Disposition and pharmacokinetics of a lubricant contaminant, 2,6-di-tert-butyl 4-nitrophenol, in grafted human skin.

Disposition and uptake/elimination profiles of topical 2,6-di-t-butyl, 4-nitrophenol (DBNP), the nitrated metabolite of an antioxidant additive of lubricant and hydraulic fluids was quantified in human skin grafted on athymic mice after a single topical 75 microg dose in corn oil. DBNP was quantified throughout the stratum corneum (SC), epidermis (E) and dermis (D) in punch biopsies collected from treated skin 0.5, 1, 2, 4, 8 and 24 h after application. SC samples were harvested from the treated skin with 20 adhesive discs. E and D were generated from the biopsy using a manual sectioning method. Detectable DBNP concentrations were measured in all skin compartments at all time points investigated. The Cmax of DBNP in SC was 1663 +/- 602 microg cm(-3), and approximately 30 and approximately 300 fold greater than the Cmax for E and D, respectively. Tmax occurred at 1.0, 0.5 and 1.0 in the SC, E and D, respectively. Over a 24 h interval (AUC0-24 h) there was 52 and 520 fold more DBNP in the SC than E and D, respectively. The elimination half-life of DBNP was 11 h from the SC and 9 h from both E and D. Thus, DBNP was quickly absorbed into the outermost layer of skin and established a steep concentration profile through human skin. The data are consistent with the vast majority of DBNP remaining on the surface (77%) or within human skin (15%) in vivo with only 0.2% of the DBNP dose quantified in the systemic blood circulation.

Characterization of the skin penetration of a hydrocarbon-based weapons maintenance oil.

Break-Free CLP is a commercial petroleum-based liquid used for cleaning, lubricating, and protecting firearms that is used in the United States by military personnel, police, and individual gun owners for maintaining a wide variety of firearms. According to its material safety data sheet (MSDS), Break-Free CLP is predominately polyalphaolefin oil but also contains dibasic ester and isoparaffinic hydrocarbons; all of these ingredients are known to induce skin irritation in laboratory animals. Studies completed in our labs found that repeated topical application of Break-Free CLP to the backs of CD-1 mice produced evidence of systemic effects. Studies were conducted to characterize the dermal penetration of Break-Free CLP in mouse, rat, and pig skin to provide insight on possible factors or causes of skin irritation and systemic effects observed in previous studies. Mouse skin was 37 times more permeable to Break-Free CLP than pig skin and 6 times more permeable than rat skin. Flux measurements from static diffusion cells showed an inverse correlation with mouse, rat, and pig skin thickness. The concentration of Break-Free CLP in mouse skin was 4.5 times higher than the amount found in rat skin and about 17 times higher than the amount absorbed by pig skin. These results support the idea that Break-Free CLP causes skin irritation and systemic effects in the mouse by both penetrating through and accumulating in the skin. The findings for rat and pig skin are probably most representative of Break-Free CLP flux into and through unprotected human skin and suggest that dermal toxicity studies in CD-1 mice overestimate the risk to humans. These results, nevertheless, suggest that persons handling or using Break-Free CLP should protect the skin from possible exposure.

Issues with the integration of technical information in planning for and responding to nontraditional disasters.

In the post-9/11 environment, it has become recognized that the response to man-made disasters (such as chemical spills, bioterrorism, and radiation dispersal) requires a much broader range of tools and technical knowledge than needed for natural disasters (i.e., hurricanes, earthquakes, or drought). This need also requires that those who develop technical information for disaster planning maintain a broader perspective of how the information will be used and what the priorities are for developing new information. In addition, the ability to communicate information within a context understandable to the "end user" has become more critical. The intent of this article is to present issues to help those who traditionally collect and interpret technical information (toxicology, risk assessment, mitigation planners, etc.) to better understand how their information is used in planning for and responding to incidents. These issues are similar to those experienced when trying to provide the users of information provided on material safety data sheets (MSDS) with an understanding of the value and limits of such information in decision making. Confounding the problem are the many sources that provide exposure limits and the limited amount of time the user has to understand the limits of the data during an emergency. While the Federal Response Plan integrates the efforts of multiple agencies, the "on-scene" responders are faced with trying to respond to contradictory strategies and applications of information. Sources of response technical information need to better communicate the limits of application/interpretation of that information in emergency situations.

Disposition of 2,6-di-tert-butyl-4-nitrophenol (DBNP), a submarine atmosphere contaminant, in male Sprague-Dawley rats.

The phenol 2,6-di-tert-butyl-4-nitrophenol (DBNP) is a contaminant found onboard submarines and is formed by the nitration of an antioxidant present in turbine lubricating oil TEP 2190. DBNP has been found on submarine interior surfaces, on eating utensils and dishes, and on the skin of submariners. DBNP exposure is a potential health concern because it is an uncoupler of mitochondrial oxidative phosphorylation. Adult male rats were dosed once by oral gavage with 15 or 40 mg/kg DBNP mixed with 14C-DBNP in kanola oil and 0.8% v/v DMSO (n = 16/group). The distribution of 14C in major tissues was measured over time for up to 240 h post-dose. Unexpectedly, 6/16 (40%) of the rats gavaged with 40 mg/kg DBNP died within 24 h of dosing. Prostration, no auditory startle response, reduced locomotor activity, and muscular rigidity persisted in survivors for up to 8 days after dosing. For animals dosed with 15 mg/kg DBNP, radioactivity levels were significantly elevated in the following tissues 24h after dosing: fat>>>liver>kidneys>heart>lungs>brain>striated muscle>spleen. Radioactivity levels were elevated for fat, liver, kidney, heart, and lungs of animals euthanized 144 h post-dosing and in the liver of animals euthanized 240 h post-dosing. These findings suggest that DBNP may accumulate in the body as a result of continuous or repeat exposures of short interval to DBNP.

N-acetyl-L-Cysteine as prophylaxis against sulfur mustard.

Sulfur mustard (HD) is a blister agent targeting the eyes, respiratory system, skin, and possibly other organs. Extensive exposure can destroy the immune system by destruction of bone marrow cells. There is no antidote for HD or effective treatment other than rapid decontamination. Clinical trials have demonstrated activity for N-acetyl-L-cysteine (NAC) against a number of significant human pathologies involving free radicals, and animal and tissue studies have suggested efficacy for NAC as a chemoprotectant against many toxic chemicals. Among these are studies demonstrating that NAC significantly reduces the effects of HD and HD simulants, both in cultured cells and animals. Given the historical effectiveness of HD, the lack of any effective treatment, the demonstrated chemoprotective properties of NAC, its low toxicity, the lack of regulatory controls, and the data supporting efficacy against HD effects, we suggest daily oral administration of the maximum safe dose of NAC to personnel entering combat zones.

Percutaneous absorption of 2,6-di-tert-butyl-4-nitrophenol (DBNP) in isolated perfused porcine skin.

DBNP (2,6-di-tert-butyl-4-nitrophenol) has been reported as a potential contaminant in submarines. This yellow substance forms when lubrication oil mist containing the antioxidant additive 2,6-di-tert-butylphenol passes through an electrostatic precipitator and is nitrated. Percutaneous absorption of 14C-DBNP was assessed in the isolated perfused porcine skin flap (IPPSF). Four treatments were studied (n=4 flaps/treatment): 40.0 microgram/cm(2) in 100% ethanol; 40.0 microgram/cm(2) in 85% ethanol/15% H(2)O; 4.0 microgram/cm(2) in 100% ethanol; and 4.0 microgram/cm(2) in 85% ethanol/15% water. DBNP absorption was minimal across all treatment groups, with the highest absorption detected being only 1.08% applied dose in an aqueous ethanol group. The highest mass of 14C-DBNP absorbed was only 0.5 microgram. The majority of the applied dose remained on the surface of the skin. This suggests that there is minimal dermal exposure of DBNP when exposed topically to skin.

Exposure assessment and the health of deployed forces.

The risk assessment process is a critical function for military Deployment Toxicology research objectives, emphasizing improved health protection of deployed forces. Reliable risk assessment methodology is essential for decision making related to risk reduction procedures during combat deployment, as well as during routine occupational activities. Such decision making must be based upon quality science that both guides sound judgments in risk characterization and management, and provides necessary health protection tools. The health and fitness of deployed forces must be considered for both acute and long-term issues. Exposure assessment specifies populations that might be exposed to injurious agents, identifies routes of exposure, and estimates the magnitude, duration, and timing of the doses that personnel may receive as a result of their exposure. Acute or short-term catastrophic risks for deployed forces are of immediate concern and must be addressed on a risk prioritization basis using Operational Risk Management (ORM) procedures. However, long-term effects of exposure to the same agents must be considered as part of the overall health concerns for deployed forces. In response to these needs, a number of military, federal government, academic and private sector organizations are currently developing new classes of biologically-based biosensors with the programmed capacity to detect the presence of virtually any environmental chemical or biological stressor with the capacity to induce health consequences in deployed personnel. A major objective of this engineering effort is development of biosensor systems that detect novel (previously unresearched) chemical or biological agents that might be used during international combat or terrorist attacks to induce acute or long-term health effects on military or civilian populations. A large portion of the discussion in this paper is devoted to describing the development, testing, and implementation of tissue-based biosensors (TBBs) that utilize small samples of living tissue from laboratory small animals for a wide range of human risk assessment applications.

The utilization of risk assessments in tactical command decisions.

Traditional risk assessments (as delineated by regulatory agencies) use health outcome endpoints of interest to society as a whole, and are based on broad assumptions about the demographics of the potentially exposed populations and the routes of exposure. Immediacy of impact is not normally a major consideration. In tactical situations, the commander must balance considerations of short-term health effects against mission accomplishment. Often the commander will decide to accept a risk that would not be considered under other circumstances. The traditional tools of human-health and environmental risk assessment may be used, but the risk levels and projected consequences must be adapted to the tactical scenario (i.e. the performance decrement associated with a short-term exposure tactical operation vs. the long-term health out-come for an exposed population under 'normal conditions'). Risk assessors and health professionals must learn to articulate risk in terms that the tactical commander can place in his operational risk management (ORM) process. The process may require that the commander weigh non-health related mission critical considerations against health outcome issues. This presentation is intended to begin a dialogue that will lead to a harmonization of the use of risk assessment tools and their application in ORM as seen by tactical commanders, and a clarification of the strengths and limits of their utility in such applications.