Chronic Effects of Mercury on Organisms:

Toxicodynamics of mercury and its compounds:
Entry route of mercury into the body


NOTE: These are notes are incomplete.
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TOXICODYNAMICS OF MERCURY AND ITS COMPOUNDS: ENTRY ROUTE OF MERCURY INTO THE BODY The picture of mercury intoxication, its character and degree of expression, is often determined by what route mercury and its compounds enter the body. N. V. Lazarev (1938) points out that the problem of entry routes of industrial poisons has important practical significance since the type of prophylactic measures are directly dependent on possible routes of entry into the organism of one or another toxic substance. The latter, depending on the prevailing physical conditions, can penetrate the body by various routes. Under production conditions the basic significance is held by the entry via respiratory tract of mercury and its compounds in the form of dust and vapor, caused on the one hand, by the high volatility of mercury and its compounds and, on the other, the discharge into the air of the toxic fumes from mercury production. Cases in which, under production conditions, mercury and its compounds commonly penetrate the organism in a form which can be quickly ingested and absorbed (vapors and finely dispersed particles), create an opportunity for the manifestation of a toxic effect. Mercury vapor, entering the respiratory tract, can be taken up during most of its journey by the mucous membranes. I. B. Gel'man (1935) stated that mercury vapor is easily absorbed by the alveolar endothelium. Mercury vapor is absorbed by the lungs if it is at or slightly below body temperature. In case of mercury vapor temperature is higher than that of the human body, mercury is not fully absorbed by the lungs. In that event part of the mercury vapor is retained by the upper respiratory tract, partly absorbed there and partly entering the gastrointestinal tract. G. Gothin (1911) considered that mercury vapor was completely removed from the air by the lungs if the concentration did not exceed 0.25 mg/m3. Under production conditions, the entry of mercury into the body of workers through the respiratory tract is of known significance. From toxic dusts the mercury compounds, formed in working process, mercury droplets setting on dust particles or condensing out of the vapors, can deposit in the upper respiratory tract and from there be swallowed into the stomach. Often mercury penetrates the body (the GI tract) while eating via dirty hands. Under production conditions mercury and its compounds enter the body through the skin and mucous membranes usually in insignificant quantities. The actual possibility of such entry cannot be ignored. Especially significant is the comparatively wide use of industry and in medicine of a variety of mercury antiseptics. A. M. Veger (1939) in the literature called attention to the case of a woman who, for six years rubbed an ointment containing mercury in to the skin of her face and developed acute mercury poisoning. A. V. Stepanov (1947) noted the possibility of poisoning through the use of large doses (10-15 gms) of mercury sulfide ointment. It is assumed that metallic mercury enters the hair follicles, sebaceous and sweat glands as a result of reactions with fatty acids yielding soluble compounds which can be absorbed. Mercury enters through damaged skin somewhat easier. Data on the possibility of poisoning via the intake of mercury through the GI tract is contaradictory. I. . Kravkov states that metallic mercury alone, taken internally, does not produce poisoning; E. Starkenstein (1931) also considers that the intake of liquid metallic mercury has almost no toxic effect because there is little possibility of its dissolving in the GI tract. With reference to literature data, A. C. Litinskiy (1940) considers that the use of metallic mercury for invagination, gout, and kidney stones does not produce intoxication. Especially indicative is a case observed in the author's practice, where a young woman, attempting suicide, swallowed a kilogram of metallic mercury. For two weeks the mercury was observed in various sections of the intestine by x-ray. During this time no clinical symptoms of intoxication were observed. E. Cholstein (1937) described an analogous case when mercury swallowed by a child was observed in the digestive tract by x-ray but no clinical symptoms of mercury poisoning appeared. At the same time there is the observation (S. M. Sidorov, 1942) that metallic mercury entering the body by multiple routes in a highly disperse state can bring about intoxication. Conversion and Circulation of mercury in the Body There are two points of view regarding conversion and circulation of mercury in the body. One postulates a dependence of the indicated changes on the state of the mercury taken into the body, another, on the contrary, states that mercury entering the body regardless of its route of entry and state, in the end is determined by a unique chemical change. How mercury is absorbed by the mucosa of the respiratory tract is almost unknown. It has been suggested that mercury entering the lung as a vapor, initially deposits there as a metal, and then undergoes further oxidation, P. Ye Syrkina (1934), G. L. Sklyanskaya-Vasiliye-vakaya (1938), F. Holzmann, A. Stock and W. Zimmermann (1929), confirmed, under experimental conditions, a noticeable content of mercury in the lungs. Note also the experiments of E. Holzmann, who detected mercury in expired air. There is another point of view which explains the adsorption of mercury in the lungs by stating that mercury vapor dissolves in fluid on the surface of the lungs and from there enters the blood as protein compounds -- mercury albuminates. In this, corresponding law of solubility of gaseous substances in liquids determines the rate and quantity of mercury entering the blood; this depends on its relative concentration in air and blood. Adsorption of mercury vapor by the lungs occurs quickly and fully. In a short time the adsorbed mercury enters the alveolar epithelium. Part of it is exhaled. Absorbed mercury, entering the stomach, causes the solution of mercury compounds in sodium chloride facilitating their transformation into complex compounds, shloroalbuminates. The latter are large complex molecules, in which mercury preserves its ionized state and carries a positive electrical charge. I. G. Gel'man (1935) states that the difference in toxic effect of mercury vapor, on the one hand, of metallic mercury and mercury salts, on the other, is explained by the hetrogeneous state of mercury circulating in the blood. According to I. G. Gel'man and G. K. Derviza (1936), the reason for the specific effect of mercury vapor lies in its atomic-disperse state, guaranteeing rapid penetration of mercury through the respiratory tract to the blood. The author surmises that mercury vapor, after entering the blood, retains its atomo-disperse state for a short time. A concurring point of view is held by C. Biondi (1931). The experiments of I. G. Gel'man and G. K. Derviz (1936) showed that if the blood is saturated with mercury vapor and pure air is bubbled through the blood, "free" mercury is observed therein. Apparently, only after a prolonged period of enzyme oxidation in the circulating blood does the "free" mercury combine with protein or salt molecules. The authors consider that atoms of mercury found in the blood are adsorbed by a protein molecule and are distributed on its surface. Later, "under favorable conditions this bond breaks and free atomic mercury can penetrate the cell and cause a toxic effect there". Simultaneously metallic mercury, having entered the blood, remains "toxically indifferent". The explanation of this is that particles of mercury, circulating in the blood, though not small, are nevertheless larger than the protein molecules. Upon entering the blood, they are covered by a protein film, which adsorbs on them, taking the role of a protective colloid. Apparently, this factor is responsible for the low toxicity of metallic mercury circulating in the blood. A very indicative case is described by Umber (cited by A. N. L'vov, 1939). A young, female x-ray technician attempted suicide by injecting herself in the right ulnar vein with about 3 gm metallic mercury. Mild symptoms appeared (diarrhea, salivation, stomatitis) but were of short duration, during which characteristic neural disintegration was not observed. X-rays of the lungs revealed multiple mercury emboli and distinct droplets of mercury in the right venticle and in the V. thoraclis lateralis. Mercury salts, as noted form complex compounds with proteins in the form of mercury albuminates circulating in the blood. Blood flow either carries mercury to a depot or to the separate organs where mercury albuminates split liberating ionized mercury as a salt (chloride or other). E. Starkenstein, E. Rost, S. Pol (1931) consider that the effect of ionized mercury salts in the body is different from that of mercury vapor and that the course of poisoning is different in each case. They consider it improper to speak of mercury "in general" disregarding the difference in effects of its compounds. The orthodoxy of this view is based on results of studying transformations of mercury in the body upon poisoning with organomercury derivatives. P. Nerr (1887), investigating in animals the effects of organomercurials (ethylmercuric chloride, ethylmercuric phosphate and diethyl mercury) showed that upon rapid intoxication, when the death of the animal occurs within two to three hours after receiving the preparation, organomercury compounds are still intact. In this case only traces of mercury are detected after prolonged presence in the organism (3-7 days after receiving the preparation) of a poisoned animal, larger quantities of mercury are observed along with intact ethylmercuric chloride. The authors maintain that during the action of organomercuricals initially the effects of the intact molecule is observed followed by the combined action of split-off mercury, the toxic effect of which becomes predominant. O. Muller (1929) and other scholars studying the action mechanisms of organometallic compounds, came to an analogous conclusion. After analyzing the preceding data and comparing it with the results of his own observations, L. I. Medved' (1946) pointed out the difference in the action mechanism of inorganic mercury salts and their organic derivatives. Inorganic salts in the first moment of entry into the body form chloroalbuminates and are not adsorbed by the cells, acting on the excretory tract. Simultaneously, the organic compounds are adsorbed and retained in the tissues producing their toxic effect. Evidently, later, under the effects of various complex factors, organic compounds react with the body, change to chloroalbuminates, and after consequently, the processes of mercury transformation in the organism depends upon the route and character of its entry. Organic mercury compounds and their vapors have toxicological features determined by the physical and chemical properties of mercury and its derivatives and by their chemical changes in the body. Therefore, remember that one mechanism underlies all traits and differences in the effects of mercury and its inorganic and organic derivatives, the presence in them of a thiol nucleus, the inactivation of functional groups (especially sulfhydril) of cellular proteins. The topography of mercury depots in the body, he dependence of infection of these or other organs on the degree of mercury accumulation on a background of intoxication -- all these problems are very pertinent from a diagnostic and therapeutic viewpoint. The Distribution of Mercury in the Body and its Accumulation in the Organs Data on the relative distribution and accumulation of mercury in the body is contradictory. Possibly this is explained by the difference differences in the accuracy of methods used for the determination of mercury. P. E. Syrkin (1934) investigating the organs of animals dead of mercury vapor poisoning, found a maximal deposition of mercury in the brain, kidneys, liver and heart. In the remaining organs mercury occurred in significantly lesser quantities. He noted the presence of the determining relationship between mercury content in the brain and kidneys: when significant quantities of mercury are present in the brain its content in the kidneys was insignificant or absent. Indicatively, when mercury is observed primarily in the brain the clinical picture of intoxication in test animals develops and progresses typically; the appearance of mercury poisoning develops distinctly. Simultaneously the presence of significant quantities of mercury in the kidneys somehow does not accompany symptoms of intoxication, excluding the finding of mercury in the urine and partial decrease in total urine output. N. P. Kravkov (1928) points out that mercury is dispersed and deposited unequally in various organs; in acute poisoning it is found mostly in the kidneys, then in the liver and spleen, N. P. Kravkov emphasizes that the mercury content in the stomach and intestinal walls increases parallel with the degree of poisoning and therefore "the large intestine, the most contaminated, contains the greatest quantity of mercury precipitates into the skeleton, liver, and to a lesser degree, the kidneys and bone marrow. N. V. Lazarev (1938) proposes that, in the body mercury deposits primarily in the liver and kidneys. He believes that mercury is retained in the liver for a long time. According to the author, the retention mechanism of heavy metals in the liver is partly explained by the formation of compounds with nuclei, and partly explained by the reduction of heavy metals and their deposition in the kupfer cells. N. D. Rozenbaum (1933) in surveying the literature data, came to the conclusion that the basic depots of mercury were in the bones, liver, spleen, bone marrow, intestines and kidneys. The author writes that mercury periodically leaves these depots, enters the bloodstream, disperses throughout the body and causes the onset of poisoning. R. Sussman (From an article of N. D. Rozenbaum, Gigiyena Truda, 1923, 5-6, 105-106.) after rubbing mercury into the back of skin of cats, observed the largest quantity of mercury in the kidneys, liver and large intestine. A. I. Cherkes (1957) noted that upon rubbing mercury in the skin, the largest quantity of it, excluding the anointed site, was discovered in the kidneys. G. L. Sklyanskaya-Vasilyevskaya (1938) obtained interesting data on the effect of various conditions under which mercury poisoning occurs, such as its deposition in the body, and its distribution in the separate organs. The determining factor in this case is prolonged action. Thus, in animals suffering from the effects of metallic mercury vapor for ten days, 78% of all mercury retained in the body was observed in the excretory organs and only 22% in other organs. In animals inoculated with mercury for a longer time (20 days), the excretory organs contained only 52% mercury. Artificial decrease in diuresis causes a great accumulation of mercury in the body. Maximal quantities of mercury occur in the kidneys, intestines, heart and brain, that is, in all organs which manifest clinical contamination. According to the author, mercury, precipitation in the organs, does not lose its activity after deposition. Material obtained by G. L. Sklyanskaya-Vasilyevskaya, as well as earlier published experimental observations of P. Ye. Syrkina (1934) confirm that the deposition of mercury in the body can occur with a change in state: upon the presence of large quantities of mercury in the kidneys indicate comparatively small quantities in the brain and vice versa. Special note should be made of the fact that mercury can leave its depot and enter the blood over a prolonged period many years after cessation of all contact with it. It can cause depression in the general functional state of the body under the effect of harmful factors. In conclusion let us comment briefly on certain data on the relative accumulation and dispersion of mercury under the effects of its compounds. According to the data of M. F. Mirochnik (1934), various researchers studying mercury chloride poisoning observed the following amounts of it in various organs: kidneys, 0.002-0.014 mg; liver, 0.002-0.004 mg; large intestine, 0.002-0.003 mg per 100 gms. In other organs (spleen, thyroid gland, muscles, small intestine less than 0.002 mg mercury was observed, and only trace amounts were found in cells of the CNS. In most studies mercury was not observed in saliva indicating that organomercury compounds, as distinct inorganic mercury, is not distribute throughout the mouth. A significant quantity of mercury is found in the urine (0.48 - 0.74 mg in the daily voidance) and feces (to 0.245 - 6 mg/day). A definite correlation between mercury level in urine, feces, other biological substrates and length of exposure of organomercury compounds was not noted (S. I. Ashbel', V. A. Tret'yakova, 1957, 1958). Prolonged circulation of mercury was observed when it was introduced as mercury salicylate (M. Ye. Zotova, 1944). About eight hours after intravenous injection of rabbits with ethylmercuric dicyandiamide, most of the mercury was found in the liver, then in the kidneys and the brain; after 44 days, most was in the brain, less in the liver and almost none in the kidneys (A. Swenson, 1959). In the course of investigating the metabolism of this compound and of mercuric chloride, the radio isotope method established that organic derivatives of mercury are more highly bound in animal organs than its inorganic salts: 10 times more mercury was found in brains, adrenals, medulla a nd spleens of rabbit poisoned by methylanercuric-dicyanodianide than in animals which had been given mercuric chloride (L. Frieberg, 1956). Still earlier, in studies on the build-up and distribution of mercury, ethylmercuric phosphate and ethylmercuric chloride in the body, we came of the analogous conclusion as to the stronger adsorption of organomercury compounds not only in relation to their inorganic derivation, but with respect to vapors of metallic mercury (I. M. Trakhtenberg, 1951). The amount of mercury in the brain and spinal cord of animals in poisonings by vapors of organic mercury compounds increases, by our data, to 22-30 times its concentration in the brains of animals poisoned by vapors of metallic mercury. Upon a single administration of organomercury compounds via the digestive tract mercury appears in the brain and medulla of animals in quantities nine to ten times those appearing after the administration of mercury chloride. According to data of N. S. Pravdin and S. N. Kremneva (1939), the mercury content in brains of rabbits poisoned by ethylmercuric phosphate was much higher than in animals poisoned by mercury chloride.