Dermal absorption rodent

Rodent and human studies have shown that MTBE is rapidly absorbed following inhalation exposure. In addition, rodent studies have shown rapid distribution of MTBE after oral and intraperitoneal exposure. Dermal absorption occurs more slowly. Evidence supports metabolic transformation of MTBE by P450 enzymes to the parent alcohol, t-butyl alcohol (TBA), and formaldehyde in rodents and humans. Further oxidative metabolism of TBA seems to be slow, and glucuronidation is a major competing pathway. Formaldehyde metabolism to formate is very rapid. The toxicokinetic parameters of MTBE and TBA depend on the dose and route of administration although they appear to be linear following inhalation exposures up to 50 ppm. 

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]. 

They dosed rats dermally with laboratory contaminated soil and observed that as the dose Increased, the liver concentration of TCDD Increased from 0.05 to 2.2%. The authors did not estimate a value for dermal bioavailablllty. On the basis of this study, Kimbrough and co-workers estimated a dermal bioavailablllty of 1% for humans (1). The use of a 1% dermal absorption factor (bioavailablllty) almost surely overestimates the actual uptake of TCDD on soil through human skin since Investigators In the dermal field generally agree that rodent skin Is approximately 10 times more permeable than human skin. As discussed In the next section, dermal bioavailablllty (like oral bioavailablllty) Is also likely to decrease with the "age of the soil. (41.42)... 

Baynes at al. (1997) Rodent, pig stin DEET. permethrin, carbaryl DEET does not enhance dermal absorption of permethrin... 

The molecular weight and structure of permethrin suggest hmited dermal absorption. However, dermal absorption stodies with rodent skin demonstrated significant dermal absorption of permethrin. For example, the hterature reported as much 63.8% absorption in 8 h in mice in vivo (Shah et al., 1981) and 49 to 57% in 72 h in rats (Shah et al.. 

Several rodent and human models have been used to predict the absorption (oral, inhalation, and dermal) from water and air, distribution, metabolism, and excretion of chloroform. 

No studies were located that specifically examined species-related differences in selenium pharmacokinetics. Similar patterns of absorption, distribution, and elimination have been reported for human and animal systems and the dermal, endocrine, and neurological effects of chronic exposure in humans are similar to those reported for animals exposed to very high doses of selenium. However, species-specific differences in toxicity are present (e.g., the main effect of selenium toxicity in rodents is damage to the liver, which is not observed in humans) and this may represent evidence of underlying differences in how selenium is metabolized. 

The basic minimum data base, which might be considered as acceptable would include acute oral and dermal LDj- s, acute inhalation LC eye, and skin irritation studiesr reeding studies of at least 90 days duration on adequate numbers of animals of at least two species, one of which would be a non-rodent species, absorption, distribution and excretion data in one of the species used in the 90 day studies, mutagenicity screening studies, possibly a multigeneration reproduction study, and any special studies indicated by the chemical structure of the compound under test. 

Compared to permethrin, the molecular weight and lipophilicty of DEEP suggest that it should be more readily absorbed across skin. This repellent is more readily absorbed across rodent skin than either porcine or human skin. About 6% of a topical dose of commercially formulated DEET (15% in ethanol) was absorbed across human skin within 8 h (Selim et al., 1995). Our laboratory also reported about 3% dose absorption in poreine skin within this same time period however, absorption in mice skin ranged from 10 to 21% of the dose (Baynes et al., 1997). These data highlight the potential problem of overestimating the risk of DEET in humans if rodent data are used in dermal risk assessment. 

While this paper introduces unique approaches to rodent dermal studies, other animals and man have been investigated using other procedures. Bartek et al (i.) compared the rat, rabbit, pig and man. Hunziker et al ( ) compared the Mexican hairless dog and man. A recent very good, extensive review on percutaneous absorption has been published by Wester and Maibach ( ). 

In an in vitro percutaneous study performed on rodent and pig skin with DEBT (diethyl-m-toluamide CAS no. 134-62-3), permethrin and carbaryl results were that no permethrin was absorbed. It was believed by the authors that DEBT inhibited the absorption of permethrin (Baynes et al. 1997). Bast et al. (1997) studied the percutaneous absorption of permethrin through the isolated perfused rabbit ear. Permethrin was applied in isopropyl myristate (reference ointment) or in ethanol. The ethanol was evaporated off skin, and the skin was covered with 1.5 (w/w) methyl cellulose in water. The authors measured the appearance rates (pmol min cm ) of 3-phenoxy benzene methanol (CAS no. 13826-35-2) and 3-phenoxybenzoic acid (CAS no. 3739-38-6) in the effusate after dermal application (3.61 pmol cm of skin). No permethrin per se was found in the effusate. The metabolites were believed to be from impurities in the permethrin. From the concentration that permethrin constitutes in a pharmaceutical brand (Ambush ) and from detection limits. Bast et al. (1997) calculated a Kp of 2.63 x 10 cm h . ... 

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