Percutaneous absorption of chemical mixtures.
Percutaneous Absorption: Drugs, Cosmetics, Mechanisms, Methods, Fourth Edition. Bronaugh RL, Maibach HI, eds., Boca Raton, FL: Taylor & Francis, 2005 Jul; :155-163
A primary route of occupational and environmental exposure to toxic chemicals is often through the skin. Although exposure to complex chemical mixtures is the norm, only mechanisms of absorption for single chemicals have been studied and most risk-assessment profiles are based on the behavior of single chemicals. Effects of co-administered chemicals on the rate and extent of absorption of a topically applied systemic toxicant may determine whether toxicity is ever realized. The application of risk assessment to dermal absorption by U.S. regulatory agencies (Environmental Protection Agency, Occupational Safety and Health Administration, Agency for Toxic Substance and Disease Registry) is varied and highly dependent upon available data (1-3). A similar concern over lack of data exists for overall risk assessment of chemical mixtures (4-7). A congressional Commission of Risk Assessment and Risk Management (8) recommended moving beyond individual chemical assessments and focusing on the broader issues of toxicity of chemical mixtures. Current approaches are based on assigning toxicological equivalent units to similar chemical congeners (e.g., dioxins) or assessing toxicity after exposure to the complete mixture. It is recognized (4) that the dose-response curves of individual mixture components should be characterized, and then a "no-interaction" hypothesis for these components in a mixture tested. With complex mixtures of hundreds of components, these approaches become exceedingly complex. Finally, mixture component interactions that involve modulation of a known toxicant's absorption, and thus systemic bioavailability, have not been defined. This problem is conceptually similar to that of dermatological formulations in the pharmaceutical arena. The primary difference is that most pharmaceutical formulation components are added for a specific purpose relative to the delivery, stability, or activity of the active ingredient. In the environmental and occupational scenarios, additives are a function on either their natural occurrence or presence in a mixture for a purpose related to uses of that mixture (e.g., a fuel performance additive) and not for their effects on absorption or toxicity of the potential toxicant. The appreciation of the importance of chemical mixture interactions to effect chemical and drug disposition, pharmacokinetics, and activity has been well recognized for many years and is extensively reviewed elsewhere (4,5,9-13). Despite the widespread knowledge base of the importance of drug-drug interactions and the importance of chemical interactions in systemic pharmacology and toxicology, very little attention outside of the dermatological and transdermal formulation arenas have been paid to interactions that may occur after topical exposure to complex mixtures. The focus of this chapter is to overview the potential mechanisms operative in topical chemical mixtures as well as to illustrate these interactions with data from our laboratory.
Skin-exposure; Skin-absorption; Absorption-rates; Chemical-kinetics; Chemical-properties; Dermatology; Biological-function; Exposure-assessment; Exposure-methods; Risk-factors; Toxins
Book or book chapter
Work Environment and Workforce: Mixed Exposures
Percutaneous Absorption: Drugs, Cosmetics, Mechanisms, Methods, Fourth Edition
North Carolina State University, Raleigh, North Carolina