Pilot: Center for Appalachian Research in Environmental Sciences: Paw Pad Model of Transdermal Absorption of PAH and PFAS

Specific Aims: The leading cause of death in the Fire Service is cancer, with firefighters being more likely to be diagnosed and die from cancer than the general public. Firefighters are exposed to many topical irritants and carcinogens, despite appropriate use of personal protective equipment (PPE). This exposure often occurs in key areas such as the jawline, neck, and nape. Combustion-based polycyclic aromatic hydrocarbons (PAH) and per- and polyfluoroalkyl substances (PFAS) in Class B aqueous film-forming foams and safety gear are specific targets based on being known and probable human carcinogens that are absorbed through the skin. Fireground conditions can be extreme, and work conducted by firefighters is vigorous, leading to thermal strain and skin stress. These factors increase inflammation, vasodilation, sweating, and temperature, resulting in substantial changes in the absorption characteristics of the skin barrier at a time when protection is critical. The overarching aim of this line of research is to develop a unique product to solve the problem of transdermal chemical absorption during thermal strain and skin stress, by counteracting local inflammation, capillary permeability and flow, and the potential entry conduits through sweat glands. This product would prevent the short-term alterations in the skin barrier of firefighters and other workers or military personnel by attenuating these local physiological responses that decrease skin barrier properties. The goal of this UK-CARES Rapid Response Mini-Grant project is to: 1) provide pilot data for proof of concept to integrate a murine ex vivo model into our human in vivo approach, 2) demonstrate that we can measure PAH and PFAS movement across the skin in this experimental model, and 3) demonstrate an analysis relationship and established methods with UK-CARES Analytical Core Services for PAH and PFAS. Thus, our specific aim is to test the independent and combined roles of sweating, mast cell degranulation, and temperature in dermal absorption of specific PAH and PFAS in mouse paw pads. This will be accomplished ex vivo in murine paw skin model using a classic Ussing chamber approach to identify alterations in skin barrier and analytical quantification PAH and PFAS from the epidermal bath compared to the hypodermal bath. Hypothesis #1: Sudorific cholinergic agonists will decrease epithelial membrane resistance to increase PAH and PFAS movement across mouse paw pad skin. Furthermore, experiments will be conducted in normal (32°C) and elevated (39°C) skin temperatures to mimic heat stress conditions. Hypothesis #2: Histamine will decrease epithelial membrane resistance to increase PAH and PFAS movement across mouse paw pad skin. Furthermore, experiments will be conducted in normal (32°C) and elevated (39°C) skin temperatures to mimic heat stress. Hypothesis #3: Combined sudorific cholinergic agonists and histamine will decrease epithelial membrane resistance to increase PAH and PFAS movement across mouse paw pad skin in an additive manner. Furthermore, experiments will be conducted in normal (32°C) and elevated (39°C) skin temperatures to mimic heat stress. Given the PAH and PFAS exposure and cancer risk to firefighters, combined with the compromised skin barrier known to occur during physiological responses to fireground conditions, we are proposing an easy-to-use countermeasure cream to be rubbed on the skin in strategic locations where PPE is less effective. This murine model R&D is a necessary step to move the potential product from primarily theory into implementation. Subsequent studies will test the deployment, use, perception, and systemic utility of the physiologically based skin barrier cream in career and volunteer Fire Departments when used in conjunction with standard firefighter PPE. We are initially targeting the fire service because of direct application but other occupational exposure mitigation would naturally be derived from the work.