Chronic Effects of Mercury on Organisms:

In Place of a conclusion


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IN PLACE OF A CONCLUSION Earlier it was considered the harmful influence of occupational and industrial factors, in this case, a variety of chemical substances, lie at the bottom of most occupational diseases. With respect to occupational pathology as a rule, the most conclusively and relatively simple aspect can be to establish a link between degeneration and working conditions, specifically human industrial activity. Recently, more and more facts have built up indicating the level and structure of "non-occupational" diseases is caused by daily contact with chemical environmental factors. Also it should be emphasized that in the past the level of chemical poisoning detected has been high, while recently it has decreased with the recent sharp decrease in toxic concentrations at work sites. In connection with this, the task of studying toxic effects on workers under modern conditions should include not only analysis of the effects of agents having pronounced effects, but of irritants which have a detectable effect at very low levels. Under suitable conditions, there occur a series of latent changes, especially biochemical, neurohumoral, and immunobiological in nature. These changes do not cause gross somatic disturbance, rather they are reflected in delicate reflex and metabolic shifts. Truly, they arise first of all as a result of the effect of toxic substances on interoceptors, especially tissue, having a high sensitivity to tissue metabolic changes. Chemical substances, as low intensity irritants should be used to study shifts at different stages of the metabolic process. The use of radioactive isotopes can detect synthetic changes in the absence of morphologic signs of destruction. In connection with this we agree with S. V. Anichkov (1958) who said that biochemical shifts precede morphological changes, as a consequence of which the synthesis of tissue proteins can be used as the indicator of the toxic effects of low concentrations of chemical substances. In analysis of proteinemic shifts developing in micromercurialism, we have already cited the research of V. A. Belitser (1954) and A. G. Pasynskiy (1952) which links the activity of specific proteins with the presence on their molecular surfaces of specific reactive centers made up of united amino acids or their separate groups. Evidently, toxic substances, which block reactive groups of protein molecules and change their chemical structures, disorganize these centers and can lower the specific reactivity of enzyme systems, immune bodies, hormones, etc. Shifts in specific protein activity in connection with a depression in synthetic processes and the predominance of destructive changes, cannot, naturally, but be reflected in the total reactivity of the organism challenged by various harmful actions. Small mercury concentrations under chronic experimental conditions produce changes in the status of immunobiological reactivity. Shifts can be detected in agglutinins, complementary activity of the blood serum, phagocytic activity of peripheral blood neutrophils, and preventive properties of sera. Toxic effects aggravate microbial pathology in animals. In mammals subjected to prolonged toxic effects, antibodies do not protect the organism from infection. This is based on data indicating that small mercury concentrations predispose the organism to influenza (1964). Prolonged exposure of mammals (white mice) to low mercury concentrations (0.008 - 0.02 mg/m3) leads to a significant increase in the susceptibility of mice to pathological influenza virus strains. This is shown by a decrease in the Ld50 and a more severe course of infection. In the experimental group more mice died (86 -90.3%), than in the unexposed animals (60.2 - 68), additionally the experimental group died more quickly. The significant difference was in the appearance and degree of pneumonia in the affected animals. The hemagglutination reaction of influenza virus was recorded more often in the lungs of animals subjected to toxic effects. One must agree with the point of view of O. G. Alekseyeva (1964) the "...the extreme lability of immunological reactions requires care in the treatment of the results obtained." Actually, such immunological indicators, for example, as the phagocytic reaction of blood neutrophils can change under the influence of external agents, the effect on the organism of which is not indicated by any unpleasant consequences. It is necessary in the use of this indicator to pay attention to the quality of the criterion of harmfulness in only a marked decrease in phagocytosis (A. F. Stoyanovskiy and T. V. Rasskazova, 1961), to evaluate the indicated reaction by not only one, but by several indicators (phagocytic index, % phagocytes, etc.). Additionally it is vital to assess the character and degree of changes in other indicators connected with immunity reactions, which apply to the mechanism of the changes arising. Prolonged exposure to small mercury concentrations leads to a depression in tissue protein resynthesis. These phenomena are closely interconnected. In humans remember that the prolonged effects of low concentrations of toxic substances depend on individual susceptibility. A given irritant produces its respective reaction only at a definite threshold level. At this level it produces a specific response depending upon the functional features of the reacting systems, and also depending on basic physiological properties of the latter. The action of an irritant at subthreshold strength, as a rule, does not produce the specific response. However, there are simultaneous corresponding changes in the activity of various organs and tissue, which, although not specific, lead to the appearance of functional and metabolic shifts, reactivity changes, excitability, lability, "readiness" for subsequent stress. Such non-specific effects produced by low concentrations of chemical substances (enzyme poisons) include those of thiol poisons which affect the enzymes having general functional groups. Thiol poisons, especially mercury and its compounds, reacting with SH- groups of proteins, lead to the lowered activity of various enzymes, containing sulfhydril groups. This produces a series of disruptions in the functional activity of many organs and tissues of the organism. These disruptions are heterogeneous and diverse in character. In persons long exposed to low mercury concentrations there are a series of monotypic functional shifts. The latter are manifested in subjective complaints, breakdown, increased fatigue, headaches, etc., and also objectively recorded, although not sharply developed, vegetative neurosis, reversible functional shifts in higher nervous activity, less muscular capacity. Analogous changes can be noted under the effects of other toxic substances. N. S. Pravdin (1934 ) spoke of "the chemical depression of work function", the depression of physiological function the destruction of which even under conditions, if pathological shifts are still absent, can lead to decreased labor productivity. Prolonged exposure to low mercury concentrations, affect the higher regions of the CNS relatively early. In this the observed damage does not differ from analogous CNS changes produced by a variety of other chemicals and these may be related to the nonspecific toxic effect. On the other hand, the appearance of CNS changes must have at their base a specific genesis. Thus, for example, in mercury experiments this is confirmed by the fact of the dependence of conditional reflex activity on tissue SH- groups. As a mammal experiments show, especially that if simultaneously with mercury preparations containing free SH- groups are given, reflex and differentiation are not destroyed. The administration of the indicated preparations on the background of an already developed pathological process can restore disrupted conditioned reflexes. Even such a universal CNS reaction of the organism to toxic action can lie in specific mechanisms of so-called primary biochemical reactions. In light of the surveyed position, morphological studies are of interest, a result of which a series of general regularities in the reaction of the nervous system was in response to the action of occupational poisons varying in action mechanism (M. S. Togskaya, 1954, 1959). Changes produced have a reversible character: after one or two months after cessation of toxic action. The results of these morphological studies indicating early response of the cortex and non-specific character appearing through the action of low concentrations of various toxic substances correspond with clinical observations during the study of the initial stages of intoxication (E. A. Drogichina, 1957). Thus in the development of the initial stages of chronic mercury, lead, CS2, etc. poisoning occurs in two phases. In the first of these, functional shifts are characterized by a state of heightened excitability of the cerebral cortex, that, evidently, is connected with weakened inhibitory processes and in the first place processes of internal inhibition; the second phase, is accompanied lowered cortical excitability, and certain inertness of cortical processes. The above discussed CNS shifts produce, initially, emotional instability, increased analyzer excitability, lability of vegetative reactions, and then an asthenic syndrome, a state of irritable weakness. These non-specific (general) CNS phenomena of various occupational poisons often precede further developing shifts and disorders, which in the developed stage of intoxication, takes on "its `specific' aspect." From the point of view of the interaction of primary biochemical reactions and non-specific functional shifts, the appearance of which are linked to these reactions, special interest can be shown in experimental analysis of the cardiotoxic activity of mercury, completing the presentation of the above data of relatively specific genesis of the disruption of higher nervous activity in experimental mercurialism. Changes in cardiac activity can arise not only through toxic efforts but under the influence of other harmful factors, in that they in their appearance have to a significant degree, a monotypic character, such as the heart responds to initiation only by the presence of changes in contractility, conduction and rhythm. However, at the basis of activity changes of a given organ, like the heart, lies fully determined biochemical mechanisms. Various irritants can affect specific steps in biochemical processes which cause corresponding functional activity changes in the organism. Our EKG data indicates that mercury-caused changes appear to be non-specific, however, experimental administration of dithiol indicates the specific genesis of the recorded disorders. This data agrees with that of Kh. S. Koshtoyants (1961), the SH- group inactivation caused by other thiol poisons, especially cadmium chloride, also produce EKG changes, negated by the effect of cysteine which then return to normal levels. On the one hand, the primary action mechanism of toxic substances on these or other enzyme processes are connected on the other hand with functional changes specific for the given organ. At the same time a "specific" (in a given case for heart function) mechanism can undergo, as described above, under the effect of the most diverse damaging factors, that give the basis to the researcher in like cases to speak of the "non-specific" character of the recorded shifts. Evidently, that similar demarcation is extremely conditional. This is accomplished by a similarity and a contrast of specific and non-specific changes on the molecular level, having a place at both the cellular and system levels. The interconnection of specific and non-specific, especially that related to multiple mechanisms, which in the end lead to a monotypical functional effect. In looking at certain principal aspects of experimental analysis of a toxic effect, it is impossible not to note that the character of the reaction of the organism to these actions depend on the strengthened duration of the chemical irritant, and on the functional state of the reacting substrate. On the basis of the action of low mercury concentrations, we can be convinced that in the dynamic of functional shifts and destruction appears general (sufficiently universal) character of the reaction of the organism to low intensity toxic effects. At the time, when under the influence of pronounced toxic actions already relatively rapidly developed depression of function, low intensity chemical irritants determine another character of response reaction; at first a certain stimulation of corresponding effect, and then, according to the increased length of the effect - its depression. Strict attention must be paid to lability and the diapason of "physiological variation" in the dynamics of this indicator, the degree of its "normal" lability. In this there cannot be a monotypic approach to the evaluation of the observed shifts, such as in some cases, even wider variations of the indicators studied fit into the "physiological norm," in others - a very insignificant already signifies the development of the pathological process. In connection with this especially important is the establishment of concrete quantitative amounts, characterizing the limits of "physiological variation." Knowledge of the "quantitative criteria" for the interpretation of the character of the changes arisen become extremely important not only during hygienic evaluation of external factors in the process of their experimental study, but also in the subsequent undertaking of production surveys as in the following example. To judge the state of hemopoeisis under various toxic stresses, in our experiments the widely used bone marrow neutrophil and erythroblast maturity index and also the nuclear shift index in the peripheral blood. when the nuclear shift index of peripheral blood neutrophils becomes higher than 0.02, the bone marrow neutrophil maturity index exceeds the 1.2 -2.1 limit, and the erythroblast maturity index falls below 0.35 - 0.7, that such variation can be considered as exceeding the physiological limits. According to data of M. M. Gimadeyev (1963), obtained in conjunction with our work, which has been described above, the decrease in SH- group content, caused by low mercury levels precede conditioned reflex activity changes, in which an SH- group drop to 12 - 21.6° does not produce any damage. Conditioned reflex activity shifts are observed only when (toward the end on the second month) the SH- group content has reached about 56% of the initial level. Even in the known variability of the quantities, sufficient shifts in cell protein SH- groups can be regarded as a toxic effect indicator of thiol poisons including mercury. There is still one more subject to deal with. In experimental modeling of toxic action, the difference in age sensitivity on a background of sharply delineated shifts and destruction can be averaged. Simultaneously, differences produced by these low intensity effects are very important. Thus, evaluation in the course of our investigations of the character and reaction features of the hypophyseal-adrenal cortical system in toxic actions, we could be satisfied that the functional activity of this system under such effects rose to a definite level. The recorded shifts were unevenly distributed among various age groups. Thus, in old animals, the functional activity of the adrenal cortex under the prolonged influence of mercury rose later and was less well expressed than in young animals. These and other data confirm the existence of important age differences in the development of the general adaptation syndrome in response to external action, that, truly, depends on the differences in aspects of neurohumoral regulation at various ages. (V. V. Frol'kis, 1967). Thus, we tried to generalize certain data obtained in mercurialism studies to show the regularities of low intensity toxic action. And now we come to one of the most important aspects of this problem - the hygienic mercury content normalization in the air of the work zone. We note that in recent years, sometimes there is a tendency toward the following formulation of the problem. What can be considered the "principal direction" in modern hygienic research - the hygienic normalization or "the study of development health improvement measures, that is, methods designed to remove the unpleasant effect of one or more factors" (Ua. Kh. Neyshtadt, 1964). In connection with this, F. G. Krotkov argued the necessity of further broadening of experimental studies, particularly in industrial hygiene, stressing that such studies "...are absolutely necessary for hygienic normalization of industrial poisons and the development of labor protection regulations..." For maximum realization of the first item under so-called "natural conditions" it is necessary to realize that all the varied factors of the industrial environment which underlie hygienic improvements, can be divided into two groups: factors which daily affect humans and their physiological adaptive mechanisms (microclimate), and factors, with which man encounters exclusively or primarily in production circumstances and in relation to which he "...does not have well developed adaptive mechanisms." (A. L. Letavet, 1962). In relation to the first group, one must determine the optimal (In a series of cases the minimum or maximum)hygienic standards for the microclimate, nutritional norms, proper housing, physical and intellectual loads, etc., and in this decision, based on research into desirable physiological conditions for the organism, also the evaluation of the second group of factors, basis significance lies in the determination of their permissible limits under industrial conditions (dust, vibration, ionizing radiation, etc.) Toxic factors belong to this group (G. Kh. Shakhbazyan, I. M. Trakhtenberg, 1965). The permissible aerial toxic content to a significant degree depends on the character and sensitivity of selected indicators. Evidently, permissible content recommendations will differ depending on whether they are based on observations of visible damage or on research into fine reflex reactions. Of interest is the position of N. V. Lazarev (1967) about the exclusive importance of "...discovering the relationship between elementary `breakdown' and adaptive reactions during prolonged low intensity toxic irritation of the organisms." It is known that the intake of poison does not produce a toxic effect in all cases. It occurs only when the organism's adaptive regulatory mechanisms are inadequate to eliminate the harmful agent. A. I. Cherkes (1939) found that during the prolonged, repeated action of small doses of poison, the latent period can be prolonged, so that in the course of which, there are no observable pathological changes in the organism characteristic of that poison. This period, according to Cherkes, is distinguished by gradual reorganization "... of the organism under the influence of foreign chemical irritants from physiology toward pathology in this can be called but has an evident applied use. On the one hand, it is necessary "always to consider how much environmental factors tax this protective function, without risk of exceeding that limit, beyond which is the pathological process." (G. V. Fol'bort, 1950), and on the other, the stress limits of this function should be taken in cognizance of the quality of one of the basic criteria for solving hygienic standardization problems. Maximum allowable quantities must not exceed those levels of established normative indicators since organisms have a broad adaptive range, the level of which may be inadequate "if the external toxic level or other stresses were to rise suddenly" (A. A. Letavet, 1962). In a series of industrial sites chlorine often is present along with mercury (electrolysis shops). There is also lead, formaldehyde, nitric oxide and isopropyl alcohol, etc. V. G. Lappo (1960) and S. A. Fridyland (1965) found that summation of toxic effect occurred when low concentration of mercury and lead or cyanide were given to animals. Mercury as a low intensity environmental factor i one of those agents under which "...adaptation to the environment often is purchased at the cost of significant morphological and functional shifts." (I. V. Davydovskiy, 1962). Thus evidence applicable to this has been obtained by B. A. Anchugin (1966), and his five years observations of normalization of mercury damage to the redox processes shows that it attains the status of compensatory mechanisms and have a temporary character. It is important to remember that even by 1930, when the first sanitation laws regulating the limits of permissible concentrations for twelve widely distributed toxic substances, mercury was last on the list, and only trace amounts in the air were permissible aerial mercury concentration was not allowed in the work zone. In that not only the "specific production conditions" but also "the concentrations, which in time can produce chronic poisoning (1933) related mercury to the number of industrial poisons, the aerial content of which, even as traces were completely forbidden. In 1939 limits were set in accordance with general sanitary norms (OST-1324-B) as 0.01 mg/m3. It becomes evident that many of the earlier established hygienic normals should be revised in the light of modern conditions and experimental evidence. A survey of foreign sources shows that the permissible mercury level in the Soviet Union is much lower than abroad (7.5 - 10 lower than that of the USA, England, West Germany and other Countries). These foreign investigators have suggested that the maximum permissible concentration be 0.1 mg/m3 at which "only 10% of poisoning cases suffer from some form of heavy damage". Others considering latent forms have set the limit at 0.02mg/m3. However there is a well known case of a university laboratory where the aerial mercury content was 0.1 mg/m3, and its personnel had symptoms of chronic mercury effects (L. Yoldwater, M. Kleinfeld, A. Berger, 1956). There was a later foreign report stating that setting the limit at 0.1 mg/m3 was no guarantee against the development of chronic intoxication. These and other materials not previously mentioned agree with our prolonged toxicological and hygienic research (M. M. Gimadeyev, 1960; E. I. Gol'dman, 1960; V. N. Kurnosov, 1962; I. L. Kurinniy, 1963, et al). Thus, in various mammal species (white mice, white rats, guinea pigs, rabbits, cats) subjected for a year or more to mercury concentrations equal to or close to 0.01 mg/m3 developed shifts in a series of biochemical processes, in the endocrine system, immunobiological reactivity, blood, and cardiovascular system. These shifts developed on a background of pathological changes involving reactions with thiol groups, and inactivation of the reversibility of changes during different biological processes. It was also established that in persons, having prolonged contact with mercury there is a tendency to develop moderate hypochromic anemia, changes in functional activity of the olfactory analyzer, increased uptake of radioactive iodine into the thyroid gland, lower muscular capacity, diminished working ability and other shifts at mercury concentrations exceeding 0.01 mg/m3 2-3 times. We feel that at these higher concentrations, a relatively large number of cases (36.5+2.49) develop an asthenovegetative syndrome of toxic etiology. The fact shows that earlier established limits do not incorporate a sufficient "reserve coefficient". Thus, on the basis of experimental studies discussed above (I. M. Trakhtenberg, 1958, 1961, 1964) the maximum permissible mercury concentration should be lowered as argued in previous works. The main conclusion arising out of the preparation of this work is that there is a need for a maximum increase in hygienic requirements for labor conditions of mercury workers. The introduction into practice of effective sanitation and health improvement measures, the combination of the latter with a series of organizational measures, especially the withdrawal of mercury and limitation of its use is endorsed by the wide circle of practicing physicians, hygienists and clinicians - from the modern aspect of the problem of the chronic action of mercury on the organism. Such a complex of problems, the successful solution of which will secure the effective prophylaxis of mercurialism.