Twenty Clinically Pertinent Factors/Observations for Percutaneous Absorption in Humans.

At least 20 clinically relevant factors affect percutaneous absorption of drugs and chemicals: relevant physico-chemical properties, vehicle/formulation, drug exposure conditions (dose, duration, surface area, exposure frequency), skin appendages (hair follicles, glands) as sub-anatomical pathways, skin application sites (regional variation in penetration), population variability (premature, infants, and aged), skin surface conditions (hydration, temperature, pH), skin health and integrity (trauma, skin diseases), substantivity and binding to different skin components, systemic distribution and systemic toxicity, stratum corneum exfoliation, washing-off and washing-in, rubbing/massaging, transfer to others (human to human and hard surface to human), volatility, metabolic biotransformation/cutaneous metabolism, photochemical transformation and photosensitivity, excretion pharmacokinetics, lateral spread, and chemical method of determining percutaneous absorption.

Percutaneous absorption and exposure assessment of pesticides.

Dermal exposure to a diverse range of chemicals may result from various uses. In order to assess exposure and estimate potential risks, accurate quantitative data on absorption are required. Various factors will influence the final results and interpretations of studies designed to assess the ability of compounds to penetrate the skin. This overview will discuss skin penetration by pesticides, emphasizing key parameters to be considered from the perspective of exposure assessment.

Dermatotoxicology: historical perspective and advances.

The fundamental principles underlying the study of dermatotoxicology were developed by Arnold Lehman and John Draize over a half century ago and remain applicable today. This discipline has proven indispensable for addressing the problems associated with skin exposure to chemicals. The 55th anniversary of Lehman's landmark publication on safety factors presents the opportunity to reflect upon the historical beginnings of dermatotoxicology and the role of regulatory policies on the development of this field over the years. The complexity and sheer volume of information that has been collected makes it difficult to comprehensively cover all aspects of this vast discipline. This overview will touch upon the general concepts of ADME, the various forms of contact dermatitis, and transdermal drug delivery systems. The traditional tests performed in animals and humans to identify allergic or irritant potential of chemicals, in addition to alternative methods such as QSAR modeling will be discussed. The subspecialties of infant and occupational dermatotoxicology, as well as dermatotoxicology of aged and ethnic skin, and skin of the vulva and vagina will also be noted.

Oxygen-dependent differentiation of human keratinocytes.

Oxygen is an essential micronutrient. Unlike many internal tissues, human epidermis obtains much of its oxygen supply from the atmosphere (21% oxygen), and it ordinarily experiences higher oxygen levels than internal tissues (estimated approximately 5%). To test whether epidermal cell growth and differentiation depend upon this higher oxygen level, keratinocyte cultures were studied at 21, 5, and 2% oxygen concentrations. Compared to 21% oxygen, culture in 5% had little effect on growth but led to profound suppression of the differentiation program as assessed by expression of differentiation markers and formation of squames in the superficial layers. Culture in 2% oxygen reduced the growth rate as well as stratification and differentiation. In low-oxygen conditions, the cells exhibited increased colony-forming ability, consistent with a lower proportion of differentiated cells, and increased expression of vascular endothelial growth factor and cyclooxygenase-2. Growth in 21% oxygen led to higher levels of glutathione and expression of oxidant-responsive genes. Electrophoretic mobility supershift assay using an involucrin activator protein 1 (AP1) response element sequence revealed altered binding by proteins of the Jun and Fos families in nuclear extracts. The present data thus demonstrate oxygen-dependent differentiation in human keratinocytes, to which altered utilization of AP1 transcriptional response elements may contribute.