occlusion and exposure duration). In order to provide relevant information for the risk assessment of pesticides, dermal absorption studies should take these aspects into account. With respect to the methods being used nowadays for the assessment of dermal absorption, it is important to realize that neither in vitro nor in vivo animal studies have been formally validated. Available data from various in vitro studies, however, indicate that the use of the total absorbed dose (i.e. the amount of test substance in the receptor medium plus amount in the skin) could be used in a quantitative manner in risk assessment. Tape stripping of the skin can be adequate to give a good indication of test chemical distribution, and hence its immediate bioavailability. 

Acrylamide is well absorbed via the gastrointestinal and respiratory tracts. It is also well absorbed through the skin but less rapidly than through the gastrointestinal tract a significant portion of the dermally applied dose remains in the skin. Upon absorption into the blood, acrylamide is rapidly distributed throughout the body with an apparent volume of distribution equal to total body water. With the exception of plasma, erythrocytes, and testes, acrylamide and glycidamide do not exhibit preferential bioconcentration in any body tissue. 

In a study using beagle dogs dermally exposed to 0.4 mg of radioactive MBOCA/cm, no measurable radioactivity was detected in blood or plasma up to 24 hours later (Manis et al. 1984). The highest concentration of radioactivity 24 hours post-exposure was found in the bile. No unmetabolized MBOCA was present in the bile. Detectable concentrations of radioactivity were found in the liver, kidney, fat, and lung. Urinary excretion of unmetabolized MBOCA was a small but consistent fraction, 0.4-0.5%, of the total urinary radioactivity, and the authors concluded that this may be a useful index of acute exposure. These results support the hypothesis that dermal absorption is a viable entry for MBOCA. They also demonstrate that the circulatory system distributes MBOCA to the liver, kidneys, fat, and lungs. In this study, intravenously exposed animals were used as controls in order to obtain a 100% absorbed dose baseline for comparison with the pharmacokinetic data obtained for dermal exposure. 

These equivocal data suggest that no universal rule can presently be established regarding the total absorbed dose for use in calculating safety margins in dermal risk assessment. Data must be generated for each compound, and the results should be carefully analyzed before assessing risk. 

The internal dose of propoxur was measured by assessing the total amount of 2-isopropoxyphenol (IPP) excreted in the urine, collected over a period of 24 hr from the start of exposure, and described in detail in previous studies (Brouwer et al., 1993 Meuling et al., 1991). Volunteer kinetics studies revealed a one-to-one relationship of absorbed propoxur and excreted IPP on a mole basis. Based on the results by Machemer et al. (1982), a pulmonary retention of 40% was used to calculate the relative contribution of the respiratory exposure to the internal exposure. To estimate the contribution of the dermal exposure, the calculated respiratory portion was subtracted from the total amount of IPP excreted in urine. 

Now consider a poorly penetrating dermally applied compound, or one that is applied for such a short time T that only a small fraction of the applied dose is absorbed. In this case, it is the concentration c of the material in the formulation (as well as other factors that determine the flux across the stratum corneum, such as the dermal penetration coefficient Kp - see below), rather than the total applied amount of material, that determines the amount absorbed both into and through the skin. In simplest terms, the total amount Q absorbed into the systemic circulation is given by the equation ... 

---