Monkey percutaneous absorption studies

Percutaneous absorption studies utilizing rhesus monkeys have one Important single advantage. That is, their skin type and absorption characteristics seem to be similar to humans. This is of utmost concern since the purpose of this study is to simulate the human case. This is not a toxicology study, and it should not be the purpose of this study to estimate a worst case scenario as in a hazard identification study. Thus, in spite of the many shortcomings of the described procedures, monkey percutaneous absorption studies could play an important role in pesticide risk assessments. 

Several problems exist in conducting percutaneous absorption studies in rhesus monkeys. 

Bronaugh RL, Maibach Fll. 1985. Percutaneous absorption of nitroaromatic compounds In vivo and in vitro studies in the human and monkey. J Invest Dermatol 84 180-183. 

Wester RC, Maibach Hl, Bucks DA, et al. 1990. Percutaneous absorption and skin decontamination of PCBs In vitro studies with human skin and in vivo studies in the Rhesus monkey. J Toxicol Environ Health 31 235-246. 

In vivo studies have been conducted in man and in several species to compare absorption fates of numerous compounds. Percutaneous absorption rates in the rat and rabbit were generally higher than in human while the skin permeability of monkeys and swine more closely resembles humans. Although these differences are not predicted by any single factor, such as epidermal thickness, they are not unexpected in light of differences in skin characteristics. There are interspecies differences in routes of excretion of some chemicals as well. This may be due in part to metabolism of the... 

Data presented in three studies have provided substantial evidence that there is very low percutaneous absorption in full-term infants and also in excessively exposed newborn rhesus monkeys. However, traces of chlorhexidine were found in adipose tissue (two of five monkeys), kidneys (five of five), and liver (one of five), suggesting some absorption percutaneously or by oral ingestion, following the rigorous bathing procedure in the above study. The grooming habits of the monkeys could have played a role (SEDA-12, 578) (4). 

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]. 

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. 

In order to assess the risk from topical exposure a number of investigators have sought animal models that could predict percutaneous absorption rates of chemicals in humans. Considerable efforts by Wester and Maibach (2-6) have shown that monkeys and pigs give dermal absorption data most comparable to humans with a range of drugs and pesticides which varied in their physicochemical properties as well as use. A similar rank order for species comparisons has been observed in in vitro (12-14) absorption data which in most cases exceeded the human values (Table I). For this reason, and because of the availability of rhesus monkeys within our facility, dermal absorption studies with rhesus monkeys were considered an appropriate model. 

Percutaneous absorption of BP has been determined in Rhesus monkeys using " C-radiolabeled BP (Bronaugh et al. 1990). It should be noted that the purpose of this study was to examine the absorption and excretion of dermally-applied compounds used in fragrances, including BP. A single dose of radiolabeled-BP in acetone was applied to abdominal skin of the monkeys, and the level of radioactivity was monitored in the urine for up to 5 days. While 92.6 % of the radiolabel did appear in the urine of the monkeys, there was no attempt to determine the chemical nature the radioactive compounds that were excreted (e.g., parent BP or its metabohtes). 

There appears to be large differences in the manner and rate of absorption of the pyrethroids from the gastrointestinal tract, implying that GI advanced compartmen-tal transit models (ACAT) need to be included in PBPK models. This is especially true of the absorption of an oral dose of tefluthrin in male rats, in which 3.0-6.9%, 41.3-46.3%, and 5.2-15.5% of the dose is eliminated in urine, feces, and bile, respectively (0-48 h after administration). Several percutaneous studies with the pyrethroids strongly support the belief that these insecticides are not readily absorbed, but remain on the surface of the skin until they are washed off. In one particular study (Sidon et al. 1988) the high levels of permethrin absorption through the forehead skin (24—28%) of the monkey was reported over a 7- to 14-days period. Wester et al. (1994) reported an absorption of 1.9% of pyrethrin that had been applied to the forearm of human volunteers over a 7-days period. 

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