Laszlo Magos

The Toxicology of Mercury and Its Chemical Compounds

This review covers the toxicology of mercury and its compounds. Special attention is paid to those forms of mercury of current public health concern. Human exposure to the vapor of metallic mercury dates back to antiquity but continues today in occupational settings and from dental amalgam. Health risks from methylmercury in edible tissues of fish have been the subject of several large epidemiological investigations and continue to be the subject of intense debate. Ethylmercury in the form of a preservative, thimerosal, added to certain vaccines, is the most recent form of mercury that has become a public health concern. The review leads to general discussion of evolutionary aspects of mercury, protective and toxic mechanisms, and ends on a note that mercury is still an “element of mystery.”

The comparative toxicology of ethyl- and methylmercury

Neurotoxicity and renotoxicity were compared in rats given by gastric gavage five daily doses of 8.0 mg Hg/kg methyl- or ethylmercuric chloride or 9.6 mg Hg/kg ethylmercuric chloride. Three or 10 days after the last treatment day rats treated with either 8.0 or 9.6 mg Hg/kg ethylmercury had higher total or organic mercury concentrations in blood and lower concentrations in kidneys and brain than methylmercury-treated rats. In each of these tissues the inorganic mercury concentration was higher after ethyl than after methylmercury.Weight loss relative to the expected body weight and renal damage was higher in ethylmercury-treated rats than in rats given equimolar doses of methylmercury. These effects became more severe when the dose of ethylmercury was increased by 20%. Thus in renotoxicity the renal concentration of inorganic mercury seems to be more important than the concentration of organic or total mercury. In methylmercury-treated rats damage and inorganic mercury deposits were restricted to the P2 region of the proximal tubules, while in ethylmercury-treated rats the distribution of mercury and damage was more widespread.There was little difference in the neurotoxicities of methylmercury and ethylmercury when effects on the dorsal root ganglia or coordination disorders were compared. Based on both criteria, an equimolar dose of ethylmercury was less neurotoxic than methylmercury, but a 20% increase in the dose of ethylmercury was enough to raise the sum of coordination disorder scores slightly and ganglion damage significantly above those in methylmercury-treated rats.In spite of the higher inorganic mercury concentration in the brain of ethylmercurythan in the brain of methylmercury-treated rats, the granular layer damage in the cerebellum was widespread only in the methylmercury-treated rats. Thus inorganic mercury or dealkylation cannot be responsible for granular layer damage in alkylmercury intoxication. Moreover, histochemistry demonstrated no inorganic mercury deposits in the granular layer.

Overview of the clinical toxicity of mercury

Mercury is ubiquitous in the environment and therefore every human being, irrespective of age and location, is exposed to one form of mercury or another. The major source of environmental mercury is natural degassing of the earths crust, but industrial activities can raise exposure to toxic levels directly or through the use or misuse of the liquid metals or synthesized mercurial compounds. The aim of this review is to survey differences in human exposure and in the toxicology of different forms of mercury. It covers not only symptoms and signs observed in poisoned individuals by a clinician but also subclinical effects in population studies, the final evaluation of which is the domain of statisticians.

The kinetics of methylmercury administered repeatedly to rats

Female rats (65–75 days old) were given orally 0.84 or 3.36 mg Hg/kg as methylmercury chloride (MeHgCl) 5 times a week for 13 and 3 weeks, respectively. The proportion of inorganic to total mercury remained as low as 6% in whole animal though it increased to above 40% in the kidneys.Differences in organ half times and the negative correlation with time for blood to liver, brain and kidney mercury ratios indicated more than one compartment for MeHg+. Brain had 26 days half time with a 32% final equilibrium concentration in relation to the body concentrations. Brain concentrations of mercury reported on rats dosed repeatedly with MeHg+ agreed with these values which justifies their use when experiments are planned to give a certain brain MeHg+ concentration.Half time for the whole body was 34 days but pathological changes — weight loss, tubular damage, slow gastrointestinal passage — disturbed the accumulation curves in the higher dose group. Blood to kidney ratio and uptake of MeHg+ by kidneys also changed significantly.ZusammenfassungWeibliche Ratten im Alter von 65–75 Tagen erhalten 5mal wöchentlich 0,84 (13 Wochen lang) oder 3.36 mg Hg/kg (3 Wochen lang) als Methylquecksilberchlorid oral. Das Verhältnis des anorganischen zum Gesamtquecksilber beträgt im Ganztier nur 6%, in den Nieren steigt es jedoch über 40%.Unterschiede in den Organ-Halbwertzeiten und die negative Korrelation der Blut/Leber-, Gehirn und Nieren-Quecksilber-Quotienten mit der Zeit sprechen für mehr als ein Kompartiment für Methylquecksilber. Im Gehirn beträgt die Halbwertzeit 26 Tage mit einer schließlichen Gleichgewichtskonzentration von 32% im Verhältnis zu den Ganzkörper-Konzentrationen. Die Quecksilberkonzentrationen im Gehirn von Ratten nach wiederholter Gabe von Methylquecksilber decken sich mit diesen Werten; damit ist ihre Anwendung gerechtfertigt bei Versuchen, bei denen eine gewisse Methylquecksilber-Konzentration im Gehirn erreicht werden soll.Die Halbwertzeit im Gesamttier beträgt 34 Tage, aber pathologische Veränderungen — Gewichtsverlust, tubulärer Nierenschaden, Verlangsamung der Passage im Verdauungstrakt — die Sättigungskurven in der höheren Dosierungsgruppe beeinträchtigten. Gleichermaßen werden die Blut/Nieren-Quotienten und die Aufnahme von Methylquecksilber durch die Nieren signifikant verändert.

Comparative study of the sensitivity of male and female rats to methylmercury.

Male and female rats were dosed daily by gastric gavage four or five times with 8.0 mg/kg Hg as methylmercury. Treatment lowered the body weight in relation to the body weight of untreated rats to the same extent in male and female rats but when body weight was related to the initial body weight, the effect of methylmercury was more pronounced in females than in males. The importance of differences in growth or loss of body weight is that in spite of the similar whole body clearance mercury concentrations were higher in females than in males. After identical doses the brains of females always contained more mercury than those of males and in both sexes the brain concentration of mercury showed a disproportionate elevation when the number of doses was increased from four to five. However, weight change alone does not explain the sex related difference in the brain concentration of mercury as this was evident even 72 h after a single dose. In agreement with the brain concentration of mercury, female rats developed more intensive co-ordination disorders and after five doses they had more extensive damage in the granular layer of the cerebellum than males.

Comparison of the protection given by selenite, selenomethionine and biological selenium against the renotoxicity of mercury

The protective effect of selenite, seleno-dl-methionine and biological selenium against the renotoxicity of mercury was tested in rats. As the source of biological selenium, the liver soluble fraction of rats given 60 μmoles/kg selenite 3 days before sacrifice was used. The aim of the experiments was to test whether protective efficiency follows the reported order of ability to form HgSe. Mercury was given subcutaneously in doses of 2.5, 5.0 and 7.5 μmoles/kg HgCl2 and selenium was given in equimolar doses at the same time as Hg2+. Liver soluble fraction, biological selenium or liver soluble fraction supplemented with selenite or seleno-dl-methionine were given orally, while in experiments without liver soluble fraction the two selenium compounds were given subcutaneously. Biological selenium was tested only at the two lower dose levels. Both biological selenium and seleno-dl-methionine decreased the urinary excretion of mercury in the first 48 h, but less so than selenite and only selenite decreased the renal content of mercury at the end of this period. Urinary alkaline phosphatase activity and plasma urea nitrogen at the 2.5 and 5.0 μmoles/kg dose levels decreased in the order of no selenium > biological selenium > seleno-dl-methionine > selenite. As the reported HgSe formation increases in the same order, the experiments support the role of HgSe formation in the protective effect. The degree of necrotic damage in the P2 and P3 regions of the proximal tubular cells increased in the same order as the biochemical indicators at the 5.0 and 7.5 μmoles/kg dose levels. Necrotic damage at the lower dose level of mercury was slight and differences between groups could be explained by random distribution.

Complex formation between selenium and methylmercury

Methylmercury, after incubation at 3k7 degrees C and pH 7.0 with selenite in the presence of rat erythrocytes, can be extracted into benzene as an unstable 2 : 1 complex with selenium. The same complex, possibly bis-methylmercury selenide, is formed when methylmercury is treated with hydrogen selenide at pH 7.0 in the absence of erythrocytes.

Postexposure preventive treatment of methylmercury intoxication in rats with dimercaptosuccinic acid

Abstract Male rats of approximately 200-g body weight were given by gavage six daily doses of 8.0 mg of Hg/kg as Me 203 HgCl with 2 days omission between the fourth and fifth doses. After five or six doses there was a progressive loss of body weight, followed by granule cells necrosis in the cerebellum and functional disturbances (flailing reflex when animal is held loosely under the forelimbs and crossing of hind legs when animal is held by the tail). Three days of treatment with dimercaptosuccinic acid (DMSA) (75 mg of DMSA/30 ml of drinking water/day/animal) commencing at 1 to 5 days after the last Me 203 HgCl dose decreased both body burden and the brain contents of 203 Hg by 60%, reversed loss of body weight, prevented the progression of cerebellar damage, and caused even some improvement in flailing reflex and hind leg crossing. As the brain content of methylmercury reached a maximum between 1 to 3 days, the present experiments indicate that the maximum concentration of methylmercury in the CNS is not the only factor which determines the outcome of methylmercury intoxication; the pattern of methylmercury accumulation and depletion is also an important factor.

The assessment of the contribution of hair to methyl mercury excretion

Due to its ability to avidly accumulate methyl mercury from blood, scalp hair has been widely used as a biological monitor for human exposure. The question arises that hair may also be an important route of elimination of methyl mercury from the body. Taking original publications and reviews on the physiology of hair (including growth by weigh and density) and on the deposition parameters for methyl mercury in the body (including the hair to blood concentration ratio of methyl mercury), one can calculate the rate of elimination of methyl mercury in hair. The result indicates that hair accounts for only a small fraction, less than 10%, of the total elimination of methyl mercury from the body. This relationship is expected to be maintained at every level when the dominant form of mercury is methyl. Other species of mercury I eliminated by hair even at a lower rate.

The stimulation and inhibition of the exhalation of volatile selenium

Administration of methylmercury (1.5-24 mumol kg-1; s.c.) to female rats simultaneously with Na2 75SO3 (0.25 or 24 mumol kg-1; s.c.) causes a dose-dependent increase in the exhalation of dimethylselenide. At the low selenite dose level, exhalation of 75Se over a 24 hr period is about fourfold greater after treatment with 24 mumol kg-1 methylmercury than that (approximately 0.75% of the dose) in the controls, but excretion by other routes (urine, faeces) and the liver and kidney contents of 75Se are not affected significantly. At the higher selenite dose level (24 mumol kg-1) exhalation of 75Se is correlated with the log dose of methylmercury. The faecal and urinary excretion remains essentially unaffected, and in rats treated with 24 mumol kg-1 methylmercury the 75Se contents of the liver, kidneys and blood are reduced by 78%, 86% and 18% respectively. The effects of the alkylmercurial are not specific since, at this selenite dose level, ethylmercury increases the exhalation and decreases the liver and kidney contents of 75Se approximately to the same extent as an equimolar dose of methylmercury. In methylmercury-treated and control animals dosed with 24 mumol kg-1 Na 75SeO3 the exhalation of 75Se is inhibited to the same extent by periodate-oxidized adenosine (PAD; 15 mumol kg-1, i.p.) in the first 6 hr. Later inhibition is less pronounced in methylmercury-treated rats. Under these conditions PAD has little effect on the renal content, but increases the hepatic content of 75Se. It seems, therefore, that the methylation of selenite occurs mainly in the liver and in both control and methylmercury-treated animals, S-adenosylmethionine is the major methyl donor. It is possible that methylmercury does not affect directly the methylation enzyme system but, by competition for protein sulphydryl groups, increases the availability of the intermediary selenide anion.