Proteome changes in rat serum after a chronic ingestion of enriched uranium: Toward a biological signature of internal contamination and radiological effect.

The civilian and military use of uranium results in an increased risk of human exposure. The toxicity of uranium results from both its chemical and radiological properties that vary with isotopic composition. Validated biomarkers of health effects associated with exposure to uranium are neither sensitive nor specific to uranium radiotoxicity and/or radiological effect. This study aimed at investigating if serum proteins could be useful as biomarkers of both uranium exposure and radiological effect. Male Sprague-Dawley rats were chronically exposed through drinking water to low levels (40mg/L, corresponding to 1mg of uranium per animal per day) of either 4% (235)U-enriched uranium (EU) or 12% EU during 6 weeks. A proteomics approach based on two-dimensional electrophoresis (2D-DIGE) and mass spectrometry (MS) was used to establish protein expression profiles that could be relevant for discriminating between groups, and to identify some differentially expressed proteins following uranium ingestion. It demonstrated that the expressions of 174 protein spots over 1045 quantified spots were altered after uranium exposure (p<0.05). Using both inferential and non-supervised multivariate statistics, we show sets of spots features that lead to a clear discrimination between controls and EU exposed groups on the one hand (21 spots), and between 4% EU and 12% EU on the other hand (7 spots), showing that investigation of the serum proteome may possibly be of relevance to address both uranium contamination and radiological effect. Finally, using bioinformatics tools, pathway analyses of differentially expressed MS-identified proteins find that acute phase, inflammatory and immune responses as well as oxidative stress are likely involved in the response to contamination, suggesting a physiological perturbation, but that does not necessarily lead to a toxic effect.

Risk of lung cancer from radon exposure: contribution of recently published studies of uranium miners.

The International Commission on Radiological Protection (ICRP) recently estimated the risk of lung cancer associated with radon exposure, and a statement was issued in ICRP Publication 115. This was based on recent epidemiological studies and the results from a joint analysis of cohorts of Czech, French, and German uranium miners, and indicated that the excess relative risk of lung cancer per unit of exposure should be expressed with consideration of chronic exposure over more than 10 years, by modelling time since median exposure, age attained or age at exposure, and taking in account, if possible, interaction between radon and tobacco. The lifetime excess absolute risk (LEAR) calculated from occupational exposure studies is close to 5 × 10(-4) per working level month (WLM) (14 × 10(-5) per hmJ/m(3)). LEAR values estimated using risk models derived from both miners and domestic exposure studies are in good agreement after accounting for factors such as sex, attained age, and exposure scenario. A sensitivity analysis highlighted the high dependence of background mortality rates on LEAR estimates. Using lung cancer rates among Euro-American males instead of the ICRP reference rates (males and females, and Euro-American and Asian populations), the estimated LEAR is close to 7 × 10(-4) per WLM (20 × 10(-5) per hm J/m(3)).

Modeling the imprecision in prospective dosimetry of internal exposure to uranium.

The dosimetry of internal exposure to radionuclides is performed on the basis of biokinetic and dosimetric models. For prospective purpose, the organ or effective dose resulting from potential conditions of exposure can be calculated by applying these models with dedicated software. However, it is acknowledged that a significant uncertainty is associated with such calculation due to the variability of individual cases and to the possible lack of knowledge about some factors influencing the dosimetry. This uncertainty has been studied in a range of situations by modeling the uncertainty on the model parameters by probability distributions and propagating this uncertainty onto the dose result by Monte Carlo calculation. However, while probability distributions are well adapted to model the known variability of a parameter, they may lead to an unrealistically low estimate of the uncertainty due to a lack of knowledge about some input parameters. Here we present a mathematical method, based on the Dempster-Shafer theory, to deal with such imprecise knowledge. We apply this method to the prospective dosimetry of inhaled uranium dust in the nuclear fuel cycle when its physico-chemical properties are not precisely known. The results show an increased estimation of the range of uncertainty as compared to the application of a probabilistic method. This Dempster-Shafer method may valuably be applied in future prospective dosimetry of internal exposure in order to more realistically estimate the uncertainty resulting from an imprecise knowledge of the parameters of the dose calculation.

Percutaneous penetration of uranium in rats after a contamination on intact or wounded skin.

The aim of this work is to assess in vivo in a hairless rat model, the percutaneous diffusion of uranium through intact or wounded rat skin. Six types of wounds were simulated by excoriation and burns with 10 N HF, 2, 5 and 14 N HNO3 and 10 N NaOH on anaesthetised hairless rats. Percutaneous penetration through wounded skin towards blood and subsequent urinary excretion of uranium was followed in vivo during 24 h. The influence of the physicochemical form (solution or powder) of uranyl nitrate (UN) on its percutaneous diffusion was also investigated. UN, even as a powder, can diffuse through intact skin. The presence of uranium in blood is more persistent and its urinary elimination is slower after an HF burn than after an HNO3 burn. Excoriation increases dramatically percutaneous absorption of UN. Thus, percutaneous diffusion of UN is largely dependent on skin barrier integrity with a particular importance of stratum corneum.

Incorporation and distribution of uranium in rats after a contamination on intact or wounded skin.

Uranium uptake can occur accidentally by inhalation, ingestion, injection, or absorption through intact or wounded skin. Intact or wounded skin routes of absorption of uranium have received little attention. The aims of our work were (1) to evaluate the influence of the type of wound contamination on the short term distribution and excretion of uranium in rats and (2) to generate data to assess the time available to treat contamination of intact or wounded skin before significant uptake of uranium occurs. Biokinetic data presented in the present paper are based on an in vivo rat model. This study shows that a significant uptake of a uranyl nitrate solution through intact skin can occur within the first 6 h of exposure. Absorption of a uranyl nitrate solution through excoriated skin is significant after only 30 min of exposure. After a 24-h exposure, uranium uptake through intact skin and excoriated skin represents about 0.4% and 38% of the initial deposit of uranium, respectively. Contaminated serious chemical skin burns induced by HNO3 or NaOH are paradoxically less important in terms of uranium uptake risk because 99% of the incorporated uranium remains trapped at the wound site and its incorporation is delayed for at least 6 h after the beginning of contamination. These results confirm that the biokinetics of a given physicochemical form of uranium incorporated after wound contamination depend largely on the physiological evolution of the considered wound. Each type of wound, with its corresponding biokinetics of a uranium species, is a particular case.

Comparison of the effects of enriched uranium and 137-cesium on the behaviour of rats after chronic exposure.

PURPOSE: A radionuclide that accumulates in the central nervous system is likely to exert both a chemical and a radiological effect. The present study aimed at assessing the behavioral effect of two radionuclides previously shown to accumulate in the central nervous system after chronic exposure--uranium and cesium. MATERIALS AND METHODS: Rats were exposed for 9 months to drinking water contaminated with either enriched uranium at a dosage of 40 mg U x l(-1) or 137-cesium at a dosage of 6500 Bq x l(-1), which correspond to the highest concentrations measured in some wells in the south of Finland (uranium) or in the milk in Belarus in the year following the Chernobyl accident (137-cesium). RESULTS: At this level of exposure, 137-cesium had no effect on the locomotor activity measured in an open-field, on immobility time in a forced swimming test, on spontaneous alternation in a Y-maze and on novel object exploration in an object recognition test. Enriched uranium exposure specifically reduced the spontaneous alternation measured in the Y-maze after 3 and 9 months exposure although it did not affect the other parameters. CONCLUSION: Enriched uranium exposure altered the spatial working memory capacities and this effect was correlated with previously described accumulation of uranium in the hippocampus which is one of the cerebral areas involved in this memory system.

Parental exposure to enriched uranium induced delayed hyperactivity in rat offspring.

Several recent reports suggest that chronic exposure to uranium could induce behavioural effects in adult rats. As the immature brains are known to be more susceptible to toxic effects, rats were observed in an open field, in a Y-maze and in an elevated plus-maze at 2, 5 and 9 months old after exposure to enriched uranium (40 mg l-1) during gestation and lactation. The rats exposed to enriched uranium showed a significant decrease in alternation in the Y-maze at 2 months old which reflects a slight decrease in the spatial working memory capacities as previously described in adult rats. However, the main result was a delayed hyperactivity in the rats exposed to enriched uranium, which appeared to a slight extent at 5 months old and was more evident at 9 months old. Although this effect could not be directly explained by some uranium accumulation in the target organs, this experiment showed that early exposure to enriched uranium can induce a very late effect on the rat behaviour and that such studies should not be restricted to the effects observed on young rats.

Short-term effects of depleted uranium on immune status in rat intestine.

In the event of ingestion, the digestive tract is the first biological system exposed to depleted uranium (DU) intake via the intestinal lumen. However, little research has addressed the biological consequences of a contamination with depleted uranium on intestinal properties such as the barrier function and/or the immune status of this tissue. The aim of this study was to determine if the ingestion of depleted uranium led to changes in the gut immune system of the intestine. The experiments were performed at 1 and 3 d following a per os administration of DU to rats at sublethal dose (204 mg/kg). Several parameters referring to the immune status, such as gene and protein expressions of cytokines and chemokines, and localization and density of immune cell populations, were assessed in the intestine. In addition, the overall toxicity of DU on the small intestine was estimated in this study, with histological appearance, proliferation rate, differentiation pattern, and apoptosis process. Firstly, the results of this study indicated that DU was not toxic for the intestine, as measured by the proliferation, differentiation, and apoptosis processes. Concerning the immune properties of the intestine, the ingestion of depleted uranium induced some changes in the production of chemokines and in the expression of cytokines. A diminished production of monocyte chemoattractant protein-1 (MCP-1) was noted at 1 day post exposure. At 3 d, the increased gene expression of interferon gamma (IFNgamma) was associated with an enhanced mRNA level of Fas ligand, suggesting an activation of the apoptosis pathway. However, no increased apoptotic cells were observed at 3 d in the contaminated animals. There were no changes in the localization and density of neutrophils, helper T lymphocytes, and cytotoxic T lymphocytes after DU administration. In conclusion, these results suggest that depleted uranium is not toxic for the intestine after acute exposure. Nevertheless, DU seems to modulate the expression and/or production of cytokines (IFNgamma) and chemokines (MCP-1) in the intestine. Further experiments need to be performed to determine if a chronic contamination at low dose leads in the long term to modifications of cytokines/chemokines patterns, and to subsequent changes in immune response of the intestine.

Effects of depleted uranium after short-term exposure on vitamin D metabolism in rat.

Uranium is a natural radioactive heavy metal. Its toxicity has been demonstrated for different organs, including bone, kidney, liver and brain. Effects of an acute contamination by depleted uranium (DU) were investigated in vivo on vitamin D(3) biosynthetic pathway. Rats received an intragastric administration of DU (204 mg/kg) and various parameters were studied either on day 1 or day 3 after contamination. Cytochrome P450 (CYP27A1, CYP2R1, CYP27B1, CYP24A1) enzymes involved in vitamin D metabolism and two vitamin D(3)-target genes (ECaC1, CaBP-D9K) were assessed by real time RT-PCR in liver and kidneys. CYP27A1 activity was measured in liver and vitamin D and parathyroid hormone (PTH) level were measured in plasma. In acute treated-rats, vitamin D level was increased by 62% and decreased by 68% in plasma, respectively at day 1 and at day 3, which paralleled with a concomitant decrease of PTH level (90%) at day 3. In liver, cyp2r1 mRNA level was increased at day 3. Cyp27a1 activity decreased at day 1 and increased markedly at day 3. In kidney, cyp27b1 mRNA was increased at days 1 and 3 (11- and 4-fold respectively). Moreover, ecac1 and cabp-d9k mRNA levels were increased at day 1 and decreased at day 3. This work shows for the first time that DU acute contamination modulates both activity and expression of CYP enzymes involved in vitamin D metabolism in liver and kidney, and consequently affects vitamin D target genes levels.

Accumulation and distribution of uranium in rats after chronic exposure by ingestion.

Data describing the biokinetics of radionuclides after contamination come mainly from experimental acute exposures of laboratory animals and follow-up of incidental exposures of humans. These data were compiled to form reference models that could be used for dose calculation in humans. In case of protracted exposure, the same models are applied, assuming that they are not modified by the duration of exposure. This work aims at testing this hypothesis. It presents new experimental data on retention of uranium after chronic intake, which are compared to values calculated from a biokinetic model that is based on experiments of acute exposure of rats to uranium. Experiments were performed with 56 male Sprague Dawley rats, from which 35 were exposed during their whole adult life to 40 mg L of uranyl nitrate dissolved in mineral water and 21 were kept as controls. Animals were euthanatized at 32, 95, 186, 312, 368, and 570 d after the beginning of contamination. Urine and all tissues were removed, weighted, mineralized, and then analyzed for uranium content by Kinetics Phosphorescence Analysis (KPA) or by ICP-MS. Experimental data showed that uranium accumulated in most organs, following a nonmonotonous pattern. Peaks of activities were observed at 1-3, 10, and 19 mo after the beginning of exposure. Additionally, accumulation was shown to occur in tissues such as teeth and brain that are not usually described as target organs. Comparison with model prediction showed that the accumulation of uranium in target organs after chronic exposure is overestimated by the use of a model designed for acute exposure. These differences indicate that protracted exposure to uranium may induce changes in biokinetic parameters when compared to acute contamination and that calculation of dose resulting from chronic intake of radionuclides may need specific models that are not currently available.

Chronic ingestion of uranyl nitrate perturbs acetylcholinesterase activity and monoamine metabolism in male rat brain.

Recent animal studies have shown that uranium can reach the brain after chronic exposure. However, little information is available on the neurological effects of chronic long-term exposure to uranium. In the present study, the effects during 1.5, 6 and 9-month periods of chronic ingestion of uranyl nitrate (UN) in drinking water (40 mg of uranium per litre) on cholinergic acetylcholinesterase (AChE) activity and on dopaminergic and serotoninergic metabolisms were investigated in several areas of male Srague Dawley rat brains. Uranium brain accumulation and distribution was also investigated after 1.5 and 9 months. Both after 1.5, 6 and 9 months of exposure, AChE activity was unaffected in the striatum, hippocampus and frontal cortex. Nevertheless, AChE activity was transitionally perturbed in the cerebellum after 6 months of exposure. After 1.5 months of exposure, DA level increased in hypothalamus. After 6 months of exposure, a tiny but significant modification of the DAergic turnover ratio was detected in the frontal cortex. And after 9 months, UN produced a significant decrease in the 5HIAA level and the 5HTergic turn-over ratio in the frontal cortex and also a decrease in the DOPAC level and DAergic turn-over ratio in the striatum. Uranium brain accumulation was statistically significant in striatum after 1.5 months and in striatum, hippocampus and frontal cortex after 9 months of exposure. Although neurochemical changes did not always correlated with increased accumulation of uranium in specific areas, these results suggest that chronic ingestion of UN can cause chronic and progressive perturbations of physiological level of neurotransmitter systems. Considering previous reports on behavioural uranium-induced effects and the involvement of neurotransmitters in various behavioural processes, it would be crucial to determine whether these neurochemical disorders were accompanied by neurobehavioral deficits even at 40 mg of uranium per litre exposure.

Absorption of uranium through the entire gastrointestinal tract of the rat.

The aim was to determine the gastrointestinal segments preferentially implicated in the absorption of uranium. The apparent permeability to uranium (233U) was measured ex vivo in Ussing chambers to assess uranium passage in the various parts of the small and large intestines. The transepithelial electrical parameters (potential difference, short-circuit current, transepithelial resistance and tissue conductance) were also recorded for each segment. Determination of in vivo uranium absorption after in-situ deposition of 233U in digestive segments (buccal cavity, ileum and proximal colon) and measurements of uranium in peripheral blood were then made to validate the ex vivo results. In addition, autoradiography was performed to localize the presence of uranium in the digestive segments. The in vivo experiments indicated that uranium absorption from the digestive tract was restricted to the small intestine (with no absorption from the buccal cavity, stomach or large intestine). The apparent permeability to uranium measured with ex vivo techniques was similar in the various parts of small intestine. In addition, the experiments demonstrated the existence of a transcellular pathway for uranium in the small intestine. The study indicates that uranium absorption from the gastrointestinal tract takes place exclusively in the small intestine, probably via a transcellular pathway.

The chemical speciation of uranium in water does not influence its absorption from the gastrointestinal tract of rats.

Studies of the chemical speciation of uranium in water can enhance the knowledge of the mechanisms of its absorption from the gastrointestinal tract and its storage in the body. They can also help to improve the dosimetric models recommended by the International Commission on Radiological Protection (ICRP). The aim of this work was to assess the influence of uranium speciation on its absorption from the gastrointestinal tract by using both computer speciation modeling and direct measurement of the fractional absorption in vivo in rats after ingestion of five different samples of contaminated water. Preliminary ex vivo studies with human saliva and gastric juice showed that 90% of uranium was recovered with the natural components of the fluid studied. The computer studies of uranium speciation among the electrolytes of these fluids showed that under the set conditions, the chemical species changed in a broadly similar manner under the influence of fluid composition and pH. In vivo studies in rats validated these observations by indicating an average fractional absorption of about 0.4% for each of five different water samples. It is concluded that the chemical form of uranium in the water ingested did not influence its absorption into the body.

The brain is a target organ after acute exposure to depleted uranium.

The health effects of depleted uranium (DU) are mainly caused by its chemical toxicity. Although the kidneys are the main target organs for uranium toxicity, uranium can also reach the brain. In this paper, the central effects of acute exposure to DU were studied in relation to health parameters and the sleep-wake cycle of adult rats. Animals were injected intraperitoneally with 144+/-10 microg DU kg-1 as nitrate. Three days after injection, the amounts of uranium in the kidneys represented 2.6 microg of DU g-1 of tissue, considered as a sub-nephrotoxic dosage. The central effect of uranium could be seen through a decrease in food intake as early as the first day after exposure and shorter paradoxical sleep 3 days after acute DU exposure (-18% of controls). With a lower dosage of DU (70+/-8 microg DU kg-1), no significant effect was observed on the sleep-wake cycle. The present study intends to illustrate the fact that the brain is a target organ, as are the kidneys, after acute exposure to a moderate dosage of DU. The mechanisms by which uranium causes these early neurophysiological perturbations shall be discussed.

Effect of U and 137Cs chronic contamination on dopamine and serotonin metabolism in the central nervous system of the rat.

Following the Chernobyl accident, the most significant problem for the population of the former Soviet Union for the next 50-70 years will be chronic internal contamination by radionuclides. One of the few experiments carried out in this field reported that neurotransmitter metabolism in the central nervous system of the rat was disturbed after feeding with oats contaminated by 137Cs for 1 month. The present study assessed the effect of chronic contamination by depleted U or 137Cs on the metabolism of two neurotransmitters in cerebral areas of rats. Dopamine and serotonin were chosen because their metabolism has been shown to be disturbed after external irradiation, even at moderate doses. Dopamine, serotonin, and some of their catabolites were measured by high-pressure liquid chromatography coupled with an electrochemical detector in five cerebral structures of rats contaminated over a 1-month period by drinking water (40 mg U.L -1 or 6500 Bq 137Cs.L -1). In the striatum, hippocampus, cerebral cortex, thalamus, and cerebellum, the dopamine, serotonin, and catabolite levels were not significantly different between the control rats and rats contaminated by U or 137Cs. These results are not in accordance with those previously described.

Efficacy of 3,4,3-LI(1,2-HOPO) for decorporation of Pu, Am and U from rats injected intramuscularly with high-fired particles of MOX.

This study aimed to assess the efficacy of 3,4,3-LI(1,2-HOPO) for reducing uranium, plutonium and americium in rats after intramuscular injection of (U-Pu)O2 particles (MOX). Sixteen rats were contaminated by intramuscular injection of a 1 mg MOX suspension and then treated daily for 7 d with LIHOPO (30 or 200 micromol kg(-1)) or DTPA (30 micromol kg(-1)). LIHOPO was inefficient for removing Pu, Am and U from the wound site. However, it reduced Pu retention in carcass and liver by factors of 2 and 6 respectively, and Am retention in carcass and liver by factors of 10 and 30. In contrast, the effect of LIHOPO on U was to decrease the retention in kidneys by a factor of 75. These results confirm that LIHOPO is a good candidate for use after contamination with MOX, in combination with localised wound lavage or surgical treatment aimed at removing most of the contaminant at the wound site.

Characterisation and dissolution of depleted uranium aerosols produced during impacts of kinetic energy penetrators against a tank.

Aerosols produced during impacts of depleted uranium (DU) penetrators against the glacis (sloping armour) and the turret of a tank were sampled. The concentration and size distribution were determined. Activity median aerodynamic diameters were 1 microm (geometric standard deviation, sigma(g) = 3.7) and 2 microm (sigma(g) = 2.5), respectively, for glacis and turret. The mean air concentration was 120 Bq m(-3), i.e. 8.5 mg m(-3) of DU. Filters analysed by scanning electron microscopy (SEM) and X ray diffraction showed two types of particles (fine particles and large molten particles) composed mainly of a mixture of uranium and aluminium. The uranium oxides were mostly U3O8, UO2.25 and probably UO3.01 and a mixed compound of U and Al. The kinetics of dissolution in three media (HCO3-, HCl and Gamble's solution) were determined using in-vitro tests. The slow dissolution rates were respectively slow, and intermediate between slow and moderate, and the rapid dissolution fractions were mostly intermediate between moderate and fast. According to the in-vitro results for Gamble's solution, and based on a hypothetical single acute inhalation of 90 Bq, effective doses integrated up to 1 y after incorporation were 0.54 and 0.56 mSv, respectively, for aerosols from glacis and turret. In comparison, the ICRP limits are 20 mSv y(-1) for workers and 1 mSv y(-1) for members of the public. A kidney concentration of approximately 0.1 microg U g(-1) was predicted and should not, in this case, lead to kidney damage.

Effect of DTPA on the nephrotoxicity induced by uranium in the rat.

The only treatment proposed after human contamination with MOX (mixed oxide of uranium and plutonium) is diethylenetriaminepentaacetic acid (DTPA), because plutonium is considered to be the major risk. However, both DTPA and uranium are nephrotoxic at high dosages and DTPA has been shown to increase in vitro the cytotoxicity induced by uranium on cultured epithelial tubular cells. This work aimed to test this effect in vivo. Rats were injected with subtoxic (57 microg kg(-1)) to toxic (639 microg kg(-1)) amounts of uranium as nitrate at 0 h, they received two DTPA injections (30 micromol kg(-1)) at 2 min and 24 h and were euthanased at 48 h. The nephrotoxic effects were evaluated by measurement of the body weight gain, food and water intake, measurement of biochemical parameters in urine and blood, and histological examination of one kidney. The main result was that DTPA did not increase the nephrotoxicity induced by uranium in the range of concentrations tested, which was inconsistent with the in vitro results.

Effect of absorption parameters on calculation of the dose coefficient: example of classification of industrial uranium compounds.

In the Human Respiratory Tract Model (HRTM) described in ICRP Publication 66, time-dependent dissolution is described by three parameters: the fraction dissolved rapidly, fr, and the rapid and slow dissolution rates sr and ss. The effect of these parameters on the dose coefficient has been studied. A theoretical analysis was carried out to determine the sensitivity of the dose coefficient to variations in the values of these absorption parameters. Experimental values of the absorption parameters and the doses per unit intake (DPUI) were obtained from in vitro dissolution tests, or from in vivo experiments with rats, for five industrial uranium compounds UO2, U3O8, UO4, UF4 and a mixture of uranium oxides. These compounds were classified in terms of absorption types (F, M or S) according to ICRP. The overall result was that the factor which has the greatest influence on the dose coefficient was the slow dissolution rate ss. This was verified experimentally, with a variation of 20% to 55% for the DPUI according to the absorption type of the compound. In contrast, the rapid dissolution rate sr had little effect on the dose coefficient, excepted for Type F compounds.

Reduction of uranium transfer by local chelation in simulated wounds in rats.

The aim of the paper is to develop a new approach to treat uranium-contaminated wounds. The efficacy of a local uranium chelator, carballylic amido bis phosphonic acid (CAPBP) was assessed using two different uranium compounds. Rats were contaminated by intramuscular injections of uranyl nitrate or an industrial U04 compound to simulate wound contamination. CAPBP was injected intramuscularly (i.m.) or intraperitoneally (i.p.) at a dosage of 30 micromol kg(-1). In one experiment, the local administration of CAPBP was combined with a systemic administration of ethane-1-hydroxy-1,1-biphosphonate (EHBP). The local CAPBP treatment resulted in increased retention of uranium at the wound site: about 30% for uranyl nitrate or U04 after the first day and about 15% of UO4 after the third day. Consequently, it reduced uranium translocation into the blood and deposition in the kidneys and bone. The combined treatment reduced the uranium deposits in the kidneys, bone and carcass to about one-half of those observed in controls 3 days after U04 contamination. The local CAPBP treatment increased the interval of time between contamination and uranium deposit in the target organs. Thus, it can increase the efficacy of nonspecific local treatments or specific systemic treatments. It could be given rapidly through spray or gel after an accident.