By Dr. Asaf Durakovic
The medical and environmental consequences of contamination by uranium compounds constitute both a moral and legal requirement to control exposure to uranium at levels below those that cause death or pathological alterations, both due to its immediate and long-term action.
The purpose of this paper is to present a summary of the metabolic pathways of uranium compounds and isotopes, the medical consequences of uranium poisoning, and an evaluation of therapeutic alternatives in cases of internal uranium contamination. The chemical toxicity of uranium has been described for more than two centuries. Both animal and human studies are inconclusive regarding the nephrotoxicity and adverse metabolic effects of uranium compounds. The radiation toxicity of uranium isotopes has been known since the beginning of the nuclear age, as well as the mutagenic and carcinogenic consequences of internal uranium contamination. Natural uranium (U238), an alpha emitter with a half-life of 4.5 × 109 years, is one of the primordial substances in the universe. It is found in the earth's crust, combined with U235 and U234, alpha, beta, and gamma emitters with half-lives of 7.1 × 108 and 2.5 × 105 years, respectively. Depleted uranium deserves a special mention. The legacy of radioactive waste, the health and environmental hazards of the nuclear industry, and, more recently, military use on the battlefield, necessitate a new review of the toxicology of depleted uranium. The current controversy over the chemical and radiological toxicity of the depleted uranium used in the Gulf War justifies further research, both experimental and clinical, of its effects on the biosphere and on the human body.
Uranium is element number ninety-two in the Periodic System, it has 15 isotopes, with mass numbers from 227 to 240. Two of these, U235 and U238, are considered the primordial substances of the universe due to their half-lives of 7.1 × 108 and 4.49 × 109 years, respectively. The relative relationship between U235 and U238 is 0.72% and 99.27%, with the difference due to the abundance of U234 that exists in nature as one of the decay products of U238. When a uranium nucleus reaches a state of excitation capable of crossing the fission barrier, it undergoes a nuclear fission process, either through interaction with neutrons, with electrons, with photons, with mesons, or with charged particles such as deuterons and protons. If a nucleus penetrates the fission barrier, spontaneous fission occurs. In any of the processes, the nucleus is predominantly divided into two large particles of similar size, emitting neutrons or, less frequently, alpha particles. Sometimes the nucleus splits into three or more rapidly exciting nuclei fragments with a kinetic energy of 70-100 MeV. These nuclei emit neutrons, beta particles, x-rays, or gamma rays and remain radioactive even after reaching their ground state. The fission of uranium releases a total energy of ~ 200 Mev (1). Uranium can disintegrate by spontaneous fission, although induced fission is a more likely mode of decay for uranium isotopes. Fission induction is an extremely important factor in nuclear reactor technology and the probability of its occurrence is proportional to the reactor cross-sections for uranium isotopes (233U, U235, U238) and thermal neutrons (2 ). The energy released in fission is the sum of the energies of the fragments, the neutrons, and the photons of the fragments, and of the neutrons, electrons, photons, and antineutrinos emitted by the fragments. The two fragments typically released by fission in a large number of cases, result in a different mass distribution of the fragments of uranium isotopes that interact by thermal fission or with high-energy neutrons. The neutrons emitted in the actual fission, in the de-excitation of the fragments, or in the radioactive decay, are called cleavage neutrons or delayed neutrons, respectively. The number of fission neutrons is determined by the energy of the incident neutrons (3).
Uranium is the fourth element in the group of actinides (Z = 89-103) and the first in the group of urans. It can be produced in metallic form by various methods, including the reduction of uranium oxides, halides, and thermal disintegration of uranium halides. The most common method, the reduction with calcium or magnesium of uranium metal from uranium ore, has been studied extensively and has been described in detail in numerous texts and references (4). Uranium is a dense metal. The physical properties of its three allotropic forms depend on its microstructure, the purity of the sample, and the metallurgical origin. Uranium reacts with most non-metallic elements as a powerful reducing agent. The pyrophoretic properties of uranium have been extensively studied (5). It can produce spontaneous ignition at room temperature both in air and in oxygen or in water. At 200-400 ° C, uranium can ignite spontaneously in an atmosphere of carbon dioxide or nitrogen. Pyrophoricity depends on the heat produced in the metal's micropores. The oxidation of uranium can lead to an explosion. The lower limit for uranium dust cloud explosion is 55 mg / L. Aluminum and zincorium, mixed with powdered uranium, can be pyrophoric and explosive. Uranium compounds with other metallic elements have been extensively studied in order to be used as nuclear fuels. These include uranium hydride, fluorides (group IIIA), carbides, silicides (group IVA), nitrides, phosphides, and arsenides (group VA), oxides, sulfides, selenides, and tellurides (group VIA), fluorides , chlorides, bromides and iodides (group VIIA), uranium salts (carbonates, phosphates, halides) with polyatomic anions of uranium, uranates, and peri-uranates. Uranium solutions are relatively stable in an inert atmosphere. Said stability depends on the acidity of the medium and the chemical nature of the acid. In hydrochloric acid solutions the stability increases proportionally to the acid concentration; however, uranium ions are quite unstable in perchloric or sulfuric acid solutions regardless of concentration (6).
Uranium ions form complexes with organic ligands such as ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTA), and hexaethylene diamine tetraacetic acid (HDTA) (7). These complexes are stable. The properties of uranium to form complexes in aqueous solutions are well known. In the liquids of the human organism it interacts with a great variety of compounds that compete to bind to uranium ions. The uranium-bicarbonate complex is of particular importance, since it increases the solubility of uranium in serum. This compound is quite insoluble in water due to the complexity of the bond between uranium ions and bicarbonate. This mechanism determines the transport of ultrafiltrable uranium from the places of contamination to the tissues and target organs (8). In blood, the uranium-bicarbonate complex establishes an equilibrium with unfilterable uranium ions bound to proteins, with 60% uranium-bicarbonate and 40% uranium-proteins (9). In other studies, 74% of uranium in blood was found in the inorganic compartment of plasma, 32% bound to proteins and 20% to red blood cells (10). Complexes of uranyl salts with bicarbonate are less stable than complexes of uranous salts. Reduction of uranium in plasma is unlikely, but uranium salts can be reduced in the intracellular environment (11). The deposition sites for uranous salts (IV) are the bones and the kidney, while uranyl ions (VI) accumulate in the liver and spleen before being redistributed to the renal and skeletal systems. 60% of the uranium administered intravenously is excreted in the urine in 3 days, with the mineral phase of the bone being the main retention site. Each of the uranyl ions binds to two phosphate ions on the surface of bone crystals, simultaneously releasing two calcium ions. The uranous ion produces a toxic effect on living cells by altering carbohydrate metabolic processes by inhibiting certain enzyme systems, particularly hexokinase, at ATP-dependent surface formation sites through magnesium hexokinase. The adsorption process results in the sixth glucose carbon atom joining with a phosphorylated ATP atom, and in inhibiting the re-entry of a negatively charged glucose-6-phosphate through a point on the cell surface. negatively charged. A uranyl ion that replaces a magnesium ion binds the ATP molecule to hexokinase. This ATP-uranyl-hexokinase complex blocks the release of phosphate to glucose, thus inhibiting the first step of its metabolic utilization with non-metabolized glucose in the extracellular medium (12).
Various mechanisms have been studied in order to reduce the effects of uranium contamination. These include:
1) add phosphate or polyphosphate ions to the system;
2) add uranium complexing agents to remove uranium bound to phosphate groups; Y
3) remove the uranium already deposited in the target organs.
Among the potential therapeutic agents, including bicarbonate, citrate, lactate, and fumarate, bicarbonate was the most effective ion scavenger. This is probably due to the fact that most complexes, once metabolized, leave an alkaline residue in the form of bicarbonate. The toxic effects of uranium in rats were reduced 12 hours after uranium administration (13). The mortality rate of rats pretreated with bicarbonate 2-3 days prior to uranium administration decreased from 80% to zero.
Other agents studied for uranium removal include hydroxyaspartate and citrate (14), catechol disulfonate (15), calcium salts of polyphosphates (16), and chelating agents. Polyphosphates, although they reduce the mortality rate associated with uranium poisoning, cause metabolic acidosis and hypocalcemia, which makes their use impractical as a treatment for uranium contamination (16). The effects of EDTA have also been shown to be beneficial, with a toxicity of 3.8 g / kg in rats (16). Isolated injection is less effective than multiple parenteral injections of EDTA-Ca prior to intraperitoneal injection of uranyl nitrate. EDTA-Ca, however, does not reduce uranium retention once incorporated into bone (17). Other chelating agents used in experimental rodents include diethylene triamine pentaacetic acid (DTPA), triethylene tetraamine hexaacetic acid (TTHA), diamine diethylthioether tetraacetic acid (DDETA), and ethylene diamine tetraacetic acid (EDTA), DTPA being the more effective compared to other chelating agents (18). Some Russian studies have shown an increase in uranium removal in vivo with the use of diemino diethylthioether tetraacetic acid (DDETA) in rats (19).
Other actinides that can cause significant contamination of the biosphere include plutonium and transplutonian elements. While the toxicity of uranium has been studied for more than a century, plutonium was theoretically postulated as element 94 in 1941 when it was isolated by Glenn Seaborg and Edwin McMillan at Berkeley, at the University of California. No element in the periodic system attracted as much attention and controversy as plutonium. Its original amount of 0.5 mg in March 1941, has reached the tens of thousands of kilograms in today's world of strategic nuclear arsenal and plutonium reactors. Although there are references to plutonium as the most toxic substance known to man (20), there is ample experimental evidence for its carcinogenic properties (21), particularly on osteogenic sarcoma (22).
Another actinide important for its medical effects is americium, produced by the capture of neutrons by Pu239 to form Pu 241 and Am 241 by dividing the mass fraction 241 from a plutonium sample. Its 458-year half-life, high-energy alpha monoenergetic emissions (E = 5.44-5.49 MeV) and gamma monoenergetic emission (E = 59.6 KeV), as well as the production of hundreds of kilograms per year, generate a risk of pollution internal (23). The pulmonary, hepatic and skeletal deposition places Am241 close to plutonium in terms of the radiological danger of actinides (24).
Another actinide of interest is thorium (Th227-Th232), with biological effects on the lung, liver, bone, and kidney (25).
Other transplutonian elements of interest include curium (element 96), berkelium (element 97), californium (element 98), einsteinium and fermium (elements 99 and 100), mendelevium (element 101), and nobelium ( element 102), as well as the subsequent controversial elements of Lawrencio, Rutherfordium, Hahnio, and future heavy and superheavy elements, for the moment only of theoretical interest.
The first studies carried out at the University of Tübingen (Gmelin 1824) on the biological effects of uranium indicated that orally administered uranium is a weak poison, but it is fatal in intravenous injection. This work was carried out with pure uranium oxide prepared in the form of citrate, sulfate, and uranyl chloride and was carried out in experimental dogs and rabbits by means of the oral and intravenous administration of uranium salts. Oral administration of uranium in the form of sulfate (300 mg) or nitrate (900 mg) did not demonstrate any immediate symptoms, but a 4-g dose of uranyl nitrate produced emesis in dogs. Uranium chloride administered by gastric tube (2 g) caused death in a rabbit in 52 hours. The pathomorphological examination showed diffuse inflammatory changes of the gastric mucosa with extravasation of leukocytes. The intravenous administration of 600 mg of uranyl nitrate or 180 mg of chloride killed one dog in one minute, the autopsy findings being blood clots in the right ventricle and in the great vessels, as well as a considerable pericardial effusion. Only 3 of the 18 metals studied in Gmelin's work produced similar results: barium, palladium, and uranium (26).
Thirty years after the publication of Gmelin's work, Leconte described the peculiar and unique effects of uranium in the form of acetate and nitrate on the uropoietic system. Uranium salts produce anuria, oliguria, and glucosuria (27) in dogs, the dose being 0.6-1 g lethal in rabbits (27). This work also confirmed Gmelin's findings regarding pathological changes in the stomach, heart, and great vessels, and posited asphyxia as the leading cause of death. Anuria was interpreted as impaired renal circulation, and glucosuria as impaired sugar metabolism due to uranium-induced liver disorders. Leconte's findings were immediately used in homeopathic medicine, directed towards the treatment of diabetes mellitus in humans (28). Uranium was then studied in patients with diabetes and kidney dysfunction (29). A reduction in polydipsia, polyuria, and glycosuria was observed in> 80% of cases after oral administration of uranyl nitrate. This use continued even until 1930, with the last commercial preparation of "vin urané" for the treatment of diabetes. Commercial uranium preparations were abandoned due to associated kidney pathology and considerable side effects, including dyspepsia, diarrhea, increased uric acid excretion, and weight gain. Finally, its use was discontinued because it was a dangerous drug, contraindicated in diabetes.
The toxicity of uranium was recognized early, leading to its widespread use in experimental pathophysiology, primarily to produce experimental glomerulonephritis. Renal damage, both structural and functional, is limited to the terminal third of the proximal convoluted tubule, even after administration of small doses of uranium salts, whereas glycosuria, which was initially considered a consequence of liver injury, later appeared be of renal origin. This is also true for hematuria, albuminuria, hyaline and granular bodies, azotemia, and tubular necrosis (30).Experimental work showed that parenteral administration of uranium produces extreme toxicity and some authors rated it as the most toxic of metals (31). Damaged tubular epithelium was also found to show a considerable rate of atypical cell regeneration (32). The toxic effects of uranium increased with the administration of calcium (33) or ephedrine (34), while with the administration of epinephrine the toxic effects were less severe (35). Studies on the renal toxicity of uranium have been conducted since the mid-nineteenth century. For more than 100 years, experimental models and pathology and clinical studies have demonstrated the association between uranium poisoning and chronic Bright's disease, from nephromegaly with tubular and glomerular abnormality to small, granular kidneys with a functional pattern. of polyuria, albuminuria, tubular casts, glucosuria, oliguria, and terminal anuria (36). These studies provided conclusive evidence that uranium was one of the most dangerous kidney poisons in the category of tubular toxins, acting similar to mercury and chromium. Later studies also demonstrated glomerular alterations (37), which showed that the nephrotoxicity of uranium was not limited only to the tubular system. Small doses of uranium cause glomerular damage, with necrosis, coagulation, capsular and glomerular edema, obstruction of efferent vessels, and hyaline degeneration (38). The uranium-damaged tubular system had rapid regeneration, with the appearance of large nuclei, meiotic activity, and replacement of damaged cells, as well as proliferation of connective tissue. Regeneration originated in the narrow portion of the loop of Henle, the terminal portion of the proximal convoluted tubule, and the upper portion of the descending loop. The regenerated epithelium was as vulnerable to uranium as the original epithelium prior to injury (39). With exposure to higher and repeated doses, kidney tissue began to show resistance to the toxic effects of uranium (40). This resistance was associated with atypical cells of the regenerated tubular epithelium (41). However, if the repair process was not completed and if the tubular epithelium was repaired with undamaged tubular cells, resistance to subsequent uranium-induced poisoning no longer occurred. The exact mechanism of this resistance has not been fully clarified (42). The granular obstruction of the tubule induced by uranium and the granular and hyaline casts do not appear to be the consequence of a biochemical alteration of the blood, but rather a specific alteration produced by uranium (43). Regarding the histomorphological alterations of the kidney, numerous studies have confirmed the alteration of kidney function (44), as well as changes in acidity and the excretion of acetone, ketone bodies, and organic acids, in animals (45) and in workers with professional exposure to uranium (46). Other functional changes - an increase in the specific gravity of urine, an initial increase and a delayed decrease in chlorine excretion, and a similar pattern of sodium and potassium excretion, an acidosis with altered urine composition - have been well documented as consequences of uranium poisoning (47). Blood changes on exposure to uranium have also been well documented. These include: 1) increased nitrogen retention (48); 2) a decrease in serum albumin (49) and other proteins; and 3) an increase in serum of: creatinine, ammonia, ureic nitrogen and uric acid. Sodium and chloride concentrations decreased, calcium, potassium, phosphate and magnesium concentrations did not change, while total lipids and cholesterol, as well as blood glucose, increased in uranium poisoning (50). Studies on the effects of uranium on the liver have been inconclusive, although there is consistent evidence of fatty degeneration in experimental animals with chronic uranium poisoning, centrilobular necrosis, dilated and congested sinusoids, and granular degeneration, described as a similar entity. to hepatophoria (44). Biliary excretion does not appear to be altered, although uranium is excreted in the bile (51). The effects described by uranium poisoning on the nervous system have been hind leg paralysis, blindness, and a loss of coordination in rabbits, in the terminal phase of poisoning (52). The effects of uranium on muscle tissue have not been significant, although in cardiac perfusion studies it was observed that uranium decreased contractility when administered as UNO3 in Ringer's solution.
The chemical toxicity of uranium has been known for 200 years and its radiation toxicity for a century, with the discovery of radioactivity in 1896. During the Manhattan project, medical and basic research paid special attention to the toxic properties of uranium. This was a turning point for the production and use of uranium in various physical and chemical forms, both in the military and in industrial projects. The toxicity of uranium has been classified into three groups based on its transportability: high, moderate, and slightly transportable. The high transportability group includes uranium compounds with a biological half-life of days, the moderate group of weeks to months, and the mildly transportable group of months to years. Transportability is determined by the mobility of uranium from the target organ to the extracellular fluid and the bloodstream. Other classifications of uranium toxicity are based on the percentage of U235 present in the uranium materials and its origin within the reactor (54). Materials with> 5-8% U235 have a serious risk of nephrotoxicity if they are in highly transportable form, whereas the same rate of U235 in a less transportable form does not present the same danger to the kidney or lungs. Some uranium materials with less than 5-8% U235 concentration can present a significant risk from exposure to their radiation, even solely from external irradiation. This is mainly due to the first and second decay products of U238: Th234 and Pa234 (UX and UX2) which are powerful beta emitters. At high temperatures, such as during molten uranium processing or the impact of a projectile, these isotopes can cause a risk of external radiation to personnel, whose exposure must be reduced by suitable protective clothing. Materials with <5-8% U235 have less radiation hazard. Environmental monitoring is an essential prerequisite for the correct assessment of the risk of exposure, including the concentration of uranium in the air, the amount released into the biosphere and the residue of uranium material in the incident area, as well as the taking of samples to determine surface contamination. Personnel monitoring is also essential, including biological studies, in vivo monitoring and analysis of target tissues.
Exposure to uranium isotopes poses both a chemical and toxic hazard to the human body, and has been extensively studied from the earliest data on uranium miners to the more recent depleted uranium controversy in the Gulf War. The inhalation of radioactive dust with the consequent risk of internal contamination by U238, U234, Th230 and Ra226, has been well documented in the literature in studies originating in different parts of the world (55), with a particular reference to exposure to radon and its subsidiary products Po213, Pb214, and Po214, formed in radon decay processes in mines (56). The North American Uranium Registry, funded by the Department of Energy and managed by the Hanford Foundation for Environmental Health, is responsible for three major medical areas related to uranium. This registry, founded about 20 years ago, defined three major areas of registration related to uranium: 1) inspection of facilities where uranium is used; 2) the review of epidemiological studies; and 3) the internal deposit in humans of uranium and its degradation products (57).
The United States Transuranium Registry (USTR) was another program established in 1968 as the National Plutonium Registry. He carried out actinide biodistribution studies in humans (58). Most recent studies indicate a significantly higher frequency of malignant diseases in uranium workers (59), with an increase in mutations in underground miners (60) and connective tissue diseases, including lupus erythematosus (61). In a recent Chinese study, reproductive toxicity of uranium includes chromosomal aberrations in spermatogonia, leading to DNA modifications in spermatocytes and sperm disruption (62). This has serious implications for the current controversy over depleted uranium and the Desert Storm syndrome (63), and the relationship of Al Eskan's disease (64) to depleted uranium ammunition and weapons.
Metabolic Pathways of Uranium
Early observations in the early nineteenth century noted the nephrotoxicity of uranium, with necrosis in the proximal convoluted tubule and a moderate degree of fibrotic and inflammatory changes resulting in a scarred kidney (65). In cases of non-fatal poisoning, the damaged tubular epithelium rapidly regenerated (66), and subsequently developed tolerance to high doses of uranium (67). The regenerated epithelium was metaplastic, different from normal epithelium, and the postulated mechanism of tolerance was the inability of uranium compounds to interact with renal tubular cells (68). Toxic effects were also observed in liver (69), central nervous system (70), and blood (71). The key event, which brought uranium studies to the highest level of scientific attention, was the outbreak of World War II. There was the largest experimental investigation of any toxicant in such a short period of time (72), carried out as part of the Manhattan Project. The University of Rochester Research Center concentrated predominantly on uranium dust inhalation studies, while various research projects at the University of Chicago studied the metabolic pathways of uranium and its toxicology after ingestion or parenteral administration in various animal models. and in human volunteers (73). Animal studies were carried out after oral, intravenous, or intraperitoneal administration, application to the eye and skin, and after inhalation. There are three main routes of internal contamination by uranium: 1) gastrointestinal system; 2) skin and wounds; and 3) transalveolar transfer by inhalation into the bloodstream.
Gastrointestinal absorption of uranium isotopes is relatively low in the adult human body but still constitutes a considerable biomedical hazard because of its long half-life, nephrotoxicity, and retention in skeletal tissue. While U234 and U235 have a high potential to induce malignancy of bone and hematopoietic tissues, the dangers of depleted uranium (DU) are predominantly its nephrotoxicity and general metabolic toxicity (102). The radiological hazard depends on the mechanism of entry and retention in the body.
Oral routes of exposure have been studied since the early twentieth century. Even then, it was shown that, although uranium predominantly enters both animals and the human body through the respiratory route, it can also be ingested, thus accessing the gastrointestinal system (74). In one of the studies, nine uranium compounds were investigated in rats, mice, rabbits, and dogs. Metabolic pathways were also investigated in several experimental designs, with histopathology and mortality studies. Although death occurred at different time intervals, depending on the dose of uranium, the sex of the animal, the age, and the nutritional status, all exposed groups suffered kidney damage. Ingestion of uranium compounds resulted in higher concentrations in kidney and skeletal tissue in animals fed soluble materials. In experiments in rats, it was found that a content in the diet of 0.5% of UO2F2 for 1-2 years resulted in a skeletal retention of 60 g / kg, while the ingestion of uranyl following a similar experimental protocol, resulted in retention in bone 150-200 g / g in the bone mineral phase. These results are of tremendously significant importance in the panorama of the radiological risk of uranium retention in bone, where the maximum dose allowed was considered 25 g / g of wet bone, which would reproduce an approximate dose of 0.45 rem (<0.5 mSv ) / 24 hr. Since the studies were carried out in relatively short-lived rodents, these findings are of considerable interest in human toxicology in view of the lower turnover of non-exchangeable bone minerals. Actinide absorption is rather low in the gastrointestinal tract, higher in young experimental animals than in mature ones, and considerably lower in the form of insoluble oxides than in insoluble nitrates (75). These results were consistent across species - mice, rats, guinea pigs, dogs, and pigs. Greater absorption of uranium ingested with food of animal origin was observed; in association with the vegetarian diet it was also increased compared to absorption in solution form. Uranium absorption also increased with fasting (76). Oral administration of uranium in humans has been studied for about 150 years. It was originally used in the treatment of diabetes mellitus (77). It was subsequently used as a metabolism stimulant, administered in increasing doses from 30-60 mg to 1.8 g of uranyl nitrate in aqueous solution (78). Oral administration in humans was finally discontinued in 1936, when its toxicological risks were declared to be greater than any of its undefined health benefits (79). However, oral administration continued in uranium workers. They were administered an oral dose of uranyl nitrate in water and the pattern of excretion was studied. An absorption of less than 1% of the administered uranium and a renal excretion of 66% of the absorbed dose were found (80). The studies were carried out in hospitalized volunteer patients with no previous history of gastrointestinal or kidney disease. The metabolic pathways of uranium were studied after oral administration of 10 mg of uranyl nitrate. The content in feces and urine was analyzed and it was found that urinary excretion was in a range between 0.3-3.0% of the ingested dose, with about 30% of the absorbed uranium incorporated into the kidney and bone. The distribution and retention of uranium in the internal environment, particularly in kidney and bone, seem similar in humans and experimental animals. The gastrointestinal tract of internal uranium contamination produces adverse clinical symptoms that include diarrhea and vomiting, with the consequent decrease in intestinal absorption (81). The gastrointestinal route is the least unfavorable of the possible routes of uranium poisoning.
Animal studies carried out over 150 years show that intravenous administration of small doses of several micrograms per kg of uranium compounds results in urinary elimination of 60-80% within the first 24 hours. The hexavalent salts of uranium, forming complexes with proteins, phosphates, citrates, or bicarbonates, are filtered in the glomerular system, while a smaller quantity, between 10-20%, is retained in the bone (82). In human metabolism studies, blood, urine, and fecal samples were analyzed and kidney function tests were performed; the excretion curves indicated a rapid elimination of 50% of hexavalent uranium, while 14-30% was slowly excreted during days after administration. Acute parenteral toxicity was studied at much higher large doses in experimental animals with different uranium compounds. Uranium fluoride was shown to be more toxic than nitrate or tetrachloride, with a lethal dose of 2 g / kg. In human experiments conducted at Massachusetts General Hospital and Boston Veterans Administration Hospital by the Oak Ridge Laboratory team, patients who were given intravenous injections of uranium suffered from terminal central nervous system disease and almost all fell into a coma at the time. injection. The intravenous dose of uranium covered a range of 72-907 mg / kg. Excretion at 24 hours averaged 56.2%, while fecal excretion was less than 0.03%. Most of the retained uranium was in the kidney and bone, with minimal retention in 21 other tissues and organs (83). The experimental use of intravenous uranium in humans has been used as a database for the evaluation of a wide variety of bone disorders.This is due to the verified ability of the uranyl ion to form stable compounds with phosphate groups in bone crystals, both in the exchange and non-exchange phase (84).
Contamination through Skin and Wounds
Internal contamination through wounds and the entry of DU into the systemic circulation were described in the Gulf War (1991). Although those soldiers with wounds containing uranium fragments were identified, there are no updated data on this patient population. However, studies of carcinogenicity markers in rats showed a significant 1000-fold increase in uranium levels six months after the implantation of shrapnel particles. The alteration of oncogene expression was dose and time dependent. These results indicate that UE may be a decisive factor in the induction of malignant diseases in humans. UE induces phenotypic transformation of the tumorigenic cell at a relatively low radiation dose (0.13 Gy), indicating both chemical and radiotoxic properties of UE in oncogenic expression of the cell (103).
Dermal exposure to soluble uranium compounds results in severe poisoning and death, with extensive experimental evidence of significant amounts of uranyl nitrate, fluoride, pentachloride, trioxide, sodium diuranate, and ammonium into the bloodstream after skin absorption. Insoluble oxides (UO2, UO4, U3O8) and uranium tetrafluoride (UF4) do not appear to present a significant toxic risk in transdermal application. There is a very important interspecies difference in the lethal effect of uranium compounds applied through the skin, with decreasing susceptibility in rabbits, rats, guinea pigs and mice. However, the toxicological manifestations of transcutaneous contamination by uranium compounds, which include kidney alterations, weight loss and death, are similar in all the species studied. Repeated exposure to uranium compounds by dermal application results in tolerance to cumulative doses, which would produce a fatal effect in a single initial application.
Internal contamination with depleted uranium by inhalation is the most important route of entry to the extracellular fluid, through the bronchoalveolar tree. Inhaled UE particles are absorbed in the upper bronchial tree, and through the alveolar surface. If it is a soluble uranium compound, it passes into the systemic circulation.
The bronchoalveolar deposition of radioactive particles has been actively studied for decades (104). The radiation hazard of inhaled radioactive particles was studied with different actinides (105) and the general pattern of metabolic behavior in the respiratory system was formulated in 1955 by the International Commission on Radiation Protection (ICRP), including recommendations of parameters for study of respiratory routes of contamination (106). The experimental model was later revised, emphasizing uranium, plutonium, and their fission products (107). According to this model, about 25% of the radioactive particles are deposited in the bronchial tree, 25% are immediately exhaled, while 50% pass into the nasopharynx and are swallowed, with consequent gastrointestinal absorption. Intestinal absorption of DU is negligible, which places the respiratory tract in the category of the greatest radiotoxicological hazard. One of the therapeutic targets in internal contamination by DU should include the transfer of inhaled particles to extrapulmonary routes. The deposit of UE particles on the alveolar surface will result in their absorption, depending on their solubility; approximately 10% of the particles are deposited in the lungs and will reach the systemic circulation, the remaining 15% will rise to the nasopharynx by expectoration and end up in the gastrointestinal tract. The soluble uranium compounds absorbed from the pulmonary tree are deposited in bone within a few weeks, with a biological half-life in the lung of 120 days. In the case of inhalation of uranium oxides, the expected retention in the lung is considerably longer, about 1470 days. Fatal cases of respiratory uranium poisoning have been described in patients with nephrotoxic syndrome, including glomerular and tubular damage, azotemia, albuminuria, and tubular necrosis. Less soluble compounds are not as rapidly absorbed through the respiratory system (108). Compartment analysis, kinetics, and autopsy data have not been defined in animals or human exposure to depleted uranium. Additional studies in experimental animals and human exposure data will be necessary to have a more complete understanding of the toxicity of depleted uranium.
The fraction of DU in the air comprises a range from 0.9% to 70%, depending on the penetration, the speed, and the material of which the target is made (109). The impact of a 150mm penetrator releases 2.4 kg of DU into the air. Half of the UE particles released into the air during tests with 105mm projectiles were in the respirable range and were capable of reaching the non-ciliated portion of the bronchial tree (110). In other studies, 70% of the DU particles released into the air after impact were less than 7 mcm, within the respirable range. An aerodynamic equivalent diameter (DAE) of 10 mcm is considered non-breathable, 5 mcm 25%, 3.5 mcm 50%, 2.5 mcm 75%, and 2.0 mcm 100% breathable (110). Particles larger than> 5 mcm and very small particles less than <0.2 mcm are not significant when considering inhalation hazard. Particles in the respirable range can be retained in the lung, causing damage by local radiation, or be deposited in target organs after passing into the bloodstream. Retention is determined by the concentration of particles, their density, size, shape, and the respiratory pattern of the exposed person. Soluble DU compounds quickly enter the bloodstream and primarily exert a toxic effect on the kidney as a chemical agent rather than as a radioactive substance. Insoluble compounds remain in the lungs, with a biological half-life of 120 days, and represent a radiation hazard to alveolar tissue. One study reported that 60% of insoluble uranium was retained in lung tissue for 500 days (111). Uranium oxide is considered relatively insoluble, while uranium dioxide is moderately soluble.
Although the bronchoalveolar route is itself the most important route of entry of uranium to the internal environment in the human body, there have been very few controlled exposures of man to uranium compounds by inhalation. The size of dust particles in uranium mines or in the uranium industry is considered too large to reach the micro-bronchiolar and alveolar compartment of the human lung. It was assumed that these particles would deposit in the nasopharyngeal region, where they could be swallowed and eliminated by the gastrointestinal tract (85). In uranium plants, particle size sampling indicated a probability of up to 99% that the dust concentrated in the upper respiratory tract. One experiment, called a "miniature cyclone," simulated the distribution of uranium dust particles between the upper and lower airways. Urinary excretion after inhalation only showed a mean rapid elimination time of about 7 hours. The half time slow elimination of about 100 hours. The average size of the respirable uranium dust particle was much larger than the size of a UO3 aerosol particle. Given that 85% of the UO3 found in the micro-bronchial and alveolar tree is in the form of UO3, which is excreted by the kidney, it has been postulated that uranium is mobilized from the lungs to the systemic circulation; about 60% is deposited in bone and kidney and 40% is excreted in urine (86). Industrial exposure to uranium dust includes particles that vary in size and uniformity. Postmortem studies in uranium workers provided the basis for the differentiation between inhaled soluble uranium deposited in bone and insoluble uranium in the tracheobronchial tree. The dissolution kinetics by alveolar macrophages was studied in the uranium oxide retained in the bronchoalveolar tree (87). Respiratory radiation toxicity has been known for several decades; inhalation chemical toxicity for two centuries. Recent evidence of a high incidence of systemic sclerosis in the lungs of German uranium miners further confirms the importance of airway contamination (88). The most recent reports confirm the association between the uranium mine environment and squamous cell carcinoma (89). This fact implies a reconsideration of the relationship between genetic cancer and environmental cancer.
Depleted uranium is natural uranium in which the content of U235 is reduced from 0.7% to 0.2%. The enrichment process that enables the use of uranium in reactors and nuclear weapons results in a by-product, partially depleted, with a U235 content of approximately one third of its original content in natural uranium. Uranium is present in the environment in low concentrations throughout the world; the most abundant deposits are in sedimentary rocks. The main areas with rich uranium deposits are the Colorado Plateau in Wyoming in the United States, the Blind River and Beaver Lodge in Canada, the Erz Mountains in Central Europe, the Ural Mountains in Russia, the Rand Mountains in South Africa, the French Alps, Radium Hill in Australia and the Pyrenees in Spain. Open mines have been the preferred way of obtaining uranium, but some deposits are too deep for this form of excavation and have necessitated deep underground mining. The uranium content of most minerals is in a range between 0.1-1.0% of U3O8. However, it is often found in a much higher concentration, presenting a serious hazard to workers from beta irradiation and inhalation of airborne dust in the mine environment. Inhalation toxicities are highly dependent on the size of the respirable particles, specifically the portion of inhaled dust that is deposited in the non-ciliated portion of the lung. The 10 mcm particles are not respirable, while the 2 mcm particles have practically free access to the alveolar compartment. The aerosols commonly found associated with uranium oxide have more DAE than the sand of the Arabian desert, and about 80% is deposited in the alveolar portion of the lungs, 10% in the lymph nodes of the thorax, and the rest in the upper respiratory tree. This demonstrates the importance of the airway as a port of entry in the Gulf War. Studies of Persian Gulf Syndrome and Al Eskan disease point to the small size (<1 mcm) and uniformity of fine Arabian desert dust particles as contributing factors in Desert Storm Disease.
Estimates of radiation from uranium mines in Japan, Australia, France, Spain, and Mexico are in the range of 0.02 to 4.0 mrem / hour, although in areas of uranium-rich deposits, gamma radiation can reach 20 mrem / hour ( 94). The primary radiation hazards to lung tissue in uranium mines come from Radon-222 and its daughters Po218, Pb214, and Po214 (95).
Depleted uranium, a by-product resulting from the enrichment of natural uranium, presents an internal danger due to its passage through the parenteral route into the extracellular fluid and the incorporation of uranium into the target organs, that is, the skeletal tissue in the case of uranyl salts (VI) and the kidney for uranous compounds (IV). While the less soluble uranium compounds have primarily long-term risk of depositing in bone, the more soluble compounds are predominantly nephrotoxic to the proximal convoluted tubule (96)
The enrichment process increases the percentage of fissile fuel in the center of the reactor, leaving behind the depleted uranium with a reduced content of U235 and U234, which is not a fissile material. The chemical and metallic properties of depleted uranium (DU) are practically identical to those of natural uranium ore from uranium oxides. Natural uranium has a specific activity of 6.77 × 10-7 A / g, and depleted uranium 3.6 × 10-7 A / g. The isotope content of U238 in natural uranium is 99.27%; U235 is 0.72%, and U234 is 0.006%. The isotopic composition of enriched uranium is U238 = 97.01%, U235 = 2.96% and U234 = 0.03%. EU contains U238 = 99.75%, U235 = 0.25% and U234 = 0.005%. All three isotopes undergo degradation resulting in a cascade of residual compounds. However, most of the 238U decay products are removed in the gaseous diffusion process (97). Radon is unlikely to constitute a contamination risk for personnel exposed to the impact of DU penetrators, even if it is one of the compounds resulting from the decay of U238 (98)
The high density of UE (19 g / cm3) makes it an excellent penetrating armor material (99). In the American Air Forces the UE is used in an alloy with 0.75% titanium; the Navy with 2% molybdenum, and the Army uses an alloy (QUAD) that contains 0.5% titanium, 0.75% molybdenum, 0.75% zirconium, and 0.75% niobium. DU metal does not differ from natural uranium in its chemical properties and internal contamination by DU has the same toxicity as natural uranium. It oxidizes at room temperature and in water vapor, necessitating the use of protective aluminum clothing (100). The American Nuclear Regulatory Commission classifies the EU as a source material, regulated by general and specific regulations. General regulations regulate the use and transport of UE and fixes a maximum amount of 15 pounds each time and a maximum of 150 pounds per year. The specific regulations refer to larger amounts of EU. Requirements for granting a license include written documentation of the intended use of the UE equipment, compliance with safety measures in terms of health, environment and safety, as well as staff training (101). The medical consequences of internal contamination by EU are similar to those of natural uranium (metabolic pathways, chemical toxicology and radiation). The effects of internal radiation of UE depend on the amount, the size of the particle, its solubility, the route of entry and the physiological pathways that determine its metabolic fate. The high organ-specificity of UE can cause chemical and radiation damage to target organs, mainly kidney and bone; its excretion is determined by the biological half-life and by the elimination kinetics of the contaminated organism. As UE is a radioactive material with marked trophism in bone tissue, its incorporation into non-exchangeable bone crystals produces long-lasting biological retention. The result is a high probability of malignancy of the radiosensitive tissues of the target organs, due to their long half-life and particle radiation (alpha and beta).
Alpha radiation from UE is not a significant external hazard due to its low penetration and low specific radioactivity of U238. However, beta radiation is the predominant component of the DU penetrator, with the most energetic of the particles 2.29 MeV (Pa234) and a maximum penetration of 0.5 cm into aluminum. Approximately 91% of the beta particles come from Pa234 and 8% from Th234. Both are effectively protected by the metallic component of the UE, without significant Bremsstrahlung component. Gamma rays are the main type of radiation, with photon energies from 700 KeV to 1 MeV. The surface area of a 120 mm UE bare penetrator (1R = 2.58 × 10-4 LC / kg) produces a beta exposure of 217 ± 20.4 mR / hr, and a gamma exposure of 26 ± 2.7 mR / hr. The surface of an unshielded UE metal produces an exposure of 225 mR / hr, only 1% from gamma radiation. A discovered phalanx penetrator produces a beta exposure of 52.2 mR / hr and a gamma exposure of 2.5 mR / hr (112). These exposure rates are similar to those of natural uranium. Although x-rays and gamma rays are always detectable in the immediate environment surrounding UE munitions, their levels are very low and do not constitute a danger from external irradiation. The main danger of the UE comes from internal contamination.
The impact of a depleted uranium penetrator exposes personnel present to a radiation hazard that exceeds the maximum allowable dose, with an average post-impact aerosol concentration from a 120 mm projectile exceeding 47 × 10-8 Ci / mL (1 Ci = 3.7 × 104 Bq) two minutes after being fired (112).Due to the radiation hazard, the CRN sets limits for the maximum permissible airborne concentration of 7 × 10-11 Ci / mL for soluble DU and 1 × 10-10 Ci / mL for insoluble DU in order not to exceed 15 rem in lung and kidney over a 50-year working life (101).
Depleted uranium penetrators do not pose a significant chemical hazard in solid metallic form. However, they can present a significant risk of heavy prométal poisoning due to their nephrotoxicity, once they have reached the bloodstream through the inhalation inlet, if the particles are of respirable size. EU Chemical Toxicity Threshold Limit Values (VULs) have been determined by the Occupational Safety and Health Administration (OSHA) at 0.25 mg / cm3 for insoluble and 0.05 mg / cm3 for soluble depleted uranium. However, airborne concentrations of 69-1664 mg / cm3 measured in the vicinity of the UE penetrator test zones tremendously exceed the VUL limits. The application of controls has been recommended to ensure safe radiological conditions. Special emphasis on personal monitoring includes personal dosimeter, respiratory protection, protective clothing, SOPs, and record keeping. All persons involved in the military use of UE should be radiologically controlled with dosimeters for skin and total body exposure, in addition to routine pulmonary and biochemical (urine) monitoring. All personnel handling UE must receive annual UE hazard and radiation safety training. Various samples of surrounding water and soil, as well as air and waste should be analyzed by health physicists, and faithfully documented. These measures must be observed both by the army and by civilians who run the UE. Toxicity and Radiation
The medical aspects of uranium exposure lead us to the silver mines in Europe, mainly those in the Erz, Schneeburg and Joachimstall mountains (Jachmov, now in Germany). Long before the discovery of radioactivity in 1896, mine workers were observed for five centuries to die of "black lung disease." Medical studies from this century showed a 50% incidence of lung cancer in these areas (113). The current radiation hazard in such places is estimated to be about 2.9 × 10-9 Ci. The estimated danger in the early days was higher, in the range of 1.5 × 10-8 Ci. Canadian data on uranium miners in Newfoundland showed that 51 of 142 cancer deaths were due to lung cancer in workers who spent 2,000 hours in underground mines. Uranium was the only cancer risk element identified in that study (114). North American studies of the biological effects of uranium exposure in Colorado mines showed that of 4,146 miners, 509 died during the eighteen-year observation period, with 386 deaths expected in that population (115). The deaths were predominantly caused by lung cancer and kidney disease. Similar data have been found in different parts of the world, such as recent studies of reproductive toxicity in Chinese uranium workers (62), silicosis and incidence of lung cancer in New Mexico (116), recent German studies describing changes in the immune system of uranium miners (88), and chromosomal and endocrine alterations in Namibian miners (117). All studies agree as to the toxic properties of uranium compounds for the population.
The toxicity of uranium as a heavy metal has been extensively studied for two centuries. The main parameter in the evaluation of its toxicity was mortality and LD50 at different doses in single administration or as a function of time. Other widely studied parameters include survival time, effects on growth and development, excretion of uranium in urine, deposition in tissues and organs, and general and local health consequences. During the Manhattan Project, acute toxicity studies were conducted at various National Centers in the United States; the most exhaustive investigation was carried out at the University of Rochester in an animal model (rat) with uranyl nitrate, fluoride and tetrachloride in parenteral administration.
Further preparation of UF6 by oxidation or fluorination provides the basis for the combination between UF6 and metal fluoride. Uranyl fluoride was shown to be more toxic than uranyl nitrate or uranium tetrachloride, with the fatal dose of uranyl nitrate being 2 mg / kg subcutaneously or 0.4 mg / kg by intravenous injection. The insoluble compounds UO2, U3O8, and UF4 were shown to be non-toxic by the oral route in rats, while six other soluble compounds had considerable. Uranyl nitrate had a more toxic effect on mature rats than on newborn rats. The main chemical toxicity was observed in the proximal convoluted tubule of the kidney. Experiments in dogs with an oral administration of 0.2 mg / kg of soluble UO2F2 to 10 mg / g of insoluble UO2, as well as 0.2 g / kg of uranyl nitrate and 0.05 g / kg of uranium tetrachloride, demonstrated tubular changes in the cortical kidney with very little evidence of necrosis. Renal pathology was a common finding for different uranium chemical compounds administered parenterally.
The percutaneous application of uranium was studied with soluble compounds that included uranyl fluoride, nitrate, pentachloride and trioxide, and sodium and americium diuranate. All the compounds tested absorbed through the skin into the bloodstream and in excessive doses were capable of causing severe poisoning and death. In contrast, insoluble uranium compounds, such as oxides and tetra fluoride, did not produce significant toxicity when applied to the skin. There is a considerable interspecies difference in dermal toxicity of uranium compounds. Rabbits are the most sensitive followed by rats, guinea pigs, and mice. There is a difference of up to a hundred times the LD50 between rabbits and mice. The organ that suffers the greatest toxicity is the kidney, with changes similar to those observed in other types of parenteral toxicity.
The application of uranium to the eye has been studied as a possible route of entry of uranium to the internal environment of the living organism, given the risk of ophthalmic exposure of uranium workers. Uranium application was carried out on the conjunctiva of rabbits, guinea pigs, and rats in the form of uranium peroxide, dioxide, tetrafluoride, nitrate, fluoride, sodium and ammonium diuranate. There was a local lesion that ranged from conjunctivitis to corneal ulcer. Of all compounds tested, the most severe reactions occurred with dry uranium pentachloride. Periorbital tissue necrosis followed in death in 50% of the animals. Uranyl nitrate, fluoride, and sodium diuranate were absorbed through the conjunctiva and produced systemic poisoning. Uranium tetrafluoride and diuranate caused systemic poisoning with very little local irritation.
Chemical poisoning by uranium compounds after respiratory exposure has been studied extensively in order to establish safety standards for the control of possible health risks related to uranium dust. These experimental studies of intoxication by heavy metals through the respiratory tract have been carried out according to different experimental designs (118).
The study of eleven uranium compounds in different trials of elaborate experimental design, from the Manhattan project to the most recent ones, suggests that soluble uranium compounds are definitely toxic, frequently resulting in death (0.2 m / m3), mainly due to of lung and kidney toxicity. Less soluble dust, such as UF4 and high-grade mineral, produces relatively little kidney damage, at a level of 2.5 mg / m3. Tritaoctoxide (U3O8) did not produce any systemic toxicity. Toxicity, mortality, and kidney damage vary enormously between different species. Chronic toxicity studies in dogs, rats, rabbits, mice, and guinea pigs, in which uranyl nitrate hexahydrate, hexafluoride, tetrachloride dioxide, and tetrafluoride were tested, did not reveal significant abnormalities in the administration of low doses during a year. Two years of exposure did cause chronic kidney injury. In the five years of follow-up, there was evidence of malignant lung tumors, including adenomas and adenocarcinomas (119), mostly in the dog and monkey studies.
Radiation Uranium Toxicity
Natural uranium contains 99.28% U238, 0.72% U235, and 0.006% U234. The decay of uranium-238 produces thorio (Th234), which becomes protactinium (Pa234), and uranium-234. The physical half-life of U238 is 4.5 × 109 years, U235 = 7.1 × 108, and U234 = 2.5 × 105. Uranium isotopes and their decay products are alpha, beta, and gamma emitters and are spontaneously fissile. Radon (Rn222), an alpha emitter, one of the decay products of U238, presents a considerable inhalation hazard in uranium mines. Uranium ore (U3O8) is obtained from mines, concentrated, and processed into americium diuranate, which is fluorinated and, once enriched, can be used as fuel in reactors and nuclear weapons. The by-product of the enrichment process is depleted uranium. All steps of uranium isotope mining and processing are associated with radiation risk and internal contamination.
In the decay process of U238, its daughter products Th234 and Pa234 reach secular equilibrium with their original isotope in approximately 6 months, disintegrating at the same rate as U238. They emit alpha and beta particles and gamma rays. Gamma radiation interacts with the internal environment through photoelectric and Compton reactions; it can pass through layers of several hundred cells, producing radiation-induced alterations in tissues. Protactinium-234 beta particles (E = 2.29 MeV) have powerful ionizing radiation that can pass through several hundred cells. Alpha particles, although low penetration, present a high risk of radiation because of their mass, their positive charge, and their powerful ionization capacity. Alpha particles can present considerable genetic or carcinogenic risk when localized in the vicinity of highly radiosensitive, undifferentiated cells such as pluripotent stem cells. All three forms of disintegration constitute a biological risk of internal contamination, mainly when inhaled or enters the body through damaged skin or wounds from projectile fragments.
Uranium waste products interact with the internal environment by direct ionization as charged particles and by indirect interaction as electromagnetic radiation, producing an energy transfer to the tissue by ionization and excitation, as well as by formation of free radicals. Structural changes in molecules include hydrogen bond breaking, molecular disintegration, and cross-linking. Structural modifications of molecular integrity give rise to functional changes with the consequent metabolic alterations, which can alter the genetic transcription and translation of the macromolecular codes of both DNA and RNA. This happens mainly in the nucleus, which is the main target of the lethal effects of ionizing radiation. According to the target hypothesis, several alpha particles that generate a dose of 25 cGy can kill the cell if they target the nucleus, while a dose of the same alpha radiation would have to be 2-4 thousand times higher to kill the cell if goes to the cytoplasm. While 97% DNA repair can occur after a single radiation exposure, constant exposure to internally deposited alpha emitters can lead to chromosomal aberrations, mutations, or cell malignancy.
Radiation-induced modifications of uranium compounds are well documented. Lung cancer in uranium miners has been associated with internal contamination with uranium waste products (120). Animal toxicology data for uranium compounds has been used to simulate environmental exposures of the human population. The Beagle dog was used as an appropriate human extrapolation model of uranium toxicity in internal organs (121). Synergistic effects have also been described between uranium inhalation and tobacco use (122).
The relationship between enriched uranyl fluoride and DNA damage in the stages of spermiogenesis in mice was studied with doses of UO2F2 of 6mg / kg administered parenterally (123). Alteration in mitosis was found. The genetic toxicity of uranyl nitrate, which has a potential teratogenic effect in the fetal stages of the mouse, has recently been described (124). The carcinogenic effects of ionizing radiation have recently been described in a study that demonstrated an increase in non-melanoma skin cancer among uranium miners (125). In a recent German study of uranium workers, precancerous bronchopulmonary stages have been described, implicating uranium as one of the professional agents of carcinogenesis (126).
The cancer susceptibility of the uranium-exposed population, as assessed by genetic polymorphism and host reactivation assays in a mutant phenotype, indicate that uranium may be one of the mutagens that cause impaired DNA repair (127). These results emphasize the need for additional epidemiological studies to better understand the radiation risk in cancer incidence in the nuclear industry, specifically in uranium mines (128).
Radioactive protection criteria have been established to limit personal and general population exposure to uranium, and refer to the quarterly and annual dose received by the worker. The principles of radioactive protection include cumulative exposure throughout life and averages of quarterly and annual limits, generally expressed in Ci (Sv) / year. The tolerable dose rate, 0.05 rem / 24 h, which corresponds to a uranium retention of 24 g / g of tissue, depends on multiple constant and dynamic parameters, resulting in wide fluctuations in dose limits. The purpose of radiation protection is to control and limit the delayed radiotoxicological effects of uranium such as tissue necrosis, shortened survival, impaired homeostasis, and cancer. Although individual exposures are frequently low, organ-specific corpuscular radiation and long physical and biological half-lives make uranium a non-threshold radiological hazard in the internal environment of the contaminated organism. Despite the extensive literature on maximum permitted levels, protection criteria, professional standards, elaborate methods for setting limits when the target is radiological toxicity, uranium continues to be a chemical and radiological hazard to both the biosphere and for the inadequately known human organism. The relevance of this fact is increasing every day due to the less strict control that is carried out in the uranium industry and, lately, in modern warfare. The association of depleted uranium with mutagenesis, carcinogenesis, and diseases of the immune system in humans has been postulated in the EU measurements of environmental radioactivity in the United States. Although surface contamination levels from uranium facilities are strictly regulated, with a maximum allowable level of 35 pCi / g, surface contamination levels found in ground samples after DU penetrator testing routinely exceeded the maximum dose. permissible. DU radiation toxicity should be considered an inherent aspect of the risk of exposure to DU. The maximum allowable concentration in air, 7 × 10-11 Ci / mL, was not exceeded in UE's controlled missile range environment. Compliance with decontamination regulations is expensive and time consuming. Decontaminating the facilities of an EU penetrator factory requires 40 thousand man-hours and costs about 4 million US dollars (129). In one study, the 60-75 g penetrator of mean weight of DU produced an activity of 8.6 × 10-9 Ci / mL in air (129). However, other examples demonstrate non-compliance with radioactivity limits, such as the National Lead Industry Plant in Colonie, New York, which exceeded New York State radioactivity limits by 150 Ci for the release of UE in one month. . 150 Ci corresponds to 387 g of UE metal, which can be equated to 272 g of UE of a typical 30 mm (130) projectile. The size of a respirable particle of DU (uranium dioxide) is 10 mm in diameter. An estimated 300 tonnes of DU were deposited on the battlefield in the Gulf War. Three to six million grams of aerosol particles from DU entered the air although 1-2% of this DU burned.There is a radioactive hazard as a result of inhaling waste products of U238. One milligram of DU generates about 1 billion alpha and beta particles per year, which, together with the gamma-emitting radionuclides from the U238 progeny (Th234, Pa234), constitute an internal radiation hazard.
The reality of the EU waste legacy and its use in the recent tactical war justify detailed studies regarding its effect on the biosphere and the human population.
Treatment of Uranium Contamination
The primary goal of treating patients with internal uranium deposits should be to prevent absorption from the site of entry and to remove the uranium from the blood stream or target organs. Regardless of the therapeutic alternatives used, it is vitally important to start treatment quickly after exposure. This should consist of the prevention and reduction of uranium absorption from the entry route, treatment with agents that remove uranium compounds from the initial deposit sites, and a therapy that favors excretion via the gastrointestinal, renal, or through the respiratory tract. Finally, medical intervention in internal uranium contamination includes the use of chemical agents that bind inorganic ions to non-ionized complexes and facilitate their urinary excretion when present in soluble form.
Although the gastrointestinal absorption of uranium is low, it is of utmost importance to reduce its passage into the systemic circulation and its deposition in the target organs. There are several methods to decrease the intestinal absorption of uranium and other actinides and to promote their elimination. These include the use of emetic agents, gastric lavage, ion exchange agents, antacids containing aluminum salts, barium sulfate, sodium phytate, and glucoric and mannuronic acid salts.
Gastric lavage is very useful in treatment or quickly after ingestion. It is done by placing a nasogastric tube in the stomach; then it is washed several times with water or physiological saline under negative pressure, until the aspiration is free of the contaminant. This procedure requires appropriate medical training to achieve complete lavage of gastric contents and prevent aspiration of contaminated fluid into the respiratory system.
The use of emetics is complementary to gastric lavage, although it can be performed as an independent procedure. This method is used only after a very careful diagnostic evaluation of the contaminated patient. It is clearly contraindicated in patients in a state of confusion or shock, and after ingestion of oil and other corrosive substances. The most common uses of emetics include subcutaneous administration of apomorphine or oral preparations of ipecac. These interventions require a correct clinical understanding of the procedure. The most common method is the administration of an emetic after the patient drinks 250 ml of water. Apomorphine works primarily by stimulating the vomiting center in the area postema. It is used in a single 5-10mg dose subcutaneously, while ipecac preparations can be administered in multiple doses until vomiting is induced. Both drugs are readily available. Side effects include nausea, weakness, tachypnea, tachycardia, and hypotension. They do not usually require special clinical treatment and can be managed with symptomatic treatment.
The use of laxatives is a common therapeutic approach to reduce internal contamination. Purging agents can be administered in a number of ways, such as agents that act to release linoleic acid, stimulating peristalsis of the small intestine. The continued use of laxatives inhibits the absorption of actinides due to the formation of insoluble salts. Its hypertonic action produces the extraction of water from the intestinal mucosa and the cathartic elimination of intestinal contents. A clinical evaluation and detailed understanding of the type and amount of contaminant is required before laxative treatment. The use of laxatives is contraindicated in acute abdomen or undiagnosed pain in the stomach. The numerous side effects include tachypnea, dyspnea, tachyarrhythmias, intestinal irritation, rash, and syncope, which require professional medical attention.
Treatment of patients contaminated by inhalation of uranium compounds includes the use of therapeutic agents that decrease the viscosity of endobronchial mucosa. The use of mucolytic substances, which act on the mucopolysaccharides and nucleoproteins of the respiratory tree, favors the elimination of actinides by expectoration. However, the use of these substances, such as pancreatic dornase, triton, Tween-90, and F-68 has not proven to be very successful in practice.
The mobilization of uranium and other actinides from the bone structure by means of parathormone (PTH) was studied in several experimental models, but this method does not offer a practical alternative to reduce the burden of uranium contamination in the body. Actinides are not controlled by homeostatic mechanisms. Alkaline earth series radioisotopes can be removed from bone by PTH-induced resorption, along with uranium bound to bone crystals. This process of demineralization of bone has been shown to be a mechanism for reducing uranium retention. However, it has no practical value in dealing with internal contamination. This applies to all actinides (131), whether they are bound to the mineral (uranium) or to sialoproteins (plutonium, which accumulates on the endosteal surface of bone).
Treatment of internal uranium contamination with complexing agents relies on the ability of a ligand to form non-ionized ring complexes with inorganic ions, which are then eliminated by the kidney. This treatment has to be instituted as soon as possible, before the uranium enters the target organs. These substances are not useful for binding to actinides solidly incorporated into the cell due to their hydrophilic properties. Current research focuses on the synthesis of lipophilic chelating agents, capable of reaching cellular radionuclides and facilitating their excretion by the kidney. Among the many complexing agents tested in clinical trials, only a few have practical application in the treatment of uranium contamination.
Ethylene diamine tetraacetic acid (EDTA) has been used in animal experiments and in human medicine for the treatment of poisoning by inorganic substances. It has been shown to be useful and effective in the treatment of lead, zinc, copper, chromium, manganese, and nickel poisoning and in contamination with transuranium elements (132). EDTA is administered intravenously as a 5% glucose infusion in water or physiological saline. It is essential to assess kidney function before starting treatment because its use is contraindicated in patients with kidney disease. Na-EDTA is used in doses of 50 mg / kg. The total amount should not exceed 300 mg during 6 days of treatment. It is not administered orally or intramuscularly. Parenteral use of Na-EDTA can lead to hypocalcemia. The use of Ca-EDTA at the therapeutic dose of 15-30 mg / kg does not have a hypocalcemic effect.
Diethylene triamine pentaacetic acid (DTPA) is a chelating agent of the polyaminocarboxylate series, which, in parenteral use, binds to many polyvalent heavy metal radionuclides. It forms very stable complexes, which are soluble in water and are excreted by the kidney. The North American FDA (Food and Drug Administration) approves the use of calcium and zinc salts of DTPA in case of human contamination with transuranium elements. Ca-DTPA is effective in treating actinide contamination (133). The therapeutic efficacy of both Ca-DTPA and Zn-DTPA depends on the chemical form and solubility of the transuranium elements. Both agents are useful in the removal of soluble uranium salts, such as nitrates or chlorides, but they have a rather low efficiency in poorly soluble compounds such as oxides (134). Both are used by intravenous injection, intravenous infusion, intramuscular injection, or by inhalation in the form of an aerosol. The mode of administration depends on the circumstances of uranium poisoning, its chemical form, and the route of contamination. Ca-DTPA is more effective than Zn-DTPA if used early after contamination (135), but they do not differ in efficacy if administered at later time intervals. DTPA therapy has been associated with a loss of trace elements, but it is a reversible process, with no detrimental effect on the body being demonstrated so far. Injecting 1 g of Ca-DTPA per week in long-term treatment did not produce toxic effects in actinide-contaminated patients (136). In contrast, a constant infusion of Ca-DTPA did cause severe toxic effects in experimental animals, which ended in death after several days (137). The toxicity of Zn-DTPA was shown to be 30 less than that of Ca-DTPA in fractionated use, it did not produce loss of micro-elements and did not demonstrate teratogenic effects (138). In the early treatment of decontamination by transuranium elements in humans, Ca-DTPA constitutes the treatment of choice, while in the planning of a long-term treatment, Zn-DTPA is preferably used because of its lower effect on trace metals. It is also used in patients with kidney disease, decreased bone marrow activity, and in pregnancy, where Ca-DTPA is contraindicated.
Other agents used in internal actinide contamination include deferoxamine (DFOA), which has been shown to be effective orally, intramuscularly, and in intravenous administration. Its therapeutic effect is enhanced when used in conjunction with DTPA, but must be used with caution because of side effects, which include rash, tachycardia, and hypotension (139). Biscarboxymethylaminodiethyl ether (BAETA) is another agent that has been shown to be effective in contamination by transuranium elements, but less so than DTPA. From the point of view of elimination of the most dangerous radionuclides of the transuranium series, DTPA is the most effective, even than other more recently studied agents, such as the sulfonated tetrameric catecholamines (LICAM-C and LICAM-S), which have been proven effective in treating contamination. However, its use has been limited due to toxicity (140).
There have been numerous attempts to produce a lipophilic chelating agent that would allow better access to the intracellular environment through the fatty layers of the cell membrane. Among the compounds in this category, a lipophilic agent Puchel, produced in Harwell, England, was found to be more effective than DTPA when administered by inhalation (141), with better therapeutic effects when used in combination.
Recent studies of liposomes as possible agents of choice for internal actinide contamination have focused on specific locations such as the reticuloendothelial system (142). In addition to recent studies of synthetic catecholamines (143), natural chelators have also been isolated from cultures of different microorganisms, for example Pseudomona aeruginosa (144). Recent studies of multidentate catecolate and hydroxypyridinonate ligands for in vivo chelation of soluble uranyl ions appear promising because of their low toxicity, efficacy, and reasonable cost (145). Siderofor-like chelating agents (LIHOPO compounds) have recently represented a very significant advance in the early treatment of uranium contamination (146).
The medical and environmental consequences of contamination by uranium compounds constitute both a moral and legal requirement to control exposure to uranium at levels below those that cause death or pathological alterations, both due to its immediate and long-term action. The increased use of uranium compounds in industry, and more recently in warfare, in the form of depleted uranium, calls for an additional look at the complex biomedical aspects of internal uranium contamination and its toxicological consequences, as well as a dangerous heavy metal as for its radiological hazard. While it is theoretically possible to reduce uranium contamination to as low a level as is reasonably feasible, the evidence of the increasing passage of uranium into the biosphere, due to industrial and military use, requires a thorough understanding of the physical, chemical and toxicological properties of the uranium. uranium. At the present time when levels are increasing, such knowledge is essential to provide protection against somatic and genetic injuries. The objective of this review is to provide an overview of the physical, chemical and toxicological properties of uranium as a true pollutant of the environment and the human body. The possible role of the medical profession in this interdisciplinary field requires knowledge of the medical and environmental consequences of uranium contamination, which currently goes far beyond the mere theoretical interest of conventional toxicology.
* Dr. Asaf Durakovic is a US Army Medical Colonel Expert in radioactive contamination. Department of Nuclear Medicine, Georgetown University School of Medicine, Washington D.C., USA. - 1997 Croatian Medical Journal.
March 1999 (Volume 40, Number 1) - Published in Weapons Against War - http://www.amcmh.org
The author wishes to express his appreciation to Sharon W. Graham for her invaluable help in the preparation of this manuscript.
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