Assessment of skin absorption and penetration of JP-8 jet fuel and its components.

Dermal penetration and absorption of jet fuels in general, and JP-8 in particular, is not well understood, even though government and industry, worldwide, use over 4.5 billion gallons of JP-8 per year. Exposures to JP-8 can occur from vapor, liquid, or aerosol. Inhalation and dermal exposure are the most prevalent routes. JP-8 may cause irritation during repeated or prolonged exposures, but it is unknown whether systemic toxicity can occur from dermal penetration of fuels. The purpose of this investigation was to measure the penetration and absorption of JP-8 and its major constituents with rat skin, so that the potential for effects with human exposures can be assessed. We used static diffusion cells to measure both the flux of JP-8 and components across the skin and the kinetics of absorption into the skin. Total flux of the hydrocarbon components was 20.3 micrograms/cm(2)/h. Thirteen individual components of JP-8 penetrated into the receptor solution. The fluxes ranged from a high of 51.5 micrograms/cm(2)/h (an additive, diethylene glycol monomethyl ether) to a low of 0.334 micrograms/cm(2)/h (tridecane). Aromatic components penetrated most rapidly. Six components (all aliphatic) were identified in the skin. Concentrations absorbed into the skin at 3.5 h ranged from 0.055 micrograms per gram skin (tetradecane) to 0.266 micrograms per gram skin (undecane). These results suggest: (1) that JP-8 penetration will not cause systemic toxicity because of low fluxes of all the components; and (2) the absorption of aliphatic components into the skin may be a cause of skin irritation.

Mechanistic insights aid the search for CFC substitutes: risk assessment of HCFC-123 as an example.

An international consensus on the need to reduce the use of chlorofluorocarbons (CFCs) and other ozone-depleting gases such as the halons led to the adoptions of the 1987 Montreal Protocol and Title VI of the 1990 Clean Air Act Amendments, "Protecting Stratospheric Ozone." These agreements included major provisions for reducing and eventually phasing out production and use of CFCs and halons as well as advancing the development of replacement chemicals. Because of the ubiquitous use and benefits of CFCs and halons, an expeditious search for safe replacements to meet the legislative deadlines is of critical importance. Toxicity testing and health risk assessment programs were established to evaluate the health and environmental impact of these replacement chemicals. Development and implementation of these programs as well as the structural-activity relationships significant for the development of the replacement chemicals are described below. A dose-response evaluation for the health risk assessment of the replacement chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) is also presented to show an innovative use of physiologically based pharmacokinetic (PBPK) modeling. This is based on a parallelogram approach using data on the anesthetic gas halothane, a structural analog to HCFC-123. Halothane and HCFC-123 both form the same metabolite, trifluoroacetic acid (TFA), indicative of the same metabolic oxidative pathway attributed to hepatotoxicity. The parallelogram approach demonstrates the application of template model structures and shows how PBPK modeling, together with judicious experimental design, can be used to improve the accuracy of health risk assessment and to decrease the need for extensive laboratory animal testing.

Significance of the dermal route of exposure to risk assessment.

The skin is a route of exposure that needs to be considered when conducting a risk assessment. It is necessary to identify the potential for dermal penetration by a chemical as well as to determine the overall importance of the dermal route of exposure as compared with inhalation or oral routes of exposure. The physical state of the chemical, vapor or liquid, the concentration, neat or dilute, and the vehicle, lipid or aqueous, is also important. Dermal risk is related to the product of the amounts of penetration and toxicity. Toxicity involves local effects on the skin itself and the potential for systemic effects. Dermal penetration is described in large part by the permeability constant. When permeability constants are not known, partition coefficients can be used to estimate a chemical's potential to permeate the skin. With these concepts in mind, a tiered approach is proposed for dermal risk assessment. A key first step is the determination of a skin-to-air or skin-to-medium partition coefficient to estimate a potential for dermal absorption. Building a physiologically-based pharmacokinetic (PBPK) model is another step in the tiered approach and is useful prior to classical in vivo toxicity tests. A PBPK model can be used to determine a permeability constant for a chemical as well as to show the distribution of the chemical systemically. A detailed understanding of species differences in the structure and function of the skin and how they relate to differences in penetration rates is necessary in order to extrapolate animal data from PBPK models to the human. A study is in progress to examine anatomical differences for four species.

Air Force approach to risk assessment for halon replacements.

Finding safe, environmentally acceptable, and effective replacements for Halon fire-extinguishing agents and other chemicals banned by the Montreal Protocol is a formidable task for Air Force research and development organizations. One factor that makes this task a challenge is the uncertainty in relating toxicology studies in laboratory animals to the human situation. This uncertainty from toxicology studies affects the risk assessment process by calling for very conservative decisions. Because of this uncertainty, public pressure and politics also impact the regulatory process. The Air Force approach to assessing health hazards for Halon replacements is to provide scientific information that directly applies to the parts of the extrapolation process that are responsible for the most uncertainty. Most regulatory agencies readily incorporate scientific information, when it is available, which can reduce uncertainty. These Air Force studies will be used to provide realistic exposure levels for replacement chemicals which will allow mission accomplishment and provide safety for the worker and the populace.

Behavioral thermoregulation, core temperature, and motor activity: simultaneous quantitative assessment in rats after dopamine and prostaglandin E1.

These studies were designed to determine the dose-response autonomic and behavioral thermoregulatory effects and the motor effects of dopamine (DA) and prostaglandin E1 (PGE1) injected into the lateral cerebral ventricles of rats. These studies were made possible with a computer-controlled thermocline that permits freely moving rats to select preferred ambient temperatures ranging between 7 and 39 degrees C. All rats were studied with the thermocline gradient both on and off to control for nonspecific effects. PGE1 (0, 0.1, 0.2, 0.5, 1.0 micrograms) produced a dose-related increase in core temperature and produced a dose-related selection of warmer ambient temperatures. Dopamine (0, 50, 100, 200, 400 micrograms) produced a dose-related hypothermia and cold-seeking behavior. Without the gradient, DA-injected rats did not become as hypothermic as in the gradient-on condition. When the gradient was available, rats showed a significant rebound increase in core temperature 50-80 min after DA which did not occur when the gradient was off. Overall, DA induced increases in motor activity, but, during the first 10 min after injection while the gradient was on, the rats made stable selections of cool ambient temperatures and showed reduced activity. Conversely, the behavioral effect of PGE1 did not facilitate the autonomically mediated heat gain. These results emphasize the necessity of creating behavioral options for animals in order to fully evaluate drug effects on thermoregulation.