Percutaneous absorption assessment

Moore MR, Meredith PA, Watson WS, et al. 1980. The percutaneous absorption of lead-203 in humans from cosmetic preparations containing lead acetate, as assessed by whole-body counting and other techniques. Food Cosmet Toxicol 18 399-405. 

R. C. Wester, J. L. Melendres, and H. I. Maibach. In vivo percutaneous absorption of acetochlor in the rhesus monkey Dose-response and exposure risk assessment. Food Chem. Toxicol. 34 979-983 (1996). 

As part of the safety assessment the assessor must consider the chemical structure and all the available information regarding the toxicological profile of the material. The decision to proceed with human testing should only be made if the information available provides sufficient confidence that the volunteer will not be exposed to undue risk. Key toxicological endpoints of concern for moisturizing products include skin corrosivity, percutaneous absorption, genotoxicity, skin sensitization, skin irritation, systemic toxicity, reproductive toxicity, and phototoxicity. 

Bartek MJ, LaBudde JA (1975) Percutaneous absorption in vitro. In Maibach HI (ed) Animal Models in Dermatology. Churchill Livingstone, New York, pp 103-120 Bronaugh R, Maibach HI (1999) Percutaneous Absorption. 3rd edn. Marcel Dekker, New York and 4thedn in press Guy RH, Wester RC, Tur E, Maibach HI (1983) Noninvasive assessments of the percutaneous absorption of methyl nicoti-nate in humans. J Pharm Sci 72(9) 1077-1079 Guy RH, Tur E, Bugatto B et al. (1984) Pharmaco-dynamic measurements of methyl nicotinate percutaneous absorption. Pharm Res 1 76-81... 

The next level of in vitro systems employed is the use of isolated perfused skin flap preparations that are surgically prepared vascularized skin flaps harvested from pigs and then transferred to an isolated organ perfusion chamber. This model allows absorption to be assessed in skin that is viable and anatomically intact and that has a functional microcirculation. Studies conducted to assess the percutaneous absorption of drugs and pesticides in this model compared to humans show a high correlation. Validation of these in vitro methods is a prerequisite for regulatory acceptance. 

Riviere et al. (1999) used the isolated perfused porcine skin flap model to study absorption and disposition of JP-8. The percutaneous absorption and cutaneous disposition of topically applied neat Jet-A and JP-8 jet fuels were assessed by monitoring the absorptive flux of the marker components 14C naphthalene and 3H dodecane simultaneously. Absorption of 14C hexadecane was estimated from JP-8. Data were not reported in absolute amounts or concentrations. Instead, the objectives were to determine the relative absorption of the individual marker components from jet fuel, and the effect of a specific jet fuel s composition on the absorption of a specific marker. Having evaluated the absorption of only three of the 228 major nonadditive hydrocarbon constituents of the fuels, the authors stated that this is insufficient information to conduct risk assessments on jet fuels. However, the authors conclusions are informative. Naphthalene penetrated the skin more rapidly than dodecane or hexadecane, but the latter compounds had a larger fraction of the dose deposited in the skin. There were also differences in naphthalene and dodecane absorption and skin deposition between the fuels. These findings reinforce the difficulty of predicting risk for complex mixtures such as jet fuels. 

Doucet, O., N. Gracia and L. Zastrow (1998). Skin culture model a possible alternative to the use of excised human skin for assessing in vitro percutaneous absorption, Toxicol In Vitro, 12, 423-430. 

Howes, D., R. Gny, J. Hadgraft, J. Heyhngs, U. Hoeck, F. Kemper, H. Maibach, J.P. Marty, H. Merk, J. Parra, D. Rekkas, I. Rondelh, H. Schaefer, U. Tauber and N. Verbiese (1996). Methods for assessing percutaneous absorption. The report and recommendations of ECVAM Workshop 13, ATLA, 24, 81-106. 

There are many different animal models that have been used to assess the percutaneous absorption of toxic chemicals. There is little question that while in vivo human studies are best for predicting the absorption of percutaneous applied chemical warfare agents, ethics preclude conducting such studies. Rats have been widely used in the study of skin contamination, wounds, and healing and the efficacy of different decontamination modalities (Wester and Maibach, 2000 Shah et al, 1987 Baynes et al., 1997). 

Goodman, M. and Barry, B. W. Action of penetration enhancers on human stratum comeum as assessed by differential scanning calorimetry. In Percutaneous Absorption. Mechanisms, Methodology, Drug Delivery. R. L. Bronaugh and H. I. Maibach, ed. Dekker New York, 1989, pp. 567-593. 

Different methods of human exposure assessment vary with respect to the input data or information required and the degree of uncertainty associated with resulting estimates. Eor example, the film-thickness approach to dermal exposure assessment is a screening-level methodology that assumes a uniform layer of material (e.g., a liquid consumer product) is on the skin, and that a portion of the material in this layer is absorbed, per the dermal absorption characteristics of the chemical. In contrast, dermal exposure assessment and percutaneous absorption methods can include metrics that account for time-dependent exposure and absorption processes. Eor example, in the case of secondary dermal contact with chemicals on surfaces (e.g., transfer of pesticide residues from... 

These linear kinetic models and diffusion models of skin absorption kinetics have a number of features in common they are subject to similar constraints and have a similar theoretical basis. The kinetic models, however, are more versatile and are potentially powerful predictive tools used to simulate various aspects of percutaneous absorption. Techniques for simulating multiple-dose behavior evaporation, cutaneous metabolism, microbial degradation, and other surface-loss processes dermal risk assessment transdermal drug delivery and vehicle effects have all been described. Recently, more sophisticated approaches involving physiologically relevant perfusion-limited models for simulating skin absorption pharmacokinetics have been described. These advanced models provide the conceptual framework from which experiments may be designed to simultaneously assess the role of the cutaneous vasculature and cutaneous metabolism in percutaneous absorption. 

In Vitro Techniques From a cursory review of the literature on percutaneous absorption it is evident that much of our current understanding of the mechanism of percutaneous absorption was derived from in vitro investigations. In vitro experiments generally afford the investigator the ability to manipulate and control the experimental conditions, and the approach provides the unique opportunity to monitor the rate and extent of percutaneous absorption in skin tissues removed from the confounding influences of the rest of the body. In vitro methods, primarily those involving excised skin mounted in diffusion chambers, are the most frequently employed techniques used in the assessment of skin absorption. 

Table 4 Experimental design considerations with in vitro assessments of percutaneous absorption...

Assessment of percutaneous absorption for any topically applied drug or chemical, can be classified based either on a model s level of biological complexity (in silico, in vitro, in vivo) or on the specific species studied (human, laboratory rodent, monkey, pig). The goal of the research should also be taken into consideration. Is the work being conducted to study the mechanism of absorption (e.g., identify a specific mathematical model or assess the effect of a vehicle) or to quantitatively predict absorption in humans Is the study designed to look at a local effect in skin or a systemic effect after absorption That is, are skin concentrations the relevant metric or is flux of chemical across skin important Model systems and approaches in use today to assess dermal absorption have recently been extensively reviewed [1]. 

Goodman M, Barry BW. Action of penetration enhancers as assessed by differential scanning calorimetry. In Bronaugh RL, Maibach HI, eds. Percutaneous Absorption. 2nd ed. New York Marcel Dekker, 1989 567-593. 

In a related study. Wester et al. (1990,1993) assessed the in vivo percutaneous absorption of PCBs in adult female Rhesus monkeys. " C-Labeled Aroclor 1242 and 1254 were separately administered iv and topically to Rhesus monkeys and urinary and fecal excretion of radioactivity was measured for the next 30 days. Following iv administration, the 30-day cumulative excretion was 55% of the administered dose (39% urine, 16% feces) for Aroclor 1242 and 27% (7% urine, 20% feces) for Aroclor 1254. The percentage of the dose absorbed following topical administration to abdominal skin (after light clipping of hair) was estimated from the ratio of the total urinary and fecal excretion following topical and iv administration. Topical administration of Aroclor 1242 in soil, mineral oil, tiichlorobenzene, or acetone resulted in 14, 20, 18, and 21% absorption of the administered dose, respectively. In contrast to the above in vitro results with human skin, the vehicle had little effect on the systemic absorption of the PCBs applied to the skin of monkeys. This may be due to the uncertain viability of the human skin used in the in vitro studies and the fact that the in vitro study primarily assessed retention of PCBs in human skin and could not estimate systemic absorption. 

Dermal absorption of agricultural chemicals and animal drugs in food-producing animals must be considered as a potential route from which tissue residues of drugs and chemicals may occur. This has been supported in studies of topical pesticide exposure in cows and sheep. Despite the many advances made in in vitro and in vivo techniques for assessing percutaneous absorption in laboratory animals and man, very little systematic attention has been focussed on food-producing animals. The only exception is the pig since it is an accepted model for human studies. The purpose of this manuscript is to overview the literature on dermal xenobiotic absorption in food-producing animals to illustrate the risk that is present, and to outline how in vitro and in vivo methods could be applied to this problem. 

The majority of the research articles identified in a search of the literature of dermal absorption in food-producing animals were concerned with studies utilizing pour-on or dipped pesticides in small groups or even individual animals. In almost all instances, specific formulations were used with quantitative data on dosimetry variables not reported. Although as will be discussed, percutaneous absorption can unequivocally be documented, data is not available in the open literature to quantitatively assess the mechanisms of absorption in different species. 

Gardner, R.S. Walker, M. Hollingsbee, D.A. A sensitive high-performance liquid chromatographic method for the assessment of percutaneous absorption of topical corticosteroids. J.Pharm. Biomed.Anal., 1990, 8, 1083-1085... 

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