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Break-Free CLP((R)) is a commercial cleaning, lubricating and preserving compound used in both the military and civilian sectors for maintenance of small- and large-caliber weapons. Like many commercial mixtures, there is very little information available on the toxicity of Break-Free CLP. Studies were conducted to characterize the biological effects of single or repeat dermal application of Break-Free CLP to the clipped backs of CD-1 mice. Break-Free CLP was applied neat, 50 microl three times of week for up to 2 weeks. Foci of epithelial ulceration were observed in skin sections from 22% of Break-Free CLP-treated animals in conjunction with markedly thickened epithelium suggesting that robust epithelial regeneration was occurring in these animals. Skin histopathology of Break-Free CLP-treated animals closely matched the histopathology from mice treated repeatedly with 2% croton oil in acetone (dermal irritation positive control). Serum alkaline phosphatase activity was significantly (P < 0.05) lower for mice treated with Break-Free CLP, 2% croton oil or 7,12-dimethylbenz[a]anthracene (DMBA) compared with negative and vehicle control mice. Skin nitric oxide (NO) levels were not significantly elevated for mice treated with Break-Free CLP but were significantly elevated for mice treated with dermal irritation positive control compound DMBA. The cumulative skin changes in Break-Free CLP-treated animals support conducting a subchronic dermal application study. The observed decreases in serum alkaline phosphatase activity suggest that future studies should include the liver and bone as possible target organs. Additionally, dermal penetration studies could provide key health risk assessment information for characterizing the potential health risks associated with chronic dermal exposure to Break-Free CLP.

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PCBs have been identified on surfaces and in component materials and equipment from inactive U.S. Navy nuclear submarines commissioned prior to 1970. Health risks associated with PCBs present onboard submarines were estimated for hypothetical crew members and shipyard workers. Median non-cancer hazard quotients for shipyard workers and submarine crew ranged between 0.4-54.6, with the highest quotients estimated for unprotected shipyard workers. Median cancer risk estimates ranged from 7.3 x 10(-6) to 1.1 x 10(-3) with the highest estimated risk calculated for unprotected shipyard workers. Our findings suggest that PCB surface concentrations found onboard inactive nuclear submarines commissioned prior to 1970 may be high enough to constitute a possible risk to the health of persons involved in dismantling of Navy submarines if PCB exposure is not minimized. Potential sources of uncertainty in our risk assessment include the correlation between PCB contamination levels on inactive versus active nuclear submarine vessels, the relationship between wipe sample concentrations and human exposure, dermal contact frequency with PCB-contaminated surfaces, carcinogenicity of PCBs in humans, and uncertainties inherent with the PCB cancer slope factor and oral RfD. Our findings support Navy policy that shipyard workers should wear personal protective equipment when PCB contamination is suspected or has been identified and that IH surveys should continue to identify sources of PCB contamination onboard vessels and reduce PCB contamination to concentrations that are reasonably achievable.

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U.S. Navy submarines reported a yellowing of metal surfaces on their internal surfaces. The yellowing was initially identified on the painted steel bulkheads but further examination indicated that it was not limited to steel surfaces and included bedding, thread tape, Formica, plastisol covered hand-wheels, and aluminum lockers. Crew members also reported to the medical department that their skin turned yellow when they came in contact with these contaminated surfaces and requested information on the effects of exposure. Studies conducted by General Dynamics' Electric Boat Division (EBD) determined that the agent was 2,6-Di-tertbutyl-4-Nitrophenol (DBNP). 2,6-Di-butylphenol (DBP) is an antioxidant additive used in lubricating oils and hydraulic fluids. In the enclosed atmosphere of a submarine, the oil mist could be spread throughout the boat by venting the lube oil to the atmosphere. Submarines use electrostatic precipitators (ESP) to clean the air of particulate materials. During passage through the ESP, oil mist containing DBP is nitrated to DBNP, which is then moved throughout the boat in the ventilation system. Analysis of the EBD data indicated 24-hour exposure concentrations to be in the range of <3.0 to 122 ppb in the laboratory and submarine settings. Submarine crews may be exposed to these concentrations for as many as 24 hours/ day for 90 days during underway periods. Toxicity studies regarding the oral and dermal uptake of DBNP were conducted. From the literature the lethal dose to 50 percent of the population (LD50) of DBNP (rat) was reported by Vesselinovitch et al. in 1961 to be 500 mg/kg. Our studies indicated that the LD50 is in the range of 80 mg/kg in the rat. Our work also includes dermal absorption studies, which indicated that DBNP is not well absorbed through intact skin. Within this study, no no-observable adverse effect level (NOAEL) or lowest observable adverse effect level (LOAEL) was identified. Calculation of a reference dose was completed using standard methods based on the LD50 as a numerator with several uncertainty and modifying factors. EBD's determination of airborne concentrations aboard submarines fall in the range of these anticipated allowable concentrations and could indicate significant chronic exposures. No adverse effects from DBNP exposures have been reported to date.

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This article explores protein conjugation of 7-oxodehydroabietic acid, a resin acid found in both aerosol from soldering with rosin flux and in rosin solids. In a murine model, conjugation (haptenation) of resin acids to proteins is required to generate antibodies against rosin. Hydroperoxy resin acids are dermal sensitizers, with haptenation thought to occur via radical mechanisms. Dermal sensitization to 7-oxodehydroabietic acid has been observed, although no radical haptenation mechanism has been proposed to explain the sensitizing properties of this compound. Conjugation of L-lysine to 7-oxodehydroabietic acid was predicted, with a Schiff base (or imine) linkage formed between C-7 of the resin acid and a free amino group of lysine. Fast atom bombardment mass spectrometry provided evidence of the conjugate; a small peak was seen for the conjugate (M+H)+ ion in aqueous ethanol with 20 mM concentrations of the free resin and amino acids. A larger conjugate peak was observed with addition of tertiary amine as a mild basic catalyst, and the intensity of the conjugate peak exceeded that of the precursors upon replacement of the ethanol with benzene. Resin acids accumulate in the plasma membrane, a non-aqueous environment apparently conducive to conjugation of 7-oxodehydroabietic acid with lysine side chains of membrane proteins. The result would be dehydroabietic acid covalently bound to protein, which could lead to interaction with immune cells having resin acid specificity. The haptenation mechanism presented may be involved in allergic contact dermatitis and occupational asthma observed from exposure to resin acid solids and aerosols. As sampling and analytical methods have been previously demonstrated for 7-oxodehydroabietic acid, this compound may be a useful exposure marker with relevance to negative health effects such as occupational asthma.

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Solvating gas chromatography (SGC) involves a mobile phase that is a supercritical fluid at the column inlet (typically 100-350 atm) and a gas upon exiting the column at ambient pressure. SGC has characteristics of both supercritical fluid chromatography and gas chromatography, and may be adaptable to a system with characteristics approaching a "universal chromatograph" capable of analyzing many classes of compounds on one instrument. We have recently found that using a solvating mobile phase such as CO2, together with small, spherical particle-packed capillary columns can offer significant advantages for rapid chemical analysis. A need exists in operational military settings to rapidly detect a wide range of chemicals with potential adverse health effects for exposed personnel. A separation step improves analytical capability by reducing or eliminating chemical background for better detection limits, and purifies or isolates target analytes and unknowns for improved identification. SGC, coupled to a high volume vapor/aerosol sampler and a rapid mass spectrometric detector such as a time-of-flight mass spectrometer could provide rapid, positive identification of separated compounds, with the resulting chromatographic and mass spectral data stored in digital format for future retrieval. Such a system will significantly advance the ability of military commanders to detect airborne chemical agents rapidly and accurately, protecting the health of military personnel.

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Exposure to rosin during a variety of uses has been associated with dermal and pulmonary sensitization. Oxidized resin acids are present in many rosin products, and have been regarded as the main sensitizing rosin compounds in cases of dermal sensitization. This research describes oxidized resin acids identified in aerosol produced during soldering with rosin core solder. Oxidized resin acids found were 7-oxodehydroabietic acid, 15-hydroxydehydroabietic acid, and 7-hydroxydehydroabietic acid. The presence of oxidized compounds known to be dermal sensitizers in aerosol from rosin flux soldering supports the hypothesis that resin acid compounds are pulmonary sensitizers as previously proposed. Changes in the composition of resin acid aerosol derived from heated rosin core solder (compared with the parent material) are described.

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A quality-management program (QMP) has been launched at the Naval Medical Research Institute Toxicology Detachment to support the planning, assessment, interpreting, and reporting of toxicology study data. The QMP conforms to the intent of the Good Laboratory Practice established by the Food and Drug Administration and the Environmental Protection Agency for regulatory compliance. The biomedical data necessary to characterize the toxicity of materials of interest to the Navy are used to formulate occupational and environmental health-hazard evaluations and risk assessments, including appropriate exposure limits for personnel for Navy-specific circumstances of exposure. The goal of the QMP is to help management and investigators ensure the quality and integrity of the data collected in laboratory animal toxicology studies. These data are used to reduce or eliminate potential health risks from exposure to toxicants during Navy operations. The primary purpose of the risk-reduction program is to help ensure readiness to accomplish the military mission. This article briefly reviews the need for the QMP and the military relevance of the quality-assurance requirements. The pros and cons of establishing the QMP are discussed, and examples of specific research projects and programs that support the need for a quality management program are presented. Aspects of integrating the QMP program to ensure compliance with Good Laboratory Practice are reviewed, and the value of the improvements in the quality of data from the Naval Medical Research Institute/Toxicology Detachment is summarized.

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Various uses of rosin and exposure to its resin acid constituents have been associated with dermal and pulmonary sensitization. Methodology is presented to detect resin acids common to rosin (such as abietic and dehydroabietic acid) found in aerosol from heated rosin flux. Air filtration, solvent filter extraction, and gas chromatography/mass spectrometry were used to provide qualitative and quantitative information on the resin acid content of aerosol produced during soldering with rosin flux. Abietic acid and dehydroabietic acid were identified and quantified in aerosol derived from heated rosin flux, in samples collected in the field and in laboratory generated samples. Other resin acids (including several apparently oxidized resin acids) were detected, but not quantified. Laboratory mass balance experiments using soldering temperatures and liquid rosin flux showed that much of the nonvolatile material originally present in unheated flux may be captured on a sampling filter following heating and aerosolization. The data presented suggest that resin acids are a major component (with regard to mass) of the airborne contaminants produced during soldering with rosin flux. Abietic acid was shown to be unstable on sampling filters held for a period of weeks, while dehydroabietic acid and total solvent-soluble material were not found to degrade under the same conditions. Rosin aerosol produced in the laboratory using a soldering iron and liquid rosin flux produced particles shown to be of respirable size using scanning electron microscopy.

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Components of colophony (rosin) resin acids are sensitizers through dermal and pulmonary exposure to heated and unheated material. Significant work in the literature identifies specific resin acids and their oxidation products as sensitizers. Pulmonary exposure to colophony sensitizers has been estimated indirectly through formaldehyde exposure. To assess pulmonary sensitization from airborne resin acids, direct measurement is desired, as the degree to which aldehyde exposure correlates with that of resin acids during colophony heating is undefined. Any analytical method proposed should be applicable to a range of compounds and should also identify specific compounds present in a breathing zone sample. This work adapts OSHA Sampling and Analytical Method 58, which is designed to provide airborne concentration data for coal tar pitch volatile solids by air filtration through a glass fiber filter, solvent extraction of the filter, and gravimetric analysis of the non-volatile extract residue. In addition to data regarding total soluble material captured, a portion of the extract may be subjected to compound-specific analysis. Levels of soluble solids found during personal breathing zone sampling during electronics soldering in a Naval Aviation Depot ranged from below the "reliable quantitation limit" reported in the method to 7.98 mg/m3. Colophony-spiked filters analyzed in accordance with the method (modified) produced a limit of detection for total solvent-soluble colophony solids of 10 micrograms/filter. High performance liquid chromatography was used to identify abietic acid present in a breathing zone sample.

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The human skin grafted congenitally athymic (nude) mouse, pig skin grafted nude mouse, hairless dog, and weanling Yorkshire pig were evaluated as models for predicting skin penetration in man. Nine radiolabelled compounds previously tested on man were applied topically (4 micrograms/cm2) to each model. These compounds included caffeine, benzoic acid, N, N-diethyl-m-toluamide, three steroids, and three insecticides. To correct for incomplete excretion of the label following topical absorption, per cent penetration was calculated by dividing the per cent of the topically applied radioactive dose recovered in the excreta by the corresponding percentage after parenteral administration and multiplication by 100. Calculated values of per cent penetration were confirmed in the case of the grafted nude mouse because significant correlations (r = 0.78 for human skin grafted athymic nude mouse and r = 0.97 for pig skin grafted athymic nude mouse) were found between the calculated values and the actual values obtained by summing the radioactivity recovered in the urine, faeces, tissues, and carcass. The results also revealed a significant correlation between human skin grafted athymic nude mouse values and human values (r = 0.74, P = 0.05) and between weanling Yorkshire pig values and human values (r = 0.83, P = 0.05). In contrast, no significant correlation existed between human values and those of the hairless dog and the pig skin grafted athymic nude mouse.

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The human skin grafted athymic nude mouse, pig skin grafted athymic nude mouse, hairless dog, and weanling Yorkshire pig were evaluated as models for predicting skin penetration in man. Nine radiolabeled compounds previously tested on man were applied topically (4 micrograms/cm2) to each animal. These compounds included caffeine, benzoic acid, N,N-diethyl-m-toluamide, three steroids, and three insecticides. To correct for incomplete excretion of the label following topical absorption, percentage penetration was calculated by dividing the percentage of the topically applied radioactive dose recovered in the excreta by the corresponding percentage after parenteral administration and multiplication by 100. In the case of the grafted athymic nude mouse, calculated values of percentage penetration were confirmed because significant correlations (r = 0.78 for the human skin grafted athymic nude mouse and r = 0.97 for the pig skin grafted athymic nude mouse) were found between the calculated values and percentage penetration determined by summing radioactivity recovered in the urine, feces, tissues, and carcass. The results revealed a significant correlation between human skin grafted athymic nude mouse values and human values (r = 0.74, p = 0.05), and between weanling Yorkshire pig values and human values (r = 0.83, p = 0.05). In contrast, no significant correlation existed between human values and those of the hairless dog and pig skin grafted athymic nude mouse. The disposition of radioactivity following topical application of the radiolabeled nerve agent analog ( diisopropylfluorophosphonate ) and simulant (diethyl malonate) was determined in the weanling pig and the human skin grafted athymic nude mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

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Because a large body of evidence suggests that the presence of circulating humoral factors could play a role in the induction/maintenance/resolution of psoriasis and because few investigators have explored their potential, we elected to conduct a survey analysis of the effects of the noncellular component of blood, serum, from normal and psoriatic subjects on assays of the inflammatory/immune system and on cell proliferation. Sera from psoriatic subjects are less chemotactic for monocytes than normal; this does not appear to be secondary to excess inhibitors for the chemoattractants, ZAS and bacterial factor. Preincubation of monocytes in psoriasis sera and normal sera results in an equal degree of inhibition of subsequent chemotaxis by monocytes. Relative to media alone, both normal and psoriasis sera equally inhibit DNA synthesis of HeLa cells. The addition of psoriasis sera to mitogenically stimulated lymphocytes will selectively suppress the blastogenic response in comparison to normal sera. These differences prompted a 2-d gel electrophoresis analysis of sera of psoriatic subjects. Specific differences are noted in the group of proteins migrating in the area of alpha 1 antitrypsin. These findings suggest that the noncellular component of the humoral system must also be factored into considerations of the etiopathology of psoriasis.

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The possibility that products released by inflammatory cells may play a role in the induction/maintenance of psoriasis is suggested by the observation that psoriasis, a disease of excess epidermal proliferation, is linked to inflammatory events. As an assessment of this possibility, the effects of supernatants from antigen stimulated and unstimulated peripheral blood mononuclear cells from normal and psoriatic subjects on the proliferation of HeLa cell cultures are presented. Data demonstrate that supernatants contain factors which both inhibit and enhance cell proliferation, both of which are released in greater quantities from antigen stimulated peripheral blood mononuclear cells. Dilutional and pulsing experiments show that proliferation enhancing factors present in these supernatants have an apparent greater affinity for HeLa cells than does the inhibitory component. Relative to HeLa cell proliferation in fresh media, both antigen stimulated and control supernatants from peripheral blood mononuclear cells of subjects with psoriasis have significantly less inhibitory and more of the enhancing effect than similar supernatants from normal subjects. Individual, as well as pooled, supernatants from subjects with psoriasis demonstrate these differences. The kinetics of this response are the same, normal vs. psoriasis. This "net effect" of supernatants from patients with psoriasis favoring proliferation is in harmony with the concept of inflammatory events playing a role in cell proliferation, and may be important in the induction/maintenance of psoriasis.

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Intradermal skin testing of normal and psoriatic subjects with common antigens, SKSD, Derm-O and PPD, reveals psoriatic subjects to have a decrease in both the amount (not incidence) of erythema (p less than 0.005) and in-duration (p less 0.005) to SKSD. Among all subjects having more than 10 mm erythema to Derm-O and SKSD, 49% of psoriatic and 77% of normal subjects have more than 10 mm induration (p less than 0.001). After sensitization, the response to 30 microgram challenge dose of dinitrochlorobenzene is positive in 50% of psoriatic and 88% of normal subjects (p less than 0.02). Uptake of (3)H thymidine by mitogen stimulated lymphocytes from psoriatic subjects is suppressed at each point of the linear component of a dose response curve. The mitogen dose to produce peak responses in psoriatics was 125% greater than that for normal subjects. In one-way mixed lymphocyte responses to pooled allogeneic stimulator lymphocytes, peripheral blood mononuclear cells from psoriatic subjects show suppression, the mean stimulation index was 55% of that of normal (p less than 0.01). Finally, in vitro polymorphonuclear leukocyte functions (chemotaxis, phagocytosis, and NBT reduction) appear to be within normal limits. When the foregoing parameters were compared with disease activity, there was no correlation.

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We have previously confirmed that subjects with psoriasis have an alteration of cell-mediated immune responses. We now report a possible in vitro corollary; the amount of lymphokine (lymphocyte-derived chemotactic factor) released by both antigen-stimulated and control lymphocytes is decreased in psoriatic subjects; 61% of similar values for normal subjects. Monocyte migration to complement-derived chemotactic factors is reported to directly correlate to skin tests; however, in psoriasis the relation is inverse, i.e., a 200% increase in complement factors and 136% increase to lymphocyte-derived chemotactic factor in monocyte migration is noted in psoriatic subjects when compared with normal subjects. This increased migration does not correlate with amount of disease and is still present in "disease-free" subjects. Culturing monocytes from psoriatic subjects in media alone demonstrates they reduce more (205%) nitroblue tetrazolium than do monocytes of normal subjects. These data demonstrate that monocytes from subjects with psoriasis are altered and suggest an apparent inherent metabolic disorder.

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