Absorption - Pesticide Biotransformation and Disposition - page 31

Compared to the epithelium in the small intestine, the skin is relatively impermeable
to aqueous solutions and ions, but it may be permeable in varying degrees to a large
number of drugs or xenobiotics. Drug or xenobiotic delivery pathways in the skin
and GI tract can hypothetically involve intercellular and intracellular passive diffusion
across the epidermis and transappendageal routes via hair follicles and sweat pores in
the skin. Transappendageal pathways are considered to contribute very little to the der-
mal transport of most drugs compared to transport across the epidermis ( Barry, 1991 ).
It is possible for very small and/or polar molecules to penetrate through these append-
ages or shunts, but very unlikely for many classes of highly lipophilic pesticides. The
stratum corneum cell layer in human skin (10-50 m) and pig skin (15 m) is non-
viable and is considered to be the rate-limiting barrier in percutaneous absorption of
many drugs and pesticides ( Monteiro-Riviere et al., 1990 ). Most available research has
concentrated on the stratum corneum as the primary barrier to absorption, although
the viable epidermis (ca. 80 m in humans and 60 m in pigs) and dermis (3-5 mm in
humans) may contribute significantly to the percutaneous penetration of drugs and
ultimately their bioavailability. Scheuplein (1972) proposed that polar drugs diffused
through the hydrated keratin of the dead cells in the stratum corneum, whereas non-
polar drugs traversed the intracellular lipid. The accepted hypothesis is that the domi-
nant pathway for polar molecules resides in the aqueous region of the intercellular
lipid with the hydrophobic region of the lipid chains providing the nonpolar route
( Elias, 1981 ). The intercellular region, as depicted in the brick and mortar model of the
stratum corneum, and now considered the most likely path for absorption of lipophilic
drugs and pesticides, is filled with neutral lipids (complex hydrocarbons, free sterols,
sterol esters, free fatty acids, and triglycerides), which make up 75% of the total lipids,
and polar lipids, such as phosphatidylethanolamine, phosphatidylcholine, lysolecithin,
ceramides, and glycolipids ( Magee, 1991 ). Percutaneous and GI absorption through the
intercellular pathway is by passive diffusion and it is often correlated to the partition
coefficient. The rate of absorption of the penetrant can be described by Fick's law of
diffusion.
Continuous blood flow removes the xenobiotic from the site of absorption in the
skin and GI tract, thus maintaining a concentration gradient and enhancing continued
absorption. For many of the lipophilic pesticides, penetrating molecules are thought
to enter the systemic circulation at the dermis/epidermis interface in skin and do not
necessarily traverse the full thickness of the dermis. For rapidly absorbed chemicals,
equilibrium may be established between the blood and the site of absorption, and the
rate of entry into the blood is limited by blood flow rather than by diffusion across the
membrane. In this case, an increase in blood flow will increase the rate of absorption of
the chemical and absorption is said to be perfusion (or blood-flow) limited. For poorly
absorbed chemicals, however, absorption is not sensitive to blood flow and is said to be
diffusion-rate limited.