Review
Factors determining percutaneous metal absorption

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Abstract

Metals play a vital role in human, animal and plant physiology, and important research, past and ongoing, is directed towards exploring the interrelated mechanisms that govern their penetration through skin. Much insight has been gained through these efforts, but our understanding of the process is still incomplete, mainly due to the failure to allow for the effects of chemical speciation of metallic elements, especially the transition metals. Also, the skin as target organ presents imponderable and wide margins of variability. In vivo permeability is subject to homeostasis regulating the overall organism; in vitro, the sections of skin used for diffusion experiments are likely to present artifacts. Endeavors to define rules governing skin penetration to give predictive quantitative structure–diffusion relationships for metallic elements for risk assessment purposes have been unsuccessful, and penetration of the skin still needs to be determined separately for each metal species, either by in vitro or in vivo assays. Phenomena observed by us and other investigators, which appear to determine the process of skin permeation for a number of metals, are reviewed, separating the exogenous factors from the characteristics of the skin or other endogenous factors.

Introduction

Mathematically-derived (mechanistic) models predictive of percutaneous penetration of organic molecules have been developed based on in vitro and in vivo data through regression analysis of experimental results. They serve to predict diffusivity of untested structures. Within limits of molecular parameters such as size, lipid solubility or hydrogen bonding, these models apply to organic compounds such as drugs, pesticides, cosmetic ingredients etc., and now predict their dermal absorption with increasing accuracy (Flynn, 1990, Abraham et al., 1995, McCarley and Bunge, 2000, Lim et al., 2002). Potts and Guy (1995) could state that, in testing the predictive algorithm they had derived for non-electrolyte transport through the skin, the elements required for construction of such a model could be reduced to the criteria of structure and physical properties. However, no such reduction is feasible when modeling electrolytes. Attempts to model the dermal absorption process of metals species and of transition metal species in particular have been thwarted owing to a number of confounding factors, as became obvious from in vivo and in vitro experiments. Because movement through biological membranes is highly element- and chemical species-specific, molecular physicochemical parameters alone do not suffice to model migration of the various possible elemental species into and through the strata of the skin. Certain factors are closely interrelated and their combined effects are neither entirely understood nor predictable. Unless the dynamics of in-situ changes in valence (oxidation state) or electrophilic reactivity, among others, can be factored in, the permeation activity of metallic element species will elude modeling. Experimental data available so far from in vitro and in vivo studies have been acquired under disparate conditions and are too scarce considering the number of metals and metalloids of variable valence existing as free ions, or forming chelates, co-ordination compounds or complexes with electron donors such as oxygen, sulfur or phosphorus abundant in biological systems. The number of specific metals that can be properly discussed in this review is limited, mostly involving nickel, chromium, mercury and lead. This is due to priorities set by most scientists and government agencies so far on those industrial materials which carry special risks from exposure for their investigations, as toxicants in general, or having carcinogenic or immunogenic potential in particular. The database for other metals and metalloids is small.

It is the objective of this review to analyze the numerous effects which need to be considered when evaluating in vivo or in vitro data from various sources and in planning for future experiments. In this review the term “metal” refers to a given metallic element in all its forms of occurrence: metallic state, electrolytic (ionized) form, as well as organometallics, complexes, co-ordination compounds or chelates.

Section snippets

Descriptors of skin penetration—their scope and limitations

To correctly interpret the data presented in this review it is important to critically weigh their validity by accounting for the considerable margins of errors involved in the determination of skin permeabilty.

Rarely have metals been investigated in a consistent fashion for their ability to permeate the skin. Even more sparse are the quantitative data that allow deduction of flux, permeability coefficient or percent of “dose” absorbed by human skin. Even those results that are amenable to

Dose

Rate of diffusion of certain transition metals is not commensurate with applied concentration. Absolute absorption can reach a plateau value, then decrease with a further increase in concentration. Again for others absorption steadily decreases with increasing dose. This is probably due to the build up of a secondary diffusion barrier as consequence of electrophilic metals forming stable bonds with proteins of the skin. Thereby a depot accumulates in the SC retarding further penetration in

Age of the skin

Little is known about how aging affects percutaneous penetration of xenobiotics in humans, aside from an incomplete barrier function observed in infants and young children, which gradually increases to values seen in the skin of mature individuals. Neonatal or infant skin has been found to be more permeable to lipophilic compounds than is adult skin (McCormack, 1982). Feldmann and Maibach (1967) studied percutaneous penetration of taurocholic acid in vitro through male thigh skin in function of

Conclusions

The process of barrier diffusion by metals is complex. It is difficult to rationalize because a number of determining factors are closely interrelated, as exemplified by the factors influencing chromium diffusion as a function of pH, oxidation state, size and solubility. Reduction of relatively diffusible chromate to poorly soluble trivalent chromic ion occurs in transit through the skin; the change from dichromate to chromate is a function of rising pH; at higher pH values the chromium species

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